SU1431678A3 - Method of producing optically active ketals - Google Patents

Abstract

The invention relates to heterocyclic compounds, in particular, to the preparation of optically active ketals of the formula I Br-SOch nL N SOPS QX Ar CH-RI X where Ar is phenyl, substituted by keel or halogen atom, naphthyl, substituted by lower alkyl, lower al- a coxy group or a halogen atom; R is C1-C4-alksh1; R and RS are the same, hydroxy, -OR4 or N is (Ry) (R) -group, where lower alkyl; Rj- and R are both C -C-alkyl; X is a C1, J or Br atom, a hydroxy group, a lower acyloxy group, a 4-methylphenylsulfonyloxy group or a lower alkylsulfonyloxy group; The carbon atoms marked with an asterisk are simultaneously in the R and S configurations that are used in medicine. The preparation of the target compounds is carried out from L (+) or B (-) - tartaric acid or its derivative R1-CO-CH (OH) -CH (OH) -CO-R3, where R and Rj have the indicated values, and the corresponding ketone or a ketal of the formula (R-, 0) (Ar) -C- (ORg) (CHX-R), where Ar, R, and X have their assigned meanings; R7 and Rg are C-C-alkyl, in a stream of inert gas in the presence of trifluoromethanesulfonic acid or tri-i alkyl chloroformate. at 50-90 ° C (in the case of using a ketone) or in the presence of thionyl chloride and methanesulphonic acid at 65-125 ° C (in the case of using ketal). The process is carried out with isolation of the desired product of the formula I, where, OR, ... or is converted into a compound of formula I, where, by the action of a strong base followed by acidification or prod: formulG I, where, translated into a compound of formula 1, where N (R5 ) (R), the action of amine. , § w Oil One F 1 oo s

Description

This invention relates to a process for the preparation of new optically active ketals, which are used as intermediates in the synthesis of alpha-aryl-alkanoic acids, io1E1 1x with valuable anti-inflammatory and analgesic agents, such as ibuprofen, phenoprofen or naproxen

 The purpose of the invention is to obtain no-optical active ketals, posl w1 (to obtain them optically active; alpha-aryl alkanoic acids with equivalent or with increased optical; purity relative to the initial keta-; leu.

Example 1 Ketalizatsiya 2-bro-MO-1- (6-methoxy 2-phenyl) -propan-1-one with 2 (R) 5 3 (P) -dihydroxy complex dime: tilovy ether L () butanediic acid -; dimethyl tartrate „

; A mixture of 2-bromo- (6-methoxy-2 naphthyl) propane-1-one (i, 465 g; 0, 005 mol); L () -dimethyl tartrate (7.5 g) of trime-; toxymethane (2.5 g; 0.0236 mol) and trifluoromethanesulfonic acid (0.075 g | 0.0005 mol) were stirred under the action of nitrogen for 60 hours. The reacting mixture was poured in a 0%. -nH wAd sodium carbonate solution and extracted with dichloromethane. Organic, tp phase was washed with water and dried over sodium sulfate. By evaporation of the solvent under reduced pressure, raw materials were obtained which were purified by chromatography in a column (silica gel, eluent: hexane: diethyl ether 8: 2)

A mixture of two diastereoisomers of 2 (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -, 3-dioxolane-4 (K) 5 5 (R) was obtained. complex dimethyl. esters of i and 2d carboxylic acid (0.9 g O, 002 mol) in a ratio (determined 200 MHz),

H-NMR (200 MHz, CDCl1.-Tetramethyl silane) 5 d s / (h / th):

Diastereoisomer 1 (RRS); 1.68 (d, 3N, J 7.5 Hz); 3.54 (S, 3N) 3.90 (S, 3N); 4.08 (S, 3N);

4.48 (q, W, 5 Hz); 4.94 (2H, ABg, /..8, 2 Hz); 7.1-8.0 (6H aromatic protons) "

Dynastereoisomer 2 (RRR): 1. ,, 64 (d, 3N, 5 Hz); 3.58 (S, 3N); 3.89 (S, ЗН); 4.08 (); 4.50 (g, W, 5 Hz); 4.89 (2H, ABg, & 36.3,

J = 6.3 Hz); 7.1-8.0 (6H, aromatic protons).

PRI mme R 2. Preparation of a diastereomeric mixture of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) dicarboxylic acid in the ratio of 1: 1,

A mixture of two diastereoisomers of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolan-4 (11), 5 (R) -diethyl ester 3 and 4 of dicarboxylic acid (prepared by described in example 1) (21.18 g; 0.014 mol; ratio), caustic soda (3.52 g; 0.088 mol), dimethoxyethane (35 ml) and water (35 ml) were suspended by stirring at room temperature e for 2 h. reactive mixture. diluted with water and extracted with diethyl ether. The aqueous phase was acidified with hydrogen chloride to pH 1 and extracted with diethyl ether. The organic phase was washed with water and dried over sodium sulfate. By evaporation of the solvent under reduced pressure, two diastereoisomers, 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane 4 (R), 5 (R) -dicarboxylic acid 5, were obtained. and 6 (16 g; O, 0367 mol, yield 85.5%) in a ratio (determined by H-NMR 200 MHz),

A sample obtained by etherification in diethyl ether with diazomethane gave a mixture of two diastereoisomers of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1, 3-dioxolane-4 (R), 5 (R -dimethyl ester 1 and 2 of dicarboxylic acid in the ratio (determined by preparative thin layer chromatography (HRP) of HPL C and H-NMR 200 MHz)

Example 3: Preparation of 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolan-4 (R), 5 (R) -dimethyl dicarboxylic ester.

