Method of producing enantiomeric forms of derivatives of 1,3-cyclohexanediol in cis orientation

FIELD: chemistry.

SUBSTANCE: invention relates to versions of the method of producing chiral non-racemic compound of formula I where R1 represents . Values of the rest of the radicals are given in the formula of invention. Formula I compound is obtained in several steps. The starting material used is cis-1,3-cyclohexanediol. One of the key steps is enzymatic formation of ester or enzymatic splitting of ester.

EFFECT: method is described for production of enantiomeric forms of derivatives of 1,3-cyclohexanedio in cis orientation.

8 cl, 80 ex

 

The invention relates to a method for producing a chiral, narramissic 1,3-disubstituted cyclohexanones formula (I) in the CIS-configuration

Variously substituted with CIS-configuration of 1,3-disubstituted cyclohexane derivatives (compounds of formula (I) when R1≠R2,are the Central structural elements or precursors described in WO 03/020269 medicinal active substances, which are generally suitable for treating disorders of lipid metabolism, such as type II diabetes, syndrome X, and other

Described in patent application WO 03/020269 methods of synthesis narramissic having the CIS-configuration of derivatives of 1,3-cyclohexane, are not suitable as a process: for example, alkylation by means of NaH/DMF) in multi-kg scale reliability is not feasible (C&EN, September 13, 1982,5). In addition, the alkylation according to the method Bu2SnO-scale experimental setup requires unacceptably high costs; the Department of compounds of tin from the desired product using chromatographic separation techniques are also very difficult and often incomplete. Disposal of zinc compounds is the next problem or economic factor. Separation of enantiomers (splitting of the racemate), by chromatography on chiral phase is also trudem them and too expensive. In addition, for the chromatographic separation of enantiomers is required to racemic compound had good chemical purity, which often can only be achieved by additional, pre-held chromatography.

Other described in the literature methods for the synthesis of CIS-1,3-cyclohexandione structural elements or derivatives, such as, for example, disclosure of epoxycyclohexane (P.Crotti, V. Di Bussolo, L.Favero, M.Pineschi, F.Marianucci, G.Renzi, G.Amici, G.Roselli, Tetrahedron 2000, 56, 7513-7524 and cited literature) or catalyzed by metals hydroporinae derivatives of cyclohexene (J.A.Brinkmann, T.T.Nguyen, J.R.Sowa, J. Org. Lett. 2000, 2, 981-983; C.E.Garrett, G.C.Fu, J. Org. Chem. 1998, 63, 1370-1371)are in respect of Regio - and stereoselectivity in the vast majority of the poor. In addition, the total number of stages is noticeably higher. Therefore, as industrial methods, they do not fit.

The synthesis of derivatives of CIS-1,3-cyclohexanediol of CIS,CIS-1,3,5-cyclohexatriene or derivatives of CIS,CIS-1,3,5-cyclohexatriene (L.Dumortier, M.Carda, J. Van der Eycken, G.Snatzke, M. Vandewalle, Tetrahedron: Asymmetry 1991, 2, 789-792; H.Suemune, K.Matsuno, M.Uchida, K.Sakai, Tetrahedron: Asymmetry 1992, 3, 297-306) due to the large number of stages is also very expensive and uneconomical and therefore not suitable for industrial application.

The enzymatic reaction of CIS/TRANS mixtures of 1,3-cyclohexanediol with S-metiltiofosfonata also not good in quality is TBE industrial way. In addition to the almost inevitable gas when contacting with the sulfur compounds and the fact that to achieve the desired degree of reaction is released from atention must be continuously discharged described reaction leads to a mixture of 9 isomeric forms or derivatives cyclohexanediol, namely the unreacted isomer (S,S)-diol, (R,R)-diol and (R,S)-diol, in addition, manuallyand product (S,S)-monochromat, (R,R)-monochromat and (R,S)-monochromat, and thirdly, the group vasiliovna product (S,S)-dioctanoyl, (R,R)-dioctanoyl and (R,S)-dioctanoyl. Optically active, monocularly (R,S)-monochromat having a CIS-configuration is in the faction manuallyand of cyclohexanediol share of approximately 12%. Held in preparative scale, the receipt and allocation of this product is not described, however, due to the quantitative relations and the problems of separation may not be economical. In addition, it is known that partially acylated di - or polyhydroxybenzenes prone to migration of acyl groups. If this case occurs, for example, during purification (R,S)-monoacrylate (for example, by chromatography on silica gel or water extraction) or during subsequent reactions (for example, by alkylation of the free hydroxyl groups), this leads to a considerable decrease in optical purity, or RA is imitatie.

Having a CIS-konfiguriranju (R,S)-diols or diallylamine (R,S)-connection not optically active and therefore are not of interest.

Therefore, the present invention is to develop a method that does not have these disadvantages.

The present invention is a method of obtaining chiral, narramissic compounds of formula I

with R1

which means:

the cycle Andphenyl, 5-12-tier heteroaromatic cycle, which may contain from one to four heteroatoms from the group N, O or S, 8-14-tier aromatic cycle, (C3-C8-cycloalkyl;
R3H, F, Cl, Br, OH, NO2, CF3, OCF3, (C1-C6)-alkyl, (C3-C8-cycloalkyl, phenyl;
R4, R5H, F, Cl, Br, OH, NO2, CF3, OCF3, OCF2H, OCF2-CF3, OCF2-CHF2SCF3, O-phenyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl, O-(C1-C6)-alkyl-O-(C1-C3)-alkyl;
nfrom 1 to 3;

and

R2(C1-C8)-alkyl, and alkyl groups, one or more CH2-groups may be replaced by O, CO, S, SO or SO2and alkyl may be from one to three times substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxa, CO-O(C1-C6)-alkyl, tetrazolo, thiazolidin-2,4-dione, indole and (C6-C10)-aryl, and thiazolidin-2,4-dione and aryl in turn can be substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxa, CO-O(C1-C6)-alkyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl or tetrazole, or
R2OH-protective group (SG), as for example, benzoyloxymethyl, benzyl, para-methoxybenzyl or tert-butyl dimethylsilane;

characterized in that conduct:

A)

a) alkylation (Alk-R2/Alk-SG)

CIS-1,3-cyclohexanediol formula (II)

subjected to interaction with the compound of the formula (III)

where

R2defined above, and

X1means Cl, Br, I, OMs (O-mesyl), OTs (O-tosyl), OTf (O-triflate);

prisutstvie base in a suitable solvent, obtaining racemic compounds of the formula (IV)

in which R2defined above,

b1) the enzymatic formation of complex ether (EB)+split (T)

the compound obtained of the formula (IV) is subjected to stereoselective enzymatic formation of complex ether (EB), and alcohols in an organic solvent, such as dichloromethane, mixed with donor acyl groups, such as vinyl ether R6-O-CH=CH2or acid anhydride R6-O-R6where R6defined above, and an enzyme, and the resulting mixture is stirred at a temperature of from -20 to 80°C, and at the end of the reaction one of streamer is present in the form of ester of the formula (V)

where

R6means C(=O)-(C1-C16)-alkyl, C(=O)-(C2-C16)-alkenyl, C(=O)-(C3-C16)-quinil, C(=O)-(C3-C16-cycloalkyl, and one or more carbon atoms may be replaced by oxygen atoms and can be substituted by 1-3 substituents from the group F, Cl, Br, CF3, CN, NO2, hydroxy, methoxy, ethoxy, phenyl and CO-O(C1-C4)-alkyl, CO-O(C2-C4)-alkenyl, which in turn can be substituted by 1-3 substituents from the group F, Cl, Br, CF3and

R2defined above,

and other streamer remains unchanged, as SP is RT of the formula (IV), and so through the use of their differing chemical or physico-chemical properties (for example, values of Rfor difference of solubility in water or other solvents) they can be separated from each other (separation T), for example, by simple chromatography on silica gel, extraction (for example, a mixture of heptane/methanol or an organic solvent/water) or by the following sequential chemical reactions, such as alcohol, in which the ester is not involved,

or

b2) the enzymatic cleavage of ester [=chemical esterification (CV)+enzymatic cleavage (ES)]+split (T)

the compounds of the formula (IV) is subjected to stereoselective enzymatic cleavage of ester and racemic alcohols first by chemical esterification (CV), for example, by means of a carboxylic acid R6-Cl or anhydride of the acid R6-O-R6in the presence of a base, such as triethylamine, is converted into racemic ester of formula (V)

where R6and R2defined above,

then by holding stereoselective enzymatic cleavage of ester (ES) injected into homogeneous or heterogeneous, aqueous, aqueous-organic or organic medium and at a temperature of 10-80°C in risotti enzyme is introduced into the reaction in the case of hydrolysis with water, and in the case of alcoholysis with an alcohol, such as n-butanol, after which one of streamer is present as an alcohol of the formula (IV), while the other remains unchanged in the form of ester of the formula (V), and thus they can be separated from each other as described in paragraph b1), and

the enantiomers of the formula (IV)obtained as alcohol, processed further as described in paragraph (d)

or

c) chemical hydrolysis (CH)

the enantiomers of the formula (V), as the resulting ester can be amylene obtaining chemically enantiomeric alcohols by a known method, and

d) alkylation (Alk-R1)

next subjected to interaction with compounds of the formula (VI)

where

cycle A, R3, R4, R5and n are defined above and

X2means Cl, Br, I, OTs, OMs, OTf;

in the presence of a base in a suitable solvent to obtain compounds of formula (I), and

e) cleavage of the protective group SG (AbSG)

if R2means OH-protective group (SG), and R2determined, as described above, the compounds of formula (Ia)

where R1and SG defined above,

by removal of the protective group by a known method, such as, for example, in the case of removal of SG=benzoyloxymethyl or SG=benzyl-hydrogenation on Pd/C, or with whom you learn off SG=steam-methoxybenzyl - for example, by means of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone), or in the case of removal of SG=tert-butyl dimethylsilane - for example, through Bu4NF converted into compounds of formula (VII)

where R1defined above,

f) alkylation (Alk-R2)

which is then subjected to interaction with compounds of the formula (III),

where X1and R2defined above,

in the presence of a base in a suitable solvent to obtain compounds of formula (I), the product or enantiomeric form,

moreover, it is also possible the sequence of the individual reaction stages, which are described above in paragraph (A):

A) Alk-R2→EB+T/CV+ES+T [→CH]→Alk-R1[→AbSG→Alk-R2]→

product/enantiomeric form

change it to

B) Alk-R1→EB+T/CV+ES+T [→CH]→Alk-R2[→AbSG→Alk-R2]→

product/enantiomeric form

or

C) Alk-SG→EB+T/CV+ES+T→CH→Alk-R2→AbSG→Alk-R1

product/enantiomeric form

or

D) Alk-SG→EB+T/CV+ES+T→Alk-R1→AbSG→Alk-R2

product/enantiomeric form.

Further schemes I-IV presents possible way:

The method according to the invention is economical, simple and fast. The method completely prevents the risk of migration of acyl groups, it does not require an equimolar quantities of optically pure source or auxiliary substances, expensive reagents, separation of racemates by chromatography on chiral phases, disproportionately large amounts of solvent and costly stages of processing.

Typical off racemates loss of 50% can be reduced by the application of both enantiomers and the change in the sequence of alkylation. The preferred so-called enantioselective method (see scheme IV or methods C) and D)), which are, for example, as follows: alkylation of CIS-1,3-cyclohexanediol formula (II) compound of formula (III), and R2as SG is chosen so that SG during the further synthesis could again be easily and selectively removed, thus SG is, for example, benzyl or para-methoxybenzyl, or tert-butyl-dimethylsilane; the resulting compound of formula (IV) is subjected to stereoselective enzymatic formation or cleavage of ester (see above) and after the last separation of both: unreacted alcohol and ester, - separately and in different ways, transferred to the same optically pure product, the fact that alcohol (campisano in the first part) transform, for example, a compound of formula (VI), a compound of formula (Ia), which then by removal of SG-group is converted into the compound of the formula (VII), and then using the compounds of formula (III) with R2what is desired in the product is converted into the compound of formula (I), and isomeric ester, on the contrary, by simple cleavage of ester is transferred to the compound of formula (IV), which is then using the compounds of formula (III) with R2what is desired in the product is converted into the compound of the formula (VIII),

which, in turn, the removal of SG-group is converted into the compound of the formula (IV)

and then with compounds of the formula (VI) is converted into the compound of formula (I).

Preferably used compounds of the formula (III)

in which

X1means Cl, Br, I, OMs or OTs,

Particularly preferred such compounds, in which

X1means Cl, Br, or I.

A preferred method of preparing compounds of formula (I),

in which:

R1is

where

the cycle Andphenyl, 5-12-tier heteroaromatic the ski loop which may contain one or more heteroatoms from the group N, O or S, condensed/bicyclic 8-14-tier aromatic cycle, (C3-C8-cycloalkyl;
R3H, CF3, (C1-C6)-alkyl, (C3-C8-cycloalkyl, phenyl;
R4, R5H, F, Br, CF3, OCF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl;
n1 or 2;
R2(C1-C8)-alkyl, and alkyl groups, one or more CH2-groups may be replaced by O, CO, S, SO or SO2and alkyl may be from one to three times substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxa, CO-O(C1-C6)-alkyl, tetrazolo, thiazolidin-2,4-dione, indole and (C6-C10)-aryl, and thiazolidin-2,4-dione and aryl in turn can be substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz, NN-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxa, CO-O(C1-C6)-alkyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl or tetrazolo

A particularly preferred method for obtaining compounds of formula (I),

in which:

R1is

where

the cycle Andphenyl;
R3(C1-C4)-alkyl;
R4, R5H, (C1-C4)-alkyl, O-(C1-C4)-alkyl;
n1;
R2(C1-C8)-alkyl, and alkyl groups, one or more CH2-groups may be replaced by O, CO, S, SO or SO2and alkyl may be from one to three times substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxa, CO-O(C1-C6)-alkyl, tetrazolo, thiazolidin-2,4-dione, indole and (C6-C10)-aryl, and thiazolidin-2,4-dione and aryl in turn can be substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxa, CO-O(C1-C6)-alkyl, (C1-C6)-Alki the Ohm, O-(C1-C6)-alkyl or tetrazole.

Alkyl residues in the substituents R2, R3, R4and R5can be both linear and branched.

Under the heteroaromatic cycle refers to both mono-and bicyclic ring with up to 4 heteroatoms, in particular, those which contain up to 4 nitrogen atoms and/or 1 oxygen or 1 sulfur atom, such as furan, thiophene, thiazole, oxazole, thiadiazole, triazole, pyridine, triazine, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzotriazol. Aromatic cycles may be mono - or bicyclic, as well as condensed as, for example, naphthyl, benzo[1,3]dioxol, dihydro-benzo[1,4]-dioxin.

Racemic having the CIS-configuration of 1,3-derivatives of cyclohexane of the formula (IV) and formula (VII) is obtained by monoalkylammonium CIS-cyclohexanediol (compounds of formula II), but it can also be obtained reductive opening of the corresponding acetal (R.Hunter et al., J. Org. Chem. 1993, 85, 6756), in addition, so-called remedial education simple ether based on simple cyrilovich esters and aldehydes or ketones (J.S.Bajwa, X.Jiang, J.Slade, K.Prasad, O.Repic, T.J.Blacklock, Tetrahedron Lett. 2002, 43, 6709-6713).

Reagents alkylation of the formula III are commercially available or can be obtained by known literature methods, for example, by radical Galaganov is of the side chains (see literature review R.C.Larock, Comprehensive Organic Transformations, S. 313, 1989 VCH Publishers, Inc.) or from alcohols or received from them derived (see literature review R.C.Larock, Comprehensive Organic Transformations, S. 353-363, 1989 VCH Publishers, Inc.).

Further, it is known (see J. Chem.Soc. 1925, 127, 2275-2297; J. Chem. Soc. 1922, 121, 2202-2215) for various bromides 2-bromomethylphenyl acid by radical synthesized, which can then be converted by subsequent reactions with alcohols in the ester by bromomethylphenyl acid belonging to the group of reagents alkylation of the formula (III).

Reagents alkylation of the formula (VI) or alcohols X2=OH, which can serve as precursors, are commercially available or can be obtained by known literature methods [a) The Chemistry of Heterocyclic Compounds (Ed.: A.Weissberger, E.C.Taylor): Oxazoles (Ed.: I.J.Turchi); (b) Methods der Organischen Chemie, Houben-Weyl 4. Edition, Hetarene III, Teilband 1; (c) I.Simit, E. Chindris, Arch. Pharm. 1971, 304, 425; (d) Y.Goto, M.Yamazaki, M.Hamana, Chem. Pharm. Bull. 1971, 19(10), 2050-2057].

