Method for preparation of perindopril with usage of tetramethyl-uronium salts as reagent of coupling reaction

FIELD: chemistry.

SUBSTANCE: invention refers to the selective method for preparation of "АХЭ" inhibitor - perindopril with usage as initial reagent of the sterospecific amino acid N-/1-(S)-ethoxycarbonylbutyl/-(S)-alanine which is activated by tetramethyl-uronium salts in the presence of tertiary organic base and following interreaction with (2S,3aS,7aS)-octahydroindolo-2-carbonic acid or its ester. After completing of the reaction the protective group is removed by the hydrogenation, interphase hydrogenation or extraction.

EFFECT: obtaining of perindopril with usage of tetramethyl-uronium salts as reagents of coupling reaction.

5 cl, 3 ex

 

The technical field to which the invention relates.

The present invention relates to the field of synthetic organic chemistry and the method of production of an inhibitor of ache (acetylcholinesterase) perindopril.

In particular, the present invention relates to a simple and highly selective process for the preparation of perindopril, also suitable for industrial production using commercially available raw materials and chemicals.

The level of technology

Perindopril was first obtained by the method described in EP-A-0049658, which revealed chetyrehstoronny way, which leads to the formation of stereoisomers that you want to share using sophisticated techniques. Reagent for condensing both critical intermediate products was dicyclohexylcarbodiimide. Patent EP-0308339 B1 relates to the production of source materials, critical for the synthesis of perindopril, i.e. the (2S,3S,7S)-octahedron-2-carboxylic acid.

In the US 4914214 describes a method for the same original substance by hydrogenation of (S)-2-carboxyaniline. The compound obtained by hydrogenation, and then condensed with N-/1-(S)-ethoxycarbonylbutyl/-(S)-alanine using dicyclohexylcarbodiimide as a reagent for condensing and 1-hydroxybenzotriazole as a subsidiary of nucleophilic reagent. Weeks the STATCOM this method is the formation of dicyclohexylamine, which is difficult to remove from the reaction mixture.

An alternative way to get perindopril described in the patent EP-1279665 A2. In the first stage of the method N-/1-(S)-ethoxycarbonylbutyl/-(S)-alanine activate with phosgene or a polymer of phosgene with the formation of the corresponding oxazolidine, which then interacts with (2S,3aS,7aS)-octahedron-2-carboxylic acid. Another object of the invention is the condensation with the use of N,N'-carbonyldiimidazole. It is important that in this way the side carboxypropyl is unprotected. At the same time, from the chemistry of peptides is known that the condensation of amino acids that contains an unprotected side groups, increases the likelihood of adverse reactions.

The present invention is the obtaining of perindopril and its pharmaceutically acceptable salts, such as tert-butylamine salt, a new and simple way in which perindopril obtained with high yield and with high purity.

Detailed description of the invention

The first variant implementation of the present invention is a method for perindopril of formula I:

,

characterized in that the carboxyl group is stereospecific amino acid N-/1-(S)-ethoxycarbonylbutyl/-(S)-alanine of the formula II:

activates tetramethyluronium Sol is Yu formula III:

in which Y represents an aromatic atom or N, X-denotes an anion, such as tetrafluoroborate, hexaphosphate or halogen, and then the activated amino acid of formula II interacts with (2S,3S,7S)-octahedron-2-carboxylic acid, or a complex ester of the formula IV:

in which R denotes hydrogen, benzyl group, tertiary boutelou group or trimethylsilyloxy group.

Tetramethyluronium salt can be selected from the group including:

O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylpropylenediamine, abbreviation: HBTU;

O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylpropylenediamine, abbreviation: TBTU; and

O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine, abbreviation: HATU, which are commercially available.

These reagents are known from the literature (G.A.Grant, Synthetic Peptides, Oxford University Press, 1992, 119) as reagents suitable for the synthesis of peptides, which do not occur side isomerization reactions in chiral centers.

In the second embodiment, the present invention is a method of obtaining perindopril is characterized by the fact that at the stage of activation of amino acids of formula II is added a tertiary organic base. Two mol of a tertiary organic base is added to 1 mo is Yu equimolar mixture of tetramethyluronium reagent and acid compounds of formula II.