A mixture of 2-chloro-1- (6-methoxy-2-naphthyl) propan-1-one (12.4 g; 0.005 mol), 2 (R), 3 (R) -dimethyl ether, dioxybutane acid ( 75 g) and trimethoxymethane (25 g; 0.236 mol), heated to. Trifluoromethanesulfonic acid (2.4 g; O, O 6 mol) was added to the solution. The reaction mixture was kept under the action of nitrogen at 50 ° C for 45 h, then it was processed in the manner described in Example 1.

Purification of the obtained raw material (19.2 g by chromatography in a column (silica gel eluent: hexane: ethyl ether 6: 4) gave a mixture of diastereoisomers 7 and 8 (5.6 g) in a ratio of 7: 8 to 52:48 (determined by HRP);

H-NMR (200 MHz; CBC1, - tetrametesh1-silane), cG (h / th):

Diastereoisomer 7 (RRS): 1.49 (d, 3N, J = 6.65 Hz); 3.48 (S, 3N); 3.85 (S, ЗН); 3.89 (S, ЗН); 4.41 (g, 1H, 65 Hz); 4.95 (ABg, 2H, Hz); 7.1-8.0 (6H, aromatic protons).

Diastereoisomer 8 (RRR), 1.47 (d, 3N, 65 Hz); 3.53 (S, 3N); 3.83 (S, ЗН); 3.89 (S, ЗН); 4.44 (g, 1H, 65 Hz); 4.92 (ABg, 2H, Hz); 7.1-8.0 (6H, aromatic protons).

HRP analysis was performed on a Hewett Rascara instrument. Modifications 1084/8 with a UV detector of different wavelengths: column: Brown Labe RP8 (5 µm), dimensions, 6 mm; solvent A: water, flow 0.96 ml / min; solvent B: methanol, flow 1.04 ml / min; solvent A temperature: 60 G; solvent temperature B: 40 ° C; column temperature: 50 ° C; wavelength: 254 nm; injection: 10 micrometers 3 mg / ml solution in acetonitrile; retention time: diastereoisomer 7: 12.46 min; diastereoisomer 8: 13,21 min.

EXAMPLE 4 Preparation of 2 (R) of Hydroxy-3 (R) (6-methoxy-2-naphthyl-propanol-dimethyl ester of ethane dicarboxylic acid.

A solution of silver tetrafluoroborate (2.4 g, 0.0123 mol) in 1,2-dichloroethane (8 ml) was added in an inert atmosphere, over 15 minutes to a solution of two diastereoisomers 7 and 8 (4.09 g, 0.01 mol ) in the ratio of 7: 8 52:48 with stirring and at 15 ° C. The reaction mixture was heated to 50 ° C, kept at this temperature for 16 hours and then cooled to room temperature and filtered.

The solution was diluted with dichloromethane (60 ml), washed with water (2 x 100 ml) and dried over sodium sulfate.

By evaporation of the solvent under reduced pressure, raw materials were obtained which, after purification by column chromatography (silica gel, n-heptane: diethyl elution solvent

five

0

five

0 0

five

Ether: 2: 8) led to a mixture of two dias. tereoisoneral esters A and B (2.9 g; 0.0074 mol; yield 74%) in the ratio A: B 52:48 (determined 200 MHz),

 H-NMR (200 MHz, CBC1-tetramethylsilane), c / s (h / th):.

Diastereoisomer A (RR); 1.62 (d, 3N, J-8 Hz); 3.22 (S, ЗН); 3.83 (S, ЗН); 3.92 (S, 3N); 3.21 (d, H, J 7.2 Hz); 3.95 (g, 1H, Hz); 4.68

(dd, 1H, Ja ,, 2 Hz, JCH-OH 2.47 G) 5.37 (d, 1H, 47 Hz); 7.1-7.8 (6H, aromatic proton).

Diastereoisomer B (RRR): 1.66 (d, 3N, Hz); 3.58 (S, 3N); 3.72 (S, ЗН); 3.92 (S, 3N); 3.24 (d, 1H, J 7.5 Hz); 3.97 (g, 1H, Hz); 4.78 (dd, 1H, JCH-OH 7.6 Hz, J (2.47 Hz); 5.45 (d, 1H ,, 47 Hz); 7.1-7.8 (6H, aromatic proton) .

Example 5. Preparation of 2- (6-methoxy-2-naphthyl) -propanoic acid.