Reagents alkylation of formulas III and VI in the presence of a base leads to the reaction with 1,3-cyclohexanediol or derivatives of 1,3-cyclohexanediol. Suitable bases are, for example, hydroxides, as KOH, carbonates, as Cs2CO3, alcoholate, as KOtBu, as well as compounds such as LDA, BuLi, LiHMDS, KH, NaH and NaHMDS. Suitable solvents are, for example, THF, MTBE, DME, NMP, DMF and chlorobenzene.

For separation of the racemate is in their spirits enter in organic solvents, as for example, dimethoxyethane (DME), methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), THF, n-hexane, cyclohexane, toluene, chlorobenzene, acetone, dimethylformamide (DMF), dichloromethane, 1,2-dichloroethane and tert-butanol, add acyl donor, such as vinyl acetate, finalproject, vinylboronate, 2,2,2-triptorelin-2H,2H-perpendiculat, ethoxyphenylacetic, p-nitro - or p-chlorophenylacetic, complex ether of the oxime, acetamiprid, anhydride propionic acid, anhydride of succinic acid, anhydride glutaric acid anhydride ISO-valerianic acid, 2,2,2-trichlorotoluene, 2,2,2-triptorelin-2H,2H-perpendiculat, and then the reaction mixture is mixed with a suitable enzyme and stirred at a temperature of from -20 to 80°C. the Proportion of alcohol in the solution is preferably 10-90%, but if necessary, the enzymatic reaction is performed preferably in a pure donor acyl groups, such as vinyl acetate, without co-solvents.

For the separation of racemates derived complex ester, such as acetyl, propionyl, butyryl or glutaryl, these derivatives in homogeneous or heterogeneous, aqueous, aqueous-organic or organic medium in the presence of a suitable enzyme is subjected to stereoselective hydrolysis or alcoholysis (for example, n-butanol) at a temperature of 10-80°C, optionally in the presence of the co-solvent is (see above) and buffer, and the reaction mixture preferably contains 2-50 wt.% of ester.

Obtaining the above-mentioned derivatives of ester can be carried out by known literature methods, for example by reacting the alcohol with the acid anhydrides as acetylchloride, or anhydrides, as acetanhydride, in the presence of an amine, such as triethylamine or pyridine (see literature review R.C. Larock, Comprehensive Organic Transformations, S. 978, 1989 VCH Publishers, Inc.).

Upon completion of the reaction products or the enantiomers can be divided in simple ways, for example by extraction by known literature methods [a) T.Yamano, F.Kikumoto, S.Yamamoto, K.Miwa, M.Kawada, T.Ito, T.Ikemoto, K.Tomimatsu, Y.Mizuno, Chem. Lett. 2000, 448; (b) B.Hungerhoff, H.Sonnenschein, F.Theil, J. Org. Chem. 2002, 67, 1781] or by applying chromatographic methods.

These methods consist in the fact that at the end of the enzymatic reaction significantly improve the solubility of the remaining alcohols by derivatization, for example, by acylation of cyclic anhydrides, such as, for example, glutaric acid anhydride, or a translation in kalinovy ether [(a) H.Kunz, M.Buchholz, Chem. Ber. 1979, 112, 2145; (b) M.Schelhaas, S.Glomsda, M.Hänsler, H.-D.Jakubke, H.Waldmann, Angew. Chem. 1996, 108, 82], and thus to achieve separation of water-insoluble or poorly soluble esters by extraction. After splitting the derivatization of alcohols can again be stopped by the chemical is who or enzymatic saponification.

Especially interesting is the possibility of separating enantiomers is that in the case of enzymatic acylation to choose acyl donors to acylated enantiomer was significantly better soluble in water than neproreagirovavshimi alcohol. Suitable donors acyl groups are, for example, cyclic anhydrides, as the anhydride of succinic acid. At the end of the enzymatic acylation acylation product has a free carboxyl group, which makes possible the rapid separation of the product by water extraction of the basic solution, for example, in a saturated aqueous solution of NaHCO3.

Enzymatic racemate separation by cleavage of ester are preferably so that the ester of the formula (I), for example, when R1=COCH3, COCH2CH3or COCH2CH2CH2COOH, mixed in water or an alcohol-based solution with esterase or lipase and stirred.

It may be beneficial to add to the specified buffer solution such as phosphate buffer or TRIS[=Tris(hydroxymethyl)methylamine]-buffer. The additive may be, for example, from 0.01 to 1.0 molar. A favorable range of the buffer is pH 5-10.

As the enzyme is preferably used hydrolases from the liver of a mammal, such as, for example, lipase from the pancreas of pigs (Fluka) or from the of mikroorganizmov, as for example, lipase B from Candida antarctica (Roche Diagnostics), lipase OF from Candida rugosa (Meito Sangyo), lipase SL from Pseudomonas cepacia (Meito Sangyo), lipase L-10 from Alcaligenes spec. (Roche Diagnostics) and lipase QL from Alcaligenes spec. (Meito Sangyo). If under applicable esters refers to derivatives of glutaric acid, such as mono-(3-benzyloxycarbonyl)-ester of glutaric acid, may be beneficial instead of the above lipases apply glutaryl-7-ACA-acylase (Roche Diagnostics).

Especially preferred lipase B from Candida antarctica (Roche Diagnostics), and can preferably be applied to the free enzyme or immobilized form of the enzyme, for example, one of the three currently available in the sale of products.

Each of these enzymes can be used in free or immobilized form (Immobilized Biocatalysts, W.Hartmeier, Springer Verlag Berlin, 1988). The amount of enzyme is selected arbitrarily depending on the reaction rate or the desired reaction time and the type of enzyme (for example, free or immobilized) and easy to install simple preliminary test.

Re-extraction of the enzyme can be performed by freeze-drying. Separation (and, if necessary, subsequent extraction) of the enzyme can facilitate the immobilization.

By a suitable reaction always possible to obtain optically pure at least one ANENT the Omer. If it is desirable to obtain optically pure ester, the degree of conversion in the case of the enzymatic formation of ester to be lower than (or equal to) 50%, and in the case of enzymatic hydrolysis or alcoholysis is above (or equal to) 50%. If desired optically pure alcohol, the degree of conversion in the case catalisano enzymes formation of ester should be higher than (or equal to) 50%, and in the case of hydrolysis or alcoholysis must be lower than (or equal to) 50%.

Determination of the degree of conversion of the enzymatic reaction is carried out or by HPLC directly from the reaction mixture or by calculation from the optical purity of the reaction products (of ester and acid), which was determined directly from the reaction mixture by HPLC on a chiral phase.

The following examples of the present invention is illustrated in more detail.

Examples:

All selected products or a mixture of raw foods identified by1H-NMR and mass spectroscopy or HPLC.

The optical purity of the esters and alcohols were determined by HPLC, for example, on a Chiralpak AD 250×4,6 (Daicel) or Chiracel OD 250×4,6.

To scheme Ia:

Example 1

Synthesis of racemic methyl ester of CIS-2-(3-hydroxycyclohexyl)-6-methylbenzoic acid

500 g (4.3 mol) of CIS-1,3-cyclohexanediol Rast is oraut in 5 l of NMP and mixed with 336 g (3.0 mol) of potassium tert-butylate (KOtBu). The internal temperature was raised to 28°C. Stirred for 30 min, then cooled to -5°C and added dropwise mixed with 370 grams (about 94%, about 1.4 mol) of methyl ester of 2-bromomethyl-6-methylbenzoic acid, which can be obtained, for example, by methanolysis bromide 2-bromomethyl-6-methylbenzoic acid or bromirovanii methyl ester of 2,6-dimethylbenzoic acid, stirred for 30 min and then diluted with 5 l of water. After triple washing with 3 liters of n-heptane, and removal of a solution of n-heptane, the remaining aqueous phase is extracted four times using 2.5 l of MTBE. Peeled MTBE phase once washed with 5 l of water, dried with Na2SO4and then evaporated under reduced pressure. Get 234 g of the desired compound as a yellowish oil, which without further purification used in the following reaction (for example, separation of racemates);1H-NMR (CDCl3), δ=1,27 (m, 1H), 1,45 (m, 1H), 1.55V (m, 1H), 1,74 (m, 1H)and 1.83 (m, 1H), 2.05 is (m, 1H), 2,34 (s, 3H), 3,47 (m, 1H), and 3.72 (m, 1H), 3,91 (s, 3H), 4,58 (DD, 2H), 7,15 (d, 1H), 7,20 (m, 2H), 7,27 (m, 1H).

Example 2

The separation of racemates methyl ester CIS-2-(3-hydroxycyclohexyl)-6-methylbenzoic acid

490 g of crude racemic methyl ester of CIS-2-(3-hydroxycyclohexyl)-6-methylbenzoic acid (see example 1) dissolved in 3.1 liters of methylene chloride and 850 ml of vinyl acetate, CME is more of 18 g of Novozym 435 and stirred at 21-24°C. 28 hours and add 2 g of Novozym 435. Through full 44 h the reaction is complete the filtering of the enzyme, and the filtrate is evaporated under reduced pressure, get 540 Chromatography of the residue on approximately 6 kg of silica gel (ethyl ester of acetic acid/n-heptane 1:1) to give 184 g of (1R,3S)-methyl ester 2-(3-hydroxycyclohexyl)-6-methylbenzoic acid; purity>98% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA);1H-NMR (CDCl3), δ=1,27 (m, 1H), 1,45 (m, 1H), 1.55V (m, 1H), 1,74 (m, 1H)and 1.83 (m, 1H), 2.05 is (m, 1H), 2,34 (s, 3H), 3,47 (m, 1H), and 3.72 (m, 1H), 3,91 (s, 3H), 4,58 (DD, 2H), 7,15 (d, 1H), 7,20 (m, 2H), 7,27 (m, 1H)), and 239 g of (1S,3R)-acetate (purity 93%, HPLC on Chiralcel OD/20 250×4,6, 1 ml/min, heptane/EtOH/CH3CN 100:1:0,5).

Example 3

Synthesis of 4-iodomethyl-2-(3-methoxyphenyl)-5-methoxazole

150,0 g (to 0.63 mol) of 4-chloromethyl-2-(3-methoxyphenyl)-5-methoxazole dissolved in 2.7 l of THF and mixed with 106 g (0.71 mol) of NaI. Stirred for 4 h and left overnight, suck salts, the filtrate was concentrated in vacuo. After about 1-2 hours the desired iodide becomes solid, yield: 216 g, TPL 58-59°C.1H-NMR (CDCl3): δ=2,30 (s, 3H), 3,88 (s; 3H), 4,34 (s, 2H), 6,97 (DD, 1H), 7,34 (t, 1H), 7,52 (d, 1H), 7,58 (d, 1H).

Example 4

Synthesis of (1R,3S)-methyl ester 2-{3-[2-(3-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid

184 g (0.66 mol)of(1R,3S)-methyl ester 2-(3-hydroxycyclohexyl)-6-methylbenzoic acid (see example 2) are dissolved in 2.2 l of t-BuOMe. To this add 88.0 g (approximately 55%, 1.8 mmol) NaH and stirred for 45 minutes at 20-22°C. Add 282 g (is 83.8 mmol) 4-iodomethyl-2-(3-methoxyphenyl)-5-methoxazole (see example 3), stirred for 8 hours at 22°C and left overnight. Stirred for further 4 h and then cooled carefully add the first 200 ml, and later another 1.5 liters of water. The organic phase is separated, dried (Na2SO4) and concentrate under reduced pressure. Receive 383 g of crude product, which is marked by chromatography on about 6 kg of silica gel (dichloromethane/acetone 19:1), output: 199 g of a yellowish oil;1H-NMR

(CDCl3), δ=1,15-of 1.32 (m, 4H), of 1.81 (m, 1H), 2,00 (m, 1H), 2,07 (m, 1H), 2,34 (s, 3H), 2.40 a (s, 3H), of 2.51 (m, 1H), 3.27 to (m, 1H), 3,37 (m, 1H), a 3.87 (s, 3H), 3,90 (m, 3H), 4,48 (s, 2H), 4,60 (s, 2H), of 6.96 (m, 1H), 7,12-7,35 (m, 4H), 7,53 (s, 1H), 7,58 (d, 1H).

Example 5

Synthesis of (1R,3S)-2-{3-[2-(3-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid

199 g (0.41 mol) of (1R,3S)-methyl ester 2-{3-[2-(3-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid (see example 4) are dissolved in 2 l of ethanol. Add 250 ml of 33%aqueous NaOH and boiled for 15 hours under reflux. The ethanol is distilled off in vacuum, the residue is dissolved in about 2 liters of water and twice washed with methyl tert-butyl ether, using 500 ml of the Aqueous phase when ohla the Denia acidified with concentrated hydrochloric acid to pH 1 and the resulting oily product is extracted with 1.5 liters of ethyl ester of acetic acid. A solution of ethyl ester acetic acid, dried and concentrated in vacuo. The residue is dissolved in 1.2 l DIPE at about 40°C. After crystallization and drying in vacuum at 60°C receive 132,5 g of the desired carboxylic acid; TPL 103-105°C; purity>98% (HPLC on Chiralpak AD-H 250x4,6; 1 ml/min, heptane/EtOH/CH3CN 90:7:1+0.1% of TFA);1H-NMR (CDCl3), δ=1,14-to 1.38 (m, 4H), of 1.80 (m, 1H), 1.93 and (m, 2H), 2,41(s, 3H), of 2.44 (s, 3H), 2,61 (m, 1H), 3,40 (m, 2H), 3,86 (s, 3H), 4.53-in (s, 2H), and 4.68 (DD, 2H), 6,98 (DD, 1H), 7,17 and 7.36 (m, 4H), 7,55 (s, 1H), to 7.61 (d, 1H).

Example 6

Synthesis of 4-iodomethyl-2-(4-were)-5-methoxazole

6.0 g of 4-chloromethyl-2-(4-were)-5-methoxazole dissolved in 120 ml of THF and mixed with 4,18 g (of 27.9 mmol) of NaI. Stirred for 3.5 h, add 1.5 g of NaI and heated to 35°C. After 30 minutes sucked off salt and the filtrate was concentrated in vacuo; yield: 10.1 g, TPL 104-105°C;1H-NMR (CDCl3): δ=to 2.29 (s, 3H), 2,39 (s, 3H), 4,34 (s, 2H), 7,24 (d, 2H), 7,88 (d, 2H).

Example 7

Synthesis of (1R,3S)-methyl ester 2-{3-[2-(4-were)-5-methoxazole-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid

36,0 g (0,129 mol) of (1R,3S)-methyl ester 2-(3-hydroxycyclohexyl)-6-methylbenzoic acid (see example 2) are dissolved in 430 ml of tBuOMe. Add to 17.2 g (approximately 55%, 0.35 mol) of NaH and stirred for 30 minutes at 23°C. Add 55,1 g (0,166 mol) 4-iodomethyl-2-(4-were)-5-methoxazole (example ). After 6 hours of mixing and maturation within 2 days add cooling 400 ml of water and separate the organic phase. After drying (Na2SO4) and concentration the crude product (75 g) was isolated by chromatography on silica gel (approximately 1 kg) (dichloromethane/acetone 19:1), yield: 42 g dialkylamino derived 1,3-cyclohexanediol in the form of a yellowish oil;1H-NMR (CDCl3), δ=of 1.16 to 1.31 (m, 4H), of 1.80 (m, 1H), 1,97-2,1 (m, 2H), 2,34 (s, 3H), 2,39 (s, 3H), 2.40 a (s, 3H), 2,52 (m, 1H), 3.27 to (m, 1H), 3,37 (m, 1H), with 3.89 (s, 3H), 4,47 (s, 2H), 4,59 (s, 2H), 7,13 (d, 1H), 7,20-7,28 (m, 4H), 7,88 (d, 1H).