Reaction activation described in the literature (Aldrichimica Acta, Vol.29, No.2, 1996, r.9) and involves the formation of highly reactive intermediate product of the formula V:

which interacts with an amine, for example with (2S,3S,7S)-octahedron-2-carboxylic acid or its ether complex, and turns into a dipeptide, such as perindopril.

According to the present invention a tertiary organic base may be a tertiary amine selected from the group comprising triethylamine, pyridine, lutidine and N,N-diisopropylethylamine. The preferred tertiary amine is N,N-diisopropylethylamine.

In the third embodiment, the present invention is a method of obtaining perindopril is characterized by the fact that at the stage of activation of amino acids II you can use the main reactive solvent, for example, 1-Mei. The solvent for the method of receiving perindopril proposed in the present invention, can also be selected from the group comprising N,N-dimethylformamide, N,N-dimethylacetamide, N-organic, dichloromethane and mixtures thereof.

Perindopril can be distinguished from the final reaction mixture by extraction with dichloromethane or ethyl acetate. All by-products and reagents that are soluble in water and can be removed by simple extraction with aqueous solutions. In conclusion, receiving the percent organic phase, containing perindopril, dried by evaporation of the solvent in vacuo.

Although the method proposed in this invention to react with the activated amino acid is used esters of (2S,3aS,7aS)-octahedron-2-carboxylic acid, in the end of the procedure should remove the protective ester group.

Benzyl protective group can be removed by hydrogenation using techniques of interfacial system hydrogen/catalyst (IRF), including palladium catalyst on charcoal, and the addition of a proton donor, such as ammonium formate. In this case, you can avoid the use of gaseous hydrogen, which excludes the possibility of ignition and explosion in industrial production. Tertiary boutelou protective group can be removed at the stage of selection by extraction with hydrochloric acid. Trimethylsilyl protective group can be removed in the extraction step by interaction with water.

Perindopril obtained as colorless viscous oil, which solidified in the cold. Perindopril could turn perindoprilat by crystallization from ethyl acetate or acetonitrile, after addition of tert-butylamine or by well-known methods.

The present invention is illustrated but in no way is not limited to the following when the apostrophes.

Example 1

Getting benzylpyridine

N-/1-(S)-Ethoxycarbonylbutyl/-(S)-alanine (7.2 g, 33 mmol) and TBTU (11.8 g, to 36.7 mmol) suspended in a mixture of solvents containing 40 ml of N,N-dimethylformamide and 10 ml of dichloromethane. Under stirring was added N,N-diisopropylethylamine (12.5 ml, 73 mmol) and the mixture was continuously stirred for 10 min until complete dissolution. With continuous vigorous stirring at room temperature to the reaction mixture were added 30 ml of a solution of benzyl ester of (3S, 3S, 7S)-octahedron-2-carboxylic acid (8,63 g, 33 mmol) in dichloromethane. Stirring in an atmosphere of nitrogen was continued for another 4 hours

The reaction can be monitored using HPLC (high performance liquid chromatography) under the following conditions:

column: Kromasil 100, CIS, 5 μm, 150×4.6 mm mobile phase:

- 20% acetonitrile/80% buffer solution containing 0.1% triethylamine/phosphoric acid pH of 3.2

In 60% acetonitrile/40% buffer solution containing 0.1% 10 triethylamine/phosphoric acid pH of 3.2.

gradient: from 100% a to 50% And 20 min

flow rate: 1 ml/min

detection: in the ultraviolet region at a length of water equal to 215 nm.

the retention times: benzylpyridine: 5,7 min; perindopril: 11,7 minutes

After completion of the reaction to the final reaction mixture was added 300 ml of dichloromethane. The mixture of extras who were garofali with two portions of 5% brine (400 ml, 300 ml of 2% hydrochloric acid in water, 300 ml of water, two portions of a saturated solution of sodium bicarbonate in 300 ml and finally to 300 ml of water. Then, the dichloromethane phase was treated with magnesium sulfate, was filtered and was dried by evaporation of the solvent in vacuo at a temperature not exceeding 50°C and received benzylpenicillin in the form of a slightly yellowish oil (13.5 g, 98% of theoretical yield).