A mixture of two diastereomeric esters A and B (2.2 g; 5.64 mol; in the ratio A: B 52:48 prepared as described in Example 4), 1,2-dimethoxyethane (22 ml) and Concentrated hydrochloric acid (22 ml) was kept for 2 hours. The reaction mixture was cooled at room temperature, diluted with water and extracted with dichloromethane.

The organic phase was washed with water and extracted with 10% aqueous sodium bicarbonate solution.

The main phase was acidified with concentrated hydrogen chloride and extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. By evaporation of the solvent under reduced pressure, the raw material of 2- (6-methoxy-2-naphthyl) propanoic acid was obtained. An analytical clean sample was obtained after purification by column chromatography (silica gel, solvent for hexane: 7: 3 diethyl ether). +2.2 (, chloroform).

Example 6, Preparation of 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R) S 5 (K) - dicarboxylic acid.

Following the sequence described in Example 2, start with a mixture of two diastereoisomers of 2- (1-chloro-eth1) 2 (b-c to c and i-2-tan teel) -1 3-d suit with olac 4 (R) 5 5 ( R) d1-1 methyl ester of dicarboxylic acid (3854 g of 0.094 mol, in the ratio si determined by HRP) gave a mixture of two diastereo eomers npofl-jicra 9 and 10 (32 ;. 5 g; О, 085 mol, | 90 , 0% ayhod) B ratio of 9; 10-1m

The diastereomeric ratio was determined by HRP analysis carried out on the obtained sample by etching with diazomethane,

H-MR (CBC1, - t8Tramet: lsilan) 5; cG (h / th);

 - Diastereoisomer 9: 15.44 (d, 3N, 85 Hz) 5 4.42 (g, 1H, 85 Hz); : 4.88 (AB, g, Hz); 7.0-8.0 (6H, aromatic protons); 9.0 (S, 2H),

; Diasteraoisomer 10: tt-k (d, 3N, 85 Hz) 5 4 „42 (g, W, .85 Hz;; 4.82 (ABg, 2H, J-6.7 Hz); 7.0- 8.0.; (6H ,, aromatic protons) 9,, 0

: (s / 2H).

; PRI me R 7o Preparation of 2- (1- 6-methyl ethyl) -2- (5-bromo-6-methoxy-2-naphthyl) -1S 3-dioxolane-4 (R) ,, 5 (K) - Dieth Lovy zgyra dicarboxylic acid.

A solution of bromine (1 3i, 42 g, 0.084 mol) ъ carbon tetrachloride was added: dropwise over 1 hour to a solution of two diastereoisomers of 2- (1-bromoethyl) 2 (6-methoxy 2 naphthyl) -1 , 3-dioxolane 4 (V.) 5 5 (K) di-methyl ester 3 and 4 dicarboxylic acid in a ratio (39.48 g | 0.082 mol) in four 5% carbon monoxide (475 ml), kept stirring at 0 ° С in an inert atmosphere. Reaction mixture held at 0 ° C. for 1 h; it was then poured into a well-mixed aqueous solution of sodium carbonate (500 ml). The organic phase was separated. washed with water (2500 ml) and npocyiMiOTH with sodium sulfate. Evaporation of the solvent under reduced pressure gave a diastereoisomeric mixture of 2 (l bromomethyl) 2- (5-bromo-6-methoxy-2-naphthyl) -l, 3-dioxolane-4 (R) 5 5 (K) -diethyl ether 11 and 12 dicarboxylic acid (4356 g, 98% purity and the ratio determined by HRP) „

PRI me R 8, Preparation of a 2 (1-bronetyl) -2- (6-methoxy-2 naphthl) -1e3-dioxolane ™ diastereomeric mixture (4), 5 5 (R) - N5N , N sN -amid of tetraethyl dicarboxylic acid.

A mixture of two diastereoisomers 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-da 1 Oksolan-4 (R), 5 (K) -dimethyl

esters 1 and 2 of dicarboxylic acid in the ratio. (12.5 mol; prepared by the method described in Example 1), diethylamine (27.5 ml) and water (20 ml) were held while stirring at room temperature for 15 hours. The solvents were removed at room temperature under reduced pressure, and diethyl ether (50 ml) was added to the residue. The precipitate was filtered and dried in vacuo. Got a diastereomeric mixture of 2 - (- bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolan-4 (K), 5 (R) -N, N, N, N-amide of tetraethyl 13 and 14 dicarboxylic acid (11 mol; yield 88%) in the ratio 13:14 1: 1 (determined by n-NMR 200 MHz).

PRI me R 9. Preparation of a 2- (1-acetoxyethyl) -2- (5-bromo-6-metoxy-2-naphthyl) -3-dioxolane-4 (R) diastereoisomer mixture ) -dimethyl ester of dicarboic acid.