Example 8

Synthesis of (1R,3S)-2-{3-[2-(4-were)-5-methoxazole-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid

42,0 g (0.09 mol) of (1R,3S)-methyl ester 2-{3-[2-(4-were)-5-methoxazole-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid (see example 7) are dissolved in 420 ml of ethanol. Add 45 ml of 33%aqueous NaOH and heated for about 20 hours under reflux. The ethanol is distilled off in vacuum, the residue is dissolved in 500 ml of water and the solution is washed four times by a simple MTB ether, using 100 ml. of the Aqueous phase when cooled, acidified with concentrated hydrochloric acid (pH 1) and the resulting oily product is extracted with ethyl ether acetic acid. A solution of ethyl ester acetic acid, dried and concentrated in vacuo. The remainder of the process is Aut in 250 ml of DIPE warm. Upon cooling, crystallization starts. After crystallization and drying in vacuum at 60°C to obtain 28.4 g of the desired carboxylic acid; TPL 117-119°C; purity>98% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 90:7:1+0.1% of TFA);1H-NMR (CDCl3), δ=1,14-of 1.36 (m, 4H), of 1.80 (m, 1H), 1.91 a (m, 2H), 2,39 (s, 3H), 2.40 a (s, 3H), of 2.46 (s, 3H), of 2.64 (m, 1H), 3,40 (m, 2H), of 4.54 (s, 2H), and 4.68 (DD, 2H), 7,17-7,30 (m, 5H), to $ 7.91 (d, 2H).

Example 9

Synthesis of 4-iodomethyl-2-(3-were)-5-methoxazole

6.0 g of 4-chloromethyl-2-(4-were)-5-methoxazole dissolved in 120 ml of THF and mixed with 4.5 g (30 mmol) of NaI. Stirred for 5 h and left overnight. The separation of the solid phase and concentration of the filtrate in vacuo gives 10.2 g of the desired iodide; TPL 32°C;1H-NMR (CDCl3): δ=2,30 (s, 3H), 2.40 a (s, 3H), 4,34 (s, 2H), 7,24 (d, 1H), 7,32 (m, 1H), to 7.77 (d, 1H), 7,83 (d, 1H).

Example 10

Synthesis of (1R,3S)-methyl ester 2-{3-[2-(3-were)-5-methoxazole-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid

36,0 g (0,129 mol) of (1R,3S)-methyl ester 2-(3-hydroxycyclohexyl)-6-methylbenzoyl (see example 2), is dissolved in 430 ml of tBuOMe. Add 17,19 g (approximately 55%, 0.35 mol) of NaH and stirred for 30 minutes at 20-22°C. Add 55,1 g (0,166 mol) 4-iodomethyl-2-(3-were)-5-methoxazole (see example 9). After 6 hours of mixing and incubation for 2 days add in ohlord the Institute of 400 ml of water and separate the organic phase. After drying (Na2SO4) and concentration the crude product (75 g) was isolated by chromatography on silica gel (1.2 kg) (dichloromethane/acetone 19:1), yield: 49 g of (1R,3S)-methyl ester 2-{3-[2-(3-were)-5-methoxazole-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid;1H-NMR (CDCl3), δ=of 1.13 to 1.31 (m, 4H), of 1.80 (m, 1H), 1,97-2,1 (m, 2H), 2,34 (s, 3H), 2.40 a (s, 3H), 2,41 (s, 3H), 2,52 (m, 1H), 3.27 to (m, 1H), 3,37 (m, 1H), 3,90 (s, 3H), 4,48 (s, 2H), 4,59 (s, 2H), 7,12-7,33 (m, 4H), 7,78 (d, 1H), to 7.84 (s, 1H).

Example 11

Synthesis of (1R,3S)-2-{3-[2-(3-were)-5-methoxazole-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid

49,0 g (0.09 mol) of (1R,3S)-methyl ester 2-{3-[2-(3-were)-5-methoxazole-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid (see example 10) was dissolved in 500 ml of ethanol. Add 50 ml of 33%aqueous NaOH and heated to about 14 hours under reflux. The ethanol is distilled off in vacuum, the residue is dissolved in 500 ml of water and the solution three times washed with methyl tert-butyl ether using 150 ml of the Aqueous phase when cooled, acidified with concentrated hydrochloric acid (pH 1) and the oily product is extracted with ethyl ether acetic acid. A solution of ethyl ester acetic acid, dried and concentrated in vacuo. The residue is dissolved in 250 ml of DIPE warm. Upon cooling, crystallization starts. Upon completion of the crystallization, and when the loud vacuum at 60°C gain of 29.9 g of the desired carboxylic acid; TPL 109-111°C; purity>98% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 90:7:1+0.1% of TFA);1H-NMR (CDCl3), δ=1,14-of 1.36 (m, 4H), of 1.80 (m, 1H), 1.93 and (m, 2H), 2.40 a (s, HN), a 2.45 (s, 3H), of 2.64 (m, 1H), 3,40 (m, 2H), 4.53-in (s, 2H), and 4.68 (DD, 2H), 7,17-7,34 (m, 5H), 7,81 (d, 1H), a 7.85 (s, 1H).

The scheme IIa:

Example 12

The separation of the racemate CIS-3-[2-(3-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol

24,9 g of racemic CIS-3-[2-(3-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol (obtained by alkylation of CIS-1,3-cyclohexanediol 4-iodomethyl-2-(3-methoxyphenyl)-5-metlakatla) dissolved in 100 ml of vinyl acetate, mixed with 1.0 g of Chirazyme L-2, liofilizirovannogo, and stirred at 20-23°C. After about 30 minutes, the enzyme is filtered off and the solution concentrated in vacuo, the crude product is: 25,8, After chromatography on silica gel (n-heptane/ethyl ester acetic acid 10:1 to 0:1) gain of 13.7 g of (1S,3R)-3-[2-(3-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol and 11.3 g of (1R,3S)-acetyl compounds.

Example 13

Obtaining (1R,3S)-3-[2-(3-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol

11.2 g of (1R,3S)-acetate from example 12 are dissolved in about 100 ml of MeOH, mixed with 0.5 ml of NaOMe (30%) and stirred at 20-23°C. After 3.5 h, neutralized with concentrated acetic acid to give ethyl ester of acetic acid is acid, washed with NaHCO3, dried over Na2SO4and concentrated in vacuo. After filtration through silica gel (n-heptane/ethyl ester acetic acid 10:1-0:1) to obtain 8.8 g of (1R,3S)-3-[2-(3-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol purity 92% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 90:7:1+0.1% OF TFA).

Example 14

Synthesis of (1R,3S)-methyl ester 2-{3-[2-(3-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid

1.4 g (4.4 mmol) of (1R,3S)-3-[2-(3-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexanol (see example 13) is introduced into 15 ml of tBuOMe, at 24-27°C is mixed with 1.20 g (10,7 mmol) KOtBu and stirred for about 30 minutes. Cooled to 0-5°C, are added dropwise 1,89 g (about 94%, about 7.4 mmol) methyl ester 2-bromomethyl-6-methylbenzoic acid and first stirred for 30 minutes at 0-5°C. In the absence of additional cooling, the reaction mixture over 1.5 hours has a temperature of about 20°C. After stirring over night and add about 200 mg of KOtBu reaction was completed after one hour stirring at 22°C. Distillation of the solvent in vacuo, the distribution of the residue between water and tBuOMe and drying contains the product of the organic phase gives, after concentration in vacuum 1.6 g of (1R,3S)-methyl ester 2-{3-[2-(3-methoxyphenyl)-5-methoxazole-4-illcox the]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid in the form of a yellowish oil; 1H-NMR (CDCl3), δ=1,15-of 1.32 (m, 4H), of 1.81 (m, 1H), 2,00 (m, 1H), 2,07 (m, 1H), 2,34 (s, 3H), 2.40 a (s, 3H), of 2.51 (m, 1H), 3.27 to (m, 1H), 3,37 (m, 1H), a 3.87 (s, 3H), 3,90 (s, 3H), 4,48 (s, 2H), 4,60 (s, 2H), of 6.96 (m, 1H), 7,12-7,35 (m, 4H), 7,53-of 7.60 (m, 2H).

Example 15

Synthesis of (1S,3R)-methyl ester 2-{3-[2-(3-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid

On the basis of (1S,3R)-3-[2-(3-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol from example 12, it is possible analogously to example 14 by alkylation to obtain (1S,3R)-methyl ester 2-{3-[2-(3-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid; data1H-NMR identical with the data of example 14.

Example 16

The separation of the racemate CIS-3-[2-(4-forfinal)-oxazol-4-ylethoxy]-cyclohexane-1-ol, obtain (1S,3R)-3-[2-(4-forfinal)-oxazol-4-ylethoxy]-cyclohexane-1-ol

30 mg of racemic CIS-3-[2-(4-forfinal)-oxazol-4-ylethoxy]-cyclohexane-1-ol is administered in about 3 ml of dichloromethane, mixed with 60 mg of p-nitrophenylacetate and 10 mg Novozyme 435, stirred at 20-23°C. After 70 h, filtered immobilized enzyme. The analysis of the optical purity directly from the concentrated reaction mixture gives for (1S,3R)-3-[2-(4-forfinal)-oxazol-4-ylethoxy]-cyclohexane-1-ol purity>95% (HPLC on Chiralpak AD 250×4,6; 1 ml/min, acetone the Rila), and (1R,3S)-acetate purity 95% (HPLC on Chiralpak AD 250×4,6, 1 ml/min, acetonitrile). To highlight (1S,3R)-3-[2-(4-forfinal)-oxazol-4-ylethoxy]-cyclohexane-1-ol crude mixture allocate by chromatography on silica gel (EA/n-heptane); output 12 mg, purity 96%.

Example 17

Synthesis of (1S,3R)-methyl ester 2-{3-[2-(4-forfinal)-oxazol-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid

On the basis of (1S,3R)-3-[2-(4-forfinal)-oxazol-4-ylethoxy]-cyclohexane-1-ol from example 16 by alkylation with 2-bromomethyl-6-methylbenzoic acid methyl ester receive (1S,3R)-methyl ester 2-{3-[2-(4-forfinal)-oxazol-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid (see example 35).

Example 18

The separation of the racemate 3-[2-(4-were)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol

(and R4=p-Me-, R5=H and R3=Me)

16.3 g of racemic 3-(2-(4-were)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol are dissolved in 100 ml of vinyl acetate are mixed with 1.9 g of Chirazyme L-2, liofilizirovannogo, and stirred at 20-23°C. After about 30 minutes, the enzyme is filtered off and the solution concentrated in vacuo, the crude product is: 16,6, After chromatography on silica gel (n-heptane/ethyl ester acetic acid 10:1-0:1) to obtain 8.6 g of (1S,3R)-3-[2-(4-were)-5-methoxazole-4-ylethoxy]-qi is logican-1-ol and 6.8 g of (1R,3S)-acetate.

Example 19

Obtaining (1R,3S)-3-[2-(4-were)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol

6.8 g of (1R,3S)-acetyl compound from example 18 are dissolved in about 65 ml of MeOH, mixed with of 0.32 ml of NaOMe (30%) and stirred at 20-23°C. After 4 h, neutralized with acetic acid, concentrated in vacuo, introducing ethyl ester acetic acid, washed with NaHCO3, dried (Na2SO4) and concentrated in vacuo. After filtration through silica gel (n-heptane/ethyl ester acetic acid 10:1-0:1) to obtain 8.8 g of the desired (1R,3S)-3-[2-(4-were)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol with a purity of 95% (HPLC on Chiralpak AD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 90:7:1+0.1% OF TFA).

Example 20

The separation of the racemate CIS-3-[2-phenyl-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol

2.0 g of racemic CIS-3-[2-phenyl-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol dissolved in 50 ml of vinyl acetate are mixed with 0.1 g of Chirazyme L-2, liofilizirovannogo, and stirred at 20-23°C. After approximately 5 h, the enzyme is filtered off and the solution concentrated in vacuo. After chromatography on silica gel (n-heptane/ethyl ester acetic acid 2:1-1:2) to obtain 1.0 g of (1S,3R)-3-[2-phenyl-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol as a pale yellow solid phase and 0.96 g of acetylated (1R,3S)-connection in the form of best is to maintain oil.

Example 21

Obtaining (1R,3S)-3-[2-phenyl-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol

0.96 g of (1R,3S)-acetyl compound from example 20 is dissolved in approximately 5-10 ml of MeOH, mixed with 0.1 ml of NaOMe (30%) and stirred at 20-23°C. After 3 h, neutralized with acetic acid and concentrated in vacuo, introducing ethyl ester acetic acid, washed with saturated NaHCO3, dried (MgSO4) and concentrated in vacuo. After filtration through silica gel (n-heptane/ethyl ester acetic acid 10:1 to 0:1) obtain 0.84 g of the desired (1R,3S)-3-[2-phenyl-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol with a purity of 95% (HPLC on Chiralpak AD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 22

The separation of the racemate CIS-3-[2-(4-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol

2.0 g of racemic CIS-3-[2-(4-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol dissolved in 50 ml of vinyl acetate are mixed with 0.1 g of Chirazyme L-2, liofilizirovannogo, and stirred at 20-23°C. After approximately 5 h, the enzyme is filtered off and the solution concentrated in vacuo. After chromatography on silica gel (n-heptane/ethyl ester acetic acid 2:1-1:2) gain of 1.16 g of (1S,3R)-3-[2-(4-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol and 0.79 g of (1R,3S)-acetate.

Example 23

Obtaining (1R,3S)-3-[2-(4-m is toxigenic)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol

0,79 g of the acetate of example 22 was dissolved in approximately 5-10 ml of MeOH, mixed with 0.1 ml of NaOMe (30%) and stirred at 20-23°C. After 3 h, neutralized with diluted acetic acid and concentrated in vacuo, introducing ethyl ester acetic acid, washed with saturated NaHCO3, dried (MgSO4) and concentrated in vacuo. After filtration through silica gel (n-heptane/ethyl ester acetic acid 10:1-0:1) to obtain 0.84 g of (1R,3S)-3-[2-(4-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol as a yellow oil with a purity of 92% (HPLC on Chiralpak AD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 90:7:1+0.1% OF TFA).

Example 24

The separation of the racemate CIS-3-[2-(4-forfinal)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol

1.70 g of racemic CIS-3-[2-(4-forfinal)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol dissolved in 50 ml of vinyl acetate are mixed with 0.1 g of Chirazyme L-2, liofilizirovannogo, and stirred at 20-23°C. After about 1.5 h, the enzyme is filtered off and the solution concentrated in vacuo. After chromatography on silica gel (n-heptane/ethyl ester acetic acid 5:1-1:1) to obtain 1.0 g of (1S,3R)-3-[2-(4-forfinal)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol and 0.75 g of (1R,3S)-acetate.

Example 25

Obtaining (1R,3S)-3-[2-(4-forfinal)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol

0.75 g of the acetate of example 24 is dissolved in about 30 ml of MeOH, mixed with 0.2 ml NaOMe (30%) and stirred at 20-23°C. After 1 h, neutralized with diluted acetic acid and concentrated in vacuo, introducing ethyl ester acetic acid, washed with saturated NaHCO3, dried (MgSO4) and concentrated in vacuo, output: 0,59 g of (1R,3S)-3-[2-(4-forfinal)-5-methoxazole-4-ylethoxy]-cyclohexane-1-ol as a white solid phase with a purity of 94% (HPLC on Chiralpak OD/19 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 110:2:1+0,05% TFA).

The scheme IIb:

Example 26

Stereoselective hydrolysis of 3-[2-(4-forfinal)-oxazol-4-ylethoxy]-cyclohexylamino ester acetic acid, (obtaining (1R,3S)-3-[2-(4-forfinal)-oxazol-4-ylethoxy]-cyclohexane-1-ol

Approximately 10 mg of racemic 3-[2-(4-forfinal)-oxazol-4-ylethoxy]-cyclohexylamino ether acetic acid (obtained by the reaction of 3-benzyloxycarbonyloxy-1-ol with acetic anhydride, similar to the synthesis of mono(3-benzyloxycarbonylamino)-ester of glutaric acid, see example 39) was injected in 2 ml of phosphate buffer (0,1M, pH 7.0) and 2 ml of DME and at 20-23°C and stirred for about 20-24 hours with approximately 5 mg of Chirazyme L-2, liofilizirovannogo. The reaction mixture is extracted with dichloromethane. The organic phase is mixed with toluene and evaporated in vacuum. Determination of optical purity gives for (1R,3S)-3-[2-(4-CFT is henyl)-oxazol-4-ylethoxy]-cyclohexane-1-ol purity of 99.4% (HPLC on Chiralpak AD 250×4,6; 1 ml/min, acetonitrile) and (1S,3R)-acetate purity 98,9% (HPLC on Chiralcel OD 250×4,6, 1 ml/min, heptane/EtOH/CH3CN 110:5:1+0.1% OF TFA).

