Derivatives of d-proline

 

The invention relates to a derivative of D-Proline General formulaorwhere R is SH, benzyl or phenyl, optionally substituted by a hydroxy-group or a lower alkoxygroup, or a group of the formulaR1is hydrogen or halogen; X represents -(CH2)n-; -CH(R2)(CH2)n-; -CH2O(CH2)n-; CH2NH-; benzyl, -C(R2)=CH-; CH2CH (OH)- or thiazol-2,5-diyl; Y represents-S -; (CH2)n; -O-; -NH-; -N (R2)-; -CH=CH-; -NHC(O)NH-; -N(R2)C(O)N(R2)-; -N[CH2With6H3(Och3)2]-; -N(CH2With6H5)-; -N(CH2With6H5)C(O)N(CH2With6H5)-; -N(alkoxyalkyl)-; -N(cyclooctylmethyl)-; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl or diphenylene; 1,2-phenylene; 1,3-phenylene or 1,4-phenylene, where phenylenebis group optionally substituted by 1-4 substituents selected from the group comprising halogen, lower alkyl, lower alkoxygroup, the hydroxy-group, carboxypropyl, -COO-lower alkyl, nitrile, 5-tetrazol, (2-carboxypropyl-1-yl)-2-Okeechobee, N-hydroxycarbamide diazoles; X' represents -(CH2)n-; (CH2)nCH(R2)-; -(CH2)nOch2-; -NHCH2-; benzyl, -CH= C(R2)-; -CH(OH)CH2or thiazol-2,5-diyl; R2denotes lower alkyl, lower alkoxygroup or benzyl and n = 0-3, their pharmaceutically acceptable salts, mono - and diesters, except (R)-1-[(R)- and (R)-1-[(S)-3-mercapto-2-methylpropionyl] pyrrolidin-2-carboxylic acid; medicinal product with amyloidoses activity, and the method of obtaining these derivatives. 3 S. and 12 C.p. f-crystals, 2 tab.

The present invention relates to D-prolinal formulaor
where R is SH, benzyl or phenyl, optionally substituted by a hydroxy-group or a lower alkoxygroup, or a group of the formula

R1denotes hydrogen or halogen;
X is -(CH2)n-; -CH(R2)(CH2)n-; -CH2O(CH2)n-; -CH2NH-; benzyl, -C(R2)=CH-, -CH2CH(OH)- or thiazol-2,5-diyl;
Y represents-S -;- (CH2)n-; -O-; -NH-; -N(R2)-; -CH=CH-; -NHC(O)NH-; -N(R2)C(O)N(R2)-; -N[CH2With6H3(Och3)2]- ; N- (CH2C6H5)-; -N(CH2 is Anil; 2.5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl; diphenylene; 1,2-phenylene; 1,3-phenylene or 1,4-phenylene, where phenylenebis group optionally substituted by 1-4 substituents selected from the group comprising halogen, lower alkyl, lower alkoxygroup, the hydroxy-group, carboxypropyl, -COO-lower alkyl, nitrile, 5-tetrazol, (2-carboxypropyl-1-yl)-2-Okeechobee, N-hydroxycarbamoyl, 5-oxo[1,2,4]oxadiazolyl, 2-oxo[1,2,3,5] oxadiazolyl, 5-thioxo[1,2,4]oxadiazolyl and 5-tert-butylsulfonyl[1,2,4] oxadiazolyl;
X' represents -(CH2)n-; -(CH2)nCH(R2)-; -(CH2)Och2-; -NHCH2-; benzyl, -CH=C(R2)-; -CH(OH)CH2or thiazol-2,5-diyl;
R2denotes lower alkyl, lower alkoxygroup or benzyl and
n = 0-3,
to their pharmaceutically acceptable salts, mono - and diesters.

Compounds of formulas I-A and I-B are new, except (R)-1-[(R)- and (R)-1-[(S)-3-mercapto-2-methylpropionyl]pyrrolidin-2-carboxylic acid. These compounds are described in WO 97/10225 as having antibacterial activity against B. fragilis. Moreover, in J. Comput. -Aided Mol. Des. (1987), 1(2) 133-42, described their use in theoretical study of inhibitors of angiotensin-convert the way the present invention includes all stereoisomeric forms of the compounds of formulas I-A and I-B, including each of the individual enantiomers and mixtures thereof.

Unexpectedly, it was found that D-Proline formulas I-A and I-B can be used for the treatment or prevention of all forms of Central and systemic amyloidosis, which is a consequence of disorders of protein metabolism, which are soluble in the normal state of autologous proteins are deposited in tissues in the form of abnormal insoluble fibrils, causing structural and functional abnormalities. The most common diseases that are caused by amyloidosis is Alzheimer's disease (ad), the onset age of diabetes or amyloidosis
as a significant cause of noiselessly heart failure,
- as a complication of chronic hemodialysis in renal failure,
- as a complication of monoclonal gammapathy,
as a result of chronic inflammatory diseases,
as a result of chronic infectious diseases,
as a result of cancer of some type.

Moreover, amyloidosis covers many different diseases, such as hereditary forms of amyloidosis, cassim feature of these diseases is the extracellular deposition of the so-called amyloid proteins in b-structured fibers and the same particular color.

Amyloid component P serum (AR) is a normal plasma protein and amyloid precursor component, universal average abnormal deposits in the tissues in amyloidosis. It is resistant to the action of proteases and, therefore, plays a key role in the persistence of amyloid in vivo. For treatment were found pharmaceutically active compounds which, apparently, prevents the interaction of APC with amyloid fibrils. It was shown that this interaction is more of an interaction with a protein fiber, and not the interaction with the more General fibrous components, such as glycosaminoglycans.

ARS is pentamer 5 identical ecovalence related pozvani. Two pentamer can be ecovalence connected in decamer through two pentamers descapotable rings that interact directly with each other. ARS is Kalnyshevsky ligand binding protein. It is produced and decays only in hepatocytes and exclusively racks outside the liver.

ARS participation in the pathogenesis or amyloidosis in vivo is evidence that the inhibition due to amyloid fibrils is of considerable interest since t is mentioned compounds of the formulae I-A and I-B, their salts and esters as such and as therapeutically active substances, obtaining them and their use for therapeutic purposes and, accordingly, for the preparation of appropriate medicines and drugs containing the compounds of formulas I-A and I-B, their salts and esters, and the preparation of such drugs for such purposes.

The term "lower alkyl" denotes remotemachine or branched saturated hydrocarbon residues, preferably with 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, 2-butyl, isobutyl and tert-butyl.

The term "halogen" denotes chlorine, iodine, fluorine and bromine.

Compounds of formulas I-A and I-B can form salts with metals, for example salts of alkali metals such as sodium and potassium salts, or salts of alkaline-earth metals such as calcium salts and magnesium, with organic bases, for example salts with amines, such as N-ethylpiperidine, procaine and dibenzylamine, or salts with basic amino acids, such as salts with arginine and lysine. These salts can be obtained and highlight using methods in the art are well known.

These compounds can also be used in e is e and phenolic esters. The most preferred esters are alkyl esters derived from C1-4alkanols, especially methyl and ethyl esters.

Compounds of formulas I-A and I-B can also be used in the form of their prodrugs with one or two carbonyl functions. As examples of the esters, inner esters, phosphate esters, dual ethers, esters aminoglycosides acid, glycerine associated derivatives, dihydropyridine derivatives and 8-(hydroxymethyl)-1-naphthylethylene esters. Prodrugs can increase the value of the proposed compounds through absorption, pharmacokinetics in the distribution and transfer to the brain (WO 95/14705; N. Bundgaard and other, Drugs of the Future, 16, 443, 1991; A. N. Saab and others , Pharmaceutical Science, 79, 802, 1990; D. M. Lambert and others, Current Medical Chemistry 1, 376, 1995).

Preferred are the compounds of formula I-A. In the framework of the present invention particularly preferred compounds of formula I-A are those in which X represents-CH(R2)(CH2)n- where R2denotes a methyl or methoxy group, and n=0 or 1. Their examples are the following compounds:
(R)-1-{ (S)-3-[(S)-3-[(R)-2-carboxypropyl-1-yl] -2-methyl-3-oxopropylidene] -2-methylpropionyl} pyrrolidin-2-carboxylic acid,
(R)-1-{ 6-[(R)-2-carboxypropyl-1-yl] -2,5-dimethyl-6-oxohexanoyl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers).

Especially preferred are also compounds in which X represents -(CH2)n-, a n=0 or 1.

These compounds include:
(R)-1-{ 7-[(R)-2-carboxypropyl-1-yl] -7-oxoethyl}pyrrolidine-2-carboxylic acid,
(R)-1-{ 6-[(R)-2-carboxypropyl-1-yl] -6-oxohexanoyl}pyrrolidin-2-carboxylic acid,
(R)-1-{ 5-[(R)-2-carboxypropyl-1-yl] -5-oxopentanoic]pyrrole-DIN-2-carboxylic acid,
(R)-1-{ { 4-[2-[(R)-2-carboxypropyl-1-yl] - 2-oxoethyl} phenyl} acetyl} pyrrolidin-2-carboxylic acid,
(R)-1-{ 3-[2-[(R)-2-carboxypropyl-1-yl] -2-oksidoksi] ureido} pyrrolidin-2-carboxylic acid,
(R)-1-{ { benzyl-[2-[(R)-2-carboxypropyl-1-yl] -2-oxoethyl] amino} acetyl} pyrrolidin-2-carboxylic acid,
(R)-1-{ CIS-4-[(R)-2-carboxypropyl-1-carbonyl] cyclohexanecarbonyl} pyrrolidin-2-carboxylic acid and
(R)-1-{[3-[2-[(R)-2-carboxypropyl-1-yl] -2-oxoethyl] phenyl} acetyl} pyrrolidin-2-carboxylic acid.

In addition, preferred compounds of formula I-A in which X represents-CH2O-.

Their examples are the following compounds:
(R)-1-{ { 2-[2-[(R)-2-carboxypropyl-1-yl] - ethoxy] phenoxy} acetyl} pyrrolidin-2-carboxylic acid,
(R)-1-{ { 4-[2-[(R)-2-carboxypropyl-1-yl] - 2-oksidoksi]-2-methoxyphenoxy} acetyl} pyrrolidin-2-carboxylic acid,
(R)-1-{ { 3-[2-[(R)-2-carboxypropyl-1-yl] - 2-oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid,
(R)-1-{ { 3-[2-[(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -2-methylphenoxy} acetyl} pyrrolidin-2-carboxylic acid and
(R)-1-{ { 5-[2-[(R)-2-carboxypropyl-1-yl] -2-oksidoksi] naphthalene-1-yloxy} acetyl} pyrrolidin-2-carboxylic acid.

Additional preferred compounds are those in which X represents-CH2NH.

An example of such compounds is (R)-1-{{4-[2-[(R)-2-carboxypropyl-1-yl] -2-oxoethylidene] phenylamino} acetyl} pyrrolidin-2-carboxylic acid.

Preferred further compounds, in which X represents-CH2CH(OH)-.

This connection is, for example, (2E,4E)-(R)-1-{6-[(R)-2-carboxypropyl-1-yl] - 2,5-dimethyl - 6 - oxohexyl -2,4-dienoyl} pyrrolidin - 2-carboxylic acid.

The above compounds of formulas I-A and I-B can be obtained in accordance with the invention
a) converting the compounds of formula

in connection formulas

and then in the connection formula

the compound of the formula

obtaining the compounds of formula 1 by removal of the protective group, where X, Y and X' have the above values, a R4denotes a hydroxy-group or halogen, or
the interaction of the compounds of formula

with an amine of the formula
NH2R5
and removing the protective group from compounds of formula

where R1and R3have the above significance, and R5denotes hydrogen, lower alkyl, lower alkoxygroup, benzyl, lower alkoxyalkyl, cyclooctylmethyl or-CH2With6H3(Och3)2or
g) the interaction of the compounds of formula

with the compound of the formula

and removing the protective group from compounds of formula

where R1, R3and X have the above values, or
d) the interaction of the compounds of formula

with the compound of the formula

and removing the protective group from compounds of formula

and

where R, R1X, Y and X' have the above values, a R3denotes a protective group, to obtain compounds of the formula IA or IB and optionally converting the compounds of General formula IA or IB in pharmaceutically acceptable salt or mono - or diesters.

In accordance with variant a) method a compound of formula I-A-1 is produced by conversion of the compounds of formula II, for example 1-[(S)-3-acetylmethadol-2-methylpropionyl] -(R)-pyrrolidin-2-carboxylic acid, compound of formula I-B-1, and then the compound of formula I-A-1. This reaction should be carried out in an inert atmosphere at room temperature in the presence of ammonia in a solvent such as methanol. After stirring for about 2 h, the compound is isolated and subsequently the reaction product can be processed to the desired eating the above-mentioned compounds at room temperature in a solution of CuSO4in the water. Specific conditions for the reaction are described in more detail in the examples.

In accordance with the reaction stage b) D-Proline with a protective group handle corresponding dicarboxylic acid or the corresponding acetylchloride at 0oC. following Preferred dicarboxylic acid: 2,4-dimethylglutaric acid, 2,3-dimethylxanthene acid, cyclohexane-1,4-dicarboxylic acid, cyclohexane-1,3-dicarboxylic acid, cyclohexane-1,2-dicarboxylic acid, 1,4-phenyleneoxy acid, 1,3-phenylendiamine acid, benzene-1,4-dicarboxylic acid, benzene-1,3-dicarboxylic acid, pyridine-2,6-dicarboxylic acid, thiophene-2,5-dicarboxylic acid, furan-2,5-dicarboxylic acid, adipic acid, 1,4-phenyleneoxy acid, 1,2-phenylendiamine acid, (4 - carboxymethylation-1-yl) acetic acid, (6-carboxymethylamino - 2-yl) acetic acid, (5-carboxymethylthio-2-yl)acetic acid, 2,5-dimethoxybenzoquinone, 2,5-dibenzylamine-3-indicolite and 2.5-diisopropyl-3-indicolite. The detailed methodology is described in the examples section "General procedure a".

In reaction stage b) provides processing amines, such as Propylamine, cyclopropanemethylamine, Metacity 20-80oWith in a solvent such as acetonitrile.

In accordance with option g) receive compound of formula I-b To the compound of formula XV in dichloromethane at 0oTo add the corresponding bromatologia derivative, such as bromoacetamide, and the compound of formula V. the Removal of the protective group can be performed according to methods that are known in the art.

Compounds in which Y denotes an optionally substituted 1,2-, 1,3 - or 1,4-fenelonov group can be obtained according to variant d). To the compound of formula XV add the corresponding dihydroxypropane formula XVII. The reaction of lead in dimethylformamide at room temperature. Preferred following dihydroxypropane: hydroquinone, tetrafluorohydroquinone, chlorhydroxide, methoxyhydroquinone, resorcinol, 2,6-dihydroxytoluene, 5-methoxyisatin, 3,5-dihydroxybenzoate, 3,5-dihydroxybenzoate, phloroglucin, pyragollole-1-methyl ether, 3-methylcatechol, tetrachlorocatechol, 2,6-dihydroxynaphthalene, 1,5-dihydroxynaphthalene, 2,3-dihydroxynaphthalene, 2,2'-dihydroxydiphenyl, 1,4-naphthoquinone and 2.7-dihydroxynaphthalene.

In accordance with variant (e) of the method of the compounds of formula III or IV to remove the protective group, receiving soedineniya, obviously, you can only use those protective groups which can be removed using methods, the implementation of which other structural elements remain unaffected. Preferred O-protective groups are tert-bucilina group and benzyl group. The process carried out in the usual way. For example, the compound of formula III is dissolved in an acceptable solvent or mixture of solvents, such as ethanol and ethyl acetate, at room temperature and under atmospheric pressure hydrogenized in the presence of Pd on charcoal grill.

Pharmaceutically acceptable salts and esters can be obtained in accordance with methods that are known in the art.

In schemes 1-9 shows processes of preparing compounds of formulas I-A and I-on the basis of known compounds or compounds which can be obtained by known methods.

The initial compounds of formulas V, VI, VIII, IX, X, XII, XIV, XVII, XX and XXIV are commercially available products or can be obtained by known methods.


and

The formation of compounds of formulas I-A and I-B are shown in table. 1, described in more detail in the examples 1-104.

As mentioned above, sedimantary. They can be used against all forms of Central and systemic amyloidosis, which is a consequence of disorders of protein metabolism, which are soluble in the normal state of autologous proteins are deposited in tissues in the form of abnormal insoluble fibrils, causing structural and functional abnormalities.

Compounds of General formula I-A and I-B were tested according to the following procedure.

Test method
Linking ARS (amyloid component P serum) with amyloid fibrils And(1-42)
96-well tablets Nunc Fluoro Polysorp were covered with 0.5 μg/well And(1-42), which was kept for 7 days at 37oC. the Tablets were dried for 3 days at 37oWith off, washed with 2 portions 150 μl of vehicle (10 mm Tris, 138 mm NaCl, 6 mm CaCl2, 0,05% NN3with pH 8.0) with 1% bovine serum albumin. Then to each well was added 50 μl of vehicle containing 8% bovine serum albumin, 25 μl of compound CU and 25 μl of 40 nm serum amyloid protein [125I] in TE (10 mm etilenditiodiuksusnoi acid (EGTC) instead of Sa). Incubation was performed over night at room temperature and the wells washed twice with 180 μl of vehicle containing 1% cow sivaram the ora TopCount (Packard company) was measured radioactivity. IR50(in μm) is preferred compounds of formulas I-A and I-B were in the range of about 0.2 to 2.0.

The ability of compounds according to the invention to bind APC (amyloid component P serum) with amyloid fibrils(1-42). Below is evidence of a link between this ability and the suitability of therapeutic agents for the treatment of amyloidosis. Amyloidosis is a consequence of disorders of protein metabolism, which are soluble in the normal state of autologous proteins are deposited in tissues in the form of abnormal insoluble fibrils, which leads to structural and functional disorders. The core structure of the fibrils is always the same and is an ordered polypeptide chains (cross-laying--fibers). Another common characteristic for all types of amyloidosis is the interaction of normal plasma proteins, in particular amyloid component P serum (ARS), with fibrils. ARS participation in the pathogenesis of amyloidosis confirms that inhibition of the interaction of APC with amyloid fibrils is eye-catching therapeutic target for the treatment of human diseases, such as illness Oltenia is the discovery of therapeutic agents for amyloidosis, which inhibit the interaction of amyloid component P: serum amyloid fibrils. The appropriate test methods described in the description. In table. 2 presented at the end of the description, given some specific data on the binding of APC.

Compounds of formulas I-A and I-B, and their pharmaceutically acceptable acid additive salt, mono - and diesters and cyclic imides can be used as medicines, for example in the form of pharmaceutical preparations. These pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions and suspensions. But now they can be administered rectally, for example in the form of suppositories, parenterally, e.g. in the form of solutions for injection or intranasal.

When the pharmaceutical preparation of the compounds of formulas I-A and I-B, as well as their pharmaceutically acceptable acid additive salts and esters can be combined with pharmaceutically inert, inorganic or organic carriers. As such carriers for tablets, coated tablets, dragées and hard gelatin capsules can be used, nepitism for soft gelatine capsules are, for example, vegetable oils, waxes, solid fats, semi-solid and liquid polyols etc., However in the case of soft gelatin capsules, depending on the nature of the active substance carriers usually are not required. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils, etc., are Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, solid fats, semisolid and liquid polyols, etc.,

Moreover, the pharmaceutical preparations can include some preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigentov, salts for varying the osmotic pressure, buffer additives, coating materials and antioxidants. They may also contain other therapeutically active substances.

Pharmaceutical preparations containing a compound of formula I-A or I-B or its pharmaceutically acceptable acid additive salt, mono - or fluids and a therapeutically inert carrier are also an object of the present invention, as the method of their preparation, which includes making one or more compounds of formulate together with one or more therapeutically inert carriers.

In accordance with the invention, compounds of General formulas I-a and I-B, as well as their pharmaceutically acceptable acid additive salts and mono - and diesters can be used for the treatment or prevention of Central and systemic amyloidosis. The most common diseases associated with amyloidosis is Alzheimer's disease (ad), the onset age of diabetes or amyloidosis
as a significant cause of noiselessly heart failure,
- as a complication of long-term hemodialysis in renal failure,
- as a complication of monoclonal gammapathy,
as a result of chronic inflammatory diseases,
as a result of chronic infectious diseases,
as a result of cancer of some type.

Moreover, amyloidosis covers many different diseases, such as hereditary forms of amyloidosis, often family amyloid polyneuropathy (SPP), scabies and disease Creutzfeld-Jacob.

In addition, the proposed connection can be used in the preparation of the appropriate drugs. The dose can vary within a wide range, and it obviously should be selected in compliance with the formula I-A or I-B or the corresponding amount of its pharmaceutically acceptable acid additive salts or mono - or diapir is in the range from about 0.1 mg to a single reception to about 5000 mg per day, although, if this is shown, this upper limit can be exceeded.

The essence of the present invention is illustrated in more detail in the following examples, but they should not be construed as limiting the scope of the invention. The temperature in all cases specified in degrees Celsius.

Example 1
(R)-1- { (S)-3- [(S)-3- [(R)-2-carboxypropyl-1-yl] -2-methyl-3-oxopropylidene] -2-methylpropionyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ester 1-[(S)-3-(acetylsalicyl)-20-methylpropionyl]-(R)-pyrrolidin-2-carboxylic acid tert-butyl ester 1-[(R) -3- (acetylsalicyl) -20-methylpropionyl] - (R) -pyrrolidin-2-carboxylic acid
18.6 ml of triethylamine at 0-5oIt was introduced in the mixed solution of 23.2 g (135 mmol) of tert-butyl methyl ether D-Proline in 230 ml of dry dichloromethane. At this temperature for 1 h was added a solution of 24.5 g (135 mmol) of the ester 8-(3-chloro-2-methyl-3-oxopropyl)identically in 116 ml of dichloromethane, and stirring was continued at room temperature for 2 hours the Precipitate was removed by filtration. The solution was washed with water and dried with sodium sulfate. In the evaporation of the solvent under reduced pressure got to 41.4 g of colorless product in the form of oil, which chromatogra the butyl ester 1- [(R)-3- (acetylsalicyl)-20-methylpropionyl] -(R)-pyrrolidin-2-carboxylic acid, 18.2 g (43%) of tert-butyl ester 1-[(S)-3-(acetylsalicyl) -20-methylpropionyl] - (R) -pyrrolidin-2-carboxylic acid and 1.6 g of a mixture of epimeres.

MS m/e (%)= 315 (M+, 3), 259 (10), 242 (10), 214 (100), 172 (10), 145 (32), 70 (22);
[]D=of-0.7o(1% tO).

MS m/e (%)=315 (M+,4), 259 (7), 242 (9), 214 (100), 172 (9), 145 (33), 70 (33);
[]D=+156,7o(1% tO).

b) 1- [(S) -3- (Acetylsalicyl) -2-methylpropionyl] - (R) -pyrrolidin-2-carboxylic acid
15,45 g (48,9 mmole) of tert-butyl ester 1- [(S)-3- (acetylsalicyl) -20-methylpropionyl] -(R)-pyrrolidin-2-carboxylic acid in a stream of argon for three hours was mixed with 99 ml triperoxonane acid and 55 ml of anisole. The mixture was evaporated in vacuum. The residue was dissolved in about 100 ml ice ethyl acetate and washed with approximately 200 ml ice water solution of sodium bicarbonate. Under ice cooling concentrated hydrochloric acid was added until pH 1-2. The aqueous phase is four times was extracted with ice-ethyl acetate, dried with sodium sulfate and evaporated. Received 11.6 g (yield 91%) of l-[(S)-3-(acetylsalicyl) -2-methylpropionyl] - (R) -pyrrolidin-2-carboxylic acid, which was used without further purification.

[]4
and six times was extracted with dichloromethane. The organic layers are washed twice with 5% solution of KHSO4three times 1H. hydrochloric acid and dried over sodium sulfate. In the evaporation of the solvent and crystallization from ethyl acetate/hexane received 6.25 g (64%) of 1-[(S)-3-mercapto-2-methylpropionyl]-(R)-pyrrolidin-2-carboxylic acid with a melting point 99-101oC.

[]D=+40,7o(1% EtOH).

g) (R)-1- {(S)-3- [(S)-3- [(R)-2-carboxypropyl-1-yl] -2-methyl-3-oxopropylidene] -2-methylpropionyl} pyrrolidin-2-carboxylic acid
At room temperature the solution 749 mg (3.0 mmole) CuSO45H2O in 90 ml of water was injected into the solution 651,85 mg (3.0 mmole) of 1-[(S)-3-mercapto-2-methylpropionyl] -(R)-pyrrolidin-2-carboxylic acid in 90 ml of dichloromethane. The mixture for 10 min intensively stirred and filtered. The aqueous phase is washed 5 times with dichloromethane, the organic phase was washed with brine and dried sulfate IAHS)-2 - carboxymyoglobin -1 - yl] - 2 - methyl - 3 - oxopropylidene] - 2 - methylpropionyl} pyrrolidin-2-carboxylic acid with a melting point 142-144oC.

[]D=+42,8o(1% l3).

Example 2
(R)-1-{ (R)-3-[(R)-3-[(R)-2-carboxypropyl-1-yl] -2-methyl-3-oxopropylidene] -2-methylpropionyl} pyrrolidin-2-carboxylic acid
a) 1- [(R)-3-(Acetylsalicyl)-2-methylpropionyl] -(R)pyrrolidin-2-carboxylic acid
of 18.9 g (60,0 mmol) tert-butyl ester 1-(3-acetylmethadol-2-methylpropionyl)pyrrolidin-2-carboxylic acid with 120 ml triperoxonane acid and 75 ml of anisole was stirred in a stream of argon for three hours. The mixture was evaporated in vacuum. The residue was dissolved in ice ethylacetate and washed with ice water solution of sodium bicarbonate. Ice concentrated hydrochloric acid was added until pH 2-3. The aqueous phase three times was extracted with ice-ethyl acetate, dried with sodium sulfate and evaporated. The way it was received and 15.3 g (98%) 1-[(R)-3-(acetylsalicyl)-2-methylpropionyl] -(R)-pyrrolidin-2-carboxylic acid, which was used without further purification.

[]D=+127,8o(1% EtOH).

b) 1- [(R)-3-mercapto-2-the- (R)-pyrrolidin-2-carboxylic acid at room temperature in a stream of argon was dissolved in 15 ml of methanol, purged of oxygen with argon. After adding 15 ml of 10h. solution of ammonia in methanol stirring continued for two hours at room temperature. Then at room temperature in vacuum drove the solvent. The residue was dissolved in 5% aqueous solution of KHSO4and six times was extracted with dichloromethane and three times with ethyl acetate. The organic layers are washed twice with 5% solution of KHSO4three times 1H. hydrochloric acid and dried over sodium sulfate. After evaporation of the solvent and crystallization from ethyl acetate/hexane received 1,59 g (64%) of 1-[(R)-3-mercapto-2-methylpropionyl] - (R)-pyrrolidin-2-carboxylic acid with a melting point 98-100oC.

[]D=+128,8o(1% EtOH).

C) (R)-1-{ (R)-3-[(R)-3-[(R)-2-carboxypropyl-1-yl] -2-methyl-3-oxopropylidene] -2-methylpropionyl} pyrrolidin-2-carboxylic acid
Similarly outlined in example 1G).

MS m/e (%): (M+, 2) 217(100), 184(76), 172(67), 142(13), 70(79), 41(21).

Example 3
(R)-1- {3- [3- [(R)-2-carboxypropyl-1-yl] -3-oxopropanenitrile] propionyl} pyrrolidin-2-carboxylic acid
0.9 g (4 mmole) of 1-(3-mercaptopropionyl)- (R)-pyrrolidin-2-carboxylic acid (starting material) was dissolved in dichloromethane and ekstragirovannye the organic phase was filtered, was dried with magnesium sulfate and evaporated. Chromatography with dichloromethane/Aceto-nom/formic acid in the ratio 80/10/1 in the form of a colorless oil were obtained 70 mg (R)-1-{ 3-[3- [(R)-2-carboxypropyl-1-yl] -3-oxopropanenitrile] propionyl} pyrrolidin-2-carboxylic acid.