Example 2

Receiving perindopril

a) Hydrogenation with interphase transport of hydrogen (IRF)

Benzylpyridine obtained in example 1 (13.5 g), was dissolved in 300 ml of methanol, to the solution was added 1.35 g of catalyst (10% palladium on charcoal) and 1.35 g of ammonium formate. The mixture was stirred at room temperature for 30 minutes and Then the catalyst was filtered and washed with 50 ml of methanol. The resulting solution was evaporated in vacuum at 50°C. the residue was dissolved in 100 ml of dichloromethane and extracted with two separate portions of 5% brine 100 ml, two portions of water, 100 ml. Then dichloromethane phase was treated with magnesium sulfate, was filtered and was dried by evaporation of dichloromethane at 50°C in vacuum. The rest was a crude transparent and colorless oil that solidified in the cold - perindopril (9,8 g, 90%). The compound obtained was identical with the standard compound - perindopril (HPLC, IR (infraclass the e) and MS (mass spectra) spectra).

b) Classical hydrogenation with gaseous hydrogen

Benzylpyridine obtained in example 1 (13.5 g), was dissolved in 300 ml of methanol, to the solution was added 1.35 g of catalyst (10% palladium on charcoal). The mixture was stirred at room temperature under a moderate stream of hydrogen for a further 5 hours and Then the catalyst was filtered off, washed with 50 ml of methanol and the solution evaporated at 50°C in vacuum. The rest was a crude and transparent 15 colorless oily compound that hardens in the cold, and was identical to the sample perindopril (10.2 g, 94% of theoretical yield).

Example 3

Receiving perindopril

N-/1-(S)-ethoxycarbonylbutyl/-(S)-alanine (7.2 g, 33 mmol) and HATU (13,95 20 grams of 36.7 mmol) suspended in 25 dry N-methylpyrrolidone and 25 ml of dry dichloromethane. To the mixture with continuous stirring were added triethylamine (10,2 ml, 73 mmol, previously dried over NaOH and distilled in the presence of ninhydrin). After 10 min stirring was added a solution of trimethylsilyl ether (2S,3S,7S)-octahedron-2-carboxylic acid (8.0 g, 33 mmol) in 30 ml of dry dichloromethane. The solution was stirred for another 4 h at room temperature. Then the reaction mixture was diluted with 250 ml of dichloromethane and extracted with two separate portions of 5% brine (400 ml, the two portions 2% chloride, the hydrogen of the acid in water 300 ml 300 ml of water, 300 ml ice saturated solution of sodium bicarbonate and finally to 300 ml of ice water. Then the dichloromethane phase was treated with magnesium sulfate, was filtered and was dried by evaporating the solvent in vacuum at 50°C. was Obtained 9 g (83% of theoretical yield) of a clear colorless oil that solidified in the cold, identical to perindopril (HPLC, IR, MS).

1. The way to get perindopril of formula I:

characterized in that the carboxyl group is stereospecific amino acid N-/1-(S)-ethoxycarbonylbutyl/-(S)-alanine of the formula II:

activates tetramethyluronium salt of the formula III:

in which Y represents an aromatic atom C or N, and X' denotes an anion, such as tetrafluoroborate, hexaphosphate or halogen, and then the activated amino acid of formula II interacts with (2S,3S,7S)-octahedron-2-carboxylic acid, or a complex ester of the formula IV:

in which R denotes hydrogen, benzyl group, tertiary boutelou group or trimethylsilyloxy group,
and after completion of the reaction, the protective group R is removed by hydrogenation, phase hydrogenation or extraction.

2. The method according to claim 1, characterized in that tetramethyluronium salt selected from the group including
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylpropylenediamine,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylethylenediamine, and
O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine.

3. The method according to any one of claims 1 and 2, characterized in that the activation of the carboxyl group tetramethyluronium salts increase through the use of a tertiary organic base.

4. The method according to claim 3, wherein the tertiary organic base selected from the group comprising N,N-diisopropylethylamine and triethylamine.

5. The method according to claim 1, characterized in that the protecting group R is a benzyl group.

6. The method according to claim 5, characterized in that the benzyl protective group is removed by means of interfacial hydrogenation without the use of gaseous hydrogen.