2-Acetoxy-1,1-dimethoxy-1- (5-bromo-6-me-to-2-naphthyl) propane (1.22 g; 3.46 mmol) was added, under the action of argon, to the solution obtained by heating with 65 ° С mixture of 2 (R), 3 (R) -AH-Dioxyethanedicarboxylic acid methyl ester (20 g) j of thionyl chloride

(1 ml) and methanesulfonic acid (0.03 g). The reaction mixture was heated at 30 minutes; then it was poured into a 10% aqueous solution of sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography

(silica gel, solvent for elution dichloromethane: hexane 9: 1) a 2- (1-acetoxyethyl) -2- (5-bromo-6-methoxy-2-naphthyl) -1, 3-dioxolan-4 diastereoisomer mixture ( R), (5R) dimethyl ester 15 and 16 of dicarboxylic acid (0.7 g; 1.37 mmol; yield 40%) in a ratio of 15:16 65:35 (determined by H-NMR and HRP). Crystallization of methanol gave a diastereomeric mixture in the ratio 15:16 95: 5,

 H-NMR (90 MHz, CDcij-tetramethylsilane), s (h / th):

Diastereoisomer 15 (basic): 1.28 (3N, d, Hz); 1.93 (3N, S); 3.47 (3N, S); 3.87 (3N, S); 4.00 (3N, S); 4.96 (2H, ABg, 4y 12.35, J g 5 Hz); 5.38 (W, g, Hz); 7.23-7.30 (5H, aromatic protons).

Diastereoisomer 15 (minor): 1.23 (3N, d, Hz); 2.05 (3N, S); 3.60 (3N, S); 3.87 (3N, S); 4.00 10 (3N, S); 4.90 (2H, ABg,, 96, Hz); 5.38 (1H, g,); 7.23-8.30 (5H, aromatic protons).

Example 10. Preparation of a diastereoisomeric mixture of 2- (1-acetoxy-15 ethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (K), 5 (K) - dimethyl ester of icarboxylic acid.

2g Acetoxyg1, -dimethoxy-1- (6-metoxy-2-naphthyl) propane (23.5 g, 20 73.8 mmol) was added under the action of argon to the solution obtained by heating at 65 ° С a mixture of 2 (R) , 3 (K) -di-hydroxy-dimethyl ester of ethanedi-arboxylic acid (150 g), tin-25 loride (15.6 ml) and methanesulfonic oxides (0.8 g, 7.4 mmol). The reacting mixture was heated at 95 ° C for 30 minutes, then it was poured into an aqueous solution of sodium bicarbonate and Ext-30 agitated with dichloromethane. The combined organic extracts were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. 35

Purification of the residue by chromatography in a column (silica gel, eluent dichloromethane: hexane 7: 3) gave a 2- (1-acetoxyethyl) -2- (6-me- 10) diastereoisomeric mixture.

toxi-2-naphthyl) -1, 3-dioxolan-4 (R), 5 (k) -dimethyl ether 7 and 18 of dicarboxylic acid (15 g | 34.7 mmol yield 47%) in the ratio 17:18 64:36 (certain N-ЖР and THEIR). 45

 H-NMR (90 MHz, CBC1-tetramethylsilane), f (h / th):

Diastereoisomer 17 (basic): 1.23 (3N, d,); 1.95 (3N, S); 3.45 (3N, S); 3.83 (3N, S); 3.88 (3N, 50 S); 4.90 (2H, ABg ,, 62 ,., 4 Hz); 5.33 (IH, g, J 6 Hz-); 7.06-8.00 (6H, aromatic protons).

Diastereoisomer 18 (minor): 1.20 (3N, d, Hz); 2.00 (3N, 55 S); 3.57 (3N, S); 3.81 (3N, S); 3.88 (3N, S); 4.80 (2H, ABg, Lii l5.54, 6 Hz); 5.33 (W, g ,, Hz);

7.06-8800 (bN; aromatic protons).

Example 11, Preparation of a dystereoisomer of a mixture of 2 (1-hydroxygtil} - 2- (6-methoxy-2 - naphthyl) -1,; 3 - dioxolane-4 (R), 5 (K) dimep-1l dicarboxylic ester.

A solution of a diastereoisomeric mixture of 2- (1-acetoxyethyl) -2- (6 methoxy-2- naphthyl) -1,3-dioxolane 4 (R), 5 (K) –dimethyl 17 ester of 17 and 18 dicarboxylic acid in a ratio of 17 : 18 1: 1 (4.33 g I 10) in methanol (20) was added dropwise at room temperature in pacTBQp sodium hydroxide (4 g; 1000 mol) in water (40 ml). The reaction mixture was quenched at room temperature for 24 4j, then acidified with concentrated hydrogen chloride and extracted with diethyl ether. The combined organic extracts were washed with water, dried with sodium sulfate and filtered. Evaporation of the solvent and under reduced pressure gave a diastereomeric mixture of 2- (1-hydroxyethyl) -2- (6-methoxy 2-naphthyl) -1.3-dioxolane-4 (R), 5 (R) -dicarboxylic acid (3.26 g },