ISN-MS: 403 (M-N)-.

Example 4
(R)-1- { 9- [(R)-2-carboxypropyl-1-yl] -9-Oconnor} pyrrolidin-2-carboxylic acid
a) Benzyl ether of (R)-1-{9-[(R)-2-benzyloxycarbonylamino-1-yl] -9-Oconnor} pyrrolidin-2-carboxylic acid
0.97 g (4 mmole) of the hydrochloride of D-proinvestirovalo ester in 25 ml of dichloromethane in a stream of argon at room temperature was mixed with 450 mg (2 mmole) of ateliergalerie and 1.12 ml (8 mmol) of triethylamine for 20 hours Extraction 2n. hydrochloric acid and brine, drying with sodium sulfate and evaporation in the form of oil was obtained 1.2 g of product, which was chromatographically with acetoacetate on silica gel to produce in the form of a colourless oil, 0.9 g (80%) of benzyl ester of (R)-1-{9-[(R)-2-benzyloxycarbonylamino-1-yl] -9-Oconnor}pyrrolidin-2-carboxylic acid.

1H-NMR (Dl3, frequent. /million): 1,1-2,4 (m, 22H), 3,4-3,7 (m, 4H), 4,4-4,6 (m, 2H), 5,1-5,3 (haw, 4H), 7,34 (m, 10H).

b) (R)-1- {9- [(R)-2-carboxypropyl-1-yl] -9-Oconnor}pyrrolidin-2-canol} pyrrolidin-2-carboxylic acid in 20 ml of ethanol was hydrogenosomal for two hours at room temperature in the presence of 20 mg of 5% Pd on coal. Filtration and evaporation in the form of a colorless oil were obtained 60 mg of (R)-1- {9- [(R)-2-carboxypropyl-1-yl] -9-Oconnor} pyrrolidin-2-carboxylic acid.

ISP-MS:383 (MH)+.

Example 5
(R)-1- {8- [(R)-2-carboxypropyl-1-yl] -2,7-dimethyl-8-oxooctanoate] pyrrolidin-2-carboxylic acid
1.2 g (5.0 mmol) of 2,7-dimethyl-8-attentionwhore was dissolved in 100 ml mix of dimethylformamide, was added to 1.15 g (10 mmol) D-Proline and 1.4 ml (10 mmol) of triethylamine and the mixture was stirred for five minutes at 50oC. Stirring was continued at room temperature overnight. Drove the solvent and the residue was dissolved in 30 ml of 2n. of hydrochloric acid. As a result of extraction with ethyl acetate, drying with sodium sulfate, evaporation and chromatography on silica gel with chloroform/acetone/formic acid in the ratio of 80/15/5 in the form of a colorless oil was obtained 0.11 g of (R)-1-{8-[(R)-2 - carboxypropyl - 1-yl] -2,7-dimethyl - 8 - oxooctanoate] pyrrolidin - 2-carboxylic acid.

ISP-MS: 397 (MH)+.

Example 6
(R)-1- {8- [(R)-2-carboxypropyl-1-yl]-2,7-dimethoxy-8-oxooctanoate] pyrrolidin - 2 - carboxylic acid
a) Benzyl ether of (R)-1-{8-[(R)-2-benzyloxycarbonylamino-1-yl]-2,7-dimethoxy-8-oxooctanoate]pyrrolidin-2-carboxylic shall ulali a solution of 0.35 g (2.1 mmole) of carbonyldiimidazole in 15 ml of tetrahydrofuran. After stirring at room temperature for two hours was added 0.52 g (2,16 mmole) of the hydrochloride of D-proinvestirovalo ester in 10 ml of dichloromethane and 0.54 g of triethylamine and stirring continued for 18 hours After filtration the solvent is kept off, the residue was dissolved in ethyl acetate and was extracted with 2n. hydrochloric acid and water. In the drying with sodium sulfate, evaporation of solvent and chromatography on silica gel with ethyl acetate as a colourless oil was obtained 0.21 g of benzyl ester of (R)-1- {8- [(R)-2-benzyloxycarbonylamino -1 - yl] -2,7-dimethoxy - 8 - oxooctanoate] pyrrolidin - 2 - carboxylic acid.

S-ISP: 609 (M+N)+.

b) (R)-1- { 8- [(R)-2-carboxypropyl-1-yl]-2,7-dimethoxy-8-oxooctanoate] pyrrolidin-2-carboxylic acid
182 mg (0.3 mmole) of the benzyl ether of (R)-1-{8-[(R)-2-benzyloxycarbonylamino-1-yl] -2,7-dimethoxy-8-oxooctanoate] pyrrolidin-2-carboxylic acid in 10 ml of methanol was hydrogenosomal in the presence of 30 mg of 5% Pd on coal. Filtration and evaporation of the solvent in the form of a colorless oil was obtained 109 mg (84%) of (R)-1- {8-[(R)-2-carboxypropyl-1-yl] -2,7-dimethoxy-8-oxooctanoate] pyrrolidin-2-carboxylic acid.

MS: 427 (M-N)-.

Example 7
(R)-1-{ 7- [(R)-2-carboxypropyl-1-rolina and 1.4 ml (10 mmol) of triethylamine in 100 ml of dimethylformamide was heated until until it formed a clear solution, and then stirred at room temperature overnight. In vacuum drove the solvent. The residue was dissolved in 2n. hydrochloric acid and was extracted with dichloromethane. In the evaporation of the solvent and chromatography on silica gel with chloroform/acetone/formic acid in the ratio of 80/15/5 in the form of oil was obtained 0.27 g of (R)-1-{ 7-[(R)-2-carboxypropyl-1-yl]-7-oxoethyl] pyrrolidin-2-carboxylic acid.

MS:353 (M-N)-.

Example 8
(R)-1- { 6- [(R)-2-carboxypropyl-1-yl] -6-oxohexanoyl]pyrrolidin-2-carboxylic acid
a) Benzyl ether of (R)-1-{6-[(R)-2-benzyloxycarbonylamino-1-yl]-6-oxohexanoyl] pyrrolidin-2-carboxylic acid
0.97 g (10 mmol) of the hydrochloride of D-proinvestirovalo ester in 70 ml of dichloromethane at room temperature in a stream of argon was stirred from 0.92 g (5 mmol) of editorchoice and 2.8 ml (20 mmol) of triethylamine from Friday evening until Monday morning. As a result of extraction 2n. hydrochloric acid and water, drying with sodium sulfate, evaporation and chromatography on silica gel with acetoacetate in the form of a colorless oil was obtained at 0.42 g (16%) of benzyl ester of (R)-1- {6- [(R)-2-benzyloxycarbonylamino-1-yl] -6-oxohexanoyl] pyrrolidin-2-kurbonboeva acid
410 mg (0,79 mmole) benzyl ester of (R)-1-{6-[(R)-2-benzyloxycarbonylamino-1-yl] -6-oxohexanoyl] pyrrolidin-2-carboxylic acid in 100 ml of methanol was hydrogenosomal in the presence of 50 mg of 5% Pd on coal. Filtration and evaporation of the solvent in the form of a colorless oil was obtained 160 mg (59%) of (R)-1-{ 6-[(R)-2-carboxypropyl-1-yl]-6-oxohexanoyl] pyrrolidin-2-carboxylic acid.

MS: 339 (M-N)-.

Example 9
(R)-1- {5- [(R)-2-carboxypropyl-1-yl] -5-oxopentanoic] pyrrolidin-2-carboxylic acid
a) Benzyl ether of (R)-1-{5-[(R)-2-benzyloxycarbonylamino-1-yl] -5-oxopentanoic]pyrrolidin-2-carboxylic acid
0.97 g (10 mmol) of the hydrochloride of D-proinvestirovalo ester in 70 ml of dichloromethane overnight at room temperature in a stream of argon was mixed with 0.85 grams (5 mmol) of glutaraldehyde and 2.8 ml (20 mmol) of triethylamine. As a result of extraction 2n. hydrochloric acid and brine, drying with sodium sulfate, evaporation and chromatography on silica gel with acetoacetate in the form of a colorless oil was obtained of 0.44 g (17%) of benzyl ester of (R)-1- {5-[(R) -2-benzyloxycarbonylamino-1-yl] -5-oxopentanoic] pyrrolidin-2-carboxylic acid.

ISP-MS: 507 (M+N)+.

b) (R)-1- {5- [(R)-2-carboxypropyl-1-yl] -5-oxopentanoic] pyrrolidin pentanoyl] pyrrolidine-2-carboxylic acid in 100 ml ethanol was hydrogenosomal in the presence of 40 mg of 5% Pd on coal. Filtration and evaporation of the solvent in the form of a colorless oil was obtained 130 mg (46%) of (R)-1-{ 5-[(R)-2-carboxypropyl-1-yl]-5-oxopentanoic] pyrrolidin-2-carboxylic acid.

ISP-MS: 327 (M+N)+.

Example 10
(R)-1- { 4- [(R)-2-carboxypropyl-1-yl] - 4-oxobutyryl] pyrrolidin-2-carboxylic acid
a) Benzyl ether of (R)-1-{4-[(R)-2-benzyloxycarbonylamino-1-yl] -4-oxobutyryl]pyrrolidin-2-carboxylic acid
In a mixed solution of 300 mg (1.2 mmole) of the hydrochloride of D-proinvestirovalo ether and 0.35 ml (2.5 mmole) of triethylamine in 9 ml of dichloromethane at 0oWith was added dropwise 68 ml (0.6 mmole) of succinylcholine and stirring continued at room temperature for 24 h Then the reaction mixture is then washed with a saturated solution of ammonium chloride, saturated sodium bicarbonate solution and finally with water and the aqueous phase was subjected to back extraction with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuum to produce in the form of a pale yellow oil 286 mg (94%) specified in the connection header.

MS m/e (%): 510 (M+NH+4, 20), 493 (M+N+, 100), 288 (80).

b) (R) -1- {4- [(R) -2-carboxypropyl-1-yl] -4-oxobutyryl] pyrrolidin-2-carbonsteel] pyrrolidin-2-carboxylic acid in 5 ml of ethanol for 16 h at room temperature was mixed with 13 mg of 10% palladium on coal under hydrogen pressure of 1 ATA. After filtration to remove the catalyst and concentration in vacuum in the form of a colorless viscous oil was obtained 170 mg (100%) of (R)-1-{4-[(R)-2-carboxypropyl-1-yl] -4-oxobutyryl] pyrrolidin-2-carboxylic acid.

MS m/e (%): 313 (M+N+, 100).

Example 11
(R)-1- {{2- [2- [2-[(R)-2-carboxypropyl-1-yl]-2-oksidoksi]ethoxy] ethoxy} acetyl}pyrrolidin-2-carboxylic acid
A mixture of 1.04 g (4 mmole) of 2,2'-[oxobis(2,1-candiracci)]biscathorpe, 0,92 g (8 mmol) D-Proline and 1.2 ml of triethylamine in 200 ml of dimethylformamide was stirred for three days at room temperature. In vacuum drove the solvent. The residue was chromatographically on silica gel with methanol to produce in the form of a beige hygroscopic solids 0,42 g (R)-1- { {2- [2- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] ethoxy] ethoxy} acetyl} pyrrolidin-2-carboxylic acid.

ISP-MS: 417 (M+N)+.

Example 12
(R)-1- {3- {4- [3- [(R)-2-carboxypropyl-1-yl] -3-oxopropyl] phenyl} propionyl} pyrrolidin-2-carboxylic acid
A mixture of 1.30 g (5 mmol) of 1,4-benzodipyrrolenine and 1.15 g (10 mmol) D-Proline and 1.5 ml of triethylamine in 100 ml of dimethylformamide was stirred for 24 h at room temperature. The suspension was filtered and vacuum drove dissolve what was referable on silica gel with dichloromethane/acetone/formic acid in the ratio 80/5/15 obtaining in the form of a colorless foam of 0.48 g (R)-1- {3- {4- [3- [(R)-2-carboxypropyl-1-yl] -3-oxopropyl] phenyl} propionyl} pyrrolidin-2-carboxylic acid.

ISP-MS: 417 (M+N)+.

Example 13
(R)-1- {{4- [2- [(R)-2-carboxypropyl-1-yl] -2-oxoethyl] phenyl} acetyl} pyrrolidin-2-carboxylic acid
A mixture of 1.15 g (5 mmol) of 1,4-benzodiazepinones from 1.15 g (10 mmol) D-Proline and 1.5 ml of triethylamine in 100 ml of dimethylformamide was stirred for 20 h at room temperature. In vacuum drove the solvent. The residue was dissolved in 30 ml of 2n. hydrochloric acid, treated with ultrasound, filtered and dried to obtain 1.19 g of brown solid. It was stirred and boiled under reflux for 30 min in 300 ml of methanol. Filtration, evaporation and recrystallization from methanol/acetoacetate in the form of yellow crystals was obtained 0.18 g (R)-1-{{4-[2- [ (R) -2-carboxypropyl-1-yl] -2-oxoethyl] phenyl} acetyl} pyrrolidin-2-carboxylic acid with a melting point 210-214oC.

ISP-MS: 389 (M+N)+.

Example 14
(R)-1- {{2- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid
a) Benzyl ether (R)-1-{{2-[2-[(R)-2-benzyloxycarbonylamino-1-yl]-2-oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid
To 0,566 g (2.5 mmole) of 1,2-phenylendiamine acid in 60 ml of tetrahydrofuran was added to the solution 0,81 g (5 mmol what hours were added to 1.21 g (5 mmol) of the hydrochloride of D-proinvestirovalo ester in 30 ml of dichloromethane and 1.4 ml of triethylamine and stirring continued from Friday evening until Monday morning. The mixture was extracted with 2n. hydrochloric acid and brine. In the drying with sodium sulfate, evaporation of solvent and chromatography on silica gel with ethyl acetate as a colourless oil was obtained 0.25 g of benzyl ether (R)-1- {{2- [2- [(R)-2-benzyloxycarbonylamino-1-yl] -2-oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid.

MS m/e (%): 600 (1, M+), 509 (1), 368 (25), 246 (17), 217 (19), 204 (14), 91 (100).

b) (R)-1- { { 2- [2- [(R)-2-carboxypropyl-1-yl] - 2 - oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid
230 mg (range 0.38 mmole) benzyl ether (R)-1-{{2-[2-[(R)-2-benzyloxycarbonylamino-1-yl] -2-oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid in 100 ml ethanol was hydrogenosomal in the presence of 30 mg of 5% Pd on coal. The result of the filter and evaporate the solvent in the form of a colorless glassy mass was obtained 0.2 g (R)-1- {{2- [2-[(R)-2-carbox-superolein-1-yl] -2-oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid (which still contained a small amount of ethanol).

ISP-MS: 421 (M+N)+.

Example 15
(R)-1- { 3- {6- [3- [(R)-2-carboxypropyl-1-yl] -3-oxopropyl]pyridine-2-yl} propionyl} pyrrolidin-2-carboxylic acid
a) 3- [6-(2-carboxyethyl)pyridine-2-yl]propionic acid
A mixture of 25.6 g (0.2 temperature. After cooling to -15oWith solution was added 5,72 ml of 0.1 mol) of acetic acid in 10 ml of tetrahydrofuran and stirring continued at room temperature for three hours. Then added a 13.3 g (0.5 mole) 2, b-bis(methyl bromide)of pyridine in 65 ml of tetrahydrofuran and stirring continued over night at room temperature. Was added 200 ml of diethyl ether and the mixture was extracted with water. The aqueous layers were filtered through a layer of 200 ml of ion exchange resin BioRad AG1-X8. The ion exchanger was washed with water until neutral, and then elution was performed with acetic acid/water. The contained product fractions were evaporated, dissolved in water and liofilizirovanny obtaining in the form of a light yellow powder of 3.9 g(35%) 3- [6-(2-carboxyethyl)pyridine-2-yl]propionic acid.

MS m/e (%): 223 (M+, 15), 178 (100), 160 (81), 132 (68), 104 (16), 77 (13).

b) Benzyl ether (R)-1- {3- {6- [3- [(R)-2-benzyloxycarbonylamino-1-yl] -3-oxopropyl] pyridine-2-yl}propionyl} pyrrolidin-2-carboxylic acid
To 0.45 g (2.0 mmole) of 3-[6-(2-carboxyethyl)pyridine-2-yl] propionic acid in a mixture of 25 ml of tetrahydrofuran with 25 ml dichloromethane was added a solution of 0.65 g (4.0 mmole) of carbonyldiimidazole in 20 ml of tetrahydrofuran. After stirring at room temperature in those who ethylamine and the stirring was continued for 18 hours Next, to the mixture was added ethyl acetate, followed by extraction with water. In the drying with sodium sulfate, evaporation of solvent and chromatography on silica gel with ethyl acetate/hexane in a ratio of 2/8, then ethyl acetate, then ethyl acetate/methanol in a ratio of 95/5 followed by the second chromatography containing the product fractions on silica gel with acetone/hexane in a ratio of 6/4 in the form of a colorless oil was obtained 0.18 g (15%) of the benzyl ether (R)-1-{ 3-{6-[3-[(R)-2-benzyloxycarbonylamino-1-yl] -3-oxopropyl] pyridine-2-yl} propionyl} pyrrolidin-2-carboxylic acid.

ISP-MS:598 (M+H)+.

in) (R)-1- {3- {6- [3- [(R)-2-carboxypropyl-1-yl] -3-oxopropyl]pyridine-2-yl} propionyl} pyrrolidin-2-carboxylic acid
0.17 g (0,29 mmole) benzyl ether (R)-1-{3-{6-[3-[(R)-2-benzyloxycarbonylamino-1-yl] -3-oxopropyl] pyridine-2-yl} propionyl} pyrrolidin-2-carboxylic acid in 100 ml ethanol was hydrogenosomal in the presence of 35 mg of 5% Pd on coal. The result of the filter and evaporate the solvent in the form of a colorless oil was obtained 0.11 g (92%) (R)-1- {3- {6- [3- [(R)-2-carboxypropyl-1-yl] -3-oxopropyl] pyridine-2-yl} propionyl} pyrrolidin-2-carboxylic acid.

ISP-MS: 418 (M+N)+.

Example 16
(R)-1- {3-{[3-[(R)-2-carboxilic rolpasrolel-2-carboxylic acid
In a mixed solution of 390 mg (1.6 mmole) of the hydrochloride of D-proinvestirovalo ether and 0.47 ml (3.4 mmole) of triethylamine in 20 ml dichloromethane at 0oWith was added dropwise 0.2 ml (2.4 mmole) of akriloilkhlorida and stirring continued at room temperature for 24 h Then the reaction mixture is then washed with water, 1 M hydrochloric acid and again with water and the aqueous phase was subjected to back extraction with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to obtain a colourless oil, 420 mg (100%) of the benzyl ether of (R)-1-acryloylmorpholine-2-carboxylic acid.

MS m/e (%): 259 (M+, 25), 124 (100), 91 (25), 70 (21).

b) Benzyl ether (R)-1- {3- {6 [3- [(R)-2-benzyloxycarbonylamino-1-yl] -3-oxopropyl] propylamino} propionyl} pyrrolidin-2-carboxylic acid
A solution of 400 mg (1.5 mmole) of the benzyl ether of (R)-1-acryloylmorpholine-2-carboxylic acid and 63 ml (0.75 mmole) of Propylamine in 5 ml of acetonitrile for 16 h and was stirred at room temperature, then for 6 h at 45oAnd finally for 16 hours at 80oC. In the result, concentration in vacuo and flash-chromatography (20% N2About in acetone) in the form of pale yellow oil was obtained-3-oxopropyl] propylamino} propionyl} pyrrolidin-2-carboxylic acid.

MS m/e (%): 578 (M+N+, 100).

in) (R)-1- {3- {[3- [(R)-2-carboxypropyl-1-yl] -3-oxopropyl] propylamino} propionyl} pyrrolidin-2-carboxylic acid
84 mg (0.15 mmole) solution of benzyl ether (R)-1-{3-{[3-[(R)-2-benzyloxycarbonylamino-1-yl] -3-oxopropyl] propylamino} propionyl} pyrrolidin-2-carboxylic acid in 3 ml of ethanol for 16 h at room temperature was mixed with 10 mg of 10% palladium on coal under hydrogen pressure of 1 ATA. After filtration to remove the catalyst and concentration in vacuum in the form of a white solid substance was obtained 58 mg (100%) (R)-1-{ 3-{ [3-[(R)-2-carboxypropyl-1-yl]-3-oxopropyl] propylamino} propionyl} pyrrolidin-2-carboxylic acid.

MS m/e (%): 398 (M+N+100).

Example 17
(R)-1- { 3- [2- [(R)-2-Carboxypropyl-1-yl] -2-oksidoksi]ureido} pyrrolidin-2-carboxylic acid
a) Benzyl ether of (R)-1-tert-butoxycarbonylmethylene-2-carboxylic acid
to 1.21 g (5 mmol) of the hydrochloride of D-proinvestirovalo ether was dissolved in 100 ml dichloromethane and stirred with 0.7 ml of triethylamine. The mixture was extracted with water, dried with sodium sulfate and evaporated. The residue was dissolved in a mixture of 100 ml of tetrahydrofuran and 50 ml of chloroform. Was added with stirring to 1.03 g (5 mmol) N,N'-decollatura. Added five drops of acetic acid and after a 10-minute exposure at room temperature the mixture was filtered and drove away from the solvents. The residue was dissolved in acetoacetate, washed with aqueous citric acid, aqueous sodium bicarbonate and water, dried with sodium sulfate and drove the solvent. The result chromatography on silica gel with dichloromethane/methanol 99/1 ratio in the form of a colorless oil was obtained 1,43 g (79%) of benzyl ester of (R)-1-tert-butoxycarbonylmethylene-2-carboxylic acid.

MS m/e (%): 398 (M+N+, 1), 303 (29), 289 (10), 114 (44), 91 (76), 70 (100), 57 (64).

b) Benzyl ether (R)-1- {3- [2- [(R)-2-benzyloxycarbonylamino-1-yl] -2-oksidoksi]ureido}pyrrolidin-2-carboxylic acid
8,6 ml triperoxonane acid at 0oWith added in a mixed solution of 1.57 g (4,34 mmole) benzyl ester of (R)-1-tert-butoxycarbonylmethylene-2-carboxylic acid 8.6 ml of dichloromethane, and stirring was continued for half an hour at room temperature. The solution is washed with aqueous sodium bicarbonate, dried with sodium sulfate and evaporated. The residue was dissolved in 200 ml dichloromethane and mixed with 0.21 g (0.7 mmole) of triphosgene and 1.8 ml (13 mmol) of triethylamine in for four hours is received in the amount of 1.15 g of the residue was chromatographically on silica gel with dichloromethane/methanol in the ratio of 96/4 and the contained product fraction was again chromatographically on silica gel with dichloromethane/acetone/formic acid in the ratio of 80/15/5 obtaining in the form of oil 0,23 g (33%) of the benzyl ether (R)-1-{3-[2-[(R)-2-benzyloxycarbonylamino-1-yl] -2-oksidoksi] ureido} pyrrolidin-2-carboxylic acid.

MS:551 (M+N)+.

in) (R)-1- {3- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -ureido} pyrrolidin-2-carboxylic acid
0.14 g (of 0.36 mmole) benzyl ether (R)-1-{3-[2-[(R)-2-benzyloxycarbonylamino-1-yl] -2-oksidoksi] ureido} pyrrolidin-2-carboxylic acid in 60 ml of ethanol was hydrogenosomal in the presence of 40 mg of 5% Pd on coal. In the filtration, evaporation of the solvent and crystallization from methanol/ethyl acetate was obtained 0.07 g (52%) of white crystals with a melting point 157-160oC.

Example 18
CA-salt (R)-1- { 10- [(R)-2-carboxypropyl-1-yl] -10-octadecanoyl} pyrrolidin-2-carboxylic acid (1:1)
A mixture of 1.20 g (5 mmol) of seborrhoea from 1.15 g (10 mmol) D-Proline and 1.4 ml (10 mmol) of triethylamine in 100 ml of dimethylformamide was stirred from Friday evening until Monday morning at room temperature. In vacuum drove the solvent. The residue was dissolved in 40 ml aqueous citric acid and extracted with ethyl acetate. In the evaporation of the solvent and chromatography on silica gel with chloroform/acetone/formic acid in the ratio 80/5/15 in the form of oil received 1,21 g (R)-1-{10-[(R)-2-carboxy-pyrrolidin-1-yl] -10-octadecanoyl} pyrrolidin-2-carboxylic acid.

ISP-MS: 397 (M+N)+.

0,89 g (2,24 mmole) is the Zia was filtered. The solid residue was dissolved in 15 ml of water, was heated up to 80oWith, hot filtered and evaporated. The residue is suspended in diethyl ether, filtered and washed with diethyl ether to produce in the form of a white solid, 0.5 g of CA-salts of (R)-1- {10- [(R)-2-carboxypropyl-1-yl] -10-octadecanoyl} pyrrolidin-2-carboxylic acid (1:1).

With (calculated): 55,28; N (calculated): of 6.96; N (calculated): 6,45; (found): 55,29; N (found): 7,11; N (found): between 6.08.

Example 19
CA-salt (R)-1- { 8- [(R)-2-carboxypropyl-1-yl] -8-oxooctanoate} pyrrolidin-2-carboxylic acid (1:1)
A mixture of 1.10 g (5 mmol) of suberoylanilide from 1.15 g (10 mmol) D-Proline and 1.5 ml (10 mmol) of triethylamine in 100 ml of dimethylformamide was stirred for 20 h at room temperature. In vacuum drove the solvent. The residue was dissolved in 40 ml aqueous citric acid and extracted with ethyl acetate. In the evaporation of the solvent and chromatography on silica gel with chloroform/acetone/formic acid in the ratio 80/5/15 in the form of oil was obtained 0.8 g (R)-1-{8-[(R)-2-carboxypropyl-1-yl] -8-oxooctanoate}pyrrolidin-2-carboxylic acid.

ISP-MS: 367 (M-N)-.

0,79 g (2,15 mmole) of this oil was dissolved in 40 ml of ethanol for 20 h stirred the ml of water. The solution was filtered and evaporated to produce in the form of a white solid, 0.5 g of CA-salts of (R)-1-{ 8-[(R)-2-carboxypropyl-1-yl] -8-oxooctanoate} pyrrolidin-2-carboxylic acid (1:1).

Example 20
(R)-1- { 4'- [(R)-2-carboxypropyl-1-ylcarbonyl] - [2.2]-betazole-4-yl} pyrrolidin-2-carboxylic acid
a) Benzyl ether (R)-1-{4'-[(R)-2-carboxypropyl-1-ylcarbonyl] - [2,2] -betazole-4-yl}pyrrolidin-2-carboxylic acid
2 ml of thionyl chloride was added to a solution of 0.26 g (1 mmol) [2,2'] -betazole-4,4'-dicarboxylic acid in 20 ml of tetramethylrhodamine and the mixture was stirred for three days at room temperature. The excess thionyl chloride and solvent drove under reduced pressure in a vacuum. The residue three times was dissolved in dimethylformamide was evaporated and then dissolved in 50 ml of pyridine. Added 0.28 g (1.1 mmole) of the hydrochloride of D-proinvestirovalo ether and stirring continued at room temperature for 24 hours the Solvent is kept off, the residue was dissolved in acetoacetate and was extracted with 2 N. Hcl and brine. In the drying with sodium carbonate, evaporating the solvent and chromatography on silica gel with acetoacetate/hexane in the ratio of 1:1 was obtained 0,094 g benzyl ester (R) -1- {4' [(R) -2-carboxyamide(51), 380 (25), 329 (33), 313 (30), 223 (38), 194 (83), 180 (66), 145 (24), 137 (21), 91 (100).

b) (R)-1- {4'- [(R)-2-carboxypropyl-1-ylcarbonyl] - [2.2] -betazole-4-yl} pyrrolidin-2-carboxylic acid
0.51 g (0.08 mmole) of the benzyl ether (R)-1-{4'-[(R)-2-benzyloxycarbonylamino-1-yl] - [2,2] -betazole-4-yl} pyrrolidin-2-carboxylic acid in 50 ml of methanol at room temperature was stirred for 64 h with 5 ml of 2n. the sodium hydroxide solution. After adding 2n. hydrochloric acid to pH 1, the mixture was extracted with dichloromethane. The extracts were dried with sodium sulfate and evaporated. The result chromatography on silica gel with dichloromethane/acetone/formic acid in the ratio of 80/15/5 in the form of a colorless solid was obtained 0.04 g (R)-1- {4'- [(R)-2-carboxypropyl-1-ylcarbonyl] - [2,2] -betazole-4-yl} pyrrolidin-2-carboxylic acid.