The scheme IIIA

Example 27

Synthesis of racemic CIS-3-benzyloxycarbonyloxy-1-ol

150,0 g (1,29 mol) of CIS-1,3-cyclohexanediol dissolved in 1.5 liters of NMP, mixed with 111,6 g (0,99 mol) of potassium tert-butylate (KOtBu) and stirred at 25-27°C. After about 30 minutes, cooled to 0°C and added dropwise to 78.1 g (0.46 mol) of benzylbromide. Stirred for 15 min at about 0°C and then added to 1.5 l of water. After triple washing 700 ml of n-heptane, and the discharge of a mixture of n-heptane, the aqueous solution extracted four times MTBE using 500 ml. Concentrated MTBE phase washed twice with water, using 1 l), dried (Na2SO4) and then evaporated under reduced pressure. Get to 48.0 g of the desired compound in the form of a clear yellow oil;1H-NMR (CDCl3), δ=1,29 (m, 1H), 1,43-of 1.93 (m, 6H), to 2.06 (m, 1H), 2,55 (W), 1H), of 3.56 (m, 1H), 3,74 (width, 1H), 4,55 (DD, 2H), 7,25 was 7.36 (m, 5H).

Example 28

The separation of the racemate 3-benzyloxycarbonyloxy-1-ol

of 20.3 g of CIS-3-benzyloxycarbonyloxy-1-ol are dissolved in 35 ml of vinyl acetate and 125 ml of methylene chloride, mixed with 2.0 g of Novozym 435 and stirred for 6 h at 20-23°C. After maturation during the night the enzyme is filtered off. Select a sample and issue the mandate in a vacuum. The enantiomeric residue (1S,3R)-3-benzyloxycarbonyloxy-1-ol is>99% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA), the enantiomeric residue (1R,3S)-acetate is 78% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 100:1:0,5).

Example 29

The separation of the racemate 3-benzyloxycarbonyloxy-1-ol

100.0 g of CIS-3-benzyloxycarbonyloxy-1-ol are dissolved in 170 ml of vinyl acetate and 630 ml of methylene chloride, mixed with 5.0 g of Novozym 435 and stirred for 26 h at 20-23°C. the Enzyme is filtered off, select the sample and evaporated in vacuum. The enantiomeric residue (1S,3R)-3-benzyloxycarbonyloxy-1-ol is >99% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA), the enantiomeric residue (1R,3S)-acetate is 90% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 100:1:0,5).

Example 30

The allocation of (1S,3R)-3-benzyloxycarbonyloxy-1-ol, separation of a mixture of acetate and alcohol with pyridine-SO3

to 1.9 g of a crude mixture of acetate/alcohol from stereoselective enzymatic acetylation of 3-benzyloxycarbonyloxy-1-ol (from example 29) in 10 ml of pyridine and 2 ml of DMF was stirred at 20-22°C with 2 g of pyridine-SO3. After 4 h the transformation Benzylalcohol in the pyridine salt of the ester of sulfuric acid is almost quantitative. The reaction mixture is diluted with 40 ml of water and twice extracted with the help of the approximately 20 ml of MTBE. MTBE phase quantitatively contain unmodified (1R,3S)-acetate. The remaining, not containing acetate aqueous phase is evaporated in vacuum. The residue is mixed with MTBE, the product of sulfation becomes solid; yield: 2,7,

2.7 g pyridine salt of the ester of sulfuric acid and (1S,3R)-benzylchloride-1-ol is stirred for 2 h at 55°C in 45 ml of THF, 4 ml of water and 1 ml of concentrated sulfuric acid. Diluted with 40 ml of water, add about 10 ml of MTBE, the phases are separated and the aqueous phase is once extracted with MTBE. Purified organic phase is dried (Na2SO4) and evaporated; output: 640 mg of light yellow oil. Data of NMR are identical to those described in example 16; check the optical purity gives purity >99%.

Example 31

The allocation of (1S,3R)-3-benzyloxycarbonyloxy-1-ol, separation of a mixture of acetate and alcohol by extraction

10 g crude mixture acetate/alcohol from example 29 is introduced into 90 ml of methanol and about 70 ml of water and washed three times with n-heptane, using about 50 ml of Purified heptane phase (containing mainly acetate) is extracted with 50 ml methanol/water 1:1. Purified water phase is again washed with n-heptane. After concentration of the aqueous phase obtain 3.6 g of the desired (1S,3R)-3-benzyloxycarbonyloxy-1-ol, the concentration of purified heptane phase gives 5.5 g of (1R,3S)-acetate.

Example 32

Synthesis of 4-iodomethyl-2-(4-Fortini is)-oxazole

4.0 g (of 18.9 mmol) 4-chloromethyl-2-(4-forfinal)-oxazole dissolved in 80 ml THF and mixed with 3,18 g (of 21.2 mmol) of NaI . Stirred for 3 h at 20-23°C and about 12 h at 50°C, sucked off the salt and the filtrate was concentrated in vacuo, output: 6,1, the Product crystallized; TPL 100-102°C;1H-NMR (CDCl3): δ=4,34 (s, 2H), 6,97 (DD, 1H), 7,14 (m, 2H), 7,68 (s, 1H), 8,03 (m, 2H).

Example 33

Synthesis of (1S,3R)-4-(3-benzyloxycarbonyl-1-oxymethyl)-2-(4-vermeil)-oxazole

2.0 g (9.7 mmol) of (1S,3R)-3-benzyloxycarbonyloxy-1-ol are dissolved in 35 ml of tBuOMe. Add 1.3 g (55%, for 43.7 mmol) of NaH and stirred for 60 minutes at 22°C. Add 3,9 g (12.9 mmol) of 4-iodomethyl-2-(4-vermeil)-oxazole (example 32) and stirred for about 3 hours at 22-23°C. After incubation over night stirred for 11 h at 22-23°C. Upon cooling, add water (about 30 ml) and separate the organic phase. Drying (Na2SO4), concentration (crude yield: 4.5 g) and chromatography on silica gel (dichloromethane/acetone 19:1) to give 2.4 g of the desired, having the CIS-configuration, optically pure, dialkylamino derived 1,3-cyclohexanediol in the form of a white solid phase; TPL 61-62°C;1H-NMR (CDCl3), δ=1,11-of 1.39 (m, 4H), equal to 1.82 (m, 1H), 2,07 (m, 2H), by 2.55 (m, 1H), 3,38 (m, 2H), 4,55 (s, 2H), 4,57 (s, 2H), 7,13 (m, 2H), 7,25-to 7.35 (m, 5H), 7,63 (s, 1H), 8,02 (m, 2H).

Example 34

Synthesis of (1R,3S)-3-[2-(4-FPO is phenyl)-oxazol-4-ylethoxy]-cyclohexanol by hydrogenation

2.4 g of (1S,3R)-4-(3-benzyloxycarbonyl-1-oxymethyl)-2-(4-vermeil)-oxazole dissolved in about 40 ml of methanol, mixed with Pd/C, taken at the tip of a spatula (10%, 50% water), at 20-23°C and normal pressure and hydronaut approximately 8 hours. The filtering off the catalyst and concentrating the remaining solution gives 1.8 g of the desired, having the CIS-configuration, monoalkylamines derived 1,3-cyclohexanediol in the form of oil, which crystallized upon addition of DIPE; yield 1.6 g; TPL 81-82°C;1H-NMR (CDCl3), δ=1,25-2,14 (m, 9H), 3,63 (m, 1H, in), 3.75 (m, 1H), 4,55 (DD, 2H), 7,13 (m, 2H), to 7.64 (s, 1H), 8,02 (m, 2H); MS (DCl): 292,3 (100%).

Example 35

Synthesis of (1R,3S)-methyl ester 2-{3-[2-(4-forfinal)-oxazol-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid

0.8 g (a 2.75 mmol) of (1R,3S)-3-[2-(4-forfinal)-oxazol-4-ylethoxy]-cyclohexanol (example 34) was injected in 10 ml of tBuOMe, mixed with 0,78 g (6.95 mmol) of KOtBu and stirred for about 30 minutes at 22-27°C. is Cooled to 0-5°C, are added dropwise 1.24 g (about 94%, about 4.8 mmol) of methyl ester of 2-bromomethyl-6-methylbenzoic acid, is stirred first for 2 hours at 3°C and one hour at 20°C. and Left to mix overnight at 18-21°C, and then the solvent is distilled off. The residue is partitioned between water and tBuOMe. The organic phase is dried (Na2SO4and the end of tryout in vacuum; yield: 1.04 g of (1R,3S)-methyl ester 2-{3-[2-(4-forfinal)-oxazol-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid in the form of a yellowish oil;1H-NMR (CDCl3), δ=1,15-of 1.32 (m, 4H), equal to 1.82 (m, 1H), 1,98-2,1 (m, 2H), 2,34 (s, 3H), of 2.50 (m, 1H), 3.27 to (m, 1H), 3,39 (m, 1H), 3,90 (s, 3H), of 4.54 (s, 2H), 4,60 (s, 2H), 7,11-7,30 (m, 5H), 7,63 (s, 1H), 8,02 (m, 2H).

Example 36

Synthesis of (1R,3S)-4-(3-benzyloxycarbonyl-1-oxymethyl)-2-(3-methoxyphenyl)-5-methoxazole

4.6 g (of 22.3 mmol) of (1R,3S)-3-benzyloxycarbonyloxy-1-ol are dissolved in 70 ml of chlorobenzene. Added 6.6 g (58.8 mmol) KOtBu, stirred for 30 minutes at 22°C and then added 10.3 g (31,3 mmol) 4-iodomethyl-2-(3-methoxyphenyl)-5-methoxazole. The temperature was raised to 35°C. the Reaction mixture was slightly cooled and stirred for further 2 hours at 22-23°C. After the distillation of chlorobenzene in a vacuum the residue is partitioned between tBuOMe and water. The organic phase is dried (Na2SO4) and concentrated in vacuo; yield of dry product: 10,6, the Substance used without further purification in the next reaction (hydrogenation, see example 37).

Example 37

Synthesis of (1R,3S)-(3-[2-(3-methoxyphenyl)-oxazol-4-ylethoxy]-cyclohexanol by hydrogenation

of 10.5 g of (1R,3S)-4-(3-benzyloxycarbonyl-1-oxymethyl)-2-(3-methoxyphenyl)-oxazole dissolved in about 120 ml of methanol, mixed with 2 g of Pd/C (10%with 50% water) and hiderou is at 20-23°C and normal pressure during the night. The filtering off the catalyst and concentrating the remaining solution, the distribution between MTB-ether and water and drying of the organic phase gives 6.4 g of the desired, having the CIS-configuration monoalkylamines derived 1,3-cyclohexanediol in the form of a yellow oil. 1 g of the substance divided by chromatography on silica gel (ethyl ester of acetic acid); obtain 0.8 g of colorless oil;1H-NMR (CDCl3), δ=1,25-1,90 (m, 7H), 2,12 (m, 2H), 2,41 (s, 3H), 3,61 (m, 1H, in), 3.75 (m, 1H), a 3.87 (s, 3H), 4,48 (DD, 2H), of 6.96 (d, 1H), 7,33 (t, 1H), 7,53 (s, 1H), 7,58 (d, 1H); MS(ES+): 318,27 (83%), 243,18 (100%).

Example 38

Synthesis of (1R,3S)-methyl ester 2-{3-[2-(3-methoxyphenyl)-5 methoxazole-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid

136 mg (0.4 mmol) of (1R,3S)-(3-[2-(3-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexanol (example 37, hydrogenation) was dissolved in 1 ml of chlorobenzene, at 24-27°C is mixed with 120 mg (1.07 mmol) of KOtBu and stirred for about 30 minutes. Cooled to 0-5°C, are added dropwise 189 mg (about 94%, about 0.78 mmol) methyl ester 2-bromomethyl-6-methylbenzoic acid and stirred first for 30 minutes at 0-5°C. In the absence of additional cooling for 1.5 hours, the temperature of the reaction mixture is about 20°C. After incubation over night and add about 20 mg of KOtBu the reaction is complete after addition is about stirring at 22°C for 1 hour. Distillation of chlorobenzene in a vacuum, the distribution of the residue between water and tBuOMe and drying of the organic phase to give after concentration in vacuum of 160 mg of (1R,3S)-methyl ester 2-{3-[2-(3-methoxyphenyl)-5-methoxazole-4-ylethoxy]-cyclohexyl-1-oxymethyl}-6-methylbenzoic acid in the form of a yellowish oil;1H-NMR (CDCl3), δ=1,15-of 1.32 (m, 4H), of 1.81 (m, 1H), 2,00 (m, 1H), 2.06 to (m, 1H), 2,34 (s, 3H), 2.40 a (s, 3H), of 2.51 (m, 1H), 3.27 to (m, 1H), 3,36 (m, 1H), a 3.87 (s, 3H), 3,90 (m, 3H), 4,48 (s, 2H), 4,60 (s, 2H), of 6.96 (m, 1H), 7,12-7,35 (m, 4H), 7,53-of 7.60 (m, 2H).

The scheme IIIb

Example 39

Synthesis of mono(3-benzyloxycarbonylamino)-ester of glutaric acid

3.0 g of 3-benzyloxycarbonyloxy-1-ol, 2.15 g of glutaric acid anhydride and 3.03 g of triethylamine is stirred in 25 ml of methylene chloride at 21-23°C. After complete conversion of water is added, extracted with ether and dried over MgSO4. After concentration in vacuo obtain 4.3 g of the desired compound;1H-NMR (CDCl3), δ=1,20 of 1.28 (m, 4H), equal to 1.82 (m, 1H), 1,90-of 1.97 (m, 3H), of 2.05 (m, 1H), 2,32-to 2.42 (m, 5H), 3,39 (m, 1H), 4,55 (DD, 2H), 4,69 (m, 1H), 7,25-7,33 (m, 5H), 8,7 (width, 1H).

Example 40

Stereoselective hydrolysis of mono-(3-benzyloxy-cyclohexylamino)-ester of glutaric acid, obtaining (1R,3S)-3-benzyloxycarbonyloxy-1-ol

20 mg of racemic mono-(3-benzyloxycarbonylamino)-ester of glutaric acid (from example 39) distribute the 2 ml phosphate buffer, pH 8, and 3-5 drops DME, mixed with 3-5 mg of Novozym 435 and stirred at 21-23°C. Upon reaching approximately 50%conversion, the reaction solution is partitioned between saturated aqueous NaHCO3and ethyl ester of acetic acid. Phase ethyl ester acetic acid, dried and concentrated, to yield: 5 mg (1R,3S)-3-benzyloxycarbonyloxy-1-ol, enantiomeric residue is >95% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 41

Synthesis of (1R,3S)-4-(3-benzyloxycarbonyl-1-oxymethyl)-2-(4-forfinal)-oxazole

On the basis of (1R,3S)-3-benzyloxycarbonyloxy-1-ol (see example 40) by alkylation with 4-iodomethyl-2-(4-forfinal)-oxazole (see example 32) receive (1R,3S)-4-(3-benzyloxycarbonyl-1-oxymethyl)-2-(4-forfinal)-oxazole (see example 33).

Other examples of alkylation of CIS-1,3-cyclohexanediol

Example 42

Synthesis of racemic methyl ester of CIS-2-(3-hydroxycyclohexyl)-6-methylbenzoic acid

5 g (42.8 mmol) of CIS-1,3-cyclohexanediol dissolved in 50 ml of dimethoxyethane (DME), mixed with 3,36 g (30 mmol) of potassium tert-butylate (KOtBu) at 20-23°C and stirred. After about 30 minutes, cooled to 5°C and added dropwise 3.7 g (about 50%) methyl ester 2-bromomethyl-6-methylbenzoic acid, which can be obtained is, for example, by methanolysis of the acid bromide (bromide 2-bromomethyl-6-methylbenzoic acid) or bromirovanii methyl ester of 2,6-dimethylbenzoic acid. Stirred for 1 h at 5-10°C and then overnight at 20-23°C. Add water and methyl tert-butyl ether (MTBE), intensively stirred, the phases are separated, the aqueous phase is again washed with MTBE, and the purified organic phase was concentrated in vacuo. The remainder of the produce by chromatography on silica gel (ethyl ester of acetic acid/n-heptane 1:1). Receive 600 mg of the desired compound as a yellowish oil,1H-NMR (CDCl3), δ=1,27 (m, 1H), 1,45 (m, 1H), 1.55V (m, 1H), 1,74 (m, 1H)and 1.83 (m, 1H), 2.05 is (m, 1H), 2,34 (s, 3H), 3,47 (m, 1H), and 3.72 (m, 1H), 3,91 (s, 3H), 4,58 (DD, 2H), 7,15 (d, 1H), 7,20 (m, 2H), 7,27 (m, 1H).