The obtained raw material was added to a solution of methanesulfonic acid (0.086 g, 65.9 1 mol) in methanol (300 Nm). The solution was heated in a B vessel under reflux for Z hours, cooled at room temperature, diluted with dichlorote (100 ml) and added to water (100 liji). The organic phase was separated 5 with water and with a 2% aqueous solution of sodium bicarbonate, dried with sodium sulphate and filtered. The reaction raw material obtained by evaporation of the rarer at reduced pressure: crystallized from methanol to obtain a 2- (1 G1: droxylethyl) -2- (6-metoxy 2-naphthyl) -1 diastereoisomeric mixture, . 3-dioxolane 4 (K) s 5 (R) -ui; KM3THnoBoro esters of 19 and 20 dicarboxylic acid (3 g; 7.7 mmol I in hrs: o 77%) in the ratio 19:20 56:44 (.determined H- NMR)

 (90 MHz, CDCl.-tetramethyl-C1shan); J (h / th)

Diastereoisomer J9 (with a scoop): K06 (3N, d., Hz); 3.13 (IH, d, 5 Hz); 3.30 (3N, S); 3.83 (ZN, S) 5 3.50 (ZN, S) j 4/16 (W, dgs

- Sun, 6 Hz, JcH-oH 7.5 Hz); 5.06 (2H, ABg, 4), 2 Hz); 7.13-8.00 (6H, aromatic protons).

Diastereoisomer 20 (minor): 1.3 (3N, d, Hz); 3.13 (1H, d, 5 Hz); 3.56 (3N, S); 3.82 (3N, S); 3.90 (3N, S); 4.16 (1H, dp, JCM-CH 6 Hz, JCH-CH 7.5 Hz); 4.97 (2H, ABj ,, 94,, 5 Hz); 7.13-8.00 (bN, aromatic protons).

Example 12, Preparation of a diastereomeric mixture of (4-methyl-phenylsulfonyloxy) -ethyl -2- (6-metoxy-2-naphthyl) -15 3-dioxolane-4 (K), 5 (I) -dimethyl dicarboxylic ester .

A solution of 1.1 dimethoxy-2- (4-methyl; phenylsulfonyloxy) -1- (6-methoxy-2-. Naphthyl) propane (15 g; mmol) in H, 2-dichloroethane (iOO ml) was added dropwise under the action of argon in the solution obtained by heating at 95 C a mixture of 2 (R), 3 (K) -dihydroxy-dimethyl ester of ethanedicarboxylic acid (75 g), thionyl chloride (7.5 ml) and methanesulfonic acid (0.37 t; 3 , 8 mmol), the reaction. The lean mixture was heated at 25 ° C for 1 hour and 1,2-dichloroethane was distilled off during this time. Then the reaction mixture was poured into 10% aqueous solution-bicarbonate; sodium and extracted with dichloromethane.

Purification of the residue by chromatography in a column (silica gel; solvent for eluirs & no dichloromethane: hex-) gave the diastereoisomer; nom "Combined organic extracts; tracts were washed with water, dried the sul-35 mixture with 2- (1-methanesulfonyl-sodium-sodium, filtered over and concetyl) -2- (6-methoxy-2-naphthyl) -1,3-were centered in vacuo.

Purification of the residue by chromatography in a column (silica gel, eluent dichloromethane: hexane 40, ratio 23:24 63:37 (definitely 8: 2) gave diastereoisomeric. H-NMR and HRP). Crystallization of meta- mixture of 2- 1- (4-methylphenylsulfonyloxy) -ethyl -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (K) -dimethyl

dioxolan-4 (K), 5 (K) -dimesh1 Ovo ether 23 and 24 of dicarboxylic acid (20 g; 42.7 mmol, yield 63%) in sonol gave a diastereoisomeric mixture in a ratio of 23 (RRS): 24 (RRR) 80: 20.

 H-NMR (90 MHz, CDCl1-tetramethyl-45 silane), s (h / th):

ethers 2 and 22 of dicarboxylic acid (10.8 g; 19.81 mmol; yield 57%) in a ratio of 21; 22 40:60 (determined by H-NMR and HRP),

Diastereoisomer 22 (main): 1.40 (3N, d, Hz); 2.30 (3N, S); 3.43 (3N, S); 3.8G (3N, S); 3.90 (3N, S); 4.80 (2H, S); 4.90 (W, g, J 6 Hz); 6.90-7.80 (YUN, aromatic Distereoisomer 24 (RRR): 1.3 (ZN, d, Hz); 2.93 (ZN, S); 3, (ZN, S); 3.80 (ZN, S); 3.90 (3N,

cue protons

Diastereoisomer 21 (minor- 55 ° Hz); 4.97 (2H, ny): 1.37 (3H, d, Hz); 2.26 (ЗН, ABg, Л) П, 94, 3 Hz); 7.0b-S); Z.LZ (ZN, S); 3.83 (3N, S); 4.76 (2H, S); 4.90 (W, g, Hz); 6.90- 7.80 (10Н aromatic protons).

8.00 (6H, aromatic protons)

Example 14, Preparation of (6-methoxy-2-naphthyl) -gilovogs

Purification by column chromatography (silica gel, elution solvent: dichloromethane: hexane 1: 1) yielded the pure basic diastereoisomer 22.