ISP-MS: 451 (M+N)+.

Example 21
(R)-1-{ [(R)-2-Carboxypropyl-1-yl] acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-pyrrolidin-2-carboxylic acid
Specified in the title compound was obtained as described in the literature method (M. Thorsen, T. R. Andersen, U. Pedersen, C. Yde and S.-O. Lawesson, Tetrahedron 1985, 41, 5633-5636.

Using as the starting material of 25.0 g (217 mmol) D-Proline, in the form of a colorless oil by chatelperronian-2-carboxylic acid
In the solution 64,9 g (322 mmole) of bromoacetamide in 250 ml of dichloromethane at 0oWith dropwise over 40 min was added a solution of 27.5 g (161 mmol) of tert-butyl methyl ether (R)-pyrrolidin-2-carboxylic acid and 30 ml (177 mmol) of N-ethyldiethanolamine in 150 ml of dichloromethane. The reaction mixture was allowed to warm overnight to room temperature and poured into 600 ml of water. The organic phase was separated, and the aqueous phase was extracted with 600 ml of dichloromethane. The combined organic phases are washed with saturated sodium bicarbonate solution and brine, dried (magnesium sulfate) and was evaporated to produce in the form of a brown oil of 44.1 g (94%) indicated in the title compound, which upon standing at room temperature crystallized. The melting temperature of 51.5-53,2oC.

C) tert-Butyl ether (R)-1-{[ (R) -2-tert-butoxycarbonylamino-1-yl] acetyl} -pyrrolidin-2-carboxylic acid
In a solution of 34.3 g (200 mmol) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 350 ml of dichloromethane at 0oWith dropwise introduced 27.9 ml (200 mmol) of triethylamine. After stirring for 45 min at this temperature was added dropwise with 17.8 g (200 mmol) of bromoacetamide. Stirring is continued at 0oIn astorm sodium bicarbonate and brine, was dried (magnesium sulfate) and was evaporated to produce in the form of butter 45 g of a brown product. In the trituration in ethyl acetate and cooling to -78oWith received 7,1 (9%) of pale yellow solid. The melting temperature of 75.0-76,0oC.

MC m/e (%): 405 (M+Na+, 11), 383 (M+N+, 100).

g) (R)-1- { [(R) -2-carboxypropyl-1-yl] acetyl} pyrrolidin-2-carboxylic acid
A solution of 382 mg (1.0 mmol) of tert-butyl methyl ether (R) -1-{[ (R) -2-tert-butoxycarbonylamino-1-yl] acetyl} pyrrolidin-2-carboxylic acid in 4 ml triperoxonane acid at room temperature was stirred for 3 hours In a vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying as a pale yellow amorphous and hygroscopic substances received 300 mg (quantitative yield) of the product RO-64-2799/000, which still contained trace amounts triperoxonane acid.

MS m/e (%): 269 (M-N-, 4,5), 113 (CF3CO2-, 100).

Example 22
(R)-1- { { 4- [2- [(R) -2-carboxypropyl-1-yl] - 2-oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R) -1- {{4- [2- [(R) -2-tert-butoxycarbonylamino-the Aliya in 2 ml of dimethylformamide at room temperature with stirring dropwise injected with a solution of 110 mg (1.0 mmol) of hydroquinone in 2 ml of dimethylformamide. Stirring was continued for 2-3 min 1-2 min solution was added 584 mg (2.0 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 4 ml of dimethylformamide. The reaction mixture was stirred for additional 3 h at room temperature. In vacuum solvent was removed and the residue was purified Express chromatography to produce in the form of a colourless oil 380 mg (71%) specified in the connection header.

MS m/e (%): 550 (M+NH4+, 100), 477 (23), 421 (65).

b) (R)-1- { { 4-[2- [(R) -2-carboxypropyl-1-yl]-2-oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 350 mg (0,66 mmole) of tert-butyl methyl ether (R)-1-{{4-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] phenoxy} acetyl] pyrrolidin-2-carboxylic acid in 4 ml triperoxonane acid was stirred for 3 h at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder was obtained 265 mg (96%) of the connection specified in the header.

MS m/e (%): 443 (M+Na+, 48), 438 (M+NH4+, 39), 421 (M+N+, 100).

Example 23
(R)-1- { { 4- [2- [(R) -2-carboxypropyl-1-- {{4- [2- [(R) -2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -2,3,5,6-tetraterpenes} acetyl} pyrrolidin-2-carboxylic acid
To a solution of 185 mg (1.65 mmole) of potassium tert-butylate in 1 ml of dimethylformamide at room temperature with stirring dropwise injected with a solution of 137 mg (0.75 mmole) of tetrafluorohydroquinone in 1 ml of dimethylformamide. Stirring was continued for 2-3 min 1-2 min was added a solution of 438 mg (1.50 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 2 ml of dimethylformamide. The reaction mixture was stirred for additional 4 h at room temperature. In vacuum solvent was removed and the residue was purified Express chromatography to obtain a white foam 87 mg (19%) specified in the connection header.

MS m/e (%): 622 (M+NH4+, 100), 549 (32), 493 (57).

b) (R)-1- { {4- [2- [(R) -2-carboxypropyl-1-yl] -2-oksidoksi] -2,3,5,6-tetraterpenes} acetyl} pyrrolidin-2-carboxylic acid
A solution of 80 mg (0,13 mmole) of tert-butyl methyl ether (R)-1-{{4-[2-[(R)-2-tert-butoxycarbonylamino-1 - yl] - 2 - oksidoksi] -2,3,5,6-tetraterpenes} acetyl} pyrrolidin-2-carboxylic acid in 1.5 ml triperoxonane acid for 4 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In result/e (%): 491 (M-N-, 100).

Example 24
(R)-1- {{4- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -2-chlorophenoxy} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R) -1- {{4- [2- [(R) -2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -2-chlorophenoxy} acetyl} pyrrolidin-2-carboxylic acid
To a solution of 185 mg (1.65 mmole) of potassium tert-butylate in 1 ml of dimethylformamide at room temperature with stirring dropwise injected with a solution of 108 mg (0.75 mmole) of chlorohydroquinone in 1 ml of dimethylformamide. Stirring was continued for 2-3 min 1-2 min was added a solution of 438 mg (1.50 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 2 ml of dimethylformamide. The reaction mixture was stirred for additional 4 h at room temperature. In vacuum solvent was removed and the residue was purified Express chromatography to obtain a white foam 149 mg (35%) specified in the connection header.

MS m/e (%): 584 (M+NH4+, 100), 511 (48), 455 (96).

b) (R)-1- {{4- [2- [(R) -2-carboxypropyl-1-yl] -2-oksidoksi] -2-chlorophenoxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 140 mg (0.25 mmole) of tert-butyl methyl ether (R)-1-{{4-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -2-chlorophenoxy} acetyl} pyrrole In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder was obtained 126 mg (quantitative yield) specified in the connection header.

MS m/e (%): 453 (M-N-, 100).

Example 25
(R)-1- { {4- [2- [(R) -2-carboxypropyl-1-yl] -2-oksidoksi] -2-methoxyphenoxy} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-1- {{4- [2- [(R) -2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -2-methoxyphenoxy} acetyl} pyrrolidin-2-carboxylic acid
To a solution of 236 mg (2.1 mmole) of potassium tert-butylate in 2 ml of dimethylformamide at room temperature with stirring dropwise injected with a solution of 140 mg (1.0 mmole) of methoxyhydroquinone in 2 ml of dimethylformamide. Stirring was continued for 2-3 min 1-2 min solution was added 584 mg (2.0 mmole) of tert-butyl methyl ether (R) -(1)-bromoacetanilide-2-carboxylic acid in 4 ml of dimethylformamide. The reaction mixture was stirred for additional 3 h at room temperature. In vacuum solvent was removed and the residue was purified Express chromatography to produce in the form of a colourless oil 280 mg (50%) specified in the connection header.

MS m/e (%): 580 (M+NH4+, 100), 563 (M+N+, 75), 507 (62), 451 (67).

b) (R)-1- {{4- [solution of 250 mg (of 0.44 mmole) of tert-butyl methyl ether (R)-1- {{4-[2-[(R)-2-tert - butoxycarbonylamino -1-yl] - 2 oksidoksi] - 2 - methoxyphenoxy} acetyl} pyrrolidin-2-carboxylic acid in 4 ml triperoxonane acid for 3 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder was obtained 188 mg (94%) specified in the connection header.

MS m/e (%): 473 (M+Na+, 45), 468 (M+NH4+, 24), 451 (M+N+, 100).

Example 26
A mixture of (R) -1-[(4-hydroxy-3 - and-2-methoxyphenoxy)acetyl]pyrrolidin-2-carboxylic acid
a) a Mixture of tert-butyl esters of (R) -1-[(4-hydroxy-3 - and-2-methoxyphenoxy)acetyl] pyrrolidin-2-carboxylic acid
Specified in the title compound was obtained as a by-product in the process of obtaining tert-butyl ether (R)-1- {{4- [2- [(R) -2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -2-methoxyphenoxy} acetyl} pyrrolidin-2-carboxylic acid. In the separation and purification Express chromatography in the form of a colorless oil was obtained 80 mg (23%) of product RO-64-2915/000.

1H-NMR (CDCl3, part./million): of 1.41 (s, H 2,4), 1,45 (s, 6,6 H), 1,81 of-2.32 (m, 4H), 3,55-3,82 (m, 2H, in), 3.75 (s, 3H), 4,39-4,78 (m, 3H), 6,16-of 6.26 (m, 1H), 6,40-to 6.43 (m, 1H), 6,67-6,74 (m, 1H).

b) a Mixture of (R) -1-[(4-hydroxy-3 - and-2-the (R)-1-[(4-hydroxy-3 - and-2-methoxyphenoxy) acetyl] pyrrolidin-2-carboxylic acid in 1 ml of dichloromethane was injected 5 ml of 4n. hydrochloric acid in dioxane. After 24 h in vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder was obtained 65 mg (97%) indicated in the title mixture of compounds.

MS m/e (%): 296 (M+N+, 100).

Example 27
(R)-1- { {3- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi]phenoxy} acetyl}pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-1- {{3- [2- [(R) -tert-butoxycarbonylamino-1-yl] -2-oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid
In a mixed solution of 561 mg (5.0 mmol) of potassium tert-butylate in 4 ml of dimethylformamide at room temperature was dropwise introduced a solution of 275 mg (2.5 mmole) of resorcinol in 4 ml of dimethylformamide. Stirring was continued for 2-3 min 1-2 min was added a solution of 1.46 mg (5.0 mmol) of tert-butyl methyl ether (R) -(1)-bromoacetanilide-2-carboxylic acid in 5 ml of dimethylformamide. The reaction mixture was stirred for additional 3 h at room temperature. In vacuum solvent was removed and the residue was purified Express chromatography to produce in the form of a colourless oil 830 mg (62%) specified in the header-yl] - 2 oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 750 mg (1,41 mmole) of tert-butyl methyl ether (R)-1-{{3-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid in 6 ml triperoxonane acid for 3 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 15 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder was obtained 581 mg (98%) specified in the connection header.

MC m/e (%): 443 (M+Na+, 32), 438 (M+NH4+, 20), 421 (M+N+, 100).

Example 28
(R)-1- [(3-hydroxyphenoxy) acetyl] pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R) -1-[(3-hydroxyphenoxy)acetyl]pyrrolidin-2-carboxylic acid
Specified in the title compound was obtained as a by-product of the process of obtaining tert-butyl ether (R)-1- {{3- [2- [(R) -2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid. In the separation and purification Express chromatography in the form of a colorless oil was obtained 120 mg (37%) of product RO-64-2802/000.

MC m/e (%): 344 (M+Na+, 9), 322 (M+H+, 73), 266 (100).

b) (R)-1 is a (R)-1-[(3-hydroxyphenoxy)acetyl]pyrrolidin-2-carboxylic acid in 1 ml of dichloromethane was injected 5 ml of 4n. hydrochloric acid in dioxane. After 3 days in vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder was obtained 95 mg (97%) specified in the connection header.

MS m/e (%): 264 (M-N-, 100).

Example 29
(R)-1- { { 3- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -2-methylphenoxy} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-1- {{3- [2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -2-methylphenoxy} acetyl} pyrrolidin-2-carboxylic acid
In a mixed solution of 236 mg (2.1 mmole) of potassium tert-butylate in 2 ml of dimethylformamide at room temperature was dropwise introduced a solution of 124 mg (1.0 mmol) of 2,6-dihydroxytoluene in 2 ml of dimethylformamide. Stirring was continued for 2-3 min 1-2 min solution was added 584 mg (2.0 mmole) of tert-butyl methyl ether (R) -(1)-bromoacetanilide-2-carboxylic acid in 4 ml of dimethylformamide. The reaction mixture was stirred for additional 3 h at room temperature. In vacuum solvent was removed and the residue was purified Express chromatography to produce in the form of a colourless oil 335 mg (61%) in superolein-1-yl] -2-oksidoksi] -2-methylphenoxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 300 mg (0.55 mmole) of tert-butyl methyl ether (R)-1-{{3-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -2-methylphenoxy} acetyl} pyrrolidin-2-carboxylic acid in 4 ml triperoxonane acid for 3 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder was obtained 226 mg (95%) specified in the connection header.

MS m/e (%): 457 (M+Na+, 54), 452 (M+NH4+, 55), 435 (M+N+, 100).

Example 30
(R)-1- { {3- [2- [(R) -2-carboxypropyl-1-yl] -2-oksidoksi] -5-methoxyphenoxy} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R) -1- {{3- [2- [(R) -2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5-methoxyphenoxy} acetyl} pyrrolidin-2-carboxylic acid
In a mixed solution of 236 mg (2.1 mmole) of potassium tert-butylate in 2 ml of dimethylformamide at room temperature was dropwise introduced a solution of 140 mg (1.0 mmol) 5-methoxyisatin in 2 ml of dimethylformamide. Stirring was continued for 2-3 min 1-2 min solution was added 584 mg (2.0 mmole) of tert-butyl methyl ether (R) -(1)-bromoacetanilide-2-carboxylic acid is E. In vacuum solvent was removed and the residue was purified Express chromatography to produce in the form of a colourless oil 407 mg (72%) specified in the connection header.

MS m/e (%): 580 (M+NH4+, 98), 563 (M+N+, 100), 507 (54), 451 (95).

b) (R)-1- {{3- [2- [(R) -2-carboxypropyl-1-yl] -2-oksidoksi] -5-methoxyphenoxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 370 mg (0,66 mmole) of tert-butyl methyl ether (R)-1- {{3- [2- [(R)-2-tert - butoxycarbonylamino -1 - yl] - 2 - oksidoksi] -5 - methoxyphenoxy} acetyl} pyrrolidin-2-carboxylic acid in 4 ml triperoxonane acid for 3 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder was obtained 287 mg (97%) specified in the connection header.

MC m/e (%): 473 (M+Na+, 45), 468 (M+NH4+, 30), 451 (M+N+, 100).

Example 31
(R)-1-{ { 3- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -5-ethoxycarbonylmethoxy} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-1- {{3- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5-ethoxycarbonylmethoxy} acetyl} pyrrolidin-2-carboxylic KIS the temperature dropwise injected with a solution of 420 mg (2.5 mmole) of 3,5-dihydroxybenzoate in 4 ml of dimethylformamide. Stirring was continued for 2-3 min 1-2 min was added a solution of 1.46 mg (5.0 mmol) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 5 ml of dimethylformamide. The reaction mixture was stirred for additional 2 h at room temperature. In vacuum solvent was removed and the residue was purified Express chromatography to produce in the form of a colourless oil 1,01 mg (68%) specified in the connection header.

MC m/e (%): 608 (M+NH4+, 92), 591 (M+N+, 48), 535 (41), 479 (100).

b) (R)-1- {{3- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -5-ethoxycarbonylmethoxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 710 mg (1.2 mmole) of tert-butyl methyl ether (R)-1- {{3- [2- [(R)-2-tert - butoxycarbonylamino -1 - yl] - 2 - oksidoksi] - 5 - ethoxycarbonylmethoxy} acetyl} pyrrolidin-2-carboxylic acid in 10 ml triperoxonane acid for 3 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 20 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder was obtained 540 mg (94%) specified in the connection header.

MC m/e (%): 477 (M-N-, 100).

Example 32
(R)-1- { { 3-carboxy-5 - the creators of lithium hydroxide in methanol/water at a ratio of 3: 1 was administered 100 mg (0.2 mmole) of (R)-1-{{3-[2-[(R)-2-carboxypropyl-1-yl]-2-oksidoksi] -5-ethoxycarbonylmethoxy} acetyl} pyrrolidin-2-carboxylic acid. The solution was allowed to stand at room temperature for 24 hours of the Addition dropwise of a solution of hydrochloric acid the pH value of the mixture was brought to 6 and liofilizirovanny to obtain 800 mg of white powder. The product was isolated by chromatography using ion-exchange resin (product Dowex). In the lyophilization as a white powder received 20 mg (22%) specified in the connection header.

MS m/e (%): 487 (M+Na+, 61), 482 (M+NH4+, 54), 465 (M+N+, 100).

Example 33
a) tert-Butyl ether (R)-1- {{3- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5-cianfrocca} acetyl} pyrrolidin-2-carboxylic acid
In a solution of 1.35 mg (10 mmol) of 3,5-dihydroxybenzoate and 5.84 g (20 mmol) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 25 ml of dimethylformamide at room temperature was injected 7 g of anhydrous potassium carbonate. After stirring for an additional 20 h potassium salt was filtered and vacuum solvent was removed. The residue was purified Express chromatography to produce in the form of a colourless foam of 4.77 mg (86%) specified in the connection header.

MS m/e (%): 575 (M+NH4+, 100), 558 (M+N+, 42), 502 (35), 446 (85).

b) (R)-1- {{3- [2- [(R)-2-carboxypropyl-1-yl] -2-occaecat-1-{{3-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5-cianfrocca} acetyl} pyrrolidin-2-carboxylic acid in 5 ml triperoxonane acid for 18 h and was stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder was obtained 280 mg (72%) specified in the connection header.

MS m/e (%): 444 (M-H-, 100).

Example 34
(R)-1- { {3- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -5-1H-tetrazol-5-elfenix} acetyl} pyrrolidin-2-carboxylic acid
To a solution of 110 mg (0.2 mmole) of tert-butyl methyl ether (R)-1-{{3-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5-cianfrocca} -acetyl} pyrrolidin-2-carboxylic acid in 10 ml of 1,2-dimethoxyethane was administered 200 mg (0.6 mmole) azide presence of TBT. The mixture was boiled under reflux for 3 days. After cooling to room temperature the solution was barbotirovany 1.4 g of gaseous hydrochloric acid with getting 4h. hydrochloric acid in 1,2-dimethoxyethane and stirring was continued for 12 hours In vacuum solvent was removed and the oily residue triturated in diethyl ether to produce in the form of a pale yellow amorphous solids 61 mg (92%) of the connection specified in the header.

MS m/e (%): 511 (M+Na4+, 41), 506 (M+NH4+, 32), 489 (M+N+, 100).

Example 35
the
a) tert-Butyl ether (R)-1-{{3- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5-hydroxyphenoxy} acetyl} pyrrolidin-2-carboxylic acid
In a solution of 95 mg (0.75 mmole) of phloroglucinol and 438 mg (1.5 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 2 ml of dimethylformamide at room temperature was introduced 520 mg of anhydrous potassium carbonate. After stirring over night potassium salt was filtered and vacuum solvent was removed. The residue was purified Express chromatography to produce in the form of a colourless foam 50 mg (12%) specified in the connection header.

MS m/e (%): 566 (M+NH4+, 96), 549 (M+N+, 88), 493 (47), 437 (100).

b) (R)-1 {{3- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -5-hydroxyphenoxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 46 mg (0,084 mmole) of tert-butyl methyl ether (R)-1-{{3-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5-hydroxyphenoxy} acetyl} pyrrolidin-2-carboxylic acid in 1 ml triperoxonane acid for 4 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 5 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying as is.

Example 36
(R)-1- { { 3,5-bis- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-1- {{3,5-bis-[2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid
In a solution of 95 mg (0.75 mmole) of phloroglucinol and 220 mg (0.75 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 2 ml of dimethylformamide at room temperature was introduced 520 mg of anhydrous potassium carbonate. After stirring at room temperature for 2 and 6 h each time) was added 220 mg (0.75 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid and stirring continued for 18 hours Potassium salt was filtered and vacuum solvent was removed. The residue was purified Express chromatography to produce in the form of a colourless foam 465 mg (82%) specified in the connection header.

MS m/e (%): 777 (M+NH4+, 100), 760 (M+N+, 4), 704 (11), 648 (22), 592 (22).

b) (R)-1- {{3,5-bis- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] phenoxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 350 mg (0,47 mmole) of tert-butyl methyl ether (R)-1-{{3,5-bis-[2-[(R) -2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] phenoxy} acetyl} p is the atur. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a light brown powder was obtained 254 mg (92%) specified in the connection header.

MS m/e (%): 614 (M+Na+, 73), 609 (M+NH4+, 100), 592 (M+N+, 56).

Example 37
A mixture of (E)- and (Z)-(R)-1-{{3-[2-[(R)-2-carboxypropyl-1-yl]-2-oksidoksi] -5- (N-hydroxycarbamoyl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid
a) a Mixture of tert-butyl esters (E)- and (Z)-(R)-1-{{3-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5- (N-hydroxycarbamoyl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid
In a solution of 1.25 g (17.9 mmole) of hydroxylaminopurine in 6 ml of dimethyl sulfoxide was injected 1,82 g (18 mmol) of triethylamine. Insoluble material was filtered and washed with 5 ml of tetrahydrofuran. The filtrate was concentrated in vacuum, under a residual pressure of 100 mbar, removing tetrahydrofuran, was added 2.0 g (3,59 mmole) of tert-butyl methyl ether (R)-1-{{3- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5-cianfrocca} acetyl} pyrrolidin-2-carboxylic acid. After stirring for 20 h at 75oTo the reaction mixture was diluted with water and eat in an aqueous solution of 1H. the sodium hydroxide solution the pH was brought to 10 and extracted with ethyl acetate. The organic solution was washed with water, dried (sodium sulfate) and evaporated to produce in the form of a colourless foam of 1.74 g of a mixture of compounds specified in the header.

MS m/e (%): 613 (M+Na+, 7), 591 (M+NH4+, 100), 535 (21), 479 (15).

b) a Mixture of (E)- and (Z)- (R)-1-{{3-[2-[(R)-2-carboxypropyl-1-yl]-2-oksidoksi] -5- (N-hydroxycarbamoyl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 120 mg (0.2 mmole) of the mixture of tert-butyl esters (E)- and (Z)-(R)-1- { {3- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5-(N-hydroxycarbamoyl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid in 1.5 ml triperoxonane acid for 4 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a light brown powder was obtained 96 mg (quantitative yield) indicated in the title mixture of compounds.

MC m/e (%):501 (M+Na+, 31), 479 (M+H+, 100).

Example 38
(R)-1- {{3- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -5-(5-oxo-4,5-dihydro [1,2,4] oxadiazol-3-yl)phenoxy} acetyl} pyrrolidin-2-ka-oxo-4,5-dihydro[1,2,4] oxadiazol-3-yl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid
Chilled with ice a solution of 300 mg (of 0.51 mmole) of tert-butyl esters (E)- and (Z)-(R)-1- {{3- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5- (N-hydroxycarbamoyl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid and 43 mg (0.55 mmole) of pyridine in 2 ml of dimethylformamide was added dropwise to 200 mg (of 0.51 mmole) of 2-ethylhexylcarbonate. The mixture was stirred at 0oC for 30 min, diluted with water and extracted with ethyl acetate. The organic phase was dried (sodium sulfate), evaporated and the oily residue was dissolved in 20 ml of toluene. After stirring for 16 h at room temperature in toluene solution was washed with brine, dried (sodium sulfate) and filtered on silica gel to produce in the form of a viscous oil 280 mg (89%) of the connection specified in the header.

MC m/e (%): 639 (M+Na+, 51), 634 (M+NH4+, 100), 617 (M+N+, 14), 561 (40), 505 (79).

b) (R)-1- {{3- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -5-(5-oxo-4,5-dihydro[1,2,4]oxadiazol-3-yl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 220 mg (0,36 mmole) of tert-butyl methyl ether (R)-1-{{3-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5- (5-oxo-4,5-dihydro[1,2,4] oxadiazol-3-yl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid in 1.5 ml triperoxonane who was denovali in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a light brown powder was obtained 135 mg (74%) specified in the connection header.

MC m/e (%): 527 (M+Na+, 73), 522 (M+NH4+, 75), 505 (M+N+100).

Example 39
(R)-1- { {3- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -5-(2-oxo-2,3-dihydro[1,2,3,5] oxadiazol-4-yl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid (S-oxide config., R/S=1:1)
a) tert-Butyl ether (R)-1- {{3- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5-(2-oxo-2,3-dihydro[1,2,3,5]oxadiazol-4-yl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid (S-oxide config., R/S=1:1)
Chilled with ice a solution of 300 mg (of 0.51 mmole) of tert-butyl esters (E)- and (Z)-(R)-1- {{3- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5- (N-hydroxycarbamoyl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid and 80 mg (1 mmol) of pyridine in 2 ml of dichloromethane was added dropwise 60 mg (0,51 mmole) thionyl chloride (dissolved in 0.3 ml of dichloromethane). The mixture was stirred at 0oC for 45 min, diluted with dichloromethane, washed with water, dried (sodium sulfate) and was evaporated. As a result, the rapid chromatography in the form of semi-solid liquid was obtained 190 mg (59%) of the compound, b) (R)-1- {{3- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -5-(2-oxo-2,3-dihydro[1,2,3,5] oxadiazol-4-yl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid (S-oxide config., R/S=1:1)
A solution of 165 mg (0,26 mmole) of tert-butyl methyl ether (R)-1-{{3-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5-(2-oxo-2,3-dihydro[1,2,3,5] oxadiazol-4-yl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid (S-oxide configuration. , R/S=1:1) in 1.5 ml triperoxonane acid for 4 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a light brown powder was obtained 115 mg (85%) specified in the connection header.

MC m/e (%): 547 (M+Na+, 65), 542 (M+NH4+, 86), 525 (M+N+, 100).

Example 40
(R)-1- { {3- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -5-(5-tert-butylsulfonyl[1,2,4] oxadiazol-3-yl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-1- {{3- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5-(5-thioxo-4,5-dihydro[1,2,4] oxadiazol-3-yl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid
A mixture of 515 mg (of 0.87 mmole) of tert-butyl esters (E)- and (Z)-(R)-1-{{3-[2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5-(N-hydroxycarbamoyl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid 177 mg (0,94 mmole) of 1,1'-tocurb the th temperature for 4 h The mixture was concentrated in vacuum, diluted with water, with 1N. hydrochloric acid the pH value was brought to 4-5 and extracted with ethyl acetate. The extract was concentrated again, the residue was diluted with 100 ml of 1N. the sodium hydroxide solution and washed with diethyl ether. The addition of 1H. hydrochloric acid is the pH was brought to 4 and extracted with ethyl acetate. The organic phase is washed with water, dried (sodium sulfate) and evaporated to produce in the form of a pale brown foam 490 mg (89%) specified in the connection header.