Example 43

Synthesis of racemic methyl ester of CIS-2-(3-hydroxycyclohexyl)-6-methylbenzoic acid

10.0 g (86 mmol) of CIS-1,3-cyclohexanediol introduced into 150 ml of methyl tert-butyl ether (MTBE), mixed with 6,72 g (to 59.9 mmol) of tert-butyl potassium (KOtBu) at about 20°C and stirred. After about 30 minutes, the suspension is cooled to 5°C and added dropwise to 7.4 g (about 50%) methyl ester 2-bromomethyl-6-methylbenzoic acid, which can be obtained, for example, by methanolysis of the acid bromide (bromide 2-bromomethyl-6-methylbenzoic acid) or bromirovanii methyl ester of 2,6-dimethylbenzoic the Oh of the acid. Stirred for 1 h at 0-5°C, heated up to 20-23°C and left to mix overnight. Add water, intensively stirred, the phases are separated, the organic phase is again washed with water and then the organic phase was concentrated in vacuo. The residue (4.6 g) was isolated by chromatography on silica gel (ethyl ester of acetic acid/n-heptane 1:1). Obtain 1.2 g of the desired compound as a yellowish oil,1H-NMR (CDCl3), δ=1,27 (m, 1H), 1,45 (m, 1H), 1.55V (m, 1H), 1,74 (m, 1H), equal to 1.82 (m, 1H), 2.05 is (m, 1H), 2,34 (s, 3H), 3.46 in (m, 1H), and 3.72 (m, 1H), 3,91 (s, 3H), 4,58 (DD, 2H), 7,15 (d, 1H), 7,20 (m, 2H), 7,27 (m, 1H).

Example 44

Synthesis of racemic methyl ester of CIS-2-(3-hydroxycyclohexyl)-6-methylbenzoic acid

5 g (42.8 mmol) of CIS-1,3-cyclohexanediol dissolved in 40 ml of chlorobenzene and 10 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, dimethylpropyleneurea), mixed with 3,36 g (30 mmol) of tert-butyl potassium (KOtBu) at 20-23°C and stirred. After 10-15 minutes, cooled to 15-20°C and added dropwise 3.7 g (about 50%) methyl ester 2-bromomethyl-6-methylbenzoic acid. Stirred for 1.5 h at 20°C and add water. The organic phase is isolated and concentrated under reduced pressure. The residue is introduced into a mixture of NMP/water and to remove impurities washed twice with n-heptane. Then to highlight the product twice extracted with MTBE. Peeled MTBE-f the s washed with water, dried (Na2SO4) and concentrated in vacuo. The residue (1.2 g) was isolated by chromatography on silica gel (ethyl ester of acetic acid/n-heptane 1:1). Obtain 580 g of the desired compound as a yellowish oil,1H-NMR (CDCl3), δ=1,27 (m, 1H), 1,45 (m, 1H), 1.55V (m, 1H), 1,74 (m, 1H)and 1.83 (m, 1H), 2.05 is (m, 1H), 2,34 (s, 3H), 3,47 (m, 1H), and 3.72 (m, 1H), 3,91 (s, 3H), 4,58 (DD, 2H), 7,15 (d, 1H), 7,20 (m, 2H), 7,27 (m, 1H).

Further examples of racemate cleavage by stereoselective enzymatic formation of ester (EB)

Example 45

The separation of racemates methyl ester CIS-2-(3-hydroxycyclohexyl)-6-methylbenzoic acid

730 mg of racemic methyl ester of CIS-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid are dissolved in 5 ml of methylene chloride and 2 ml of vinyl acetate, heated to 38°C and mixed with 100 mg of Novozym 435.

After about 5 hours the reaction is complete by filtering off the enzyme and by HPLC to determine the optical purity of the formed acetate and unreacted alcohol (HPLCacetate: Chiralcel OD 250×4,6, 1 ml/min, heptane/EtOH/CH3CN 100:1:0,5; HPLCalcohol: Chiralpak AD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA). Determination of optical purity gives for (3S,1R)-methyl ester 2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid purity of 98% and (3R,1S)-acetate purity of 86%.

<> Example 46

The separation of racemates methyl ester CIS-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid

20 mg of racemic methyl ester of CIS-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid dissolved in 2 ml of chlorobenzene and 1 ml of vinyl acetate, mixed at 22-25°C with 8 mg of Chirazyme L-2, liofilizirovannogo (Roche), and mix. After about 6 hours the reaction is completed by filtering the enzyme and by HPLC to determine the optical purity of the formed acetate and unreacted alcohol (HPLCacetate: Chiralcel OD 250×4,6, 1 ml/min, heptane/EtOH/CH3CN 100:1:0,5; HPLCalcoholChiralpak AD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA): (3S,1R)-methyl ester 2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid: purity 84%, (3R,1S)-acetate: purity 95%.

Example 47

The separation of racemates methyl ester CIS-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid

1.0 g of methyl ester of CIS-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid dissolved in 10 ml of 1,2-dichloroethane and 2 ml of finalproject, mixed with 25 mg of Chirazyme L-2, liofilizirovannogo (Roche) and stirred for 40 h at 21-24°C., Filtering off the enzyme, concentration of the filtrate in vacuo and chromatography of the residue on silica gel (ethyl ester of acetic acid/n-is eptan 1:1) gives 0,49 g (3R,1S)-propionate with a purity of 92% (HPLC on Chiralcel OD 250×4,6, 1 ml/min, heptane/EtOH/CH3CN 100:1:0.5),and1H-NMR (CDCl3), δ=1,13 (t, 3H), 1,15-of 1.36 (m, 4H), to 1.79 (m, 1H), 1.91 a(m, 1H), 2,01(m, 1H), 2, 30 (quintet, 2H), 2,34 (s, 3H), 2,35 (m, 1H), 3,34 (m, 1H), 3,90 (s, 3H), 4,58 (DD, 2H), 4,67 (m, 1H), 7,14 (d, 1H), 7,19 (d, 1H) 7,26 (m, 1H), and 0.3 g of unreacted (3S,1R)-methyl ester 2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid with a purity of 98% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA),1H-NMR (CDCl3), δ=1,27 (m, 1H), 1,45 (m, 1H), 1.55V (m, 1H), 1,74 (m, 1H)and 1.83 (m, 1H), 2.05 is (m, 1H), 2,34 (s, 3H), 3,47 (m, 1H), and 3.72 (m, 1H), 3,91 (s, 3H), 4,58 (DD, 2H), 7,15 (d, 1H), 7,20 (m, 2H), 7,27 (m, 1H).

Example 48

The separation of racemates methyl ester CIS-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid

10 mg of racemic methyl ester of CIS-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid dissolved in 1 ml of vinyl acetate are mixed with about 4-6 mg lipase TL (Pseud. stutzeri, Meito Sangyo) and stirred at 22-25°C. after reaching the degree of conversion of>50% reaction complete by filtering off the enzyme and determine the optical purity of the unreacted (3S,1R)-methyl ester 2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid: purity >98% (HPLC on Chiralpak AD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 49

The separation of racemates methyl ester CIS-2-(3-hydroxycyclohexyl)-6-methylben oinoi acid

of 3.9 g of racemic methyl ester of CIS-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid are dissolved in 25 ml of methylene chloride and 10 ml of vinyl acetate, heated to 45°C and mixed with 250 mg of Novozym 435.

Upon reaching the degree of conversion of about 45% complete reaction by filtering off the enzyme and the reaction mixture is concentrated. Chromatography of the residue on silica gel (ethyl ester of acetic acid/n-heptane 1:1) to give 1.9 g (3R,1S)-acetate (purity>95%, HPLC on Chiralcel OD 250×4,6, 1 ml/min, heptane/EtOH/CH3CN 100:1:0.5) and 1.9 grams of unreacted (3S,1R)-methyl ester 2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid (purity 82%, HPLC on Chiralpak AD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 50

The separation of racemates methyl ester CIS-2-(3-hydroxycyclohexyl)-6-methylbenzoic acid

20 mg of racemic methyl ester of CIS-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid dissolved in 2 ml of toluene and 1 ml of vinyl acetate, at 20-23°C is mixed with 6-8 mg of Chirazyme L-2, liofilizirovannogo (Roche), and mix. Upon reaching the degree of conversion of about 45% complete reaction by filtering off the enzyme and determine the optical purity of the educated (3R,1S)-acetate: purity 94% (HPLC on Chiralcel OD 250×4,6, 1 ml/min, heptane/tOH/CH 3CN 100:1:0,5).

Example 51

The separation of racemates methyl ester CIS-2-(3-hydroxycyclohexyl)-6-methylbenzoic acid

10 mg of racemic methyl ester of CIS-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid dissolved in 1 ml of vinyl acetate are mixed with about 4-6 mg of lipase QL (Alcaligenes spec., Meito Sangyo) and stirred at 20-23°C. after reaching the degree of conversion of about 52% complete reaction by filtering off the enzyme and determine the optical purity of the formed acetate and unreacted alcohol, purity of acetate: 91% (HPLC on Chiralcel OD 250×4,6, 1 ml/min, heptane/EtOH/CH3CN 100:1:0.5), and the purity of (3S,1R)-methyl ester 2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid: >98% (HPLC on Chiralpak AD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 52

The separation of racemates methyl ester CIS-2-(3-hydroxycyclohexyl)-6-methylbenzoic acid

10 mg of racemic methyl ester of CIS-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid dissolved in 1 ml of vinyl acetate are mixed with about 4-6 mg lipase SL (Pseud. cepacia, Meito Sangyo) and stirred at 20-23°C. after reaching the degree of conversion of about 52% complete reaction by filtering off the enzyme and determine the optical purity clicks the series acetate and unreacted alcohol; the purity of acetate: 90% (HPLC on Chiralcel OD 250×4,6, 1 ml/min, heptane/EtOH/CH3CN 100:1:0.5), and the purity of (3S,1R)-methyl ester 2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid: >95% (HPLC on Chiralpak AD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 53

The separation of racemates methyl ester CIS-2-(3-hydroxycyclohexyl)-6-methylbenzoic acid

39 g of methyl ester of CIS-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid are dissolved in 250 ml of methylene chloride and 50 ml of vinyl acetate, heated to 45°C and mixed with 1.0 g of Novozym 435. After 25 h, add 0.5 g of Novozym 435. After 6.5 h, the enzyme is filtered off and the reaction mixture is concentrated. Chromatography of the residue on 630 g of silica gel (ethyl ester of acetic acid/n-heptane 1:1) gives of 18.2 g of (3S,1R)-methyl ester 2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid (purity>98%, HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA),1H-NMR (CDCl3), δ=1,27 (m, 1H), 1,45 (m, 1H), 1.55V (m, 1H), 1,74 (m, 1H)and 1.83 (m, 1H), 2.05 is (m, 1H), 2,34 (s, 3H), 3,47 (m, 1H), and 3.72 (m, 1H), 3,91 (s, 3H), 4,58 (DD, 2H), 7,15 (d, 1H), 7,20 (m, 2H), 7,27 (m, 1H).

Example 54

The separation of racemates methyl ester CIS-2-(3-hydroxycyclohexyl)-6-methylbenzoic acid

20 mg of racemic methyl ester of CIS-2-(3-hydroxycyclohexyl-1 oximate is)-6-methylbenzoic acid are dissolved in 2 ml of THF and 1 ml of vinyl acetate, at 20-23°C is mixed with 6-8 mg of Chirazyme L-2, liofilizirovannogo (Roche), and mix. After about 6 hours the reaction is complete by filtering off the enzyme and by HPLC to determine the optical purity of the formed acetate and unreacted alcohol (HPLCacetate: Chiralcel OD 250×4,6, 1 ml/min, heptane/EtOH/CH3CN 100:1:0,5; HPLCalcohol: Chiralpak AD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA): purity of (3S,1R)-methyl ester 2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid: 89%, purity (3R,1S)-acetate: 95%.

Example 55

The separation of racemates methyl ester CIS-2-(3-hydroxycyclohexyl)-6-methylbenzoic acid

Approximately 15 mg of racemic methyl ester of CIS-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid are dissolved in 2 ml of tert-butanol and 1 ml of vinyl acetate, at 20-23°C is mixed with approximately 6 mg of Novozym 435 and stirred. After about 24 h the reaction is complete by filtering off the enzyme and by HPLC to determine the optical purity of the formed acetate and unreacted alcohol; (3R,1S)-acetate: the purity of 91% (HPLC: Chiralcel OD 250×4,6, 1 ml/min, heptane/EtOH/CH3CN 100:1:0.5), and (3S,1R)-methyl ester 2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid - purity 96% (HPLC: Chiralpak AD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 56

The separation of racemates m is delovogo ether of CIS-2-(3-hydroxycyclohexyl)-6-methylbenzoic acid

10 mg of racemic methyl ester of CIS-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid dissolved in 1 ml of vinyl acetate are mixed with about 4-6 mg lipase TL (Pseud. stutzeri, Meito Sangyo) and stirred at 20-23°C. after reaching the degree of conversion of>50% reaction complete by filtering off the enzyme and determine the optical purity of the unreacted alcohol: (3S,1R)-methyl ester 2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoic acid - purity>98% (HPLC on Chiralpak AD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 57

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

35-40 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol are dissolved in 0.5-1 ml of vinyl acetate and 2-3 ml of methylene chloride, mixed with about 8-10 mg of Novozym 435 and stirred at 22-25°C. After 4 days the reaction is complete by filtering off the enzyme. Optical purity of the alcohol (1S,3R)-3-benzyloxycarbonyloxy-1-ol is>98% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA), purity (1R,3S)-acetate is 82% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 100:1:0,5).

Example 58

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

10 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol is dissolved in 1 lineazeta and 3 ml of THF, mixed with approximately 5 mg of lipase L-10 and stirred at 22-25°C. after reaching the degree of conversion ≥50% response finish by filtering off the enzyme. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is ≥90% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 59

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

10 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol is dissolved in 1 ml of vinyl acetate and 3 ml of chlorobenzene are mixed with 10 mg of Novozym 435 and stirred at 22-25°C. After 4 hours the reaction is complete by filtering off the enzyme. Optical purity of the alcohol (1S,3R)-3-benzyloxyacetophenone is 68% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA), the enantiomeric purity of acetate is 95% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 100:1:0,5).

Example 60

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

10 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol is dissolved in 1 ml of vinyl acetate and 3 ml of cyclohexane, mixed with approximately 5 mg of lipase QL and stirred at 22-25°C. After 24 hours the reaction is complete by filtering off the enzyme. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is 94% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:,5+0,1% TFA).

Example 61

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

10 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol is dissolved in 1 ml of vinyl acetate and 3 ml of toluene, mixed with 10 mg of Novozym 435 and stirred at 22-25°C. After 4 hours the reaction is complete by filtering off the enzyme. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is 70% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA), purity (1R,3S)-acetate equal to 95% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 100:1:0,5).

Example 62

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

10 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol is dissolved in 1 ml of vinyl acetate and 3 ml of cyclohexane, mixed with about 10 mg of Novozym 435 and stirred at 22-25°C. After about 4 hours the reaction is complete by filtering off the enzyme. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is 95% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA), purity (1R,3S)-acetate equal to 90% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 100:1:0,5).

Example 63

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

10 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol is dissolved in 1 ml of vinyl acetate and 3 ml cyclohex the Ana, mixed with approximately 5 mg of lipase L-10 and stirred at 22-25°C. After 24 hours the reaction is complete by filtering off the enzyme. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is>95% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 64

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

Approximately 10 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol is dissolved in 1 ml of vinyl acetate and 3 ml of THF, mixed with 10 mg of Novozym 435 and stirred at 22-25°C. After 4 hours the reaction is complete by filtering off the enzyme. Optical purity of (1S,3R)-3-benzyloxyacetophenone is 73% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA), purity (1R,3S)-acetate is equal to 94% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 100:1:0,5).