Example 13: Preparation of 2- (1-methanesulfonyloxyethyl) -2- (6-methoxy-2-naphthyl) -, 3-dioxolane-4 (R), 5 (K) - dimethyl ester of dicarboxylic acid.

A solution of 1,1-dimethoxy-2-methanesulphonyloxy - (6-methoxy-2-naphthyl) -propane (24 g, 68 mmol) in 1,2-dichloro

ethane (140 ml) was added dropwise under the action of argon to the solution obtained by heating with

Si 2 (R), 3 (K) -dihydroxy dimethyl butanediic ester 120 g of thionyl chloride (12 ml) and methanesulfonic acid (0.6 g; 7.4 mmol). The reaction mixture was heated at 125 seconds for 1 hour. During this time, 1,2-dichloroethane was distilled off. Then react mixture

poured into 10% aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic extracts were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo.

Purification of the residue by column chromatography (silica gel; solvent for eluirs & dichloromethane: hex-) gave a 2- (1-methanesulfonyloxy-ethyl) -2- (6-methoxy-2-naphthyl) -1,3- diastereomer mixture

a mixture of 2- (1-methanesulfonyloxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-

the ratio of 23:24 63:37 (definite H-NMR and HRP). Crystallize Meta

dioxolan-4 (K), 5 (K) -dimesh1 Ovo ester 23 and 24 of dicarboxylic acid (20 g; 42.7 mmol, yield 63%) in the ratio 23:24 63:37 (definite H-NMR and HRP) . Crystallization meta-

nola gave a diastereomeric mixture in the ratio of 23 (RRS): 24 (RRR) 80:20.

 H-NMR (90 MHz, CDCl1-tetramethylsilane), s (h / th):

Diastereoisomer 23 (RRS): 1.38 (3N d, Hz); 2.93 (3N, S); 3.37 (3N, S); 3.90 (3N, S); 4.80 (1H, g, J 6 Hz), 5.03 (2H, ABg, 09, J 4.2 Hz); 7.07-8.00 (6H, aromatic protons).

Diastereoisomer 24 (RRR): 1.38 (3N, d, Hz); 2.93 (ZN, S); 3.53 (ZN, S); 3.80 (3N, S); 3.90 (3N, S);

   ° Hz); 4.97 (2H, ABg, L) P, 94, 3 Hz); 7,0b-

8.00 (6H, aromatic protons).

Example 14, Preparation of 2- (6-methoxy-2-naphthyl) -megyl ether 10

1 U31678

pa propanoic acid from a diastereoisomeric mixture of 2- (1-methaneulfonyl-hydroxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-A (R), 5 (I) -dimethyl dicarboxylic ester in the ratio of 80:20.

Diastereoisomeric mixture of 2- (1-methanesulfonyloxyethyl) -2- (6-methoxy-2-naphthyl) -1, 3-dioxolane-4 (R), 5 (R) - dimethyl ether 23 and 24 dicarboxylic acid in a ratio of 23: 24 80:20 (1 g, 2.13 mmol), methanol (7.5 ml) and water (2.5 ml) were heated in a sealed tube at 150 ° С for 5 h. The reaction mixture was cooled at room temperature, diluted with water and extracted with diethyl ether. The combined organic extracts were washed with water, dried, filtered and concentrated in vacuo.

Purification of the residue by chromatography in a column gave 2- (6-methoxy-2-naphthyl) methyl propanoic ester (0.4 g; 1.64 mmol, yield 77%).

M.p. . UJ + 48.02 ° (, chloroform).

 H-NMR (200 MHz) analysis was performed by column chromatography (silica gel, eluent: hexane: 1: 1 diethyl ether). Pure acid (4.83 g; 21 mmol, 70% yield) was obtained in 50% optical purity (enantiomeric excess). M.p. 154-155 C.

HRP analysis showed an enantimeric S (+): R (-) ratio of 75:25.

The enantiomeric ratio was confirmed by H-NMR (200 MHz) by the analysis carried out by the method described in Example 14 on the corresponding methyl ester.

Example 16. Preparation of 2- (6-methoxy-2-naphthyl) -propionic acid from 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1, 3-dioxolane-4 (R), 5 (R) - 20 N, N, N, N amide of tetraethyl dicarboxylic acid.

A mixture of two diastereoisomers of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxanol-4 (R), 5 (R) -N, N, N, N amide 25 of tetraethyl 13 and 14 dicarboxylic acid in a ratio of 13:14 1: 1 (1.07 g; 2 mmol) and water (4 ml) were heated with stirring with

15

16 h (acid pH). After the operations, which were performed in CDC1J using pea-30 described in Example 15, and purifying the transfer agent (europium III by chromatography in a column (silica gel, (C-) entafluoropropylhydroxymethylene, camphrate), showed the enantiomeric ratio S (+): R (-) 80:20.

Example 15. Preparation of 2- (6-methoxy-2-naphthyl) -propanoic acid From a diastereoisomeric mixture of 2- (I-bromoethyl) -2- (6-methoxy-2-naphthyl) -1, 3-dioxolane-4 (R ), 5 (R) -dicarboxylic acid.