MS m/e (%): 655 (M+Na+, 35), 650 (M+NH4+, 100), 633 (M+N+, 14), 577 (31), 521 (52).

b) (R)-1- {{3- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -5-(5-tert-butylsulfonyl[1,2,4] oxadiazol-3-yl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 315 mg (0.5 mmole) of tert-butyl methyl ether (R)-1-{{3-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -5- (5-thioxo-4,5-dihydro[1,2,4]oxadiazol-3-yl)phenoxy} acetyl} pyrrolidin-2-carboxylic acid in 1.5 ml triperoxonane acid for 4 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. The result is filtered, 4), 594 (M+NH4+, 71), 577 (M+N+, 100), 521 (37).

Example 41
(R)-1- {{2- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -3-methoxyphenoxy} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-1- {{2- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -3-methoxyphenoxy} acetyl} pyrrolidin-2-carboxylic acid
In a mixed solution of 236 mg (2.1 mmole) of potassium tert-butylate in 2 ml of dimethylformamide at room temperature was dropwise introduced a solution of 140 mg (1.0 mmol) pyragollole-1-methyl ester in 2 ml of dimethylformamide. Stirring was continued for 2-3 min 1-2 min solution was added 584 mg (2.0 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 4 ml of dimethylformamide. The reaction mixture was stirred for additional 3 h at room temperature. In vacuum solvent was removed and the residue was purified Express chromatography to produce in the form of a colourless oil 375 mg (67%) specified in the connection header.

MS m/e (%): 580 (M+NH4+, 14), 563 (M+N+, 100), 507 (14), 451 (12).

b) (R)-1- {{2- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -3-methoxyphenoxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 345 mg (0,61 mmole) of tert-butyl methyl ether (R)-1-{{2-[2-[(the notes in 4 ml triperoxonane acid for 4 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder was obtained 265 mg (96%) specified in the connection header.

MS m/e (%): 473 (M+Na+, 54), 451 (M+N+, 100).

Example 42
(R)-1- { { 2- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -3-methylphenoxy} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-1- {{2- [2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -3-methylphenoxy} acetyl} pyrrolidin-2-carboxylic acid
In a mixed solution of 236 mg (2.1 mmole) of potassium tert-butylate in 2 ml of dimethylformamide at room temperature was dropwise introduced a solution of 124 mg (1.0 mmol) 3-methylcatechol in 2 ml of dimethylformamide. Stirring was continued for 2-3 min 1-2 min solution was added 584 mg (2.0 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 4 ml of dimethylformamide. The reaction mixture was stirred for additional 3 h at room temperature. In vacuum solvent was removed and the residue was purified Express chromatography to produce in the form of a colourless oil 356 mg (65%) specified in the connection header.

MS m/e (%):} pyrrolidin-2-carboxylic acid
A solution of 325 mg (0.60 mmole) of tert-butyl methyl ether (R)-1-{{2-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -3-methylphenoxy} acetyl} pyrrolidin-2-carboxylic acid in 4 ml triperoxonane acid for 3 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder was obtained 235 mg (91%) specified in the connection header.

MS m/e (%): 457 (M+Na+, 59), 435 (M+N+, 100).

Example 43
(R)-1- { { 2- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -3,4,5,6-tetrachlorophenol} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-1- {{2- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -3,4,5,6-tetrachlorophenol} acetyl} pyrrolidin-2-carboxylic acid
In a mixed solution of 185 mg (1.65 mmole) of potassium tert-butylate in 1 ml of dimethylformamide at room temperature was dropwise introduced a solution of 186 mg (0.75 mmole) of tetrachloroethene in 1 ml of dimethylformamide. Stirring was continued for 2-3 min 1-2 min was added a solution of 438 mg (1.50 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 2 ml of dimethyl what dalali the solvent and the residue was purified Express chromatography to obtain a white foam 229 mg (45%) specified in the connection header.

MS m/e (%): 671 (M+N+, 100), 615 (19), 559 (14).

b) (R)-1- { { 2- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] -3,3,5,6-tetrachlorophenols} acetyl} pyrrolidin-2-carboxylic acid
A solution of 220 mg (0,34 mmole) of tert-butyl methyl ether (R)-1- {{2- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] -3,4,5,6-tetrachlorophenol} acetyl} pyrrolidin-2-carboxylic acid in 1.5 ml triperoxonane acid for 4 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder was obtained 172 mg (94%) specified in the connection header.

MS m/e (%): 559 (M-N-, 100).

Example 44
(R)-1- { { 6- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] naphthalene-2-yloxy} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-1- {{6- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] naphthalene-2-yloxy} acetyl} pyrrolidin-2-carboxylic acid
In a mixed solution of 236 mg (2.1 mmole) of potassium tert-butylate in 2 ml of dimethylformamide at room temperature was dropwise introduced a solution of 160 mg (1.0 mmol) of 2,6-dihydroxynaphthalene in 2 ml of dimethylformamide. Stirring is continued Raiden-2-carboxylic acid in 4 ml of dimethylformamide. The reaction mixture was stirred for additional 3 h at room temperature. In vacuum solvent was removed and the residue was purified Express chromatography to produce in the form of a white solid substance 120 mg (21%) specified in the connection header.

MS m/e (%): 605 (M+Na+, 14), 600 (M+NH4+, 92), 583 (M+N+, 5), 527 (32), 471 (100).

b) (R)-1- {{6- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] naphthalene-2-yloxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 75 mg (0,13 mmole) of tert-butyl methyl ether (R)-1-{{6-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] naphthalene-2-yloxy} acetyl} pyrrolidin-2-carboxylic acid in 1.5 ml triperoxonane acid for 18 h and was stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder were obtained 60 mg (98%) specified in the connection header.

MS m/e (%): 493 (M+Na+, 58), 488 (M+NH4+, 33), 471 (M+N+, 100).

Example 45
(R)-1- {{5- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] naphthalene - 1-yloxy} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-1- {{5- [2- [(R)-2-tert-rotoxicity a solution of 236 mg (2.1 mmole) of potassium tert-butylate in 2 ml of dimethylformamide at room temperature was dropwise introduced a solution of 160 mg (1.0 mmol) of 1,5-dihydroxynaphthalene in 2 ml of dimethylformamide. Stirring was continued for 2-3 min 1-2 min solution was added 584 mg (2.0 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 4 ml of dimethylformamide. The reaction mixture was stirred for additional 3 h at room temperature. In vacuum solvent was removed and the residue was purified Express chromatography to obtain in the form of a pale yellow foam 470 mg (81%) specified in the connection header.

MS m/e (%): 605 (M+Na+, 10), 600 (M+NH4+, 100), 527 (20), 471 (63).

b) (R)-1- {{5- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] naphthalene-1-yloxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 290 mg (0.5 mmole) of tert-butyl methyl ether (R)-1-{{5-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] naphthalene-1-yloxy}acetyl} pyrrolidin-2-carboxylic acid in 5 ml triperoxonane acid for 18 h and was stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder was obtained 230 mg (98%) specified in the connection header.

MS m/e (%): 493 (M+Na+, 45), 488 (M+NH4+, 37), 471 (M+N+100).

Example 46
(R)-
a) tert-Butyl ether (R)-1- {{3- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] naphthalene-2-yloxy} acetyl} pyrrolidin-2-carboxylic acid
In a mixed solution of 236 mg (2.1 mmole) of potassium tert-butylate in 2 ml of dimethylformamide at room temperature was dropwise introduced a solution of 160 mg (1.0 mmol) of 2,3-dihydroxynaphthalene in 2 ml of dimethylformamide. Stirring was continued for 2-3 min 1-2 min solution was added 584 mg (2.0 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 4 ml of dimethylformamide. The reaction mixture was stirred for additional 3 h at room temperature. In vacuum solvent was removed and the residue was purified Express chromatography to produce in the form of a colourless oil 310 mg (53%) specified in the connection header.

MS m/e (%): 605 (M+Na+, 27), 600 (M+NH4+, 16), 583 (M+N+, 100), 527 (16), 471 (24).

b) (R)-1- {{3- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] naphthalene - 2 - yloxy} acetyl} pyrrolidin - 2 - carboxylic acid
A solution of 230 mg (0.4 mmole) of tert-butyl methyl ether (R)-1-{{3-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] naphthalene-2-yloxy} acetyl} pyrrolidin-2-carboxylic acid in 5 ml triperoxonane acid within 18 h of peremeshivaya. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder were obtained 180 mg (96%) specified in the connection header.

MS m/e (%): 469 (M-N-, 100).

Example 47
(R)-1- { { 2'- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi]diphenyl-2-yloxy} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-1- {{2'- [2- [(R)-2-tert-butoxycarbonyl-iparralde-1-yl] -2-oksidoksi] diphenyl-2-yloxy} acetyl} pyrrolidin-2-carboxylic acid
In mix a solution of 160 mg (1.44 mmole) of potassium tert-butylate in 1.6 ml of dimethylformamide at room temperature was dropwise introduced a solution of 127 mg (0,69 mmole) of 2,2'-dihydroxydiphenyl in 1 ml of dimethylformamide. Stirring was continued for 2-3 min 1-2 min solution was added 400 mg (1,37 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 4 ml of dimethylformamide. The reaction mixture was stirred over night at room temperature. In vacuum solvent was removed and the residue was purified Express chromatography to obtain in the form of a light brown oil, 84 mg (20%) specified in the connection header.

MS m/e (%): 631 (M+Na+22), 626 (M+NH4+, 100), 609 (M+N+, 16).

b) (R)-1- {{2'- [2- [(R)-2-carboxamido is t-butyl ether (R)-1- {{2'-[2-[(R)-2-tert - butoxycarbonylamino -1 - yl] - 2 - oksidoksi] diphenyl - 2 - yloxy} acetyl} pyrrolidin-2-carboxylic acid in 1 ml triperoxonane acid for 4 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a light brown powder was obtained 31 mg (44%) specified in the connection header.

MS m/e (%): 519 (M+Na+, 62), 497 (M+N+, 100).

Example 48
(R)-1- {{4- [2- [(R)-2-carboxypropyl-1-yl] - 2 - oksidoksi] naphthalene - 1-yloxy} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-1- {{4- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] naphthalene - 1-yloxy} acetyl} pyrrolidin-2-carboxylic acid
In mix a solution of 160 mg (1.44 mmole) of potassium tert-butylate in 1.6 ml of dimethylformamide at room temperature was dropwise introduced a solution of 116 mg (0,69 mmole) of 1,4-naphthoquinone in 1 ml of dimethylformamide. Stirring was continued for 2-3 min 1-2 min solution was added 400 mg (1,37 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 4 ml of dimethylformamide. The reaction mixture was stirred for overnight is rising in the form of a light brown foam 269 mg (67%) specified in the connection header.

MS m/e (%): 600 (M+NH4+, 100).

b) (R)-1-{ { 4- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] naphthalene-1-yloxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 172 mg (0.30 mmole) of tert-butyl methyl ether (R)-1-{{4-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] naphthalene-1-yloxy} acetyl} pyrrolidin-2-carboxylic acid in 1.5 ml triperoxonane acid for 4 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a light brown powder was obtained 140 mg (quantitative yield) specified in the connection header.

MS m/e (%): 469 (M-N-, 100).

Example 49
(R)-1- {{7- [2- [(R)-2-carboxypropyl-1-yl] - 2 - oksidoksi] naphthalene - 2-yloxy} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-1- {{7- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oksidoksi] naphthalene-2-yloxy} acetyl} pyrrolidin-2-carboxylic acid
To a solution of 110 mg (0,69 mmole) of 2,7-dihydroxynaphthalene and 400 mg (1,37 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 1.5 ml of dimethylformamide at room temperature was injected 480 mg bestgene solvent was removed. The residue was purified Express chromatography to obtain a white foam 296 mg (74%) specified in the connection header.

MS m/e (%): 600 (M+NH4+, 100), 527 (25), 471 (99).

b) (R)-1- {{7- [2- [(R)-2-carboxypropyl-1-yl] -2-oksidoksi] naphthalene-2-yloxy} acetyl} pyrrolidin-2-carboxylic acid
A solution of 272 mg (0,47 mmole) of tert-butyl methyl ether (R)-1-{{7-[2-[(R)-2 - tert - butoxycarbonylamino -1 - yl] - 2 - oksidoksi] naphthalene - 2-yloxy} acetyl} pyrrolidin-2-carboxylic acid in 1.5 ml triperoxonane acid for 4 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a white powder was obtained 209 mg (95%) specified in the connection header.

MS m/e (%): 493 (M+Na+, 48), 488 (M+NH4+, 23), 471 (M+N+, 100).

Example 50
Triptorelin (R) -1- {{3- [2- [(R) -2-carboxypropyl-1-yl] -2-oxoethylidene] phenylamino} acetyl} pyrrolidin-2-carboxylic acid (2:1)
a) tert-Butyl ether (R)-1- {{3- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oxoethylidene] phenylamino} acetyl} pyrrolidin-2-carboxylic acid
In a solution of 75 mg (0,69 mmole) of 1,3-phenylenediamine and 400 mg (1,37 temperature was introduced to 0.21 ml (1.5 mmole) of triethylamine. The reaction mixture was stirred at room temperature overnight. The organic phase was washed for 1H. a solution of sodium carbonate and brine, dried (sodium sulfate) and was evaporated. The residue was purified Express chromatography to obtain in the form of a light brown foam 285 mg (78%) specified in the connection header.

MS m/e (%): 553 (M+Na+, 15), 531 (M+H+, 100), 475 (20), 419 (10).

b) Triptorelin (R)-1- {{3- [2- [(R)-2-carboxypropyl-1-yl] -2-oxoethylidene] phenylamino} acetyl} pyrrolidin-2-carboxylic acid (2:1)
A solution of 170 mg (0,32 mmole) of tert-butyl methyl ether (R)-1- {{3- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oxoethylidene] phenylamino} acetyl} pyrrolidin-2-carboxylic acid in 4 ml triperoxonane acid for 4 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying as a brown foam was obtained 130 mg (63%) specified in the connection header.

MS: 417 (M-N-, 100).

Example 51
Triptorelin (R)-1- {{4- [2- [(R)-2-carboxypropyl-1-yl] -2-oxoethylidene] phenylamino} acetyl} pyrrolidin-2-carboxylic acid (2:1)
a) tert-Butyl ether (R)-1- {{4- [2-
In a solution of 75 mg (0,69 mmole) of 1,4-phenylenediamine and 400 mg (1,37 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 4 ml of tetrahydrofuran at room temperature was injected 190 mg of anhydrous potassium carbonate. The reaction mixture was stirred at 40oWith during the night. Potassium salt was filtered and vacuum solvent was removed. The residue was purified Express chromatography to obtain in the form of a brown foam 180 mg (50%) specified in the connection header.

MS m/e (%): 553 (M+Na+, 26), 531 (M+H+, 100).

b) Triptorelin (R)-1- {{4- [2- [(R)-2-carboxypropyl-1-yl] -2-oxoethylidene] phenylamino} acetyl} pyrrolidin-2-carboxylic acid (2:1)
A solution of 168 mg (0,32 mmole) of tert-butyl methyl ether (R)-1-{{4-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oxoethylidene] phenylamino} acetyl} pyrrolidin-2-carboxylic acid in 2 ml of triperoxonane acid for 4 h and stirred at room temperature. Solvent was removed, the residue is suspended in toluene and the solvent was removed again with simultaneous removal of excess triperoxonane acid. The residue is again suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in korichneto (R)-1- {{[2- [(R)-2-carbonitriding-1-yl] -2-oxoethyl] butylamino} acetyl} pyrrolidin-2-carboxylic acid (1:1)
a) tert-Butyl ether (R)-1- {{[2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oxoethyl] butylamino} acetyl} pyrrolidin-2-carboxylic acid
To a solution of 136 mg (1,86 mmole) of butylamine and 995 mg (3,40 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 4 ml dichloromethane at room temperature was introduced to the value of 0.52 ml (3,74 mmole) of triethylamine. The suspension was stirred at room temperature overnight. The organic phase was washed for 1H. a solution of sodium carbonate and brine, dried (sodium sulfate) and was evaporated. The residue was purified Express chromatography to obtain in the form of a light brown oil 830 mg (98%) specified in the connection header.

MS m/e (%): 524 (2M+Ni+, 37), 496 (M+N+, 100), 468 (2), 440 (7).

b) Triptorelin (R)-1- {{[2- [(R)-2-carbonitriding-1-yl] -2-oxoethyl] butylamino} acetyl} pyrrolidin-2-carboxylic acid (1:1)
A solution of 50 mg (0.1 mmole) of tert-butyl methyl ether (R)-1-{{[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oxoethyl] butylamino} acetyl} pyrrolidin-2-carboxylic acid in 0.2 ml triperoxonane acid for 4 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred those whom the title compound.

MS: 382 (M-H-, 100).

Example 53
Triptorelin (R)-1- {{[2- [(R)-2-carbonitriding-1-yl] -2-oxoethyl] -(2-methoxyethyl)amino} acetyl}pyrrolidin-2-carboxylic acid (1:1)
a) tert-Butyl ether (R)-1- {{[2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oxoethyl] - (2-methoxyethyl)amino} acetyl} pyrrolidin-2-carboxylic acid
To a solution of 137 mg (1,83 mmole) of 2-methoxyethylamine and 970 mg (3.33 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 4 ml dichloromethane at room temperature was introduced 0.51 ml (3,66 mmole) of triethylamine. The suspension was stirred at room temperature overnight. The organic phase was washed for 1H. a solution of sodium carbonate and brine, dried (sodium sulfate) and was evaporated. The residue was purified Express chromatography to obtain in the form of a light brown oil 397 mg (48%) specified in the connection header.

MS m/e (%): 520 (M+Na+, 50), 498 (M+H+, 100).

b) Triptorelin (R) -1- {{ [2- [(R) -2-carbonitriding-1-yl] -2-oxoethyl] - (2-methoxyethyl)amino} acetyl} pyrrolidin-2-carboxylic acid (1:1)
A solution of 367 mg (0,74 mmole) of tert-butyl methyl ether (R)-1-{{[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oxoethyl] - (2-methoxyethyl)amino} acetyl} pyrrolidin-2-carboxylic acid in 2 ml of tripto the current suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of a light brown foam was obtained 350 mg (95%) specified in the connection header.

MS: 384 (M-H-, 100).

Example 54
Triptorelin (R) -1- {{benzyl [2- [(R) -2-carboxypropyl-1-yl] -2-oxoethyl] amino} acetyl} pyrrolidin-2-carboxylic acid (1:1)
a) tert-Butyl ether (R)-1-{{benzyl[2-[ (R)-2-tert-butoxycarbonylamino-1-yl] -2-oxoethyl] amino} acetyl} pyrrolidin-2-carboxylic acid
To a solution of 104 mg (0.97 mmole) of benzylamine and 514 mg (1,76 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 5 ml of dichloromethane at room temperature was injected with 0.27 ml (1,94 mmole) of triethylamine. The suspension was stirred at room temperature overnight. The organic phase was washed for 1H. a solution of sodium carbonate and brine, dried (sodium sulfate) and was evaporated. The residue was purified Express chromatography to obtain in the form of a light brown oil 270 mg (58%) specified in the connection header.

MC m/e (%): 552 (M+Na+, 12), 530 (M+N+, 100).

b) Triptorelin (R)-1- {{benzyl[2- [(R)-2-carboxypropyl-1-yl] -2-oxoethyl] amino} acetyl} pyrrolidin-2-carboxylic acid (1:1)
A solution of 200 mg (range 0.38 mmole) of tert-butilovomu acid in 2 ml of triperoxonane acid for 3 h and stirred at room temperature. In vacuum solvent was removed and the residue suspended in 10 ml of diethyl ether. The resulting suspension was stirred over night. In the filtration and drying in the form of white crystals were obtained 189 mg (94%) specified in the connection header.

MC m/e (%): 440 (M+Na+, 16), 418 (M+N+, 100).

Example 55
(R)-1- { { 3- [2- [(R)-2-carboxypropyl-1-yl] -2-oxoethyl] -1,3-dibutylamino} acetyl} pyrrolidin-2-carboxylic acid
a) tert - Butyl ether (R) -1 - butylaminoethyl - 2-carboxylic acid
The solution was 1.58 ml (16 mmol) of butylamine in 1 ml of dichloromethane at room temperature was dropwise introduced a solution of 470 mg (1.6 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 2 ml of dichloromethane. The suspension was stirred over night. The organic phase was washed for 1H. a solution of sodium carbonate and brine, dried (sodium sulfate) and was evaporated. The residue was purified Express chromatography to obtain in the form of a light brown oil 370 mg (81%) specified in the connection header.

MS m/e (%): 285 (M+N+, 100).

b) tert-Butyl ether (R)-1- [ {3- {2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oxoethyl] -1,3-dibutylamino} acetyl} pyrrolidin-2-carboxylic acid
To a solution of 165 mg (0,58 IMO is one of sodium carbonate. The suspension was evaporated to dryness and the residue is again suspended in 2 ml of tetrahydrofuran. Then, with stirring, were added to 1.4 ml (2.88 mmole) of 20% solution of phosgene in toluene and stirring was continued for 6 h at 50oC. Sodium salt was filtered and washed with tetrahydrofuran. The filtrate was evaporated, devlali 165 mg (of 0.58 mmole) of the product RO-64-2576/000 dissolved in 2 ml of tetrahydrofuran, and the newly added 305 mg of anhydrous sodium carbonate. After stirring overnight at 50oFrom the organic phase was washed for 1H. the hydrochloric acid solution, dried (magnesium sulfate) and was evaporated to obtain a pale brown powder (330 mg (91%) specified in the connection header.

MS m/e (%): 617 (M+Na+, 19), 595 (M+N+, 100).

in) (R)-1- {{3- [2- [(R)-2-carboxypropyl-1-yl] -2-oxoethyl] -1,3-dibutylamino} acetyl} pyrrolidin-2-carboxylic acid
A solution of 278 mg (0,47 mmole) of tert-butyl methyl ether (R)-1-{{3-[2-[(R)-2-tert-butoxycarbonylamino-1-yl] -2-oxoethyl] -1,3-dibutylamino} acetyl} pyrrolidin-2-carboxylic acid in 2 ml of triperoxonane acid for 4 h and stirred at room temperature. In vacuum solvent was removed and the residue was dried to obtain in the form of a brown foam 167 mg (74%) specified in sagalow- [(R)-2-carboxypropyl-1-yl] -2-oxoethyl] ureido} acetyl} pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (R)-1-benzylpyrrolidine-2-carboxylic acid
In a solution of 1.25 ml (11.4 mmole) of benzylamine in 1 ml dichloromethane at 0oWith dropwise injected with a solution of 335 mg (1,14 mmole) of tert-butyl methyl ether (R)-(1)-bromoacetanilide-2-carboxylic acid in 2 ml of dichloromethane. At this temperature, the suspension was stirred for 4 h the Organic phase was washed for 1H. a solution of sodium carbonate and brine, dried (sodium sulfate) and was evaporated. The residue was purified Express chromatography to obtain in the form of amorphous solids 312 mg (86%) specified in the connection header.

MS m/e (%): 319 (M+N+, 100).

b) tert-Butyl ether (R)-1- {{1,3-dibenzyl-3- [2-[ (R)-2-tert-butoxycarbonylamino-1-yl] -2-oxoethyl] ureido} acetyl} pyrrolidin-2-carboxylic acid
In a solution of 233 mg (0.73 mmole) of tert-butyl methyl ether (R)-1-benzylpyrrolidine-2-carboxylic acid in 2 ml of toluene at room temperature was introduced to 0.20 ml (1.34 mmole) of triethylamine. For 3 h in 6 portions with stirring introduced to 0.30 ml (0,70 mmole) of 20% solution of phosgene in toluene and stirring was continued for 3 h at room temperature. The organic phase was washed for 1H. solution of hydrochloric acid, 1N. a solution of carbonate of soda is the ideal light yellow oil 245 mg (50%) specified in the connection header.

MS m/e (%): 685 (M+Na+, 28), 680 (M+NH4+, 100), 663 (M+N+, 30).

C) (R)-1- {{1,3-dibenzyl-3- [2- [(R)-2-carboxypropyl-1-yl] -2-oxoethyl] ureido} acetyl} pyrrolidin-2-carboxylic acid
A solution of 220 mg (0,33 mmole) of tert-butyl methyl ether (R)-1-{{1,3-dibenzyl-3- [2- [(R)-2-tert-butoxycarbonylamino-1-yl] -2-oxo-ethyl]ureido} acetyl] pyrrolidin-2-carboxylic acid in 5 ml of 4n. hydrochloric acid in dioxane for 5 h and stirred at room temperature. The product was extracted with 1N. a solution of sodium hydroxide, the basic extract was acidified using 1N. hydrochloric acid to pH 4 and the product was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate) and was evaporated to produce in the form of a brown oil 74 mg (41%) specified in the connection header.

MS m/e (%): 549 (M-N-, 100).

Example 57
(R) -1-benzylpyrrolidine-2-carboxylic acid
Specified in the title compound was formed as a result of the decomposition of urea as a by-product of the process of obtaining (R)-1- {{1,3-dibenzyl-3- [2- [(R)-2-carboxypropyl-1-yl] -2-oxoethyl]ureido} acetyl} pyrrolidin-2-carboxylic acid. The product was isolated from the acidified aqueous solution as follows. The aqueous phase is concentrated and is Rivonia and drying in the form of a colorless foam was obtained 78 mg (45%) of (R)-1-benzylpyrrolidine-2-carboxylic acid.

MS m/e (%): 261 (M-N-, 100).

In the examples below, worked for the following methods.

General procedure a: reaction of a combination of ethylenedichloride (ejh)
In the mixed solution of the hydrochloride of D-proinvestirovalo ether (2 EQ. ), dicarboxylic acid (1 EQ.), N-methylmorpholine (6 EQ.) and hydroxybenzotriazole (2 equivalents. ) in dichloromethane at 0oWith the introduced N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (2 EQ.) and stirring continued at 0oC for 2 h and then at room temperature for 16 hours Then the reaction mixture was successively washed with 1M hydrochloric acid, saturated sodium bicarbonate solution and finally with saturated brine and the aqueous phase was subjected to back extraction with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuum. After this cleaning Express chromatography on kieselgel has been specified in the header of the connection.

General method B: the hydrogenolysis of benzyl ether
A solution of benzyl ester in isopropanol for 16 h at room temperature was mixed with 5 wt.% 10% palladium on coal under hydrogen pressure of 1 ATM. After filtration to remove the catalyst p is the second evaporator, removing the last traces of isopropanol. The resulting product (often in the form of viscous oils, semi-solid substances or foam) triturated in diethyl ether and then dried in vacuum (under a residual pressure of 10 mbar) at 50oWith over 16 PM

Example 58
(R)-1- {5- [(R)-2-carboxypropyl-1-yl] -2,4-dimethyl-5-oxopentanoic} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
a) Benzyl ether of (R)-1-{5-[ (R)-2-benzyloxypyrrolidine-1-yl]-2,4-dimethyl-5-oxopentanoic} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
In accordance with General procedure a using 6,05 g (25 mmol) of the hydrochloride of D-proinvestirovalo ester and 2.0 g (12.5 mmole) of 2,4-dimethylglutaric acid after rapid-chromatography (EtOAc) as a light yellow oil was obtained 4.3 g (64%) specified in the connection header.