Example 65

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

10 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol is dissolved in 1 ml of vinyl acetate and 3 ml of chlorobenzene are mixed with approximately 5 mg of lipase L-10 and stirred at 22-25°C. after reaching the degree of conversion ≥50% response finish by filtering off the enzyme. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is ≥92% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 6

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

Approximately 10 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol is dissolved in 1 ml of vinyl acetate and 3 ml ethyl ester acetic acid, mixed with about 10 mg of Novozym 435 and stirred at 22-25°C. After 4 hours the reaction is complete by filtering off the enzyme. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is 77% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA), purity (1R,3S)-acetate is equal to 93% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 100:1:0,5).

Example 67

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

10 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol is dissolved in 1 ml of vinyl acetate and 3 ml of chlorobenzene are mixed with approximately 5 mg of lipase SL and stirred at 22-25°C. after reaching the degree of conversion ≥50% response finish by filtering off the enzyme. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is ≥87% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 68

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

10 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol is dissolved in 1 ml of vinyl acetate and 3 ml of diisopropyl ether, mixed with 10 mg of Novozym 35 and stirred at 22-25°C. After 4 hours the reaction is complete by filtering off the enzyme. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is 90% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA), purity (1R,3S)-acetate equal to 90% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 100:1:0,5).

Example 69

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

10 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol is dissolved in 1 ml of vinyl acetate and 3 ml of MTBE, mixed with 10 mg of Novozym 435 and stirred at 22-25°C. After 4 hours the reaction is complete by filtering off the enzyme. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is 93% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1 TFA), purity (1R,3S)-acetate equal to 89% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 100:1:0,5).

Example 70

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

10 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol is dissolved in 1 ml of vinyl acetate and 3 ml of cyclohexane, mixed with approximately 5 mg of lipase SL and stirred at 22-25°C. After 24 hours the reaction is complete by filtering off the enzyme. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is >90% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 71

Once the bookmark racemate CIS-3-benzyloxycarbonyloxy-1-ol

27 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol are dissolved in 3 ml of methylene chloride, mixed with 65 mg anhydride ISO-valerianic acid and 11 mg of Novozym 435 and stirred at 22-25°C. after reaching the degree of conversion of 45-50% reaction complete by filtering off the enzyme. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is 87% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA), the enantiomeric residue (1R,3S)-derived ISO-valerianic acid is>95% (HPLC on Chiralcel OD 250×4,6;1 ml/min, heptane/EtOH/CH3CN 100:1:0,5).

Example 72

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

200 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol are dissolved in 3 ml of chlorobenzene are mixed with 100 mg of succinic acid anhydride and 10 mg of Chirazyme L-2, liofilizirovannogo, and stirred at 25-27°C. After 29 hours the reaction is complete by filtering off the enzyme. From the concentrated sample determine the optical purity as unreacted base and formed product of the acylation. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is >98% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA), optical purity derived succinic acid is 94% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3 CN 25:1:0,5+0,1% TFA).

Example 73

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

200 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol are dissolved in 3 ml of DME, mixed with 100 mg of succinic acid anhydride and 10 mg of Chirazyme L-2, liofilizirovannogo, and stirred at 25-27°C. After 29 hours the reaction is complete by filtering off the enzyme. From the concentrated sample determine the optical purity as unreacted base and formed product of the acylation. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is >95% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA), optical purity derived succinic acid is >97% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 74

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

200 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol are dissolved in 3 ml of THF, mixed with 100 mg of succinic acid anhydride and 10 mg of Chirazyme L-2, liofilizirovannogo, and stirred at 25-27°C. After 29 h the reaction is complete by filtering off the enzyme. From the concentrated sample determine the optical purity as unreacted base and formed product of the acylation. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol composition of AET 84% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA), optical purity derived succinic acid is>95% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 75

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

200 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol are dissolved in 3 ml of methylene chloride, mixed with 100 mg of succinic acid anhydride and 10 mg of Chirazyme L-2, liofilizirovannogo, and stirred at 25-27°C. After 29 h the reaction is complete by filtering off the enzyme. From the concentrated sample was determined by optical purity as unreacted base and formed product of the acylation. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is >98% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA), optical purity derived succinic acid is 88% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 76

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol

200 mg of racemic CIS-3-benzyloxycarbonyloxy-1-ol are dissolved in 3 ml of acetone, mixed with 100 mg of succinic acid anhydride and 10 mg of Chirazyme L-2, liofilizirovannogo, and stirred at 25-27°C. After 29 h the reaction is complete by filtering off the enzyme. From the concentrated sample op is edalat optical purity as unreacted base, and formed product of the acylation. Optical purity of (1S,3R)-3-benzyloxycarbonyloxy-1-ol is >99% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA), optical purity derived succinic acid is 78% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

Example 77

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol, division of alcohol and a derivative of succinic acid

8,15 g (to 39.5 mmol) of racemic CIS-3-benzyloxycarbonyloxy-1-ol are dissolved in 120 ml of THF, mixed with 3.9 g (39,0 mmol) of succinic acid anhydride and 390 mg of Chirazyme L-2, liofilizirovannogo, and stirred at 22-25°C. after reaching the degree of conversion of about 40% complete reaction by filtering off the enzyme. The filtrate was concentrated in vacuo. The remainder is injected in tBuOMe and intensively three times extracted with saturated aqueous NaHCO3using 100 ml of the Organic phase is dried (MgSO4) and concentrated in vacuo; yield: 4.4 g; optical purity (1S,3R)-3-benzyloxycarbonyloxy-1-ol is 70% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA). Optical purity dissolved in the aqueous phase derived succinic acid is >99% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA).

An aqueous solution derived amber to the slots hydrolyzing chemically by treatment with concentrated sodium hydroxide solution. Educated (1R,3S)-3-benzyloxycarbonyloxy-1-ol extracted with tBuOMe; output: 2,9,

Example 78

The separation of the racemate CIS-3-benzyloxycarbonyloxy-1-ol, division of alcohol and a derivative of succinic acid

of 5.06 g (24.5 mmol) of racemic CIS-3-benzyloxycarbonyloxy-1-ol are dissolved in 75 ml of THF, mixed with 2,52 g of 25.2 mmol) of succinic acid anhydride and 3.1 mg of Novozym 435 and stirred at 22-25°C. After 28,5 h the reaction is complete by filtering off the enzyme. The filtrate was concentrated in vacuo to approximately 15 ml of the Residue is mixed with 30 ml of water and the remaining THF is distilled off in vacuum. Add 15 ml of a saturated aqueous solution of NaHCO315 ml of water and 30 ml of methylene chloride and the mixture 15-30 min intensively stirred. After separation of the phases extracted first 90 ml of a saturated aqueous solution of NaHCO3and 150 ml of water, then 15 ml of a saturated aqueous solution of NaHCO3and 30 ml of water, washed twice with water, using 30 ml of the Organic phase is dried (MgSO4) and concentrated in vacuo; yield: 2,52 g (50%),+12,1° (c=1,0, MeOH); optical purity (1S,3R)-3-benzyloxycarbonyloxy-1-ol is >99% (HPLC on Chiralpak AD-H 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA). Purified aqueous phase is mixed with 20 ml acetic acid (glacial vinegar) and extracted twice with methylene chloride, using 20 m is. The organic phase is dried (MgSO4) and concentrate. Output: 3,55 g (47%) derived succinic acid, optical purity is>99% (HPLC on Chiralcel OD 250×4,6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0,5+0,1% TFA);1H-NMR (CDCl3), δ=1,2 was 1.43 (m, 4H), equal to 1.82 (m, 1H), 1.93 and (m, 1H), 2,04 (m, 1H), 2.40 a (m, 1H), 2,58-2,70 (m, 4H), 3,39 (m, 1H), 4,54 (m, 2H), 4,71 (m, 1H), 7.23 percent and 7.36 (m, 5H).

Example 79

Obtaining racemic CIS-3-(tert-butyldimethylsilyloxy)-cyclohexanol

To a cooled to 10°C to a solution of 1,3-cyclohexanediol (20,05 g, 0,173 mol), Et3N (28,79 ml, 1.2 EQ.) and DMAP (services, 0.844 g of 0.04 EQ.) in CH2Cl2(600 ml) is slowly added TBDMSCI (28,62 g, 1.1 EQ.). After 18 hours stirring at 20-23°C, the reaction mixture was washed with H2O (2×100 ml). The organic phase is washed with saturated NH4Cl (2×100 ml), dried over MgSO4and concentrated in vacuo. Chromatography on silica gel (n-heptane/EA 20:1) gives 18,77 g (47%) of the desired monocellular ether;1H-NMR (CDCl3), δ=0,0-0,1 (m, 6H), to 0.8-0.9 (m, 9H), 1,2-2,0 (m, 8H), 3,2 (s, W, 1H), and 3.8 (m, 1H), 3,95 (m, 1H).

Example 80

Obtain (1S,3R)-CIS-3-(tert-butyldimethylsilyloxy)-cyclohexanol

770 mg of racemic CIS-3-(tert-butyldimethylsilyloxy)-cyclohexanol are dissolved in 10 ml of acetone, mixed with 0,36 ml of vinyl acetate and 400 mg of Novozym 435 and stirred at 21-24°C. After 47 h (the degree of conversion at which Erno 50%) reaction complete by filtering off the enzyme, and the solution is evaporated in vacuum. Chromatography part on silica gel (n-heptane/EA 3:1) to give (1S,3R)-CIS-3-(tert-butyldimethylsilyloxy)-cyclohexanol with+12,8° (c=1,0, MeOH).

1. The method of obtaining chiral nerazmokaemogo the compounds of formula I

where R1

which means
cycle And - phenyl;
R3Is H, F, Cl, Br, IT, NO2, CF3, OCF3, (C1-C6)-alkyl, (C3-C8-cycloalkyl, phenyl;
R4, R5Is H, F, Cl, Br, IT, NO2, CF3, OCF3, OCF2H, OCF2-CF3, OCF2-CHF2SCF3, O-phenyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl, O-(C1-C6)-alkyl-O-(C1-C3)-alkyl;
n is 1 to 3; and
R2- (C1-C8)-alkyl, and alkyl groups, one or more CH2-groups may be replaced by O, CO, S, SO or SO2and alkyl may be from one to three times substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxa,-O(C1-C6)-alkyl, tetrazolo, thiazolidin-2,4-dione, indole and phenyl, with thiazolidin-2,4-dione and phenyl, in turn, can be substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C -C6)-alkyl, COOH, CO-benzoxa,-O(C1-C6)-alkyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl or tetrazole, characterized in that conduct the following stages:
a) alkylation (Alk-R2/Alk-SG)CIS-1,3-cyclohexanediol formula (II)

the compound of the formula (III)

in which R2defined above, or means HE is a protective group (SG), as for example, benzoyloxymethyl, benzyl, para-methoxybenzyl or tert-butyl dimethylsilane;
X1means Cl, Br, I, OMs, OTs, OTf;
in a suitable solvent in the presence of a base to obtain racemic compounds of the formula (IV)

in which R2defined above,
b1) the enzymatic formation of ester (S)in which the compound obtained of the formula (IV) is subjected to stereoselective enzymatic acylation with the formation of ester (S), and alcohols are mixed in an organic solvent with an appropriate acyl donor and an enzyme selected from the group comprising Novozym, Chirazyme, lipase and the resulting mixture is stirred at a temperature of from -20 to 80°C To produce at the end of the reaction of one stereoisomer in the form of ester of the formula (V)

where R6means C(=O)-(C1-C6)-alkyl, C(=O)-(C2-C6/sub> )-alkenyl, C(=O)-(C3-C7)-quinil, C(=O)-(C3-C7-cycloalkyl, and one or more carbon atoms can be replaced by oxygen atoms and can be substituted by 1-3 substituents from the group F, Cl, Br, CF3, CN, NO2, hydroxy, methoxy, ethoxy, phenyl and-O(C1-C4)-alkyl, CO-O(C2-C4)-alkenyl, which in turn can be substituted by 1-3 substituents from the group F, Cl, Br, CF3and
R2defined above,
and another stereoisomer, which remains unchanged, in the form of an alcohol of the formula (IV), or
b2) the enzymatic cleavage of ester [including chemical esterification (CV)+enzymatic cleavage (ES)], where the racemic compound of formula (IV) is subjected to a first chemical esterification (CV), the acid chloride of the acid R6-Cl or acid anhydride R6-O-R6in the presence of a base to obtain racemic complex ester of the formula (V)

where R6and R2defined above,
which is then subjected to stereoselective enzymatic cleavage of ester (ES) in a homogeneous or heterogeneous, aqueous, aqueous-organic or organic medium in the presence of an enzyme selected from the group comprising Novozym, Chirazyme, the lipase at a temperature of 10-80°C. and injected into the reaction, in the case of hydrolysis with water, and in the case of legaliza - with alcohol, after which one of streamer is in the form of an alcohol of the formula (IV), and the other in the form of the remaining unmodified complex ester of the formula (V),
split (T), according to which a mixture of ester of the formula (V) and alcohol of formula (IV)obtained in stage b1) or b2) are separated from each other (separation T) due to the difference in chemical and physico-chemical properties;
c) chemical hydrolysis (CH)
obtained in the form of ester, at stages b1) or b2), the enantiomer of formula (V) omelet obtaining chemically enantiomeric alcohol of the formula IV,
d) alkylation (Alk-R1)
obtained in the form of alcohol at stages (C), b1) or b2) enantiomer of formula (IV) is subjected to interaction with the compound of the formula (VI)

where the cycle A, R3, R4, R5and n are defined above and
X2means Cl, Br, I, OTs, OMs, OTf;
in a suitable solvent in the presence of a base to obtain the compounds of formula (I), when R2means a protective group, perform the following additional steps:
e) cleavage of the protective group SG (AbSG)
the compound of formula (Ia)

where R1and SG defined above,
by removal of the protective group is transferred to the compound of formula (VII)

where R1defined above,
f) alkylation (Alk-R2)
the floor is obtained on the previous stage, the compound of formula (VII) is subjected to interaction with the compound of the formula (III),

where X1and R2defined above for compounds of formula (I),
in a suitable solvent in the presence of a base to obtain the compounds of formula (I).