A mixture of two diastereoisomers of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolan-4 (R), 5 (R) -dicarboxylic acid 5 and 6 in a ratio (12.75 g; 30 mmol) and aqueous liquor from 2- (1-chloroethyl) -2- (6-methoxy-thief (180ml), prepared rast-2-naphthyl) -1,3-dioxolane-4 (R) , 5 (R) - by fermentation (26.1 g) of dicarboxylic acid. (5.7 g) in water (384 ml), heated. The mixture of two diastereoisomers of 2- (1- with stirring, with chloroethyl) -2- (6-methoxy-2-naphthyl) -1.3% h. The reactive mixture is cooled with dioxanol-4 (R), 5 (R) -dicarboxylic, or at room temperature (pH 3.7) - .-- ..h

acidified with concentrated HCl to pH 1 and extracted with diethyl ether (ml). The combined organic extracts were washed with water and — g, while stirring with heat, dried with sodium sulfate. Evaporation. The reaction mixture was cooled by the solvent under reduced pressure, the raw materials were obtained. 2-Sat-methoxy-2-naphthyl) propanoic acid, which

elution solvent hexane: diethyl ether 1: 1) obtained pure 2- (6-methoxy-2-naphthyl) propanoic acid (0.124; 0.54 mmol, yield 27%) with 40% optical purity. M.p. 154-155 ° C. 0, +26.4 (chloroform),

The enantiomeric ratio of S (+):

40 R (-) 70:30 confirmed by HRP and H-NMR analyzes carried out by the method described in Example 15.

Example 17. Preparation of 2- (6-methoxy-2-naphthyl) -propionic acid 9 and 10 in a ratio of 9:10 1: 1 (324 mmol) and an aqueous solution (168 ml: (14.6 g) and: (38 , 19 g), having a pH of 6.6, was heated at room temperature (pH 5.7), acidified with concentrated HCl to pH 1 and extracted with diethyl

purified by column chromatography (silica gel, eluent: hexane: 1: 1 diethyl ether). Pure acid (4.83 g; 21 mmol, 70% yield) was obtained in 50% optical purity (enantiomeric excess). M.p. 154-155 C.

HRP analysis showed an enantimeric S (+): R (-) ratio of 75:25.

The enantiomeric ratio was confirmed by H-NMR (200 MHz) by the analysis carried out by the method described in Example 14 on the corresponding methyl ester.

Example 16. Preparation of 2- (6-methoxy-2-naphthyl) -propionic acid from 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1, 3-dioxolane-4 (R), 5 (R) - 0 N, N, N, N amide of tetraethyl dicarboxylic acid.

A mixture of two diastereoisomers of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxanol-4 (R), 5 (R) -N, N, N, N amide 5 of tetraethyl 13 and 14 dicarboxylic acid in a ratio of 13:14 1: 1 (1.07 g; 2 mmol) and water (4 ml) were heated with stirring with

five

16 h (acid pH). After the operations described in example 15, and purification by chromatography in a column (silica gel,

lots of 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) - dicarboxylic acid. A mixture of two diastereoisomers of 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1.3-dioxanol-4 (R), 5 (R) -dicarboxylic - .-- ..h

elution solvent hexane: diethyl ether 1: 1) obtained pure 2- (6-methoxy-2-naphthyl) propanoic acid (0.124; 0.54 mmol, yield 27%) with 40% optical purity. M.p. 154-155 ° C. 0, +26.4 (chloroform),

The enantiomeric ratio of S (+):

R (-) 70:30 confirmed by HRP and H-NMR analyzes carried out using the method described in Example 15.

Example 17. Preparation of 2- (6-methoxy-2-naphthyl) -propionic acid from 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) - dicarboxylic acid. A mixture of two diastereoisomers of 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1.3-dioxanol-4 (R), 5 (R) -dicarboxylic - .-- ..h

whether under stirring with during the course of time. The reactive mixture is cooled

acids 9 and 10 in a ratio of 9:10 1: 1 (324 mmol) and an aqueous solution (168 ml: (14.6 g) and: (38.19 g), having a pH of 6.6, were heated with stirring at - reading software. Reactive coolant mixture

was given at room temperature (pH 5.7), acidified with concentrated HCl to pH 1 and extracted with diethyl 31

white ether (. -; 50 ml), 0 ;; Nychesku; about the phase of extractant hryvatsh 10% -H; 1M water: solution of sodium bicarbonate (4, s60 ml) Combined water and 5-1 extracts, acidified to pH 1 and extracorporeal. and basal - ethyl ether (4-90 ml) “Combined organic) phase was washed with water, dried with sodium sulfate and concentrated, in vacuo,

The residue (4s 8 g), 2-, di: ethoxyethane (.72 ml) and concentration of HC1: (36 ml) is heated with stirring at 75 ° C for 2 hours.