MS m/e (%): 535 (M+N+, 100).

b) (R)-1- { 5- [(R)-2-carboxypropyl-1-yl] -2,4-dimethyl-5-oxopentanoic}pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
In accordance with the General method B using 4,30 g (8,05 mmole) benzyl ester of (R)-1- {5- [(R)-2-benzyloxypyrrolidine-1-yl] -2,4-dimethyl-5-oxopentanoic} pyrrolidin-2-carboxylic acid (mixture of 3 diastereomers) as a white foam was obtained 2.58 g (91%) of the DIN-1-yl] -2,3-dimethyl-4-oxobutyryl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
a) Benzyl ether of (R)-1-{4-[ (R)-benzyloxycarbonylamino-1-yl]-2,3-dimethyl-4-oxobutyryl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
In accordance with General procedure a using 2.0 g (8.2 mmole) of the hydrochloride of D-proinvestirovalo ether and 600 mg (4.1 mmole) of 2,3-dimethylethanol acid after rapid-chromatography (EtOAc) as a colourless oil was obtained 1.45 g (69%) specified in the connection header.

MS m/e (%): 521 (M+N+, 100).

b) (R)-1- {4- [(R)-2-carboxypropyl-1-yl] -2,3-dimethyl-4-oxobutyryl}pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
In accordance with the General method B using 1.45 g (2,78 mmole) benzyl ester of (R)-1- {4- [(R)-2-benzyloxycarbonylamino-1-yl] -2,3-dimethyl-4-oxobutyryl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereomers) as a white foam was obtained 780 mg (80%) specified in the connection header.

MS m/e (%): 341 (M+N+, 100).

Example 60
(R)-1- { TRANS-4- [(R)-2-carboxypropyl-1-carbonyl] cyclohexanecarbonyl} pyrrolidin-2-carboxylic acid
a) Benzyl ether of (R)-1- {TRANS-4- [(R)-2-benzyloxycarbonylamino-1-carbonyl] cyclohexanecarbonyl} pyrrolidin-2-carboxylic acid
In accordance with General procedure a using 2.0 g (the Les Express-chromatography (EtOAc) as a colourless oil was obtained 1,67 g (76%) specified in the connection header.

MS m/e (%): 547 (M+N+, 100).

b) (R)-1- {TRANS-4- [(R)-2-carboxypropyl-1-carbonyl} cyclohexanecarbonyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 1,61 g (2,95 mmole) benzyl ester of (R)-1- {TRANS-4- [(R)-2-benzyloxycarbonylamino-1-carbonyl] cyclohexanecarbonyl} pyrrolidin-2-carboxylic acid as a white foam was obtained 1.07 g (99%) specified in the connection header.

MS m/e (%): 367 (M+N+, 100).

Example 61
(R)-1- { CIS-4- [(R)-2-carboxypropyl-1-carbonyl] cyclohexanecarbonyl} pyrrolidin-2-carboxylic acid
a) Benzyl ether of (R)-1- {CIS-4- [(R)-2-benzyloxycarbonylamino-1-carbonyl] cyclohexanecarbonyl} pyrrolidin-2-carboxylic acid
In accordance with General procedure a using 2.0 g (8.2 mmole) of the hydrochloride of D-proinvestirovalo ether and 700 mg (4.1 mmole) of CIS-cyclohexane-1,4-dicarboxylic acid after rapid-chromatography (EtOAc) as a colourless oil was obtained 2.0 g (91%) specified in the connection header.

MS m/e (%): 547 (M+N+, 100).

b) (R) -1- {CIS-4- [(R) -2-carboxypropyl-1-carbonyl] cyclohexanecarbonyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 2.0 g (3,66 mmole) benzyl ester of (R)-1- [CIS-4- [Oh foam received 930 mg (69%) specified in the connection header.

MS m/e (%): 365 ([M-H]-, 100).

Example 62
(R)-1- { 3- [(R)-2-carboxypropyl-1-carbonyl] cyclohexanecarbonyl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
a) Benzyl ether of (R)-1- {3- [(R)-2-benzyloxycarbonylamino-1-carbonyl] cyclohexanecarbonyl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
In accordance with General procedure a using 5.6 g (23,2 mmole) of the hydrochloride of D-proinvestirovalo ester and 2.0 g (of 11.6 mmole) cyclohexane-1,3-dicarboxylic acid after rapid-chromatography (EtOAc) as a colourless oil was obtained 4.4 g (70%) specified in the connection header.

MS m/e (%): 547 (M+N+, 100).

b) (R)-1- {3- [(R)-2-carboxypropyl-1-carbonyl] cyclohexanecarbonyl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
In accordance with the General method B using 4.4 g (8,05 mmole) benzyl ester of (R)-1-{3-[ (R)-2-benzyloxycarbonylamino-1-carbonyl] cyclohexanecarbonyl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereomers) as a white foam was obtained 2.9 g (98%) specified in the connection header.

MS m/e (%): 367 (M+N+, 100).

Example 63
A mixture of (R)-1-[(1R. 2R)- and -[(1S,2S)-2-[ (R)-2-carboxypropyl-1-carbonyl] cyclohexanecarbonyl} pyrrolidin-2-karbonovy hexacarbonyl} pyrrolidin-2-carboxylic acid
In accordance with General procedure a using 2.0 g (8.2 mmole) of the hydrochloride of D-proinvestirovalo ether and 700 mg (4.1 mmole) of TRANS-cyclohexane-1,2-dicarboxylic acid after rapid-chromatography (EtOAc) as a colourless oil was obtained of 1.36 g (62%) indicated in the header connections.

MS m/e (%): 547 (M+N+100).

b) a Mixture of (R)-1-[(1R, 2R)- and -[(1S, 2S)-2-[ (R)-2-carboxypropyl-1-carbonyl] cyclohexanecarbonyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 1,36 g (2,48 mmole) of a mixture of benzyl ester of (R)-1-[(1R, 2R) - [(1S, 2S)-2-[(R)-2-benzyloxycarbonylamino-1-carbonyl] cyclohexanecarbonyl} pyrrolidin-2-carboxylic acid as a white foam was obtained 900 mg (99%) specified in the header connections.

MS m/e (%): 367 (M+N+, 100).

Example 64
(R)-1- {{2,5-dihydroxy-4- [2- [(R)-2-carboxypropyl-1-yl] -2-oxoethyl] phenyl} acetyl} pyrrolidin-2-carboxylic acid
a) Benzyl ether (R) -1- {{4- [2- [(R) -2-benzyloxycarbonylamino-1-yl] -2-oxoethyl] -2.5-dihydroxyphenyl} acetyl} pyrrolidin-2-carboxylic acid
In accordance with General procedure a using 10.7 g (a 44.2 mmole) of the hydrochloride of D-proinvestirovalo ether and 5.0 g (22,1 mmole) of 2,5-dihydroxy-1,4-phenylendiamine acid after Express chromatography.

MS m/e (%): 601 (M+N+, 100).

b) (R)-1- {{2,5-dihydroxy-4- [2- [(R)-2-carboxypropyl-1-yl] -2-oxoethyl] phenyl} acetyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 3,17 g (5.3 mmole) of the benzyl ether (R)-1- {{4- [2- [(R)-2-benzyloxycarbonylamino-1-yl] -2-oxoethyl] -2.5-dihydroxyphenyl} acetyl} pyrrolidin-2-carboxylic acid as a white crystalline solid was obtained 2.2 g (99%) specified in the connection header.

MS m/e (%): 421 (M+N+, 100).

Example 65
(R)-1- {{3- [2- [(R)-2-carboxypropyl-1-yl] -2-oxoethyl] phenyl} acetyl} pyrrolidin-2-carboxylic acid
a) Benzyl ether (R)-1- {{3- [2- [(R) -2-benzyloxycarbonylamino-1-yl] -2-oxoethyl] phenyl} acetyl] pyrrolidin-2-carboxylic acid
In accordance with General procedure a using 2.0 g (8.2 mmole) of the hydrochloride of D-proinvestirovalo ether and 800 mg (4.1 mmole) of 1,3-phenylendiamine acid after rapid-chromatography (EtOAc) as a colourless oil was obtained of 1.93 g (84%) specified in the connection header.

MS m/e (%): 586 (M+NH4+, 100), 569 (M+N+, 60).

b) (R)-1- {{3- [2- [(R)-2-carboxypropyl-1-yl] - 2-oxoethyl] phenyl} acetyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B used in the l} pyrrolidin-2-carboxylic acid as a white foam was obtained 1,21 g (97%) specified in the connection header.

MS m/e (%): 421 (M+N+, 100).

Example 66
(R) -1- { 4- [ (R) -2-carboxypropyl-1-carbonyl] benzoyl} pyrrolidin-2-carboxylic acid
a) Benzyl ether of (R)-1-{4-[(R)-2-benzyloxycarbonylamino-1-carbonyl] benzoyl} pyrrolidin-2-carboxylic acid
In accordance with General procedure a using 5.8 g (24,0 mmole) of the hydrochloride of D-proinvestirovalo ester and 2.0 g (12.0 mmol) of benzene-1,4-dicarboxylic acid after rapid-chromatography (EtOAc) as a yellow oil was obtained of 4.66 g (72%) specified in the connection header.

MC m/e (%): 558 (M+NH4+, 100), 541 (M+N+, 95).

b) (R) -1- {4- [(R) -2-carboxypropyl-1-carbonyl] benzoyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using of 4.66 g (8,62 mmole) benzyl ester of (R)-1-{4-[ (R)-2-benzyloxycarbonylamino-1 - carbonyl] benzoyl}pyrrolidin-2-carboxylic acid as colorless foam was obtained 3,05 g (95%) specified in the connection header.

MC m/e (%): 378 (M+NH4+, 100), 361 (M+N+, 55).

Example 67
(R) -1- { 3- [(R) -2-carboxypropyl-1-carbonyl] benzoyl} pyrrolidin-2-carboxylic acid
a) Benzyl ether (R)-1- {3- [((R)-2-benzyloxycarbonylamino-1-carbonyl] benzoyl} pyrrolidin-2-carboxylic acid
In accordance with the l-1,3-dicarboxylic acid after rapid-chromatography (EtOAc) as a yellow oil was obtained 4.68 g (72%) specified in the connection header.

MC m/e (%): 558 (M+NH4+, 100), 541 (M+N+, 90).

b) (R) -1- {3- [(R) -2-carboxypropyl-1-carbonyl] benzoyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 2.83 g (5,24 mmole) benzyl ester of (R)-1- {3-[ (R)-2-benzyloxycarbonylamino-1-carbonyl] benzoyl} pyrrolidin-2-carboxylic acid as colorless foam was obtained 1.9 g (100%) specified in the connection header.

MC m/e (%): 378 (M+NH4+, 100), 361 (M+N+, 35).

Example 68
(R)-1- {6- [(R)-2-carboxypropyl-1-carbonyl]pyridine-2-carbonyl} pyrrolidin-2-carboxylic acid
a) Benzyl ether of (R)-1- {6- [(R)-2-benzyloxycarbonylamino-1-carbonyl]pyridine-2-carbonyl} pyrrolidin-2-carboxylic acid
In accordance with General procedure a using 5.8 g (24,0 mmole) of the hydrochloride of D-proinvestirovalo ester and 2.0 g (12.0 mmol) of pyridine-2,6-dicarboxylic acid after rapid-chromatography (EtOAc) as a yellow oil was obtained 5.0 g (77%) specified in the connection header.

MC m/e (%): 559 (M+NH4+, 60), 542 (M+N+, 100).

b) (R)-1- {6- [(R)-2-carboxypropyl-1-carbonyl]pyridine-2-carbonyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 3.2 g (5.9 mmole) of the benzyl ether of (R)-1-{6-[ (R)-2-( received of 1.9 g (90%) specified in the connection header.

MS m/e (%): 379 (M+NH4+, 100), 362 (M+N+, 65).

Example 69
(R)-1- {5- [(R)-2-carboxypropyl-1-carbonyl]thiophene-2-carbonyl} pyrrolidin-2-carboxylic acid
a) Benzyl ether of (R)-1-{ 5-[ (R)-2-benzyloxycarbonylamino-1-carbonyl] thiophene-2-carbonyl} pyrrolidin-2-carboxylic acid
In accordance with General procedure a using 2.0 g (8.2 mmole) of the hydrochloride of D-proinvestirovalo ether and 700 mg (4.1 mmole) thiophene-2,5-dicarboxylic acid after rapid-chromatography (EtOAc) as a yellow crystalline solid was obtained 1.84 g (84%) specified in the connection header.

MC m/e (%): 564 (M+NH4+, 60), 547 (M+N+, 100).

b) (R)-1- { 5- [(R)-2-carboxypropyl-1-carbonyl]thiophene-2-carbonyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 1.84 g (3.3 mmole) of the benzyl ether of (R)-1-{5-[ (R)-2-benzyloxycarbonylamino-1-carbonyl] thiophene-2-carbonyl} pyrrolidin-2-carboxylic acid as a white crystalline substance was obtained 770 mg (63%) of compound called as RO-64-2667/000.

MS m/e (%): 365 ([M-H]-, 65).

Example 70
(R)-1- { 5- [(R)-2-carboxypropyl-1-carbonyl]furan-2-carbonyl}pyrrolidin-2-carboxylic acid
a) Benzyl ether of (R)-1- {5- [(R)-2-benzyloxycarbonyl But using 2.0 g (8.2 mmole) of the hydrochloride of D-proinvestirovalo ether and 640 mg (4.1 mmole) furan-2,5-dicarboxylic acid after rapid-chromatography (EtOAc) as a yellow oil was obtained 1.7 g (78%) specified in the connection header.

b) (R)-1- {5- [(R)-2-carboxypropyl-1-carbonyl]furan-2-carbonyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 1.7 g (3.2 mmole) of the benzyl ether of (R)-1-{5-[ (R)-2-benzyloxycarbonylamino-1-carbonyl] furan-2-carbonyl} pyrrolidin-2-carboxylic acid as a white foam was obtained 1,02 g (91%) specified in the connection header.

MS m/e (%): 351 (M+N+, 100).

Example 71
(S)-1- { 6- [(S)-2-carboxypropyl-1-yl] -6-oxohexanoyl}pyrrolidin-2-carboxylic acid
a) Benzyl ester of (S)-1-{6-[(S)-2 - benzyloxycarbonylamino -1-yl] -6-oxohexanoyl} pyrrolidin-2-carboxylic acid
In accordance with the General procedure a, using 1.0 g (4.1 mmole) of the hydrochloride of L-proinvestirovalo ether and 300 mg (2.1 mmole) of adipic acid after rapid-chromatography (EtOAc) as a colourless oil was obtained 1.07 g (100%) specified in the connection header.

MS m/e (%): 521 (M+N+, 100).

b) (S)-1- {6- [(S)-2-carboxypropyl-1-yl] -6-oxohexanoyl} -pyrrolidin-2-carboxylic acid
In accordance with the General method B using 1.07 g (2.1 mmole) of the benzyl ether (S)-1- {6- [(S)-2-benzyloxycarbonylamino-1-yl] -6-oxohexanoyl} pyrrolidin-2-carboxylic acid as a white crystalline solid is 72
(S)-1- { { 4- [2- [(S)-2-carboxypropyl-1-yl] -2-oxoethyl] phenyl} acetyl} pyrrolidin-2-carboxylic acid
a) Benzyl ether (S)-1- {{4- [2- [(S)-2-benzyloxycarbonylamino-1-yl] -2-oxoethyl] phenyl} acetyl} pyrrolidin-2-carboxylic acid
In accordance with the General procedure a, using 1.0 g (4.1 mmole) of the hydrochloride of L-proinvestirovalo ether and 400 mg (2.1 mmole) of 1,4-phenylendiamine acid after rapid-chromatography (EtOAc) as a colourless oil was obtained 1.07 g (91%) specified in the connection header.

MS m/e (%): 586 (M+NH4+, 100), 569 (M+N+, 97).

b) (S)-1-{{4-[2-[(S)-2-carboxypropyl-1-yl]-2-oxoethyl] phenyl} acetyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 1.07 g (of 1.88 mmole) benzyl ether (S)-1- {{4- [2- [(S)-2-benzyloxycarbonylamino-1-yl] -2-oxoethyl] phenyl} acetyl] pyrrolidin-2-carboxylic acid as a white crystalline solid was obtained 410 mg (56%) specified in the connection header.

MS m/e (%): 389 (M+N+, 100).

Example 73
(S)-1- { {2- [2- [(S)-2-carboxypropyl-1-yl] -2-oksidoksi]phenoxy} acetyl} pyrrolidin-2-carboxylic acid
a) Benzyl ether (S)-1- {{2- [2- [(S)-2-benzyloxycarbonylamino-1-yl] - 2-oksidoksi]phenoxy} acetyl} pyrrole Arinbasarova ether and 790 mg (2.1 mmole) of 1,2-phenylendiamine acid after rapid-chromatography (EtOAc) as a colourless oil was obtained 1.08 g (87%) specified in the connection header.

MS m/e (%): 601 (M+N+, 100).

b) (S)-1- {{2- [2- [(S)-2-carboxypropyl-1-yl] -2-oksidoksi] phenoxy] acetyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 1.08 g (1.8 mmole) of the benzyl ether (S)-1- {{2- [2- [(S) -2-benzyloxycarbonylamino-1-yl] -2-oksidoksi]phenoxy} acetyl} pyrrolidin-2-carboxylic acid as a white crystalline solid was obtained 717 mg (95%) specified in the connection header.

MS m/e (%): 421 (M+N+, 100).

Example 74
(R)-1- {{4- [2- [(R)-2-carboxypropyl-1-yl] - 2 - oxoethyl] naphthalene-1-yl} acetyl} pyrrolidin-2-carboxylic acid
a) 2-diazo-1 - (4-diazoacetates-1-yl)alanon
In a mixed solution of 3.0 g (13.9 mmole) naphthalene-1,4-dicarboxylic acid and 4,4 ml (30,6 mmole) of triethylamine in 200 ml of THF at -15oWith dropwise introduced to 2.9 ml (30,6 mmole) ethylchloride. After stirring for 15 min at 0oWith added 250 ml of ether solution diazomethane (about 0.3 M, about 75 mmol) and stirring continued for 16 h at room temperature. Next, the reaction mixture is then washed with a saturated solution of sodium bicarbonate, a saturated solution of ammonium chloride and finally with saturated brine and hell magnesium sulfate and concentrated in vacuum. As a result, the Express chromatography (gradient from 15 to 50% EtOAc/hexane) as a yellow crystalline solid was obtained 450 mg (12%) specified in the connection header.

MS m/e (%): 323 ([M+SLA]-, 100).

b) (4 - carboxymethylation -1 - yl) acetic acid
In a mixed solution of 450 mg (1.7 mmole) of 2-diazo-1-(4-diasease-trafton-1-yl)ethanone in 20 ml of THF at -20oWith sequentially added in the darkness of 1.5 ml of water, 86 mg (375 mmol) of silver benzoate (0.22 equiv.) and 687 ml (4.9 mmole) of triethylamine (2.9 EQ.) and stirring was continued for 2 h at room temperature. Next, the reaction mixture was diluted with 100 ml diethyl ether and was extracted twice with a saturated solution of sodium bicarbonate. The combined aqueous phase was extracted three times with diethyl ether, then acidified with concentrated hydrochloric acid and three times was extracted with diethyl ether. These latter organic extracts were combined and dried over sodium sulfate and concentrated in vacuum to produce in the form of a yellow crystalline solids 330 mg (80%) specified in the connection header.

MS m/e (%): 244 (M+, 100), 199 (M-CO2N, 80).

in) Petrol ether (R)-1- {{4- [2- [(R)-2-benzyloxycarbonyl the wild And using 200 mg (of 0.82 mmole) of the hydrochloride of D-proinvestirovalo ether and 100 mg (0,41 mmole) (4-carboxymethylation-1 - yl) acetic acid after rapid-chromatography (EtOAc) as a colourless oil was obtained 188 mg (75%) specified in the connection header.

MS m/e (%): 636 (M+NH4+, 100), 619 (M+N+, 75).

g) (R) -1- {{4- [2- [(R) -2-carboxypropyl-1-yl] -2-oxoethyl] naphthalene-1-yl} acetyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 130 mg (0,21 mmole) benzyl ether (R)-1- {{4- [2- [(R)-2-benzyloxycarbonylamino-1-yl] -2-oxoethyl} naphthalene-1-yl} acetyl} pyrrolidin-2-carboxylic acid as a white crystalline solid was obtained 79 mg (86%) specified in the connection header.

MS m/e (%): 437 ([M-H]-, 100).

Example 75
(R)-1- {{6- [2- [(R)-2-carboxypropyl-1-yl] -2-oxoethyl]pyridine-2-yl} acetyl} pyrrolidin-2-carboxylic acid
a) (6 - Cyanomethylene - 2 - yl) acetonitrile
In the mixed solution 3,47 g (13.1 mmole) of 2,6-bis-(methyl bromide)of pyridine in 50 ml of dichloromethane was dropwise introduced 4.1 g (26,2 mmole) of tetraethylammonium in 20 ml of dichloromethane and then the reaction mixture is kept at 45oC for 72 h Then the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, re-suspended in ethyl acetate, again filtered and the second filtrate was concentrated in vacuum. As a result, the Express chromatography (33% EtOAc/hexane) as a white crystalline is sup>+, 95), 90 (55).

b) (6-Carboxymethylamino - 2-yl) acetic acid
A solution of 3.0 g (19,1 mmole) of (6-cyanomethylene-2-yl)acetonitrile in 30 ml of concentrated hydrochloric acid at 100oWith kept for 24 hours Then the reaction mixture was cooled to room temperature and concentrated in vacuum. The residue was re-dissolved in water, was added activated charcoal and the mixture was stirred at 50oC for 30 minutes After removal of the charcoal by filtration, the filtrate was concentrated in vacuo and the residue at the 4oWith re was led out of the water getting into the not-quite-white crystalline solid 2,48 g (100%) specified in the connection header.

1H-NMR (250 MHz, D2O,): 8,42 (1H, t, J=8 Hz), 7,80 (2H, d, J=8 Hz).

C) Benzyl ether (R)-1- {{6- [2- [(R) -2-benzyloxycarbonylamino-1-yl] -2-oxoethyl] pyridine-2-yl} acetyl} pyrrolidin-2-carboxylic acid
In accordance with General procedure a using 9.7 g (40 mmol) of the hydrochloride of D-proinvestirovalo ether and 3.9 g (20 mmol) (6-carboxymethylamino-2-yl) acetic acid after rapid chromatography (gradient from 0 to 10% MeOH/EtOAc) as a yellow oil was obtained 890 mg (8%) specified in the connection header.

MS m/is-carboxylic acid
In accordance with the General method B using 890 mg (1,56 mmole) benzyl ether (R)-1- {{-6- [2- [(R) -2-benzyloxycarbonylamino-1-yl] -2-oxoethyl]pyridine-2-yl} acetyl} pyrrolidin-2-carboxylic acid as a yellow crystalline solid was obtained 410 mg (67%) specified in the connection header.

MS m/e (%): 390 (M+N+, 100).

Example 76
(R)-1- {{5- [2- [(R) -2-carboxypropyl-1-yl] -2-oxoethyl]thiophene-2-yl} acetyl} pyrrolidin-2-carboxylic acid
a) 2.5-Bischloromethyl
Is 63.4 ml of 37% aqueous formaldehyde solution under ice cooling is added dropwise introduced 15.3 ml of concentrated hydrochloric acid, and then stirring was added dropwise 20 ml of 0.25 mol) of thiophene and stirring was continued for 90 min at room temperature. Next, the reaction mixture was extracted with diethyl ether and the organic phase then washed with water, saturated sodium bicarbonate solution and finally with saturated brine. The aqueous phase was subjected to back extraction with diethyl ether and the combined organic extracts were dried over magnesium sulfate and concentrated under vacuum obtaining in the form of colored amber color oil to 38.8 g (86%) indicated in the title compound, product is.

b) (5-cyanomethylene - 2-yl)acetonitrile
In a mixed solution of 15 g (82,8 mmole) of 2,5-mechlorethamine in 500 ml of dichloromethane dropwise injected with a solution of 28.5 g (182 mmole) of tetraethylammonium in 100 ml of dichloromethane and then the reaction mixture is kept at 45oC for 24 h Then the reaction mixture was cooled to room temperature and washed twice with water. The organic phase was dried over sodium sulfate and concentrated in vacuum. As a result, the Express chromatography (20% EtOAc/hexane) as a yellow oil was obtained 4,88 g (36%) specified in the connection header.

MS m/e (%): 162 (M+, 44), 122 ([M-C2CN]+, 100).

in) (5 - Carboxymethylthio - 2 - yl) acetic acid
In a solution of 1.2 g (7.4 mmole) of (5-cyanomethylene-2-yl)acetonitrile in 5 ml ethanol and 5 ml of water was injected 1,74 g (of 31.8 mmole) of potassium hydroxide and the reaction mixture under 100oWith kept for 1 h Then the reaction mixture was cooled to room temperature and concentrated in vacuum. The residue was acidified with hydrochloric acid and three times was extracted with diethyl ether. The combined organic phases were dried over magnesium sulfate and concentrated under vacuum obtaining in the form of a brown crystalline solid of 1.3 g (88 of 100).

g) tert-Butyl ether (R) -1-{{5-[2-[(R) -2-tert-butoxycarbonylamino-1-yl] -2-oxoethyl] thiophene-2-yl} acetyl} pyrrolidin-2-carboxylic acid
In accordance with General procedure a using of 2.23 g (13 mmol) of the hydrochloride of D-proinvestirovalo ether and 1.3 g (6.5 mmole) of (5-carboxymethylthio-2-yl) acetic acid after rapid chromatography (gradient from 0 to 10% MeOH/EtOAc) as a yellow oil was obtained 2.6 g (79%) specified in the connection header.

MC m/e (%): 524 (M+NH4+, 90), 507 (M+H+, 10), 451 ([M+H-C4H8]+, 30), 395 ([M+H-2C4H8]+, 100).

d) (R)-1- { { 5- [2- [(R) -2-carboxypropyl-1-yl] -2-oxoethyl]thiophene-2-yl} acetyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 600 mg (1,18 mmole of tert-butyl methyl ether (R) -1- {{5- [2- [(R) -2-tert-butoxycarbonylamino-1-yl] -2-oxoethyl] thiophene-2-yl} acetyl} pyrrolidin-2-carboxylic acid as a beige crystalline solid were obtained 100 mg (21%) specified in the connection header.

MC m/e (%): 395 (M+N+, 100).

Example 77
(R)-1- {(2R, 5S)-6- [(R) -2-carboxypropyl-1-yl] -2.5-dimethoxy-6-oxohexanoyl} pyrrolidin-2-carboxylic acid
a) (3R, 6S)-3,6-dimethoxytoluene
Literature: J. Org. Chem. 1988, 53, 5695. In the first the howling acid in 200 ml of methanol at room temperature with a syringe for 4 h were injected solution 5,95 ml (62 mmole) of 1,3-cyclohexadiene in 5 ml of methanol and stirring was continued for an additional 16 hours The reaction mixture three times was extracted with diethyl ether and the combined organic extracts are then washed with water, 2M sodium hydroxide solution and saturated brine. The organic phase was dried over sodium sulfate and concentrated in vacuum. In the distillation by Kugeler (under a residual pressure of 6 mbar, at a temperature in the furnace 120oC) in the form of a colorless oil was obtained 5,42 g (61%) specified in the connection header.

1H-NMR (250 MHz, Dl3,): of 5.92 (2H, s), 3,70 (2H, t, J=5 Hz), 3,37 (6N, s), 1,90-of 1.65 (4H, m).

b) (2R, 5S)-2,5 - dimethoxycinnamic
Literature: J. Am. Chem. Soc. 1983, 105, 5688. In a mixed solution of 5.0 g (35,2 mmole) of (3R,6S)-3,6-dimethoxytoluene in 120 ml of acetone and 120 ml of water was added to 37.6 g (176 mmol) of periodate sodium and 50 mg (0.24 mmole) of ruthenium chloride (III) and stirring continued for 16 h at room temperature. Added 5 ml of isopropanol and the stirring continued for 30 min and then the reaction mixture was filtered and the filtrate was concentrated in vacuo to half volume. Next, portions were added 5 g of sodium bicarbonate and the mixture three times were extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried head connection.