2. The method of obtaining chiral nerazmokaemogo the compounds of formula I

where R1

which means
cycle And - phenyl;
R3Is h, F, Cl, Br, IT, NO2, CF3, OCF3, (C1-C6)-alkyl, (C3-C8-cycloalkyl, phenyl;
R4, R5Is h, F, Cl, Br, IT, NO2, CF3, OCF3, OCF2H, OCF2-CF3, OCF2-CHF2SCF3, O-phenyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl, O-(C1-C6)-alkyl-O-(C1-C3)-alkyl;
N is 1 to 3; and
R2- (C1-C8)-alkyl, and alkyl groups, one or more CH2-groups may be replaced by O, CO, S, SO or SO2and alkyl may be from one to three times substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxa,-O(C1-C6)-alkyl, tetrazolo, thiazolidin-2,4-dione, indole and phenyl, with thiazolidin-2,4-dione and phenyl, in turn, can be substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz, NH-CO-C(CH3)3, hydroxyl, OCF3,O-(C 1-C6)-alkyl, COOH, CO-benzoxa,-O(C1-C6)-alkyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl or tetrazole,
characterized in that conduct the following stages:
a) alkylation (Alk-R1) CIS-1,3-cyclohexanediol formula (II)

compound of formula (VI)

where the cycle A, R3, R4, R5and n are defined above and
X2means Cl, Br, I, OTs, OMs, OTf;
in a suitable solvent in the presence of a base to obtain racemic compounds of the formula (VII)

in which R1defined above,
b1) the enzymatic formation of ester (S)in which the compound obtained of the formula (VII) is subjected to stereoselective enzymatic acylation with the formation of ester (S), and alcohols are mixed in an organic solvent with an appropriate acyl donor and an enzyme selected from the group comprising Novozym, Chirazyme, lipase and the resulting mixture is stirred at a temperature of from -20 to 80°C To produce at the end of the reaction of one stereoisomer in the form of ester of the formula (V),'

where R6means C(=O)-(C1-C6)-alkyl, C(=O)-(C2-C6)-alkenyl, C(=O)-(C3-C7)-quinil, C(=O)-(C3-C7-cycloalkyl, and Odie is or more carbon atoms can be replaced by oxygen atoms and can be substituted by 1-3 substituents from the group F, Cl, Br, CF3, CN, NO2, hydroxy, methoxy, ethoxy, phenyl and-O(C1-C4)-alkyl, CO-O(C2-C4)-alkenyl, which in turn can be substituted by 1-3 substituents from the group F, Cl, Br, CF3and
R1defined above,
and another stereoisomer, which remains unchanged, in the form of an alcohol of the formula (VII), or
b2) the enzymatic cleavage of ester [including chemical esterification (CV) + enzymatic cleavage (ES)], where the racemic compound of formula (VII) is subjected to a first chemical esterification (CV), the acid chloride of the acid R6-Cl or acid anhydride R6-O-R6in the presence of a base to obtain racemic complex ester of the formula (V),'

where R6and R1defined above,
which is then subjected to stereoselective enzymatic cleavage of ester (ES) in a homogeneous or heterogeneous, aqueous, aqueous-organic or organic medium in the presence of an enzyme selected from the group comprising Novozym, Chirazyme, the lipase at a temperature of 10-80°C. and injected into the reaction, in the case of hydrolysis with water, and in the case of alcoholysis with ethanol, after which one of streamer is in the form of an alcohol of the formula (VII), and the other in the form of the remaining unmodified complex ester of the formula (V)',
split (T), according to which the shift of the b complex ester of the formula (V)' and alcohol of formula (VII), obtained in stage b1) or b2), separated from each other (separation T) due to the difference in chemical and physico-chemical properties;
(C) chemical hydrolysis (SN),
obtained in the form of ester, at stages b1) or b2), the enantiomer of formula (V)' omelet obtaining chemically enantiomeric alcohol of formula (VII),
d) alkylation (Alk-R2),
obtained in the form of alcohol at stages (C), b1) or b2) enantiomer of formula (VII) is subjected to interaction with the compound of the formula (III)

in which R2defined above, or means HE is a protective group (SG), as, for example, benzoyloxymethyl, benzyl, para-methoxybenzyl or tert-butyl dimethylsilane;
X1means Cl, Br, I, OMs, OTs, OTf;
in a suitable solvent in the presence of a base to obtain the compounds of formula (I);
in the case when R2means a protective group holds the following additional stages:
e) cleavage of the protective group SG (AbSG)
the compound of formula (Ia)

where R1and SG defined above,
by removal of the protective group is transferred to the compound of formula (VII)

where R1defined above,
f) alkylation (Alk-R2)
obtained in the previous phase of the compound of formula (VII) is subjected to interaction with the compound of the formula (III),

where X1and R2defined above for compounds of formula (I),
in a suitable solvent in the presence of a base to obtain the compounds of formula (I).

3. The method of obtaining chiral nerazmokaemogo the compounds of formula I

where R1

which means
cycle And - phenyl;
R3Is H, F, Cl, Br, IT, NO2, CF3, OCF3, (C1-C6)-alkyl, (C3-C8-cycloalkyl, phenyl;
R4, R5Is H, F, Cl, Br, IT, NO2, CF3, OCF3, OCF2H, OCF2-CF3, OCF2-CHF2SCF3, O-phenyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl, O-(C1-C6)-alkyl-O-(C1-C3)-alkyl;
N is 1 to 3; and
R2- (C1-C8)-alkyl, and alkyl groups, one or more CH2-groups may be replaced by O, CO, S, SO or SO2and alkyl may be from one to three times substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxa,-O(C1-C6)-alkyl, tetrazolo, thiazolidin-2,4-dione, indole and phenyl, with thiazolidin-2,4-dione and phenyl, in turn, can be substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, WITH THE N, WITH benzox,-O(C1-C6)-alkyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl or tetrazole,
characterized in that conduct the following stages:
a) alkylation (Alk-SG) CIS-1,3-cyclohexanediol formula (II)

the compound of the formula (III)

in which SG means HE is a protective group, such as, for example, benzoyloxymethyl, benzyl, para-methoxybenzyl or tert-butyl dimethylsilane;
X1means Cl, Br, I, OMs, OTs, OTf;
in a suitable solvent in the presence of a base to obtain racemic compounds of the formula (IV)'

where SG is defined above,
b1) the enzymatic formation of ester (S)in which the compound obtained of the formula (IV)' is subjected to stereoselective enzymatic acylation with the formation of ester (S), and alcohols are mixed in an organic solvent with an appropriate acyl donor and an enzyme selected from the group comprising Novozym, Chirazyme, lipase and the resulting mixture is stirred at a temperature of from -20 to 80°C To produce at the end of the reaction of one stereoisomer in the form of ester of the formula (V)

where
R6means C(=O)-(C1-C6)-alkyl, C(=O)-(C2-C6)-alkenyl, C(=O)-(C3-C7)-quinil, C(=O)-(C3-C 7-cycloalkyl, and one or more carbon atoms can be replaced by oxygen atoms and can be substituted by 1-3 substituents from the group F, Cl, Br, CF3, CN, NO2, hydroxy, methoxy, ethoxy, phenyl and-O(C1-C4)-alkyl, CO-O(C2-C4)-alkenyl, which in turn can be substituted by 1-3 substituents from the group F, Cl, Br, CF3and
SG defined above,
and another stereoisomer, which remains unchanged, in the form of an alcohol of the formula (IV)'or
b2) the enzymatic cleavage of ester [including chemical esterification (CV) + enzymatic cleavage (ES)], where the racemic compound of formula (IV)' is subjected to a first chemical esterification (CV), the acid chloride of the acid R6-Cl or acid anhydride R6-O-R6in the presence of a base to obtain racemic complex ester of the formula (V)

where R6and R2defined above,
which is then subjected to stereoselective enzymatic cleavage of ester (ES) in a homogeneous or heterogeneous, aqueous, aqueous-organic or organic medium in the presence of an enzyme selected from the group comprising Novozym, Chirazyme, the lipase at a temperature of 10-80°C. and injected into the reaction, in the case of hydrolysis with water, and in the case of alcoholysis with ethanol, after which one of streamer n which appears in the form of an alcohol of the formula (IV)', and the other in the form of the remaining unmodified complex ester of the formula (V)",
split (T), according to which a mixture of ester of the formula (V)and alcohol of formula (IV)', obtained in stage b1) or b2), separated from each other (separation T) due to the difference in chemical and physico-chemical properties;
c) chemical hydrolysis (CH)
obtained in the form of ester, at stages b1) or b2), the enantiomer of formula (V)" amylet obtaining chemically enantiomeric alcohol of formula (IV)',
d) alkylation (Alk-R2)
obtained in the form of alcohol at stages (C), b1) or b2) enantiomer of formula (IV)' is subjected to interaction with the compound of the formula compound of formula (III)

in which R2defined above,
X1means Cl, Br, I, OMs, OTs, OTf;
in a suitable solvent in the presence of a base to obtain racemic compounds of formula (Ia)'

in which R2defined above,
e) cleavage of the protective group SG (AbSG)
the compound of formula (Ia)'

where R2and SG defined above,
by removal of the protective group is transferred to the compound of formula (IV)

where R2defined above,
f) alkylation (Alk-R1)
obtained in the previous phase of the compound of formula (IV) is subjected to interaction with soedinenieto (VI)

where the cycle A, R3, R4, R5and n are defined above and
X2means Cl, Br, I, OTs, OMs, OTf;
in a suitable solvent in the presence of a base to obtain the compounds of formula (I).

4. The method of obtaining chiral nerazmokaemogo the compounds of formula I

where R1

which means
cycle And - phenyl;
R3Is H, F, Cl, Br, IT, NO2, CF3, OCF3, (C1-C6)-alkyl, (C3-C8-cycloalkyl, phenyl;
R4, R5Is H, F, Cl, Br, IT, NO2, CF3, OCF3, OCF2H, OCF2-CF3, OCF2-CHF2SCF3, O-phenyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl, O-(C1-C6)-alkyl-O-(C1-C3)-alkyl;
n is 1 to 3; and
R2- (C1-C8)-alkyl, and alkyl groups, one or more CH2-groups may be replaced by O, CO, S, SO or SO2and alkyl may be from one to three times substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxa,-O(C1-C6)-alkyl, tetrazolo, thiazolidin-2,4-dione, indole and phenyl, with thiazolidin-2,4-dione and phenyl, in turn, can be substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz, NH-CO-C(CH3) , hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxa,-O(C1-C6)-alkyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl or tetrazole,
characterized in that conduct the following stages:
a) alkylation (Alk-SG) CIS-1,3-cyclohexanediol formula (II)

the compound of the formula (III)

in which SG means HE is a protective group, such as, for example, benzoyloxymethyl, benzyl, para-methoxybenzyl or tert-butyl dimethylsilane;
X1means Cl, Br, I, OMs, OTs, OTf;
in a suitable solvent in the presence of a base to obtain racemic compounds of the formula (IV)'

where SG is defined above,
b1) the enzymatic formation of ester (S)in which the compound obtained of the formula (IV)' is subjected to stereoselective enzymatic acylation with the formation of ester (S), and alcohols are mixed in an organic solvent with an appropriate acyl donor and an enzyme selected from the group comprising Novozym, Chirazyme, lipase and the resulting mixture is stirred at a temperature of from -20 to 80°C To produce at the end of the reaction of one stereoisomer in the form of ester of the formula (V)

where R6means C(=O)-(C1-C6)-alkyl, C(=O)-(C2-C6)-lceil, C(=O)-(C3-C7)-quinil, C(=O)-(C3-C7-cycloalkyl, and one or more carbon atoms can be replaced by oxygen atoms and can be substituted by 1-3 substituents from the group F, Cl, Br, CF3, CN, NO2, hydroxy, methoxy, ethoxy, phenyl and-O(C1-C4)-alkyl, CO-O(C2-C4)-alkenyl, which in turn can be substituted by 1-3 substituents from the group F, Cl, Br, CF3and
SG defined above,
and another stereoisomer, which remains unchanged, in the form of an alcohol of the formula (IV)'or
b2) the enzymatic cleavage of ester [including chemical esterification (CV) + enzymatic cleavage (ES)], where the racemic compound of formula (IV)' is subjected to a first chemical esterification (CV), the acid chloride of the acid R6-Cl or acid anhydride R6-O-R6in the presence of a base to obtain racemic complex ester of the formula (V)

where R6and R2defined above,
which is then subjected to stereoselective enzymatic cleavage of ester (ES) in a homogeneous or heterogeneous, aqueous, aqueous-organic or organic medium in the presence of an enzyme selected from the group comprising Novozym, Chirazyme, the lipase at a temperature of 10-80°C. and injected into the reaction, in the case of hydrolysis with water, and in the case of alcoholysis with the alcohol, once one of streamer is in the form of an alcohol of the formula (IV)'and the other as the remaining unmodified complex ester of the formula (V)",
split (T), according to which a mixture of ester of the formula (V)and alcohol of formula (IV)', obtained in stage b1) or b2) are separated from each other (separation T) due to the difference in chemical and physico-chemical properties;
c) chemical hydrolysis (CH)
obtained in the form of ester, at stages b1) or b2), the enantiomer of formula (V)" amylet obtaining chemically enantiomeric alcohol of the formula IV',
d) alkylation (Alk-R1) get in the form of alcohol at stages (C), b1) or b2) enantiomer of formula (IV)' is subjected to interaction with the compound of the formula compound of formula (VI)

where the cycle A, R3, R4, R5and n are defined above and
X2means Cl, Br, I, OTs, OMs, OTf;
in a suitable solvent in the presence of a base to obtain compound (Ia)

e) cleavage of the protective group SG (AbSG)
the compound of formula (Ia)

where R1and SG defined above,
by removal of the protective group is transferred to the compound of formula (VII)

where R1defined above,
f) alkylation (Alk-R2)
received on predydushij stage, the compound of formula (VII) was subjected to the Ute interaction with the compound of the formula (III)

in which R2defined above,
X' is Cl, Br, I, OMs, OTs, OTf;
in a suitable solvent in the presence of a base to obtain the compounds of formula (I).

5. The method according to claims 1 to 4, characterized in that is used as a compound of the formula (III) or (III)',

or
in which X1means Cl, Br, I, OMs or OTs.

6. The method according to claim 5, characterized in that is used as a compound of the formula (III) or (III)',

or
in which X1means Cl, Br, or I.

7. The method according to claims 1 to 4, characterized in that the compound of formula (I)

in which
R1means

where cycle - phenyl,
R3- N, CF3, (C1-C6)-alkyl, (C3-C8-cycloalkyl, phenyl;
R4, R5Is h, F, Br, CF3, OCF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl;
n is from 1 to 2; and
R2- (C1-C9)-alkyl, and alkyl groups, one or more CH2-groups may be replaced by O, CO, S, SO or SO2and alkyl may be from one to three times substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxa,-O(C1-C6)-alkyl is m, tetrazolo, thiazolidin-2,4-dione, indole and phenyl, with thiazolidin-2,4-dione and phenyl in turn may be substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxa,-O(C1-C6)-alkyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl or tetrazole.

8. The method according to claim 7, characterized in that the compound of formula (I)in which:

in which R1means

where cycle - phenyl,
R3- (C1-C4)-alkyl;
R4, R5- H, (C1-C4)-alkyl, O-(C1-C4)-alkyl;
n - 1; and
R2- (C1-C8)-alkyl, and alkyl groups, one or more CH2-groups may be replaced by O, CO, S, SO or SO2and alkyl may be from one to three times substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxa,-O(C1-C6)-alkyl, tetrazolo, thiazolidin-2,4-dione, indole and phenyl, with thiazolidin-2,4-dione and phenyl in turn may be substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxa,-O(C1-C61-C6)-alkyl, O-(C1-C6)-alkyl or tetrazole.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , in which A is selected from one or several X and/or Y groups; X represents methylene group; Y represents C2-alkinylene group; n represent integer number from 1 to 5; R1 represents group R2, optionally substituted with one or several R3 and/or R4 groups; R2 represents group selected from pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphtyl, chinolinyl, isochinolinyl, dihydroisochinolinyl, 2-oxo-3,4-dihydrochinolinyl, indolyl, benzimidazolyl, pyrrolopyridinyl; R3 represents group selected from halogen atoms, groups C1-6-alkyl, C3-7-Cycloalkyl, C1-6-alkoxy, NR5R6 and phenyl; R4 represents group selected from groups: phenyl, naphtyl, pyridinyl; R4 group or groups can be substituted with one or several R3 groups, similar or different from each other; R5 and R6 independently on each other represent C1-6-alkyl group; R7 represents hydrogen atom or C1-6-alkyl group; R8 represents hydrogen atom or group C1-6-alkyl, C3-7-cycloalkyl, C3-7-Cycloalkyl- C1-3-alkylene; in form of base, acid-additive salt, hydrate or solvate. Invention also relates to methods of obtaining formula (I) compound by any of ii. 1-3, to compounds, determined by general formula (IV), (VII), to pharmaceutical composition, as well as to application of formula (I) compounds by any of ii. 1-3.

EFFECT: obtaining novel biologically active compounds possessing activity of enzyme FAAH inhibitors.

10 cl, 5 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds of the formula and their pharmaceutically acceptable salts used as inhibiting agent in the relation of fermentative beta-secretase and it also relates to pharmaceutical compositions based on the formula. In general formula one of RN and RN' represents hydrogen, and another represents - C(=O)-(CRR')0-6R100, or where R4 is chosen from the group including H; NH2; -NR50CO2R51; -(C1-C4)-alkyl-NR50CO2R51; where n7 is equal to 0, 1, 2 or 3; R50 represents H or C1-C6alkyl; R51 is chosen from the group including phenyl-(C1-C4)-alkyl and (C1-C6)-alkyl; X is chosen from the group including -(C1-C6)-alkylidenyl optionally substituted with 1, 2 or 3 metal groups; Z is chosen from the group including bond, SO2, SO and S; Y stands for (C1-C10)-alkyl; R1 represents -(C1-C6)-alkylphenyl where phenyl ring is optionally substituted by 1, 2, 3 or 4 halogen atoms; R and R' independently represent hydrogen or (C1-C6)-alkyl; R2 represents hydrogen; R3 represents hydrogen; Rc represents - (CR245R250)0-4-aryl; where aryl is optionally substituted by 1, 2 or 3 R200; R200 is chosen from the group including (C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups R205; halogen; C=N; R205 stands for halogen; R245 and R250 in each case stands for H; either R245 or R250 are taken together with carbon atom whereto attached to form carbocycle from 3, 4, 5, 6 or 7 carbon atoms; R100 represents 5-6-merous heteroaryl with 1-2 heteroatoms chosen from nitrogen and sulphur, -phenyl-W-heteroaryl where heteroaryl is 5-6-merous ring containing 1-2 heteroatoms, chosen from nitrogen and oxygen and where cyclic parts of each group are optionally substituted by 1, 2 or 3 groups independently chosen among C1-C6alkyl, -(CH2)0-4-CO2-NR105R'105, -(CH2)0-4-SO2-NR105R'105, -(CH2)0-4-N(R150)-CO-R105, -(CH2)0-4-N(R150)-SO2-R105; W represents -(CH2)0-4; R105 and R'105 independently represent (C1-C6)-alkyl optionally substituted with -NH2 or halogen; R150 represents hydrogen.