 

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22 cl, 15 tbl, 9 dwg, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new derivative 4-aminomethyl-5-hydroxyindole-3-carboxylate of the general formula I: where; R indicates cyclohexyl, cycloheptyl; R1 indicates C1-C3-alkyl, -CH2-X-phenyl; X indicates NH, O, S; R2 indicates C1-C5-alkyl, R3, R4 have identical value and are selected from C1-C3-alkyl, predominantly, CH3, or R3 and R4 together with a nitrogen atom form -5-10- member heterocycle, which contains 1-2- heteroatom selected from N, O, S or their pharmaceutically acceptable salts, with the exception of 6-bromine-5-hydroxy-4-dimethylaminomethyl-2-phenylthiomethyl-1-cyclohexyl-3-ethoxycarbonylindole, 6-bromine-5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylindole, 6-bromine-5-hydroxy-4-dimethylaminomethyl-2-(piperidinomethyl)-1-cyclohexyl-3-ethoxycarbonylindole, 6-bromine-5-hydroxy-4-dimethylaminomethyl-2-(pirrolidinemethyl)-1-cyclohexyl-3-ethoxycarbonylindole and methyl-1-cyclohexyl-4-piperidinomethyl-6-bromine-5-hydroxy-2-methyl-indole-3-carboxylate. The methods of obtaining compound I are described.

EFFECT: exhibit antiviral activity and can be used for treating influenza of the type A.

5 cl, 2 dwg, 2 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy, chemical technology.

SUBSTANCE: invention relates to novel substituted esters of 1H-indol-3-carboxylic acids of the general formula (1): or their racemates, or their optical isomers, or their pharmaceutical acceptable salts and/or hydrates. Compounds can be used in treatment of such diseases as infectious hepatitis, human immunodeficiency, atypical pneumonia and avian influenza. In compound of the general formula (1) R1, R41 and R42 each represents independently of one another a substitute of amino group chosen from hydrogen atom, optionally linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and possibly an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 carbon atom in ring with one or some heteroatoms chosen from nitrogen oxygen or sulfur atoms; or R41 and R42 in common with nitrogen atom to which they are bound form 5-10-membered azaheterocycle or guanidyl through R41 and R42; R2 represents an alkyl substitute chosen from hydrogen atom, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl; R5 represents a substitute of cyclic system chosen from hydrogen atom, halogen atom, cyano group, optionally substituted aryl or optionally substituted and possibly an annelated heterocycle that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms. Also, invention relates to methods for treatment, drugs and pharmaceutical compositions using compounds of this invention.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

22 cl, 3 tbl, 8 dwg, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted indole compounds of Mannich bases of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C10)-alkyl, unsubstituted phenyl or naphthyl bound through (C1-C2)-alkylene group or that monosubstituted at least with hydroxy group (-OH), halogen atom, -CF3, -CN, (C1-C6)-alkyl, (C1-C6)-alkoxy group; R2 means atoms H, F, Cl, Br, groups -CF3, -CN, -OR10, -CO(OR11), -CH2CO(OR12), -COR19, (C1-C10)-alkyl, unsubstituted phenyl or naphthyl, or that monosubstituted at least with -OH, halogen atom, -CF3, -CN, (C1-C6)-alkyl and (C1-C6)-alkoxy group; R3 means -CH(R13)N(R14)(R15); R4, R5, R6 and R7 can have similar or different values and mean atoms H, F, Cl, Br and groups -CF3, -CN, -NO2, -OR10 and others; R10 means H, -COR17, (C1-C6)-alkyl and others; R13 means unsubstituted phenyl or phenyl monosubstituted with at least (C1-C4)-alkyl, halogen atom, -CF3, -CN and -OH; R14 and R15 can have similar or different values and mean unbranched or branched (C1-C6)-alkyl, or R14 and R15 represent in common (CH2)n wherein n means a whole number from 3 to 6, or (CH2)O(CH2)2; R17 means (C1-C6)-alkyl; R19 means -NHR20, (C1-C6)-alkyl and others; R20 means H, (C1-C6)-alkyl and others, and/or their racemates, enantiomers, diastereomers and/or corresponding bases, and/or corresponding salts of physiologically acceptable acids with exception of racemates of some compounds given in claim 1. Also, invention describes method for their preparing and using as a medicinal agent possessing analgesic effect.

EFFECT: valuable medicinal properties of compounds.

42 cl, 2 dwg, 3 tbl, 103 ex

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