MC m/e (%): 205 ([M-H]-, 100).

C) Benzyl ether of (R)-1-{(2R, 5S)-6-[ (R)-2-benzyloxycarbonylamino-1-yl]-2,5-dimethoxy-6-oxohexanoyl}pyrrolidin-2-carboxylic acid
In accordance with General procedure a using 1.51 g (6.2 mmole) of the hydrochloride of D-proinvestirovalo ether and 643 mg (3.1 mmole) of (2R,5S)-2,5-dimethoxycinnamic after rapid chromatography (gradient from 10 to 100% EtOAc/hexane, then 10% MeOH/EtOAc) as a yellow oil was obtained 643 mg (36%) specified in the connection header.

MS m/e (%): 581 (M+H+, 100).

g) (R)-1- {(2R, 5S)-6- [(R)-2-carboxypropyl-1-yl] -2,5-dimethoxy-6-oxohexanoyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 640 mg (1,10 mmole) benzyl ester of (R)-1- {(2R,5S)-6- [(R)-2-benzyloxycarbonylamino-1-yl] -2,5-dimethoxy-6-oxohexanoyl}pyrrolidin-2-carboxylic acid as a yellow solid substance was obtained 440 mg (100%) specified in the connection header.

MS m/e (%): 399 ([M-H]-, 100).

Example 78
(R)-1-{ [2S, 5S)- or -{(2R, 5R)-6-[ (R)-2-hydroxyethylpyrrolidine-1-yl] -2,5-dimethoxy-6-oxohexanoyl} pyrrolidin-2-carboxylic acid
a) (1RS, 4RS)-4-ecotoxicologic-2-enjoy ether acetic acid
Literature: J. Org. Chem. 1984, 49, 4619. In a mixed solution of 2.8 g (12.5 IMO matney temperature was introduced to 26.1 g (300 mmol) of manganese dioxide and a solution of 23.8 ml (250 mmol) of 1,3-cyclohexadiene in 400 ml of pentane and the stirring continued for an additional 16 hours Two-phase reaction mixture was divided and explicilty phase was twice extracted with pentane. The combined organic extracts are then washed with saturated brine, water and 2M sodium hydroxide solution and then the organic phase was dried over sodium sulfate and concentrated in vacuum. As a result of recrystallization from pentane, in the form of not quite white crystalline solid was obtained 16,1 g (33%) specified in the connection header.

MS m/e (%): 138 ([M-Asón]+, 8), 96 (M-Asón-PINES2]+, 100), 43 (40).

b) (1RS,4RS)-cyclohex-2-ene-1,4-diol
Literature: J. Org. Chem. 1984, 49, 4619. In a mixed solution of 19.8 g (99,8 mmole) of (1RS, 4RS)-4-ecotoxicologic-2-enrobage ester of acetic acid in 500 ml of methanol was added 120 ml of 2M sodium hydroxide solution and the reaction mixture is boiled under reflux for 15 minutes After cooling to room temperature the reaction mixture was concentrated in vacuum to a residual volume of 100 ml, and then fed pellets of sodium hydroxide. The mixture was extracted again with ethyl acetate, the combined organic phases were dried over sodium sulfate and vacuum concentrated to obtain as not quite white crystalline solid washes the2With=SNON]+, 100).

C) (3RS, 6RS)-3,6-dimethoxytoluene
Literature: J. Org. Chem. 1988, 53, 5695. To 14.3 g (328 mmol) of sodium hydride (55% dispersion in oil) at 0oWith stirring was added dropwise a solution of 10.1 g (88,5 mmole) of (1RS,4RS)-cyclohex-2-ene-1,4-diol in 100 ml of THF. Then was added 34 ml (546 mmol) under the conditions and stirring continued at room temperature for an additional 48 hours the Reaction was stopped by adding a saturated solution of ammonium chloride and the reaction mixture was extracted with diethyl ether. The combined organic extracts are then washed with a saturated solution of ammonium chloride and saturated brine, dried over sodium sulfate and concentrated in vacuum to produce in the form of a yellow oil of 11.5 g (91%) specified in the connection header.

1H-NMR (250 MHz, Dl3,): 5,90 (2H, s), 3,82 (2H, broad t), 3,37 (6N, s) of 2.10 (2H, m) and 1.51 (2H, m).

g) (2RS, 5RS)-2,5-dimethoxyacetate
In a mixed solution of 6.0 g (42,2 mmole) (3RS,6RS)-3,6-dimethoxybenzene in 140 ml of acetone and 140 ml of water was added 50.5 g (236 mmol) of periodate sodium and 67 mg (0,32 mmole) chloride ruthenium(III) and stirring continued for 16 h at room temperature. Added 10 ml isopropanol in vacuo to half volume. Next, portions were added 5 g of sodium bicarbonate and the mixture three times was extracted with diethyl ether. The aqueous phase was acidified 25% hydrochloric acid and re-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuum to obtain an orange oil 1,32 g (15%) specified in the connection header, product RO-64-5650/000. In the continuous extraction of the aqueous phase within 48 h got additionally 608 mg (7%) of product.

MS m/e (%): 161 ([M-CO2N]+, 20), 113 (58), 101 (69), 85 (50), 71 (100).

d) Benzyl ether of (R)-1-{(2S, 5S)- or -{[2R, 5R)-6-[ (R)-2-benzyloxypyrrolidine -1 - yl] - 2,5-dimethoxy - 6 - oxohexanoyl} pyrrolidin - 2 - carboxylic acid benzyl ester (R)-1- {(2R, 5R)- or - {(2S, 5S)-6- [(R)-2 - benzyloxypyrrolidine - 1-yl] - 2,5-dimethoxy - 6 - oxohexanoyl} pyrrolidin-2-carboxylic acid
In accordance with General procedure a using 1,67 g (6.9 mmole) of the hydrochloride of D-proinvestirovalo ether and 250 mg (1.2 mmole) of (2RS,5RS)-2,5-dimethoxycinnamic after rapid chromatography (gradient from 50 to 100% EtOAc/hexane, then 10% MeOH/EtOAc) as a brown oil was obtained 95 mg (13%) listed in the title compounds (mixture 2 diastereoisomers) and in the form of a yellow oil 172 sup>, 100).

e) (R)-1-{(2S,5S)- or -{(2R, 5R)-6-[ (R)-2-hydroxyethylpyrrolidine-1-yl] -2,5-dimethoxy-6-oxohexanoyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 160 mg (0,28 mmole) benzyl ester of (R)-1-{ (2R, 5R)- or -{(2S, 5S)-6-[ (R)-2-benzyloxypyrrolidine -1 - yl] - 2,5-dimethoxy-6 - oxohexanoyl} pyrrolidin - 2 - carboxylic acid as a white foam was obtained 90 mg (82%) specified in the connection header.

MS m/e (%): 399 ([M-H]-, 100), 355 ([M-H-CO2]-, 61).

Example 79
(R)-1-{ (2R, 5R)- or -{(2S, 5S)-6-[ (R)-2-hydroxyethylpyrrolidine-1-yl] -2,5-dimethoxy-6-oxohexanoyl}pyrrolidin-2-carboxylic acid
In accordance with the General method B using 95 mg (0,28 mmole) benzyl ester of (R)-1-{ (2S, 5S)- or -{(2R, 5R)-6-[ (R)-2-benzyloxypyrrolidine -1 - yl] - 2,5-dimethoxy-6 - oxohexanoyl} pyrrolidin - 2 - carboxylic acid as a white foam were obtained 70 mg (100%) specified in the connection header.

MS m/e (%): 399 ([M-H]-, 100), 355 ([M-H-CO2]-, 20).

Example 80
(R)-1- { 2,5-dibenzyl-6- [(R)-2-carboxypropyl-1-yl] -6-oxohexanoyl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
a) a Mixture of diethyl ester of (E)-(2R, 5S)- and -(2RS, 5RS)-2,5-dibenzylamine-3-indicasat
In the mixed solution 688 mg (3, orida lithium and the resulting suspension was cooled to -78oC. was added dropwise 3,44 ml (6,88 mmole) 2M solution GAVE (diisopropylamide lithium) in THF and stirring was continued for 45 minutes Then added 0,82 ml (6.9 mmole) of benzylbromide and stirring was continued for 1 h at -78oC and 10 min at 0oC. At this temperature, the reaction was stopped by adding a saturated solution of ammonium chloride and the mixture three times was extracted with diethyl ether. The combined organic phases were washed with saturated brine, dried over sodium sulfate and concentrated in vacuum. As a result, the Express chromatography (5% EtOAc in hexane) as a yellow oil was obtained 927 mg (71%) specified in the connection header.

MS m/e (%): 398 ([M+NH4]+, 100).

b) a Mixture of (E)-(2R, 5S)- and -(2RS, 5RS)-2,5-dibenzylamine-3-indicasat
In a mixed solution of 200 mg (of 0.53 mmole) of a mixture of diethyl ester of (E)-(2R, 5S)- and -(2RS, 5RS)-2,5-dibenzylamine-3-indicasat in 5 ml of THF was introduced in 4.3 ml (4.3 mmole) of 1M sodium hydroxide solution. After stirring for 68 hours at room temperature by addition of 1M hydrochloric acid, the reaction mixture was acidified to pH 3, and three times were extracted with ethyl acetate. The combined organic phases are then washed with water and saturated brine, dried over sulfate natriello crystalline solid was obtained 127 mg (74%) specified in the connection header.

MS m/e (%): 342 ([M+NH4]+, 100).

C) Benzyl ester (E)- (R)-1-{2,5-dibenzyl-6-[ (R)-2-benzyloxycarbonylamino-1-yl] -6-axugex-3-enoyl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
In accordance with General procedure a using 1.04 g (4,30 mmole) of the hydrochloride of D-proinvestirovalo ether and 700 mg (2,16 mmole) of a mixture of diethyl ester of (E)-(2R, 5S)- and -(2RS, 5RS)-2,5-dibenzylamine-3-indicasat after rapid chromatography (5% Meon in EtOAc) as a yellow oil was obtained 926 mg (61%) specified in the connection header.

MS m/e (%): 716 (M+NH4+, 100), 699 (M+N+, 85).

g) (R)-1- {2,5-dibenzyl-6- [(R)-2-carboxypropyl-1-yl] -6-oxohexanoyl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
In accordance with the General method B using 926 mg (1,33 mmole) benzyl ester (E)-(R)-1- { 2,5-dibenzyl-6- [(R)-2-benzyloxycarbonylamino-1-yl] -6-axugex-3-enoyl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereomers) as a white crystalline solid was obtained 610 mg (89%) specified in the connection header.

MS m/e (%): 519 ([M-H]-, 100).

Example 81
(R)-1- {2,5-dibutil-6- [(R)-2-carboxypropyl-1-yl] -6-oxohexanoyl} pyrrolidin-2-carboxylic acid (1 of 3 possible diastereoisomer the (9,99 mmole) of diethyl ether TRANS-2-butene-1,4-dicarboxylic acid in 80 THF was introduced to 2.54 g (59,9 mmole) of anhydrous lithium chloride and the resulting suspension was cooled to -78oC. was added dropwise 10 ml (20.0 mmol) of a 2M solution GAVE in THF and stirring was continued for 45 minutes Then added 2.2 ml (20.4 mmole) butylbromide and stirring was continued for 15 min at -78oC, then 30 min at 0oWith, and then 4 h at room temperature. The reaction was stopped by adding a saturated solution of ammonium chloride and the mixture three times was extracted with diethyl ether. The combined organic phases are successively washed with a saturated solution of ammonium chloride, water and saturated brine, dried over sodium sulfate and concentrated in vacuum. As a result of successive Express chromatography (10% EtOAc in hexane in the first column, then when the gradient from 10 to 100% toluene in cyclohexane in the second column) in the form of a yellow oil was obtained 509 mg (16%) specified in the connection header.

MS m/e (%): 330 ([M+NH4]+, 100).

b) a Mixture of (E)-(2R, 5S)- and -(2RS, 5SR)-2,5-deputies-3-indicasat
In a mixed solution of 435 mg (1,39 mmole) of a mixture of diethyl ester of (E)-(2R, 5S)- and -(2RS, 5SR)-2,5-deputies-3-indicasat in 10 ml of THF were introduced 26 ml (26 mmol) of 1M sodium hydroxide solution. After stirring for 72 h at room temperature by addition of 1M hydrochloric acid the reaction mixture under the Wali water and saturated brine, was dried over sodium sulfate and concentrated in vacuum to obtain a white crystalline solid 346 mg (97%) specified in the connection header.

MS m/e (%): 255 ([M-H]-, 60), 211 ([M+H-CO2]-, 100).

C) Benzyl ester (E)- (R)-1-{2,5-dibutil-6-[ (R)-2-benzyloxycarbonylamino -1 - yl] - 6 - axugex - 3 - enoyl} pyrrolidin - 2 - carboxylic acid (mixture of 2 of the 3 possible diastereoisomers) and benzyl ether (E)-(R)-1- {2,5-dibutil-6- [(R)-2-benzyloxycarbonylamino-1-yl] -6-axugex-3-enoyl} pyrrolidin-2-carboxylic acid (mainly 1 of 3 possible diastereoisomers)
In accordance with General procedure a using 653 mg (2,70 mmole) of the hydrochloride of D-proinvestirovalo ether and 346 mg (of 1.35 mmole) of a mixture of (E)-(2R, 5S)- and -(2RS, 5SR)-2,5-deputies-3-indicasat after rapid chromatography (gradient from 33% to 50% EtOAc in hexane) was obtained as a yellow oil 148 mg (17%) indicated in the title compound, product RO-64-3271/000 (mix 2 diastereoisomers) and in the form of a yellow oil and 116 mg (14%) specified in the connection header (only diastereoisomer).

MS m/e (%): 648 (M+NH4+, 90), 631 (M+N+, 100).

g) (R)-1- { 2,5-dibutil-6- [(R)-2-carboxypropyl-1-yl] -6-oxohexanoyl}pyrolidine-2-carboxylic cyclopentolate ether (E)-(R)-1- {2,5-dibutil-6- [(R)-2-benzyloxycarbonylamino-1-yl] -6-axugex-3-enoyl] pyrrolidin-2-carboxylic acid (mainly 1 of 3 possible diastereoisomers) in the form of a colorless oil was obtained 81 mg (81%) indicated in the title compound, product RO-64-3273/000 (single diastereoisomer).

MS m/e (%): 451 ([M-H]-, 100).

Example 82
(R)-1- {2,5-dibutil-6- [(R)-2-carboxypropyl-1-yl] -6-oxohexanoyl} pyrrolidin - 2-carboxylic acid (mixture of 2 of the 3 possible diastereoisomers)
In accordance with the General method B using 110 mg (0.22 mmole) of the benzyl ether (E)-(R)-1- {2,5-dibutil-6- [(R)-2-benzyloxycarbonylamino-1-yl] -6-axugex-3-enoyl} pyrrolidin-2-carboxylic acid (mainly 2 of 3 possible diastereoisomers) as a colourless oil was obtained 69 mg (88%) specified in the connection header (diastereoisomer 2).

MS m/e (%): 451 ([M-H]-, 100).

Example 83
(R)-1- [2,5-aminobutiramida-6- [(R)-2-carboxypropyl-1-yl] -6-oxohexanoyl}pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
a) a Mixture of diethyl ester of (E)-(2R, 5S)- and -(2RS, 5SR)-2,5-diisopropylamino - 3 - indicasat
In a mixed solution of 5.0 g (25.0 mmol) of diethyl ether TRANS-2-butene-1,4-dicarboxylic acid in 120 ml of THF were introduced 6,35 g (150 mmol) of anhydrous lithium chloride and the resulting suspension was cooled to -78oC. was added dropwise 25,0 ml (50.0 mmol) of 2 M solution GAVE in THF and stirring was continued for 45 minutes Then added the 4.7 ml (50 mmol) of Isopropylamine and mperature. The reaction was stopped by adding a saturated solution of ammonium chloride and the mixture three times was extracted with diethyl ether. The combined organic phases are successively washed with a saturated solution of ammonium chloride, water and saturated brine, dried over sodium sulfate and concentrated in vacuum. As a result of successive Express chromatography (20% EtOAc in hexane in the first column, 5% EtOAc in hexane in the second column, 10% EtOAc in hexane in the third column) in the form of a yellow oil was obtained 259 mg (4%) specified in the connection header.

MS m/e (%): 302 ([M+NH4]+, 100).

b) a Mixture of (E)-(2R, 5S)- and -(2RS, 5SR)-2,5-diisopropylamino-3-indicasat
In a mixed solution of 108 mg (range 0.38 mmole) of a mixture of diethyl ester of (E)-(2R, 5S)- and -(2RS,5SR)-2,5-diisopropylamino-3-indicasat in 5 ml of THF was injected 10 ml (10 mmol) of 1 M sodium hydroxide solution. After stirring for 96 h at room temperature by addition of 1M hydrochloric acid, the reaction mixture was acidified to pH 3, and three times were extracted with ethyl acetate. The combined organic phases are then washed with water and saturated brine, dried over sodium sulfate and concentrated in vacuum to produce in the form of a yellow oil, 70 mg (81%) specified in the header is connected to ridin-1-yl] -6-axugex-3-enoyl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
In accordance with General procedure a using 114 mg (0,47 mmole) of the hydrochloride of D-proinvestirovalo ether and 54 mg (0.24 mmole) of a mixture of (E)-(2R, 5S)- and -(2RS, 5SR)-2,5-diisopropylamino-3-indicasat after rapid chromatography (gradient from 33% to 50% EtOAc in hexane) as a colorless oil was obtained 15 mg (11%) specified in the connection header.

MS m/e (%): 620 (M+NH4+, 100).

g) (R)-1- {2,5-aminobutiramida-6- [(R)-2-carboxypropyl-1-yl] -6-oxohexanoyl}pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
In accordance with the General method B using 41 mg (0.07 mmole) of the benzyl ether (E)-(R)-1- { 2,5-aminobutiramida-6- [(R)-2-benzyloxycarbonylamino-1-yl] -6-axugex-3-enoyl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers) as a colourless oil was obtained 28 mg (100%) specified in the connection header.

MS m/e (%): 423 ([M-H]-, 100).

Example 84
(R)-1- { 5- [(R)-2-carboxypropyl-1-carbonyl] -7-methoxy-2-(2-methoxyethyl)heptanoyl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
a) a Mixture of diethyl ester of (E)-(2R, 5S)- and -(2RS, 5SR)-2,5-bis-(2-methoxyethyl) Gex - 3 - indicasat
In a mixed solution of 5.0 g (25.0 mmol) of diethyl ether TRANS-2-butene-1,4-dicarboxylic acid in 125 ml of THF was introduced 6,35 g (150 mm,0 mmol) of a 2M solution GAVE in THF and stirring was continued for 45 minutes Next was added 7.4 ml (78,7 mmole) of 2-methoxyethylamine and stirring was continued for 15 min at -78oC, then 1 h at 0oC, then 2 h at room temperature. The reaction was stopped by adding a saturated solution of ammonium chloride and the mixture three times was extracted with diethyl ether. The combined organic phases are successively washed with a saturated solution of ammonium chloride, water and saturated brine, dried over sodium sulfate and concentrated in vacuum. As a result, the Express chromatography (50% in toluene EtOAc) as a yellow oil was obtained 1.29 g (16%) specified in the connection header.

MS m/e (%): 334 ([M+NH4]+, 100).

b) a Mixture of (E)-(2R, 5S)- and -(2RS, 5SR)-2,5-bis-(2-methoxyethyl)-Gex-3-indicasat
In a mixed solution of 1.29 g (4,08 mmole) of a mixture of diethyl ester of (E)-(2R, 5S)- and -(2RS, 5SR)-2,5-bis-(2-methoxyethyl)-Gex-3-indicasat in 10 ml of THF was injected 33 ml (33 mmole) in 1 M sodium hydroxide solution. After stirring for 18 h at room temperature by addition of 1M hydrochloric acid, the reaction mixture was acidified to pH 3, and three times were extracted with ethyl acetate. The combined organic phases are then washed with water and saturated brine, dried over sodium sulfate and concentrated is up>-, 100).

C) Benzyl ester (E)-(R)-1-{5-[ (R)-2-benzyloxycarbonylamino-1-carbonyl] -7-methoxy-2- (2-methoxyethyl)heptanoyl] pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
In accordance with General procedure a using 1.86 g (7,69 mmole) of the hydrochloride of D-proinvestirovalo ether and 894 mg (3,84 mmole) of a mixture of (E)-(2R, 5S)- and -(2RS, 5SR)-2,5-bis-(2-methoxyethyl)-Gex-3-indicasat after serial Express chromatography (gradient from 50 to 100% EtOAc in hexane, then 10% of the Meon in EtOAc in the first column; 20% toluene in EtOAc in the second column; 20% toluene in EtOAc in the third column with a gradient from 25% to 20% toluene in EtOAc in the fourth column) as a pale yellow oil was obtained 146 mg (7%) specified in the connection header.

MS m/e (%): 652 (M+NH4+, 50), 635 (M+N+, 100).

g) (R)-1- { 5- [(R)-2-carboxypropyl-1-carbonyl] -7-methoxy-2-(2-methoxyethyl)heptanoyl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
In accordance with the General method B using 146 mg (0,23 mmole) benzyl ester (E)-(R)-1-{5-[(R)-2 - benzyloxycarbonylamino-1-carbonyl] -7-methoxy-2- (2-methoxyethyl)heptanoyl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers) as a colourless oil was obtained 92 mg (88%) specified in the header with deatil] phenyl} propionyl}pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
a) Benzyl ether (4-benzyloxycarbonylamino) acetic acid
Stir in a suspension of 10.0 g (51,5 mmole) benzene-1,4-luxusni acid, 0,94 g (7,73 mmole) of 4-dimethylaminopyridine and 5,33 ml (51,5 mmole) of benzyl alcohol in 150 ml of dichloromethane at 0oWith introduced 11,85 g (61,8 mmole) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide and stirring continued at 0oC for 2 h and then at room temperature for 16 hours Then the reaction mixture was successively washed with 1M hydrochloric acid, saturated sodium bicarbonate solution and finally with saturated brine and the aqueous phase was subjected to back extraction with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuum. Then, as a result of rapid chromatography (50% EtOAc in hexane) as a pale yellow oil, which upon standing crystallized, has been specified in the header of the connection.

MS m/e (%): 374 (M+, 10), 283 ([M-Bn]+, 16), 239 ([M-VP-CO2]+, 18), 91 (Bn+100).

b) a Mixture of benzyl ester of (R)-2-[4-[(S)- and(RS)-2-[4-[(RS)-1-benzyloxycarbonylamino] phenyl] propionic acid
In a mixed solution of 2.0 g (5.3 mmole) of the benzyl ether (4-benzyloxycarbonylamino) acetic acid is. Was added dropwise to 10.7 ml (21,4 mmole) of 2 M solution GAVE in THF and stirring was continued for 45 minutes Then added to 1.33 ml (21.3 mmole) under the conditions and stirring was continued for 15 min at -78oC, then 20 min at 0oC. the Reaction continued at this temperature by the addition of saturated solution of ammonium chloride and the mixture three times was extracted with diethyl ether. The combined organic phases were dried over sodium sulfate and concentrated in vacuum. As a result, the rapid-chromatography (EtOAc) as a brown oil was obtained 2.1 g (100%) specified in the connection header.

MS m/e (%): 420 ([M+NH4]+, 100).

C) a Mixture of (R)-2-[4-[(S)- and(RS)-2-[4-[(RS)-1-carboxyethyl]phenyl]propionic acid
A solution of 230 mg (0.57 mmole) of a mixture of benzyl ester of (R)-2-[4-[(S)- and(RS)-2- [4- [(RS)-1-benzyloxycarbonylamino] phenyl] propionic acid in 20 ml of ethanol at room temperature for 16 h were mixed together with 5 wt.% 10% palladium on coal under hydrogen pressure of 1 ATM. After filtration to remove catalyst, the reaction mixture was concentrated under vacuum obtaining in the form of a white crystalline solid 70 mg (55%) specified in the connection header.

MS m/e (%): 222 (M+23), 177 ([M-CO2N] In accordance with General procedure a using 370 mg (1,53 mmole) of the hydrochloride of D-proinvestirovalo ether and 170 mg (0.77 mmole) of a mixture of (R)-2-[4-[(S)- and(RS)-2-[4-[(RS)-1-carboxyethyl] phenyl]propionic acid after rapid-chromatography (EtOAc) as a colourless oil was obtained 170 mg (38%) specified in the connection header.

MS m/e (%): 614 (M+NH4+, 100), 597 (M+N+, 60).

d) (R)-1- {2- {4- [2- [(R)-2-carboxypropyl-1-yl] -1-methyl-2-oxoethyl] phenyl} propionyl}pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers)
In accordance with the General method B using 170 mg (0,29 mmole) benzyl ether (R)-1- {2- {4- [2- [(R)-2-benzyloxycarbonylamino-1-yl] -1-methyl-2-oxoethyl] phenyl} propionyl} pyrrolidin-2-carboxylic acid (mixture of 3 diastereomers) as a white foam was obtained 50 mg (42%) specified in the connection header.

MS m/e (%): 415 ([M-H]-, 100).

Example 86
(2E, 4E)-(R)-1- { 6- [(R)-2-carboxypropyl-1-yl]-2,5-dimethyl-b-ecocheck-2.4-dienoic pyrrolidin-2-carboxylic acid
a) Benzyl ester of (2E, 4E)-(R)-1- {6- [(R)-2-benzyloxycarbonylamino-1 - yl] - 2,5-dimethyl - 6 - oxohexyl -2,4-dienoyl} pyrrolidin - 2-carboxylic acid
Stir in the suspension of 0.91 g (5,32 mmole) of 2,5-dimethyl-Gex-2,4-diene-1,6-decollate in 80 ml of dichloromethane is and then the reaction mixture was stirred at 50oC for 2 h the Resulting solution was cooled to 0oAnd dropwise at 0oIt was introduced into the solution to 2.57 g (10.6 mmole) of the hydrochloride of D-proinvestirovalo ether and 3.0 ml (21.5 mmole) of triethylamine in 50 ml dichloromethane. Stirring was continued for 2 h at 0oWith, and then 24 h at room temperature. Next, the reaction mixture was sequentially washed with 1 M hydrochloric acid and then with water and finally the aqueous phase was subjected to back extraction with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuum. As a result, the rapid-chromatography (EtOAc) as a colourless oil was obtained and 2.79 g (96%) specified in the connection header.

MS m/e (%): 562 (M+NH4+, 100), 545 (M+N+5). for

a) (2E, 4E)-(R)-1- {6- [(R)-2-carboxypropyl-1-yl]-2,5-dimethyl-6-oxohexyl-2,4-dienoyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 1,14 g (2,09 mmole) benzyl ester of (2E, 4E)-(R)-1- {6- [(R)-2-benzyloxycarbonylamino-1-yl] -2,5-dimethyl-6-oxohexyl-2,4-dienoyl] pyrrolidin-2-carboxylic acid and dioxane as solvent in the form of a white solid substance was obtained 127 mg (16%) specified in the connection header.

MS m/e (%): 365 (M+N+, 100).

PRC 3 diastereoisomers)
The solution 593 mg (1.09 mmole) benzyl ester of (2E, 4E)-(R)-1-{6- [(R)-2 - benzyloxycarbonylamino-1 - yl] - 2,5-dimethyl - 6 - oxohexyl-2,4-dienoyl} pyrrolidin-2-carboxylic acid in 15 ml of dioxane under a hydrogen pressure of 1 ATM was mixed with 25 mg (0.11 mmole) of platinum oxide(IV) for 72 h at room temperature. After filtration to remove catalyst, the reaction mixture was concentrated in vacuum in a rotary evaporator three times was subjected to azeotropic distillation with chloroform to remove the last traces of dioxane, and then triturated in diethyl ether to obtain a white foam (400 mg (100%) specified in the connection header.