EFFECT: compounds can be applied to prevent and treat diseases mediated by excess activity of beta-secretase such as Alzheimer's disease.

11 cl, 12 tbl, 3 dwg, 1729 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula (I): where R1 and R2 each independently represents a hydrogen atom, C1-8 alkyl or a halogen atom; R3 represents C1-8 alkyl, which can be substituted with 1-3 halogen atom(s) or phenyl; R4 represents a hydrogen atom or C1-8 alkyl; R5 and R6 each independently represents a hydrogen atom; X represents a sulphur atom or oxygen atom; ring A is 4-(trifluoromethyl)piperidin-1-yl, 2,2-difluoro-1,3- benzodioxol-5-yl or 3,4-dihydro-1H-isoquinolin-2-yl. The invention also relates to salts or solvates of this derivative, as well as medicinal preparation, pharmaceutical composition, method of preventing and/or treating diseases, caused by PPAR, and use of this derivative.

EFFECT: obtaining new biologically active compounds, which can be used for preventing and/or treating diseases caused by PPARδ.

8 cl, 39 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to a malononitrile compound with formula (I): where one of X1, X2, X3 and X4 stands for CR100, where R100 is a group with formula (II) each three of the other X1, X2, X3 and X4 is nitrogen or CR5, under the condition that, from one to three of X1, X2, X3 and X4 stands for nitrogen, Z is oxygen, sulphur or NR6. The malononitrile compound can be used a pesticide in agriculture.

EFFECT: obtaining a new pest control compound and its use as an active ingredient of a pesticide composition.

18 cl, 180 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula , in which R represents H, (C1-C12)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl. In the alkyl, one or more CH2-groups can be substituted with -O-. The invention also relates to the method of obtaining these compounds. The method involves reacting dimethylbenzoic acid ester with formula where R assumes values given above, with a chlorinating agent in an inert solvent or without a solvent at temperature above 40°C, and then cleaning, if necessary. Formula (I) compounds are essential intermediate products during synthesis of PPAR agonists with formula , in which R represents H, (C1-C12)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl. In the alkyl, one or more CH2-groups can be substituted with -O-; Y represents -(CH2)3-, 1,3-phenylene, 1,3-cyclohexanediyl; R' represents H, F, Br, CF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, phenyl; CF3; obtained from reaction of compounds with formula with formula (I) compounds in toluene, N-methylpyrrolidone or other aprotic solvents, in the presence of a suitable base, at temperature lying in the -78°C - +50°C interval, with subsequent extractive processing and, if necessary, crystallisation of the end product.

EFFECT: obtaining new compounds.

8 cl, 5 ex

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: invention concerns a compound of the formula (I) where A ring is (C3-C8)-cycloalkyl or (C3-C8)-cycloalkenyl where two carbon atoms in the cycloalkyl ring can be substituted by oxygen atoms; R1, R2 are H, F, Cl, Br, OH, CF3, OCF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl independently from each other; R3 is H or (C1-C6)-alkyl; R4, R5 are H, (C1-C6)-alkyl independently from each other; X is (C1-C6)-alkyl where one carbon atom in the alkyl group can be substituted by oxygen atom; Y is (C1-C6)-alkyl where one carbon atom in the alkyl group can be substituted by oxygen atom; and its pharmaceutically acceptable salts. The invention also concerns such compounds as (+)-cis-2-(3-(2-(4-fluorphenyl)oxazole-4-ylmethoxy)cyclohexyloxymethyl)-6-methylbenzoic acid of the formula 6b , 2-{3-[2-(3-methoxyphenyl)-5-methyloxazole-4-ylmethoxy]cyclohexyl-oxymethyl}-6-methylbenzoic acid of the formula 53 and 2-methyl-6-[3-(5-methyl-2-n-tolyloxazole-4-ylmethoxy)cyclohexylomethyl]benzoic acid of the formula 70 , or their enantiomers. The invention also concerns pharmaceutical composition exhibiting PPARα agonist effect, including one or more compounds of the formula (I) as an active component together with a pharmaceutically acceptable carrier. The pharmaceutical composition is obtained by mixing of active compound of the formula (I) with a pharmaceutically acceptable carrier and rendering it a form viable for introduction.

EFFECT: obtaining of diarylcycloalkyl derivatives applicable as PPAR-activators.

9 cl, 2 tbl, 67 ex

FIELD: chemistry; oxa-and thiazole derivatives.

SUBSTANCE: oxa- and thiazole derivatives have general formula . Their stereoisomers and pharmaceutical salts have PPARα and PPARγ activity. The compounds can be used for treating diseases, eg. diabetes and anomaly of lipoproteins through PPARα and PPARγ activity. In the general formula, x has value of 1, 2, 3 or 4; m has value of 1 or 2; n has value of 1 or 2; Q represents C or N; A represents O or S; Z represents O or a bond; R1 represents H or C1-8alkyl; X represents CH; R2 represents H; R2a, R2b and R2c can be the same or different and they are chosen from H, alkoxy, halogen; R3 represents aryloxycarbonyl, alkyloxycarbonyl, alkyl(halogen)aryloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, arylcarbonylamino, alkylsulphonyl, cycloheteroalkyloxycarbonyl, heteroarylalkenyl, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, halogenalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenylsulphonyl, heteroarylsulphonyl, arylsulphonyl, arylalkenylarylalkyl, arylalkoxycarbonyl-heteroarylalkyl, heteroaryloxyarylalkyl, where alkyl is in form of C1-8alkyl; Y represents CO2R4, where R4 represents H or C1-8alkyl; including all their stereoisomers and pharmaceutical salts, under the condition that, if A is O, then R3 is not aryloxycarbonyl or alkoxyaryloxycarbonyl.

EFFECT: the compounds can be used in curing such diseases as diabetes and lipoprotein anomalies.

10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new displaced heterocyclic derivatives that can be used in treatment of diabetes and to reduce the content of cholesterol. In formula m is 1; n is 1; Q is C; A is -(CH2)x2-0-(CH2)x3-, where x2 varies from 1 to 3 and x3 is 0; B is a bond or it is (CH2)x4, where x4 varies from 1 to 2; X represents CH or N; X2, X3, X4, X5, X6 represent C, N, O; provided that one from X2 X3 X4 X5 and X6 represents N; and at least one of X2, X3, X4, X5, and X6 represents C; R1 represents H or C1-C6alkyl; R2 is H; R2a, R2b and R2c can be equal or different and selected from H, C1-C6alkyl, C1-C6alkoxy, halogen or thyano; R3 is selected from phenyloxycarbonile, C1-C6alkyloxycarbonile, phenylcarbinol, phenyl, alkoxy; Y represents CO2R4 (where R4 represents H or C1-C6alkyl); (CH2)m can be not necessarily displaced by 1 substitute.

EFFECT: produced are pharmaceutical composition for treatment of diabetes and to reduce the content of cholesterol.

13 cl, 2 tbl, 22 dwg, 88 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

The invention relates to a new class of simple diesters and method of production thereof

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing glycol aldehyde, involving reaction of formaldehyde with hydrogen and carbon monoxide in the presence of a catalyst composition, which is based on a) rhodium source, b) ligand with general formula R1P-R2 (I), where R1 is a bivalent radical, which, together with the phosphorous atom to which it is bonded, is 2-phospha-1,3,5,7-tetraC1-20alkyl-6,9,10-trioxatricyclo[3.3.1.1{3,7}]decile group, and where R2 is a monovalent radical, which is chosen from an alkyl group, containing 4 to 34 carbon atoms or a radical with general formula: -R3-C(O)NR4R5 (II), where R3 represents methylene, ethylene, propylene or butylene, and R4 and R5 independently represent an alkyl group containing 1 to 22 carbon atoms, and c) anion source. The invention also relates to a catalyst composition used in the production of glycol aldehyde, and to a method of producing ethylene glycol from glycol aldehyde obtained using the described method.

EFFECT: easy conversion of formaldehyde to glycol aldehyde in the presence of a stable catalyst.

6 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining trans-cyclopentanediol-1,2, which is used in synthesis of fragrant, pharmaceutical, bactericidal and agricultural preparations. The method involves reacting cyclopentene with an aqueous solution of hydrogen peroxide, in molar ratio cyclopentene: hydrogen peroxide 1:(1.3-2), at temperature 50-70°C, in the presence of an interphase catalyst, at pH of the aqueous phase equal to 1-1.5, in a halogenalkyl, dichloroethylene solvent medium, with subsequent extraction of the desired product. The intephase catalyst used is quaternary ammonium salts of general formula (CnH2n+1R1R2R3)+NX, where n varies from 1 to 20, X=Cl-, Br-, I-, R1, R2, R3=CpH2p+1, where p varies from 1 to 20, molar ratio cyclopentene : tungsten salt : phosphoric acid : interphase catalyst is 1 : (2·10-3-4·10-3): (4·10-3-8·10-3): (2·10-3-7·10-3), and the reaction is carried out in the presence of water.

EFFECT: method increases efficiency of the process due to virtually complete conversion cyclopentene and multiple use of the catalyst complex without reactivation.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining optically active alcohols [(3R)-endo]- and [(3S)-exo]-1R,4S-2,2-dimethylcyclo[2.2.1]heptan-3-yl-methanols with general formula (1): [(3R)-endo] (1a) [(3S)-exo] (1b), which are used for obtaining enantiomerically pure products with high optical output. The method involves reacting camphene with a hydride bimetallic complex in form of a Zr,Al-hydride complex µ,µ-dihydro-bis[hydro-µ, chloro-diethylaluminium(bis-cyclopenta-dienylzirconium (IV))], at molar ratio camphene: [Cp2ZrH2*ClAlEt2]2:=2:1, in a benzole medium at 20°C, in an argon atmosphere for 2 hours, subsequent transmetalation of the organozirconium compound with ClAlEt2, oxidation of the reaction mass with dry oxygen and HCl decomposition.

EFFECT: method allows for stereoselective obtaining desired products under mild conditions.

1 ex

FIELD: agriculture.

SUBSTANCE: according to the present invention, there is provided a winter wheat and barley root stimulant fertiliser containing azoxy derivative formulas 1, where 1.1. R=4,4' -benzyl ethylene acetal, 1.2. R=4,4' -benzyl nitrite.

EFFECT: extension of the range of synthetically obtained biologically active substances in order to use them in agriculture as root stimulant fertilisers.

2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining optically active alcohol [(2S)-trans]- 1S,5S-6,6-dimethylcyclo[3.1.1]heptan-2-yl-methanol of general formula (1): , which is used in fine organic and metal-organic synthesis. Method lies in interaction of β-pinene with hydride bimetal complex, as such Zr,Al-hydrite complex µ,µ-dihydro-bis[hydro-µ,chlorine-diethylaluminium-(bis-cyclopentadienylzirconium(IV))] is used, with mole ratio β-pinene: [Cp2ZrH2*ClAlEt2]2=2:1, in benzene medium at temperature 20°C, in argon atmosphere during 2.5 hours, with further remetallising of obtained zirconium-organic compound by means of ClAlEt2, oxidation of reaction mass with dry oxygen and HCl decomposition.

EFFECT: obtaining target product in mild conditions during short time interval.

1 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the method for preparation of aromatic hydrocarbons accompanied with simultaneous obtaining of hydrogen, methanol, motor oils and fresh water from the unstable hydrocarbon gas condensate obtained from gas condensate and oil fields including if necessary its desulphurisation, following obtaining of synthesis gas by one-stage oxidising with air oxygen, its conversion to methanol, following catalytic conversion of methanol to motor oils, separation of the water formed on all process stages, evaporation of the hydrocarbons residues including methanol and fatty hydrocarbons from the water (united and formed on all process stages), water bioremediation and mineralisation. The initial hydrocarbon gas is unstable hydrocarbon gas condensate without preliminary separation of methane and ethane from propane and butane, the said initial gas before its conversion to synthesis gas undergoes the catalytic aromatisation during heating. Then the obtained aromatic hydrocarbon and hydrogen are separated, hydrogen is at least partially used for synthesis gas obtaining in order to change the ratio H2:CO 1.8-2.3:1), and if necessary it is partially used on the stage of desulphurisation with synthesis gas obtaining from hydrocarbon gases (unreacted and formed on the aromatisation stage). The invention refers also to the device for implementation of the method described above.

EFFECT: increasing of the processing of the efficiency of unstable hydrocarbon gas condensate with enhanced obtaining of target products, to make the process more environmentally safe, to increase the quantity and quality of the obtained fresh water.

2 cl, 5 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: method includes introduction of first hydrocarbon flow, including olefins and paraffins, which have number of carbon atoms from 4 to 30, into installation of isomerisation, where installation of isomerisation is intended for isomerisation of at least part of linear olefins in first hydrocarbon flow into branched olefins, and where at least part of components of first hydrocarbon flow, that have not reacted, and at least part of obtained branched olefins form second hydrocarbon flow; introduction of at least part of second hydrocarbon flow into installation of hydroformylation, where installation of hydroformylation is intended for hyroformylation of at least part of olefins in second hydrocarbon flow with formation of aliphatic alcohols and where at least part of obtained aliphatic alcohols include branched alkyl group and where at least part of components of second hydrocarbon flow that have not reacted, and at least part of obtained aliphatic alcohols form flow of hydroformilation reaction; separation of at least part of hydroformylation reaction flow in order to obtain flow of product, containing aliphatic alcohols, and flow of paraffins and olefins that have not reacted, and introduction of at lest part of flow of paraffins and olefins that have not reacted into installation of dehydration, where installation of dehydration is intended for dehydration of at least part of paraffins in flow of paraffins and olefins that have not reacted for obtaining olefins and where at least part of obtained olefins leave installation of dehydration forming olefin hydrocarbon flow and introduction of at least part of olefin hydrocarbon flow into installation of isomerisation.

EFFECT: obtained aliphatic alcohols can be used for obtaining surface-active substances, sulphates.

21 cl, 6 tbl, 3 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the method for methanol preparation by the reaction of hydrogen with carbon oxides fed in the form of synthesis gas in the presence of solid catalyst suspended in the liquid phase with following removal of methanol-containing liquid phase from reaction zone. The interreaction of the hydrogen with carbon oxides is carried out at temperature and pressure providing condensation of the methanol forming on catalyst surface to the liquid phase including water and methanol. The flow containing methanol and at least one compound selected from methyl formiate and ethylic alcohol is recycled to the reaction zone.

EFFECT: invention provides the easy one pass method of methanol preparation with high conversion and low by-products yield.

9 cl, 4 tbl, 1 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: proposed method involves reacting glycerine with hydrogen chloride gas at high temperature in the presence of carboxylic acids and their derivatives. The process is carried out in the presence of organic and/or inorganic heterogeneous acid type catalysts. As a rule, the inorganic heterogeneous catalysts used are silica gel, aluminium silicate, aluminium oxide and activated carbon, and the organic heterogeneous catalysts used are ion-exchange polymer materials, containing acid groups. The process is usually carried out at 100-140°C.

EFFECT: higher degree of converting glycerine and hydrogen chloride, and output of dichloropropanols.

5 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: potassium methylate in form of dry substance or anhydrous solution in methyl alcohol is used as a catalyst when splitting oils and fats, in etherification reactions during production of biodiesel, surface active substances, pharmaceutical and cosmetic preparations. The method involves reacting potassium hydroxide and methanol at high temperature with removal of the formed water using dry methyl alcohol. Synthesis is done in a reaction-separation process in a film type counterflow column reactor at 92-130°C, uniform on the entire height of the reactor, while feeding the initial solution from the top, made by dissolving potassium hydroxide in methyl alcohol, and dry methyl alcohol vapour from the bottom.

EFFECT: more efficient desorption of the formed water and output of the process and reduced energy consumption of the process.

1 tbl, 1 dwg, 5 ex

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