MS m/e (%): 369 (M+N+, 100).

Example 88
A mixture of (R)-1-{ (3R, 4R) - {3S, 4S)-3,4-dihydroxy-6-[ (R)-2-carboxypropyl-1-yl] -6-oxohexanoyl} pyrrolidin-2-carboxylic acid
a) Benzyl ether of (R)-1-{ 6-[ (R)-2-benzyloxycarbonylamino-1-carbonyl} pyridine-2-carbonyl} pyrrolidin-2-carboxylic acid
In accordance with General procedure a using 5.0 g (to 20.6 mmole) of the hydrochloride of D-proinvestirovalo ether and 1.5 g (10.3 mmole) of TRANS-3-hexandiol after rapid-chromatography (EtOAc) as a light yellow oil was obtained 3,15 g (59%) specified in the connection header.

MS m/e (%): 536 (M+NH4In a mixed solution of 3.13 g (6,04 mmole) benzyl ester of (R)-1-{6- [(R) -2-benzyloxycarbonylamino-1-carbonyl] pyridine-2-Carbo-nil}pyrrolidin-2-carboxylic acid in 10 ml of acetone and 10 ml of water was injected 980 mg (7,25 mmole) 4-methylmorpholine-4-oxide and 0.6 ml of 2.5% solution of osmium tetroxide in tert-butanol and stirring was continued for 72 h at room temperature. Further, when 0oWith added 50 ml of a 38% aqueous solution of monopotassium sodium sulfite and the stirring continued for an additional 15 minutes and Then the reaction mixture was filtered, and three times were extracted with ethyl acetate. The combined organic extracts are successively washed with 1M hydrochloric acid and saturated brine, dried over sodium sulfate and concentrated in vacuo to obtain a colourless oil 3,34 g (100%) specified in the connection header.

MC m/e (%): 575 (M+Na+, 35), 570 (M+NH4+, 55), 553 (M+N+, 100).

C) a Mixture of (R)-1-{ (3R, 4R)- I -{(3S, 4S)-3,4-dihydroxy-6- [(R)-2-carboxypropyl-1-yl] -6-oxohexanoyl} pyrrolidin-2-carboxylic acid
In accordance with the General method B using 506 mg (0,92 mmole) of a mixture of benzyl ester of (R)-1- {(3R, 4R) - {the lot in the form of a white solid substance was obtained 341 mg (100%) specified in the connection header.

MC m/e (%): 395 (M+NH4+, 55), 373 (M+N+, 100).

Example 89
(E)-(R)-1- {6- [(R)-2-carboxypropyl-1-yl] -6-ocasek-3-enoyl}pyrrolidin-2-carboxylic acid
a) tert-Butyl ether (E)-(R)-1- {6- [(R)-2-tert-butoxycarbonylamino-1-yl] -6-axugex-3-enoyl] pyrrolidin-2-carboxylic acid
In accordance with General procedure a using 1.5 g (8,76 mmole) D-Proline tert-butyl ester and 630 mg (4,37 mmole) of TRANS-3-eccenticity after rapid chromatography (10% EtOH in EtOAc) as a white crystalline solid was obtained 1,59 g (77%) specified in the connection header.

MS m/e (%): 568 (M+NH4+, 35), 451 (M+N+, 100), 395 ([M+H-C3H8]+, 32), 339 ([M+H-2C3H8]+, 40).

b) (E)-(R)-1- {6- [(R)-2-carboxypropyl-1-yl] -6-axugex-3-enoyl] pyrrolidin-2-carboxylic acid
In a mixed solution of 600 mg (1,33 mmole) of tert-butyl methyl ether (E)-(R)-1- { 6- [(R)-2-tert-butoxycarbonylamino-1-yl] -6-axugex-3-enoyl}pyrrolidin-2-carboxylic acid in 15 ml dichloromethane at 0oWith dropwise introduced to 4.4 ml (57,8 mmole) triperoxonane acid and stirring continued for 16 h at room temperature. In the result, concentration in vacuo and three azeotropic distillations of chloroform in the pop>+
, 100).

Example 90
(R)-1- { 3- {[3- [(R)-2-carboxypropyl-1-yl] -3-oxopropyl]propylamino} propionyl} pyrrolidin-2-carboxylic acid
a) Benzyl ether of (R)-1-acryloylmorpholine-2-carboxylic acid
In a mixed solution of 390 mg (1.6 mmole) of the hydrochloride of D-proinvestirovalo ether and 0.47 ml (3.4 mmole) of triethylamine in 20 ml dichloromethane at 0oWith dropwise injected 0.2 ml (2.4 mmole) of akriloilkhlorida and stirring continued at room temperature for 24 h Then the reaction mixture is then washed with water, 1 M hydrochloric acid and again with water and the aqueous phase was subjected to back extraction with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to obtain a colourless oil, 420 mg (100%) specified in the connection header.

MS m/e (%): 259 (M+, 25), 124 (100), 91 (25), 70 (21).

b) Benzyl ether (R) -1- {3- {[3- [(R) -2-benzyloxycarbonylamino-1-yl] -3-oxopropyl] propylamino} propionyl} pyrrolidin-2-carboxylic acid
A solution of 400 mg (1.5 mmole) of the benzyl ether of (R)-1-acryloylmorpholine-2-carboxylic acid and 63 ml (0.75 mmole) of Propylamine in 5 ml of acetonitrile was stirred for 16 h at room temperature, then for 6 h at 45o2About in acetone) in the form of pale yellow oil was obtained 84 mg (19%) specified in the connection header.

MS m/e (%): 578 (M+N+, 100).

in) (R)-1- {3- {[3- [(R)-2-carboxypropyl-1-yl] -3-oxopropyl] propylamino} propionyl} pyrrolidin-2-carboxylic acid
A solution of 84 mg (0.15 mmole) of the benzyl ether (R)-1-{3-{[3-[(R)-2-benzyloxycarbonylamino-1-yl] -3-oxopropyl] propylamino} propionyl}pyrrolidin-2-carboxylic acid in 3 ml of ethanol was stirred for 16 h at room temperature with 10 mg 10% palladium on coal under hydrogen pressure of 1 ATM. After filtration to remove the catalyst and concentration in vacuum in the form of a white solid substance was obtained 58 mg (100%) specified in the connection header.

MS m/e (%): 398 (M+N+, 100).

Example 91
(R)-1- { 3- { [3- [(R)-2-carboxypropyl-1-yl] - 3-oxopropyl] cyclopropanemethylamine} propionyl} pyrrolidin-2-carboxylic acid
a) Benzyl ether (R)-1- {3- {[3- [(R)-2-benzyloxycarbonylamino-1-yl] -3-oxopropyl] cyclopropanemethylamine} propionyl} pyrrolidin-2-carboxylic acid
A solution of 444 mg (1,71 mmole) benzyl ester of (R)-1-acryloylmorpholine-2-carboxylic acid and 74 ml of 0.85 mmole) of cyclopropylmethyl-Mina in 5 ml of acetonitrile was stirred for 1 h at room is matography (gradient from 0 to 100% Meon in EtOAc) as a yellow oil was obtained 220 mg (44%) specified in the connection header.

MS m/e (%): 590 (M+N+, 100).

b) (R)-1- {3- {[3- [(R)-2-carboxypropyl-1-yl] -3-oxopropyl] cyclopropanemethylamine} propionyl} pyrrolidin-2-carboxylic acid
A solution of 220 mg (0.37 mmole) of the benzyl ether (R)-1-{3-{[3-[(R)-2-benzyloxycarbonylamino-1-yl] -3-oxopropyl] cyclopropanemethylamine} propionyl} pyrrolidin-2-carboxylic acid in 20 ml of isopropanol was stirred for 16 h at room temperature with 10 mg 10% palladium on coal under hydrogen pressure of 1 ATM. After filtration to remove the catalyst and concentrating in vacuo to a yellow solid was obtained 153 mg (100%) specified in the connection header.

MS m/e (%): 408 ([M-H]-, 100).

Example 92
Triptorelin (R)-1- { 3- {(3,4-dimethoxybenzyl)- [3- [(R)-2-carboxypropyl-1-yl] -3-oxopropyl] amino} propionyl} pyrrolidin-2-carboxylic acid (1:1)
a) tert-Butyl ether (R)-1-acryloylmorpholine-2-carboxylic acid
In a mixed solution of 5.0 g (29,2 mmole) D-Proline tert-butyl ether and 4.5 ml (32,1 mmole) of triethylamine in 180 ml of dichloromethane at 0oWith dropwise injected 3.6 ml (43,8 mmole) of akriloilkhlorida and stirring continued at room temperature for 48 hours Then the reaction mixture is then washed in the back extraction with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuum to produce in the form of a yellow oil 6.6 g (100%) specified in the connection header.

MS m/e (%): 243 (M+NH4+, 33), 226 (M+N+100).

b) tert-Butyl ether (R)-1- {3- {[3- [(R)-2-tert-butoxycarbonylamino-1-yl] -3-oxopropyl] - (3,4-dimethoxybenzyl)amino} propionyl} pyrrolidin-2-carboxylic acid
A solution of 1.0 g (of 4.44 mmole) of tert-butyl methyl ether (R)-1-acryloylmorpholine-2-carboxylic acid and 0.33 ml (2,22 mmole) of vertriebene in 25 ml of acetonitrile was stirred for 16 h at 80oC. In the result, concentration in vacuo and flash-chromatography (gradient from 0 to 10% Meon in EtOAc) as a light brown oil was obtained 150 mg (10%) specified in the connection header.

MS m/e (%): 618 (M+N+, 100).

C) Triptorelin (R)-1- {3- {(3,4-dimethoxybenzyl)- [3- [(R)-2-carboxypropyl-1-yl] -3-oxopropyl] amino} propionyl} pyrrolidin-2-carboxylic acid (1:1)
In a mixed solution of 150 mg (0.24 mmole) of tert-butyl methyl ether (R)-1- { 3-{[3-[(R)-2-tert-butoxycarbonylamino-1-yl] -3-oxopropyl]-(3,4-dimethoxybenzyl) amino} propionyl} pyrrolidin-2-carboxylic acid in 5 ml of dichloromethane at 0oWith dropwise injected with 1.0 ml of triflorus the Oia in vacuum and triple azeotropic distillation with chloroform in a rotary evaporator after trituration in diethyl ether as a yellow crystalline solid was obtained 130 mg (87%) specified in the connection header.

MS m/e (%): 506 (M+N+, 100).

Example 93
Triptorelin (R)-1-{3-{[3- [(R)-2-carboxypropyl-1-yl] -3-oxopropyl] - (2-methoxyethyl)amino} propionyl} pyrrolidin-2-carboxylic acid (1: 1)
a) tert-Butyl ether (R)-1- {3- {[3- [(R)-2-tert-butoxycarbonylamino-1-yl] -3-oxopropyl] - (2-methoxyethyl)amino} propionyl} pyrrolidin-2-carboxylic acid
A solution of 1.0 mg (of 4.44 mmole) of tert-butyl methyl ether (R)-1-acryloylmorpholine-2-carboxylic acid and to 0.19 ml (2,22 mmole) of 2-methoxyethylamine in 25 ml of acetonitrile was stirred for 16 h at 80oC. In the result, concentration in vacuo and flash-chromatography (gradient from 0 to 10% Meon in EtOAc) as a light brown oil was obtained 300 mg (23%) specified in the connection header.

MS m/e (%): 526 (M+N+, 100).

b) Triptorelin (R)-1- {3-{[3-[(R)-2-carboxypropyl-1-yl] -3-oxopropyl] -(2-methoxyethyl)amino} propionyl} pyrrolidin-2-carboxylic acid (1:1)
In a mixed solution of 150 mg (0,29 mmole) of tert-butyl methyl ether (R)-1- {3- {[3- [(R)-2-tert-butoxycarbonylamino-1-yl] -3-oxopropyl] - (2-methoxyethyl) amino} propionyl} pyrrolidin-2-carboxylic acid in 5 ml of dichloromethane at 0oWith dropwise injected with 1.0 ml triperoxonane acid and stirring continued for 16 h at which the ORM in a rotary evaporator after re-suspension in water and subsequent lyophilization in the form of a yellow oil were obtained 100 mg (67%) specified in the connection header.

MS m/e (%): 436 (M+Na+, 35), 414 (M+N+, 100).

Example 94
Triptorelin (R)-1- { 3- {benzyl- [3- [(R)-2-carboxypropyl-1-yl] -3-oxopropyl] amino} propionyl} pyrrolidin-2-carboxylic acid (1:1)
a) tert-Butyl ether (R)-1- {3- {benzyl- [3- [(R)-2-tert-butoxycarbonylamino-1-yl] -3-oxopropyl] amino} propionyl} pyrrolidin-2-carboxylic acid
A solution of 1.0 mg (of 4.44 mmole) of tert-butyl methyl ether (R)-1-acryloylmorpholine-2-carboxylic acid (0.24 ml (2,22 mmole) of benzylamine in 25 ml of acetonitrile was stirred for 16 h at 80oC. In the result, concentration in vacuo and flash-chromatography (gradient from 0 to 10% Meon in EtOAc) as a yellow oil was obtained 470 mg (34%) specified in the connection header.

MS m/e (%): 558 (M+N+, 100).

b) Triptorelin (R) -1- {3- [benzyl- [3- [(R) -2-carboxypropyl-1-yl] -3-oxopropyl]amino}propionyl}pyrrolidin-2-carboxylic acid (1:1)
In a mixed solution of 200 mg (of 0.36 mmole) of tert-butyl methyl ether (R)-1- { 3- {benzyl- [3- [(R)-2-tert-butoxycarbonylamino-1-yl] -3-oxopropyl] amino} propionyl} pyrrolidin-2-carboxylic acid in 5 ml of dichloromethane at 0oWith dropwise injected with 1.0 ml triperoxonane acid and stirring continued for 16 h at room temperature. In financial p which, after trituration in diethyl ether as a yellow crystalline solid was obtained 160 mg (80%) specified in the connection header.

MS m/e (%): 468 (M+Na+, 30), 446 (M+N+, 100).

Example 95
Triptorelin (R)-1- {3- [3- [(R)-2-carboxypropyl-1-yl] -3-oxopropylidene} propionyl} pyrrolidin-2-carboxylic acid (1:1)
a) tert-Butyl ether (R)-1- {3- {[3- [(R)-2-tert-butoxycarbonylamino-1-yl] -3-oxopropyl] - (4-trifloromethyl)amino} propionyl} pyrrolidin-2-carboxylic acid
A solution of 1.0 mg (of 4.44 mmole) of tert-butyl methyl ether (R)-1-acryloylmorpholine-2-carboxylic acid and 0.32 ml (2,22 mmole) para-triphtalocyaninine in 25 ml of acetonitrile was stirred for 16 h at 80oC. In the result, concentration in vacuo and flash-chromatography (gradient from 0 to 10% Meon in EtOAc) as a light brown oil were obtained 480 mg (31%) specified in the connection header.

MS m/e (%): 626 (M+N+, 100).

b) tert-Butyl ether (R)-1-{3-{3-[(R)-2-tert-butoxycarbonylamino-1-yl] -3-oxopropylidene] propionyl} pyrrolidin-2-carboxylic acid and tert-butyl methyl ether (R)-1- {3- {[3- [(R)-2-tert-butoxycarbonylamino-1-yl] -3-oxopropyl] ethylamino} propionyl} pyrrolidin-2-carboxylic acid
A solution of 290 mg (0,46 mmole) of tert-butyl methyl ether (R)-1-{3- {[3-[(R)-2-tert-butoxycarbonylamino-1-yl] -3-oxopropyl] - (4-trifloromethyl)amino}propionyl]pyrrolidin-2-ka ATM together with 30 mg of 10% palladium on coal. The result of the filter to remove the catalyst, concentration in vacuo and flash-chromatography (gradient from 0 to 100% Meon in EtOAc containing 1% Et3N in the form of a yellow oil was obtained 36 mg (17%) indicated in the title compound, tert-butyl methyl ether (R)-1- { 3- [3-[ (R)-2-tert-butoxycarbonylamino-1-yl] -3-oxopropylidene] propionyl} pyrrolidin-2-carboxylic acid.

MS m/e (%): 468 (M+N+, 100).

As a result of further rapid chromatography of less polar fraction (with a gradient from 0 to 20% Meon in EtOAc containing 1% Et3N) in the form of a yellow oil as a by-product received 87 mg (38%) tert-butyl ether (R)-1- { 3- {[3- [(R)-2-tert-butoxycarbonylamino-1-yl] -3-oxopropyl] ethylamino} propionyl} pyrrolidin-2-carboxylic acid.

MS m/e (%): 496 (M+N+, 100).

C) Triptorelin (R)-1- {3- [3- [(R)-2-carboxypropyl-1-yl] -3-oxopropylidene] propionyl} pyrrolidin-2-carboxylic acid (1:1)
In a mixed solution of 33 mg (0.07 mmole) of tert-butyl methyl ether (R)-1-{ 3-[3-[(R)-2-tert-butoxycarbonylamino-1-yl] -3-oxopropylidene] propionyl} pyrrolidin-2-carboxylic acid in 5 ml of dichloromethane at 0oWith dropwise injected with 1.0 ml triperoxonane acid and stirring continued for 16 what cloroformo in a rotary evaporator after re-suspension in water and subsequent freeze-drying as a yellow glassy solid was obtained 19 mg (76%) specified in the connection header.

MS m/e (%): 354 ([M-H]-, 100).

Example 96
Triptorelin (R)-1- {3- {ethyl- [3- [(R)-2-carboxypropyl-1-yl] -3-oxopropyl]amino] propionyl} pyrrolidin-2-carboxylic acid (1:1)
In a mixed solution of 85 mg (0,17 mmole) of tert-butyl methyl ether (R)-1- { 3- {[3- [(R)-2-tert-butoxycarbonylamino-1-yl] -3-oxopropyl] ethylamino} propionyl} pyrrolidin-2-carboxylic acid in 5 ml of dichloromethane at 0oWith dropwise injected with 1.0 ml triperoxonane acid and stirring continued for 16 h at room temperature. In the concentration in vacuum and triple azeotropic distillation with chloroform in a rotary evaporator after re-suspension in water and freeze-drying as a yellow crystalline solid was obtained 63 mg (97%) specified in the connection header.

MS m/e (%): 442 ([M+SLA]-, 35), 382 ([M-H]-, 100).

Example 97
Triptorelin (R)-1- { 3- {[3- [(R)-2-carboxypropyl-1-yl] -3-oxopropyl] - (4-trifloromethyl)amino} propionyl} pyrrolidin-2-carboxylic acid (1:1)
In a mixed solution of 200 mg (0,32 mmole) of tert-butyl methyl ether (R)-1- {3- {[3- [(R)-2-tert-butoxycarbonylamino-1-yl] -3-oxopropyl] - (4-trifloromethyl)amino} propionyl} pyrrolidin-2-carboxylic acid in 5 ml di 16 h at room temperature. In the concentration in vacuum and triple azeotropic distillation with chloroform in a rotary evaporator after trituration in diethyl ether as a yellow crystalline solid was obtained 150 mg (75%) specified in the connection header.

MS m/e (%): 536 (M+Na+, 20), 514 (M+N+, 100).

Example 98
A mixture of (R)-1-[6-[(S)- and(RS)-1-[6-[(RS)-2-carboxypropyl-1-yl-6-oxohexanoyl} pyrrolidin-2-carboxylic acid
a) Benzyl ester 1H-pyrrole-2-carboxylic acid
Literature: J. Org. Chem. 1979, 44, 975. In a mixed solution of 5.0 g (45,0 mmole) pyrrole-2-carboxylic acid and 31.3 ml (225 mmol) of triethylamine in 100 ml of DMF was dropwise introduced 26 ml (225 mmol) of benzylbromide and stirring was continued for 72 h at room temperature. Next, the reaction mixture was concentrated in vacuo, the residue re-suspended in dichloromethane and washed twice with saturated sodium bicarbonate solution and twice with water, the aqueous phase was subjected to back extraction with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuum. As a result, the Express chromatography (25% EtOAc in hexane) as a yellow oil was obtained 8,23 g (90%) specified in the connection header.

MS m/e (%): 201 (Mil} -1H-pyrrole-2-carboxylic acid
In a mixed solution of 1.0 g (equal to 4.97 mmole) benzyl ester 1H-pyrrole-2-carboxylic acid, 0.06 g (of 0.50 mmole) of 4-dimethylaminopyridine and 0.82 ml (vs. 5.47 mmole) of 1,8-diazabicyclo [5.4.0] undec-7-ene in 40 ml dichloromethane at 0oWith dropwise introduced to 0.36 ml (2,49 mmole) of editorchoice and stirring was continued for 1 h at room temperature. Next, the reaction mixture was successively washed with 1M hydrochloric acid, saturated sodium bicarbonate solution and finally with saturated brine and the aqueous phase was subjected to back extraction with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuum. As a result, the Express chromatography (25% EtOAc in hexane) as a white crystalline solid was obtained 450 mg (35%) specified in the connection header.

MS m/e (%): 530 (M+NH4+, 100).

C) a Mixture of (R)-1-{ 6-[(S)- and(RS)-1-{6-[(RS)-2-carboxypropyl-1-yl] -6-oxohexanoyl}pyrrolidin-2-carboxylic acid
In accordance with the General method B using 800 mg (1,56 mmole) benzyl ester 1- {6- [2-benzyloxycarbonylamino-1-yl] -6-oxohexanoyl} -1H-pyrrole-2-carboxylic acid as a white crystalline solid was obtained 470 mg (91%) specified in the header of the robonova acid
a) tert-Butyl ester 1H-pyrrole-2-carboxylic acid
Literature: Tetrahedron 1985, 41, 5633. In a mixed solution of 10.0 g (90.0 mmol) of pyrrole-2-carboxylic acid in 180 ml of dioxane at 0oWith dropwise introduced 18 ml of concentrated sulfuric acid, then for 1 h with fridge with dry ice in the reaction flask are condensed 2-methylpropan and stirring continued for 16 h at 0oWith, at the same time periodically again filling the fridge with dry ice in order to maintain careful boiling 2-methylpropene under reflux. Next, the reaction mixture was carefully poured into ice mixture of 400 ml of diethyl ether and 150 ml of 2M sodium hydroxide solution. The phases were separated and the aqueous phase twice more was extracted with diethyl ether. The combined organic phases are successively washed with 2M sodium hydroxide solution, water and finally with saturated brine, then dried over sodium sulfate and concentrated in vacuo to obtain a colourless oil which still contained some amount of dioxane, 9,07 g (60%) specified in the connection header.

1H-NMR (250 MHz, Dl3,): 9,60 (1H, broad s), of 6.90 (1H, m), 6,83 (1H, m), from 6.22 (1H,sh), and 1.56 (N is lots
In a mixed solution of 1.3 g (to 7.77 mmole) of tert-butyl ester 1H-pyrrole-2-carboxylic acid, 95 mg (0,78 mmole) of 4-dimethylaminopyridine and 1.28 ml (8,56 mmole) of 1,8-diazabicyclo [5.4.0] undec-7-ene in 40 ml dichloromethane at 0oWith dropwise introduced 0,57 ml (3,91 mmole) of editorchoice and stirring continued for 16 h at room temperature. Added an additional 95 mg (0,78 mmole) 4-dimethylamino-ridine and 1.28 ml (8,56 mmole) of 1,8-diazabicyclo [5.4.0] undec-7-ene and the stirring was continued for additional 4 h at room temperature. Next, the reaction mixture was successively washed with 1M hydrochloric acid, saturated sodium bicarbonate solution and finally with saturated brine and the aqueous phase was subjected to back extraction with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuum. As a result, the Express chromatography (gradient from 10% to 20% EtOAc in hexane) as a pale yellow crystalline solid was obtained 464 mg (13%) specified in the connection header.

MS m/e (%): 462 (M+NH4+, 100).

C) 1- [6-(2-carboxyphenyl-1-yl)-6-oxohexanoyl] -1H-pyrrole-2-carboxylic acid
In a mixed solution of 55 mg (0.12 mmole) of tert-butyl ester 1-[6-(2up>With dropwise introduced 0.15 ml (1.97 mmole) triperoxonane acid and stirring continued for 16 h at room temperature. In the concentration in vacuum and triple azeotropic distillation with chloroform in a rotary evaporator in the form of not quite white crystalline solid was obtained 39 mg (95%) specified in the connection header.

MS m/e (%): 350 (M+NH4+, 100).

Example 100
(R)-1- {6- [(R)-2-carboxy-4,4-debtorprovidian-1-yl] -6-oxohexanoyl} -4,4-debtorprovidian-2-carboxylic acid
a) di-(2-benzyl, 1-tert-butyl) ester (2R)-4-oxopyrrolidin-1,2-dicarboxylic acid
A solution of 15.6 ml (to 0.22 mole) of dimethyl sulfoxide in 50 ml of dichloromethane at a temperature of -65oC for 10 min was introduced in 9,60 ml oxalicacid in 150 ml of dichloromethane. After 5 min at -65oWith added 32,1 g (0.1 mole) di-(2-benzyl, 1-tert-butyl) ester (2R,2R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid in 100 ml of dichloromethane and after an additional 15 min was added to 24.4 ml of 0.18 mol) of triethylamine. The cooling bath was removed and stirring was continued overnight and then the mixture was poured into ice water. As a result of extraction with dichloromethane, followed by washing of 0.05 N. Hcl, bicarbonate and what was alocale 11.1 g (35%) di-(2-benzyl,1-tert-butyl) ester (2R)-4-oxopyrrolidin-1,2-dicarboxylic acid.

MS m/e (%): 263 (M-isobutylene, 7), 219 (8), 184 (24), 128 (14), 91 (58), 84 (40), 57 (100). []D=+1,1o(C=1% in methanol).

b) di-(2-benzyl, 1-tert-butyl) ester (2R)-4,4-debtorprovidian-1,2 - dicarboxylic acid
Mix a solution of 0.64 g (0,002 mol) of di-(2-benzyl, 1-tert-butyl) ester (2R)-4-oxopyrrolidin-1,2-dicarboxylic acid in 3 ml of dichloromethane at 0oWith the handle of 0.79 ml (0,006 mole) of diethylaminosalicylaldehyde, stirring was continued at room temperature for 32 h and then the mixture was poured on ice. As a result of extraction with dichloromethane and filtration through silica gel, using hexane, followed by elution with dichloromethane in the form of light yellow oil was obtained of 0.62 g (90%) di-(2-benzyl,1-tert-butyl) ester (2R)-4,4-debtorprovidian -1,2-dicarboxylic acid.

MS m/e(%): 285 (1), 206 (6), 106 (33), 91 (35), 57 (100).]D= +43,0o(C=1% in methanol).

in) Hydrochloride benzyl ester (2R)-4,4-debtorprovidian-2-carboxylic acid (1:1)
100 ml dry model HC1 in diethyl ether was introduced into a solution of 7.51 g (of 0.022 mole) di-(2-benzyl, 1-tert-butyl) ester (2R)-4,4-debtorprovidian-1,2-dicarboxylic acid in a mixture of 100 ml of diethyl ether and 20 ml of dichloromethane. After pyrrolidin-2-carboxylic acid (1:1) and dried under reduced pressure.

Melting point 118-120oC; []D=+29,3o(C=1% in methanol).

g) Benzyl ether of (R)-1- {6- [(R)-2-benzyloxycarbonyl-4,4-debtorprovidian -1 - yl] - 6 - oxohexanoyl} -4,4-debtorprovidian - 2 - carboxylic acid
In a suspension of 1.11 g (0,004 mol) of the hydrochloride benzyl ester (2R)-4,4-debtorprovidian-2-carboxylic acid (1:1) in 20 ml of dichloromethane were introduced at 1.17 ml (0,008 mole) of triethylamine and of 0.29 ml (0.002 mol) of adelaideclothed in 5 ml of dichloromethane. After stirring at room temperature overnight the mixture was extracted with 1N. HCl, water and aqueous sodium bicarbonate solution and dried over sodium sulfate. The result chromatography on silica gel with dichloromethane/ ethyl acetate in a ratio of 8:2 in the form of a colorless oil was obtained 0,79 g (66%) of the benzyl ether (R-)-1- {6-[(R) -2-benzyloxycarbonyl-4,4-debtorprovidian-1-yl] -6-oxohexanoyl} -4,4-debtorprovidian - 2 - carboxylic acid.

ISP-MS: 593 (MN)+; []D=+67,3o(C=1% in methanol).

d) (R)-1- {6- [(R)-2-carboxy-4,4-debtorprovidian-1-yl] -6-oxohexanoyl}-4,4-debtorprovidian-2-carboxylic acid
0,59 g (0,001 mol) benzyl ester of (R)-1-{6-[ (R)-2-benzyloxycarbonyl -4,4-debtorprovidian-1 - yl] - 6 - oxohexanoyl} -4,4-di the th pressure in the presence of 0.12 g of a 5% palladium on coal. After completion of the reaction the catalyst was filtered, the solvent is kept off and the residue was dissolved in dichloromethane. As the result of evaporation in the form of a white foam was obtained 0.4 g (97%) of (R)-1- {6- [(R)-2 - carboxy - 4,4-debtorprovidian -1-yl] - 6 - oxohexanoyl] -4,4-debtorprovidian-2-carboxylic acid.

ISP-MS: 413 (MH)+; []D=+54,2o(C=1% in dimethyl sulfoxide).

Example 101
(R)-1-{ {2-[2-[(R)-2-carboxy-4,4-debtorprovidian-1-yl] -2-oxoethyl] phenoxy} acetyl}-4,4-debtorprovidian-2-carboxylic acid
a) Benzyl ether (R)-1- {{2- [2- [(R)-2-benzyloxycarbonyl-4,4-debtorprovidian-1-yl] -2-oxoethyl] phenoxy} acetyl} -4,4-debtorprovidian-2-carboxylic acid
In a mixture of 1.11 g (0,004 mol) of the hydrochloride benzyl ester (2R)-4,4-debtorprovidian-2-carboxylic acid (1:1), 0.45 g (0,002 mol) of 1,2-phenylenediacetic acid, 1,21 g (0,012 mol) N-methylmorpholine and 0.61 g (0,004 mol) of hydrate of 1-hydroxybenzotriazole in 90 ml of dichloromethane were introduced 0,77 g (0,004 mol) of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. After stirring at room temperature for 18 h the mixture was extracted with 1N. HCl, water, 10% aqueous solution of sodium bicarbonate and again with water. The result chromatography on silica gel with Dahl (R)-2-benzyloxycarbonyl-4,4-debtorprovidian-1-yl] -2-oxoethyl] phenoxy} acetyl} -4,4-debtorprovidian - 2 - carboxylic acid.

ISP-MS: 673 (MN)+; []D=+68,4o(C=1% in methanol).

b) (R)-1- {{2- [2- [(R)-2-carboxy-4,4-debtorprovidian-1-yl] -2-oxoethyl] phenoxy} acetyl} -4,4-debtorprovidian-2-carboxylic acid
of 0.47 g (0,0007 mole) benzyl ether (R)-1-{{2-[2-[(R)-2-benzyloxycarbonyl-4,4-debtorprovidian-1-yl] -2-oxoethyl] -phenoxy} acetyl} -4,4-debtorprovidian-2-carboxylic acid in 20 ml of ethanol was hydrogenosomal at room temperature and under atmospheric pressure in the presence of 0.09 g of a 5% palladium on coal. Upon completion of this reaction, the catalyst was filtered, the solvent is kept off and the residue was dissolved in dichloromethane. As the result of evaporation in the form of a light yellow foam was obtained 0.32 g (94%) (R)-1-{{ 2-[2-[ (R)2-carboxy-4,4-debtorprovidian-1-yl] -2-oxoethyl] phenoxy} acetyl} -4,4-debtorprovidian-2-carboxylic acid.

ISP-MS: 493 (MH)+; []D=+46,8o(C=1% in dimethyl sulfoxide).

Example 102
(R)-1- {{4- [2- [(R)-2-carboxy-4,4-debtorprovidian-1-yl] -2-oxoethyl] phenyl} acetyl} -4,4-debtorprovidian-2-carboxylic acid
a) Benzyl ether (R)-1- {{4- [2- [(R)-2-benzyloxycarbonyl-4,4-debtorprovidian-1-yl] - 2-oxoethyl] phenyl} acetyl} -4,4-debtorprovidian-2-carboxylic Kikot (0,002 mol) of 1,4-phenylendiamine acid, 1,21 g (0,012 mol) N-methylmorpholine and 0.61 g (0,004 mol) of hydrate of 1-hydroxybenzotriazole in 90 ml of dichloromethane were introduced 0,77 g (0,004 mol) of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. After stirring at room temperature for 18h mixture was extracted with 1N. HCl, water, 10% aqueous solution of sodium bicarbonate and again with water. The result chromatography on silica gel with dichloromethane/ethyl acetate in a ratio of 9:1 in the form of a colorless oil was obtained 0,72 g (56%) of the benzyl ether (R)-1-{{4-[2-[ (R)-2-benzyloxycarbonyl-4,4-debtorprovidian-1-yl] -2-oxoethyl] phenyl} acetyl} -4,4-debtorprovidian-2-carboxylic acid.

ISP-MS: 658 (NH4+); []D=+55,5o(C=1% in methanol).

b) (R)-1-{{4-[2-[(R)-2-carboxy-4,4-debtorprovidian-1-yl] -2-oxoethyl] phenyl} acetyl}-4,4-debtorprovidian-2-carboxylic acid
0.64 g (0,001 mol) benzyl ether (R)-1-{{4-[2-[ (R)-2-benzyloxycarbonyl-4,4-debtorprovidian-1-yl] -2-oxoethyl] phenyl} acetyl}] -4,4-debtorprovidian-2-carboxylic acid in 20 ml of ethanol was hydrogenosomal at room temperature and under atmospheric pressure in the presence of 0.13 g of 5% palladium on coal. After completion of the reaction the catalyst was filtered, the solvent is kept off and the residue rastvor,4-debtorprovidian-1-yl] - 2-oxoethyl] phenyl} acetyl} -4,4-debtorprovidian-2-carboxylic acid.

ISP-MS: 478 (NH4+); []D=+50,3o(C=0,33% in dimethyl sulfoxide).

Example 103
(R)-1- {6- [(R)-2-carboxy-2,5-dihydropyrrol-1-yl] -6-oxohexanoyl} -2,5-dihydropyrrol - 2 - carboxylic acid
a) Di - (2 - benzyl.1 - tert-butyl) ester (2R, 4R)-4-(toluene-4-sulfonyloxy)pyrrolidin-1.2-dicarboxylic acid
A solution of 2.35 g (0,007 mole) di-(2-benzyl,1-tert-butyl) ester (2R, 2R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid in 22 ml of pyridine in 5oWith the handle of 1.53 g (0,008 mole) p-toluensulfonate and kept in the refrigerator for 15 days. Then in vacuum drove pyridine and the residue was purified by chromatography on silica gel with dichloromethane/ethyl acetate in a ratio of 95: 5 to obtain a colourless liquid of 2.81 g (81%) di-(2-benzyl, 1-tert-butyl) ester (2R, 4R)-4-(toluene-4-sulfonyloxy) pyrrolidine -1,2-dicarboxylic acid.

MS m/e(%): 376 (2), 340 (10), 284 (6), 240 (21), 91 (48), 68 (100), 57 (63); []D=+24,5o(C=1% in methanol).

b) Di-(1-tert-butyl, 2-ethyl) ester (2R, 4R)-4-fenilselendiimidy-1,2-dicarboxylic acid
The solution to 7.99 g (0,026 mol) diphenyldisulfide in 250 ml ethanol process is ILSA in colorless. After the addition of 20.0 g (0,042 mole) di-(2-benzyl, 1-tert-butyl) ester (2R, 4R) -4- (toluene-4-sulfonyloxy)pyrrolidine-1,2-dicarboxylic acid and the mixture was boiled under reflux for 2.5 hours, the White precipitate was filtered and vacuum drove the solvent. The result chromatography on silica gel with dichloromethane/methanol in the ratio of 98/2 in the form of a colorless oil was obtained 8,48 g (51%) di-(1-tert-butyl,2-ethyl) ester (2R, 4S)-4-fenilselendiimidy-1,2-dicarboxylic acid.

MC m/e(%): 399 (7), 326 (13), 270 (18), 226 (38), 186 (35), 68 (60), 57 (100), 41 (28). []D=+40,4o(C=1% in methanol).

In addition, in the form of a colorless oil was isolated 0.6 g of di-(2-benzyl, 1-tert-butyl) ester (2R, 4S) -4-fenilselendiimidy-1,2-dicarboxylic acid.

MC m/e(%): 461 (7), 326 (21), 270 (37), 248 (48), 226 (49), 209 (30), 91 (100), 68 (54), 57 (96). []D=+33,2o(C=1% in methanol).

C) Di-(1-tert-butyl. 2-ethyl) ester (R) - 2.5-dihydropyrrol-1,2-dicarboxylic acid
In a mixed solution of 7.35 g (0,016 mole) di-(1-tert-butyl, 2-ethyl) ester (2R, 4S) -4-fenilselendiimidy-1,2-dicarboxylic acid in 80 ml of dichloromethane at 0-5oSince introduced of 1.93 ml (0,024 mole) of pyridine and 4.6 ml of 30% hydrogen peroxide and paramasivan is Oh. The result chromatography on silica gel with ethyl acetate/hexane in a ratio of 1: 5 as a colourless oil was obtained 2,99 g (77%) di-(1-tert-butyl, 2-ethyl) ester (R) -2.5-dihydropyrrol-1,2-dicarboxylic acid.

MC m/e(%): 186 (11), 168 (48), 140 (32), 112 (100), 68 (85), 57 (58). []D=+242o(C=1% in chloroform).

d) Triptorelin ethyl ester (R) -2,5-dihydro-1H-pyrrole-2-carboxylic acid (1:1)
1.5 g (0,006 mole) di-(1-tert-butyl, 2-ethyl) ester (R)-2.5-dihydropyrrol-1,2-dicarboxylic acid 5oWith stirring was dissolved in 10 ml triperoxonane acid and stirring continued at room temperature for 3 hours In the evaporation of the solvent in vacuo to a yellow oil was obtained 2,05 g (quantitative yield) of triptoreline ethyl ester (R)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (1:1).

MC m/e(%): 142 (1), 68 (100), 45 (10), 41 (15). []D=+95,4o(C = 1% in methanol).

d) Ethyl ester of (R) -1-{6-[(R) -2-ethoxycarbonyl-2,5-dihydropyrrol-1-yl] -6-oxohexanoyl} -2,5-dihydropyrrol-2-carboxylic acid
In the suspension 0,99 g (of 0.003 mole) of triptoreline ethyl ester (R)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (1:1) in 20 ml of dichloromethane was injected 1.3 ml (0,009 mole) triethylamin the giving of the night the mixture was extracted with 1N. HCl, water and aqueous sodium bicarbonate solution and dried over sodium sulfate. The result chromatography on silica gel with ethyl acetate as a yellow oil was obtained and 0.37 g (32%) of ethyl ester of (R)-1- {6- [(R) -2-ethoxycarbonyl-2,5-dihydropyrrol-1-yl] -6-oxohexanoyl} -2,5-dihydropyrrol-2-carboxylic acid.

ISP-MS: 393 (MH)+.

e) (R)-1- {6- [(R) -2-carboxy-2,5-dihydropyrrol-1-yl] -6-oxohexanoyl} -2,5-dihydropyrrol-2-carboxylic acid
0.09 g (is 0.0002 mole) of ethyl ester of (R) -1-{6-[(R) -2-ethoxycarbonyl-2,5-dihydropyrrol-1-yl]-6-oxohexanoyl] -2.5-dihydropyrrol-2-carboxylic acid was stirred at 50oC for 3 h with aqueous solution of Hcl. The solvent is evaporated, the residue was dissolved in water and liofilizirovanny obtaining in the form of a light yellow foam 0.08 g (97%) of (R)-1-{6- [(R) -2-carboxy-2,5-dihydropyrrol-1-yl] -6-oxohexanoyl} -2,5-dihydropyrrol-2-carboxylic acid.

ISP-MS: 335 (M-N])-.

Example 104
(R)-1- { {2-[2-[(R) -2-carboxy-2,5-dihydropyrrol-1-yl] -2-oxoethyl] phenoxy} acetyl}-2,5-dihydropyrrol-2-carboxylic acid
a) Ethyl ester of (R)-1- {{2- [2- [(R) -2-ethylcarboxyl-2,5-dihydropyrrol-1-yl] - 2-oxoethyl] phenoxy} acetyl} -2,5-dihydropyrrol-2-carboxylic acid
In a mixture of 0.99 g (of 0.003 mole) of triptoreline ethyl ester (R)-2,5-dihydro-Olina and 0.46 g (of 0.003 mole) of hydrate of 1-hydroxybenzotriazole in 80 ml of dichloromethane were introduced 0,57 g (of 0.003 mole) of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. After stirring at room temperature for 18 h the mixture was extracted with 1N. HCl, water, 10% aqueous solution of sodium bicarbonate and again with water. The result chromatography on silica gel with ethyl acetate as a colourless oil was obtained 0.45 g (32%) ethyl ester (R)-1- {{2- [2- [(R) -2-ethylcarboxyl-2,5-dihydropyrrol-1-yl] -2-oxoethyl] phenoxy}acetyl} -2,5-dihydropyrrol-2-carboxylic acid.

ISP-MS: 473 (MH)+.

b) (R)-1- {{2-[2-[(R) -2-carboxy-2,5-dihydropyrrol-1-yl] -2-oxoethyl] phenoxy} acetyl}-2,5-dihydropyrrol-2-carboxylic acid
0.17 g (of 0.0004 mol) ethyl ester (R)-1-{{2-[2-[(R) -2-ethylcarboxyl-2,5-dihydropyrrol-1-yl] -2-oxoethyl] phenoxy} acetyl} -2,5-dihydropyrrol-2-carboxylic acid in 50oC for 3 h was mixed with aqueous solution of Hcl. The solvent is evaporated, the residue was dissolved in water and liofilizirovanny obtaining in the form of a white amorphous powder of 0.13 g (86%) (R)-1- { { 2- [2- [(R) -2-carboxy-2,5-dihydropyrrol-1-yl] -2-oxoethyl] phenoxy} acetyl} -2,5-dihydropyrrol-2-carboxylic acid.

ISP-MS: 417 (MH)+.

An example of a
The usual procedure produced tablets of the following composition (mg/tablet:
Active ingredient: 100
Powdered lactose - 95
White corn starch - 35
Polyvin the emer B
The usual procedure produced tablets of the following composition (mg/tablet:
Active substance - 200
Powdered lactose - 100
White corn starch - 64
Polyvinylpyrrolidone - 12
Na-Carboxymethyllysine starch - 20
Magnesium stearate - 4
Weight tablets - 400
The example In
Made capsules of the following composition (mg/capsule:
Active ingredient: 50
Crystalline lactose - 60
Microcrystalline cellulose - 34
Talc - 5
Magnesium stearate - 1
The mass of the contents of a capsule - 150
The active component, characterized by an acceptable particle size, crystalline lactose and microcrystalline cellulose homogeneous mix among themselves, sift, then mix talc and magnesium stearate. Ready mix fill hard gelatin capsules of appropriate size.


Claims

1. Compounds of General formula

or

where R is SH, benzyl or phenyl, optionally substituted by a hydroxy-group or a lower alkoxygroup, or a group of the formula

R1is hydrogen or halogen;
X is -(CH2)n< CH(OH)- or thiazol-2,5-diyl;
Y - -S-S-; -(CH2)n-; -O-; -NH-; -N (R2)-; -CH=CH-; -NHC(O)NH-; -N(R2)C(O)N(R2)-; -N[CH2With6H3(Och3)2]-; -N(CH2C6H5)-; -N(CH2C6H5)C(O)N(CH2C6H5)-; -N(alkoxyalkyl)-; -N(cyclooctylmethyl)-; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl or diphenylene; 1,2-phenylene; 1,3-phenylene or 1,4-phenylene, where phenylenebis group optionally substituted by 1-4 substituents selected from the group comprising halogen, lower alkyl, lower alkoxygroup, the hydroxy-group, carboxypropyl, -COO-lower alkyl, nitrile, 5-tetrazol, (2-carboxy-pyrrolidin-1-yl)-2-Okeechobee, N-hydroxycarbamoyl, 5-oxo- [1,2,4]oxadiazolyl, 2-oxo-[1,2,3,5] oxadiazolyl, 5-thioxo-[1,2,4]oxadiazolyl and 5-tertbutylphenyl-[1,2,4]oxadiazolyl;
X' is -(CH2)n-; (CH2)nCH(R2)-; -(CH2)nOch2-; -NHCH2-; benzyl, -CH-C(R2)-;
-CH(OH)CH2or thiazol-2,5-diyl;
R2- lower alkyl, lower alkoxygroup or benzyl;
n = 0-3,
their pharmaceutically acceptable salts, mono - and diesters, except (R)-1-[(R)- and (R)-1-[(S)-3-mercapto-2-methylpropionyl]pyrrolidin-2-carboxylic acid.> is methyl or methoxy, and n = 0 or 1.

4. Connection on p. 3, which are
(R)-1{ (S)-3[(S)-3-[(R)-2-carboxypropyl-1-yl] -2-methyl-3-oxopropylidene]-2-methylpropionyl}pyrrolidin-2-carboxylic acid,
(R)-1-{8-[(R)-2-carboxypropyl-1-yl]-2,7-dimethyl-8-oxooctanoate}pyrrolidin-2-carboxylic acid,
(R)-1-{ 8-[(R)-2-carboxypropyl-1-yl] -2,7-dimethoxy-8-oxooctanoate] pyrrolidin-2-carboxylic acid and
(R)-1-{ 6-[(R)-2-carboxypropyl-1-yl] -2,5-dimethyl-6-oxohexanoyl] pyrrolidin-2-carboxylic acid (mixture of 3 diastereoisomers).

5. Connection on p. 2, where X is -(CH2)n- and n = 0 or 1.

6. Connection on p. 5, which are
(R)-1-{ 7-[(R)-2-carboxypropyl-1-yl]-7-oxoethyl}pyrrolidine-2-carboxylic acid,
(R)-1-{ 6-[(R)-2-carboxypropyl-1-yl]-6-oxohexanoyl}pyrrolidin-2-carboxylic acid,
(R)-1-{ 5-[(R)-2-carboxypropyl-1-yl]-5-oxopentanoic}pyrrolidin-2-carboxylic acid,
(R)-1-{ { 4-[2-[(R)-2-carboxypropyl-1-yl] -2-oxoethyl]phenyl}acetyl} pyrrolidin-2-carboxylic acid,
(R)-1-{3-[2-[(R)-2-carboxypropyl-1-yl]-2-oksidoksi]ureido]pyrrolidin-2-carboxylic acid,
(R)-1-{ {benzyl-[2-[(R)-2-carboxypropyl-1-yl]-2-oxoethyl]amino]acetyl pyrrolidine-2-carboxylic acid,
(R)-1-{ reservationpolicy-1-yl] -2-oxoethyl]phenyl}acetyl} pyrrolidin-2-carboxylic acid.

7. Connection on p. 2, where X is-CH2O-.

8. Connection on p. 7, which are
(R)-1-{ { 2-[2-[(R)-2-carboxypropyl-1-yl]-2-oksidoksi]phenoxy}acetyl}pyrrolidin-2-carboxylic acid,
(R)-1-{ { 4-[2-[(R)-2-carboxypropyl-1-yl]-2-oksidoksi]phenoxy}acetyl}pyrrolidin-2-carboxylic acid,
(R)-1-{ { 4-[2-[(R)-2-carboxypropyl-1-yl] -2-oksidoksi]-2-methoxyphenoxy}acetyl}pyrrolidin-2-carboxylic acid,
(R)-1-{ { 3-[2-[(R)-2-carboxypropyl-1-yl]-2-oksidoksi]phenoxy}acetyl}pyrrolidin-2-carboxylic acid,
(R)-1-{ { 3-[2-[(R)-2-carboxypropyl-1-yl] -2-oksidoksi]-2-methylphenoxy}acetyl}pyrrolidin-2-carboxylic acid and
(R)-1-{ { 5-[2-[(R)-2-carboxypropyl-1-yl]-2-oksidoksi]naphthalene-1-yloxy}acetyl}pyrrolidin-2-carboxylic acid.

9. Connection on p. 2, where X is-CH2NH.

10. Connection on p. 9, which is a (R)-1-{{4-[2-[(R)-2-carboxypropyl-1-yl] -2-oxoethylidene] phenylamino} acetyl}pyrrolidin-2-carboxylic acid.

11. Connection on p. 2, where X is-CH2CH(OH)-.

12. Connection on p. 11, which is (2E, 4E)-(R)-1-{6-[(R)-2-carboxypropyl-1-yl]-2,5-dimethyl-6-oxohexyl-2,4-dienoyl}pyrrolidin-2-carboxylic acid.

13. Drug, possess amyloidoses activity, the acid, or its pharmaceutically acceptable salt, or its mono - or fluids, and a therapeutically inert carrier.

14. Method of preparing compounds according to any one of paragraphs.1-12, which includes removing the protective group from compounds of formulas

and

where R, R1X, Y and X' are specified in paragraph 1 values;
R3denotes a protective group,
obtaining compounds of formula I-A or I-B and, if necessary, the conversion of compounds of General formula I-A or I-B in their pharmaceutically acceptable salts or mono - and diesters.

15. Compounds according to any one of paragraphs.1-12 obtained in any case by the method according to p. 14.

Priority items:
31.10.1997 on PP. 3, 5, 7, 13-15;
24.07.1998 on PP. 1, 2, 4, 6, 8-12.

 

Same patents:

The invention relates to new derivatives of dipeptides with pharmacological activity, and the way they are received, and may find application in medicine

The invention relates to nitrate ACE-inhibitor of formula I or II, where Y is phenyl, X is C(RIIIRIV, RIII, RIV, RVand RVI- hydrogen containing stoichiometric amount of nitric acid

The invention relates to a new derived neurotrophic N-glyoxal-propyl ether of the formula 1

< / BR>
where R1means1-C5alkyl linear or branched chain, possibly substituted C3-C6cycloalkyl,3- WITH5- WITH6-cycloalkyl, or AG1where Ar1selected from the group consisting of 2-tanila, 2-furanyl, 2-thiazolyl or phenyl; X is oxygen; Y represents oxygen or NR2where R2is hydrogen; Z means WITH2-C6alkyl or alkenyl with a linear or branched chain, which is substituted by one or more than one position AG2or3-C6cycloalkyl, where AG2selected from the group consisting of phenyl, 2-, 3 - or 4-pyridyl, phenyl, substituted methylenedioxy, and phenyl, having one to three substituents, which independently represent a chlorine or1-C4alkoxy, or pharmaceutically acceptable salts or hydrates

The invention relates to N-(N'-substituted glycyl)-2-cyanopyrrolidine formula I, where R denotes: a)1R1aN (CH2)m-, where R1means pyridinoline or pyrimidinyl fragment, optional one - or disubstituted independently of one another by halogen, trifluoromethyl, cyano - or nitro-group; R1adenotes hydrogen or C1-C8alkyl, m is equal to 2,3, b)3-C12cycloalkyl, optional one-deputizing in position 1 WITH1-C3hydroxyalkyl,) R2(CH2)n- where either R2denotes phenyl, optional one-, two - or tizamidine selected independently of each1-C4alkoxygroup, halogen or phenylthiourea, optional one-deputizing in the phenyl ring with hydroxymethyl; or denotes a C1-C8alkyl, [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8the alkyl, pyridinoline or nattily fragment, or cyclohexenyl, or substituted and n is 1-3, or R2denotes fenoxaprop; and n is 2; d) (R3)2CH(CH2)2-, where each R3independently represents phenyl; d) R4(CH2)p-, where R4ebony in position 1 WITH1-C3hydroxyalkyl, W) R5that means indanyl piperidinyl fragment, optionally substituted benzyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8by alkyl, substituted or1-C8alkyl, optionally one or mnogozalny independently from each other hydroxy-group, hydroxymethyl or phenyl, optional one - or disubstituted independently selected from each other WITH1-C4the alkyl, C1-C4alkoxygroup or halogen, in free form or in the form of an acid additive salt

The invention relates to new derivatives carbapenem formula I, where R1and R2may be the same or different, and each represents a modifiable group that can be hydrolyzed in the body, selected from 1-alkanoyloxy, 1-alkoxycarbonylmethyl, 5-methyl-1,3-dioxolan-2-he-4-ylmethyl; R3and R4may be the same or different and each represents lower alkyl, or R3and R4together with the adjacent nitrogen atom form a cyclic amino; or pharmaceutically acceptable salts

The invention relates to new derivatives of 1-methylcarbamate General formula (I) described in the claims

The invention relates to inhibitors of processes mediated by the action of DP-IV, which are characterized by the General formula:

A-B (Groups I and II) or

< / BR>
where is a

< / BR>
n = 1 or 2; m = 0, 1, or 2; NH or NR, where R = lower alkyl(C-C);

A is attached to Y;

-Y = -N, -CH, or C (when-CO group, A substituted group CH= CF,=),

R=H, CN, CHO, B(OH)2CC-R7or CH=N-R8;

R7=H, F, lower alkyl(C1-C6), CN, NO2OR9, CO2R9or COR9;

R8=Ph, HE, OR9, OCOR9or OBn;

R9= lower alkyl (C1-C6); and either oneor bothmay be missing

The invention relates to sulfur-containing derivative of an aryl having antibacterial and antiviral activity, in particular Aristotelianism the following formula (I), their pharmaceutically acceptable salts and solvate, a pharmaceutical composition having antibacterial and antiviral activity, and method of treating bacterial or viral infections

The invention relates to methods for selection of individual amino acids from the mixture and can be used in chemical, medical, food and other industries
The invention relates to medicine, in particular to surgery, and can be used for the treatment of critical ischemia of the lower extremities of atherosclerotic Genesis
The invention relates to medicine, namely to ophthalmology, and for the treatment of diabetic retinopathy
The invention relates to medicine, in particular cardiac, and for the prevention and treatment of heart failure after a heart attack

The invention relates to medicine, particularly cardiology and intensive care, and for the treatment of ischemic heart disease

The invention relates to new substituted the isoxazoles of General formulas I, II, III, IV, V, where R1selected from lower alkyl, carboxyamide, alkoxycarbonyl, aminocarbonyl, aminocarbonylmethyl and so on; R2choose from alkylsulfonyl, hydroxysulfonic and aminosulfonyl; R3selected from phenyl or 6-membered heterocycle containing one nitrogen atom, and phenyl may be optionally substituted by one or more radicals independently selected from alkyl, cyano, halogenoalkane, hydroxyalkyl and so on; provided that R2is aminosulfonyl, if R2- substituted phenyl radical is in the 3-position isoxazol; R4selected from lower alkyl, hydroxyl, carboxyl, halogen, lower carboxyethyl and so on; R5selected from methyl, hydroxy and amino; R6selected from phenyl or 6-membered heterocycle containing one nitrogen atom, and phenyl may be optionally substituted by one or more radicals independently selected from lower alkylsulfonyl, lower alkyl, cyano, lower halogenoalkane and so on; R7selected from lower alkyl, hydroxyl, carboxyl, halogen, lower carboxyl and so on; R8represents one or more radicals and so on

The invention relates to organic chemistry, namely to new derivatives of benzoperylene
The invention relates to medicine, namely to create herbal medicines for the treatment of patients with systemic vascular diseases of the lower and upper extremities
Up!