After treatment with a reactive mixture, such as the onsicario in Example 5, and purification by column chromatography (elicke ™ gel), the solution was expanded for hexane, diethyl sulfate 7 ° 3} and PI chist K 2 - (6 -; - 1etox - 2- naphthyl) - about pan KISM1OGU in 48% optical purity

Gs. - 31.6 (lorophorc),

En-antiomeric ratio S (-5-) i R (-) 74; 26 confirmed W; and H-NMR analyzes; those cited are described in example 15 "

PRI me R 18, Blend, h, woo. 2 ™ diastereoisomers (1-chloroethyl) -2- (b-meth-hydroxy 2-naphthy) -1 g 3-dioxolane-DCE)., 5 (R) dicarboxylic acid 9 and 10 in ratio ... (10; - (mol) and aqueous solution. (140 ml) 20 g and grgdroksya sodium (I g), having a pH of .. 9 kip std in a vessel with oepaTHbiNS. ColoDilnir: ohm in the fire 240 h

Reagirlt (mixture of OH.P., 1; Il1- at room temperature (pH, 6) and treated with the method described in Example 17 „

Semi-zhlry pure 2- (6th and then to SI-2 naphthyl) -propane o-vuyu kkslotz in 62% optical purity

Ha - 40.9 (C-1%,: storoform),

The enantiomeric ratio is better than 8 (4-); . R () 81n9 confirmed by HRP and H-5ShR analysf), J was carried out as described in Example 15

At; m and p 19 o A mixture of two .cyastereoisomers of 2- (1-bromoethyl) -2 (mo - 6-metho: cc1t -2 - nsfthyl), 3-dioxyl-4 (R) s 5 (E .) -, srlcarboxylic acid 25 and 26 in the ratio of W 25126 1: 1 (2.52 g; 5 mmol; .- j prepared using the method of Example 2, starting with diastereoisomers Pn; 2; and an aqueous solution (70 ml) КЬЬ / РО (10 g) to sodium hydroxide (К4 g) ;, having a pH of 6, heating up to about 5 h.

78 14

on a mixture of ossp: ad1 -; .. 11i at room temperature (pH 5.9) and treated by the method of example 15,

Got pure e- 2- (5-bromo-6 methoxy-2 naphthyl) propane 0 acid (0–83 g | 2.7 myol 54% yield) in 70%

poultry-clean. Mp ...

& /, + 29., 4 ° (, - chloroform).

The enantiomeric ratio S (+) g of 1 (™) 85M5 was confirmed; de-HRP and H-NMR anal: izamIe realized as described in: example 15 „

Example 20 “Mixtures of two diastereoisomers of 2- (1-bromoethyl) -2- (5-bromo-b-methoxy-2 -aphthyl). 3-dioxolane4 (R) e 5 (I) -dicarboxylic acid 25 and 26 in a ratio 25s26 III (2.52 g,

5 mmol) and an aqueous solution (70 ml) (10 g) to sodium hydroxide iOsS g) p having a pH of 5.15, heated at 90 ° C for 52 hours. The reacting mixture was cooled at room temperature (pH 4j40) and treated in the manner described in the example. 15.

Pure 2- (5-bromo-6-methanoxy-2-naphthyl) propanoic acid (Oj72 g | 2.33 mmol) was obtained in 58% optical purity. T, pl, 68170 C,

Gs; .d ,, 8 ° (, 5%, chloroform)

Enaytomeric ratio S (+): R (-) 84; I6 was confirmed by HRP and analyzes, as described in Example 15

EXAMPLE 21 Preparation of a 2 (K) -hydroxy-3- (R) r2 (6-methoxy-2-naphthyl) -propano-rsh dimethyl butanethiol-acid dimethyl ester di-stereoisomeric mixture.

A solution of triethylamine (4.45 g; 0.044 mol) in dichloromethane (10 ml) was added dropwise at -10 ° C over 5 minutes to a Mixture of 2 (R), 3 (E) -dihydroxydimethyl ether butanedis - lots (44.5 g; О ,, 25 mol) and dichloromethane (90 ml); To the obtained mixture add a solution of 2- (6-methoxy-2) dropwise at -10 ° C for 20 minutes -naf-) -propionne chloride (5 g | 0.02 mol) 3 dichloromethane (25 ml). The reaction mixture was poured into a 10% aqueous solution of sodium bicarbonate (200 ml) and extracted with dichloromethane (100 ml). The organic phase was washed with dilute HC1 water and dried over sodium sulfate. By evaporation of the solvent under reduced pressure, a raw diastereomeric mixture of 2 (K) -hydroxy-3 (K) (6-methoxy-2-yaphthyl) propanoyl 3-dimethyl ether A and B butanediic acid (5.5 g) was obtained in a ratio ( certain H-NMR).

 (200 MHz, CDCl1-tetramethylsilane), ((h / th)): all data are identical to those for diastereoisomers Q A and B of Example 4,

Crystallization of methanol, induced by the pure crystalline diastereoisomer A, gave pure diastereomer A (RRS). M.p. 77-79 ° C. 15 Cc / Jj, - - -

An example of a isomeric mixture of 2- (1-bromoethyl) -2- (6-methoxy-2-naphtsh1) -1,3-dioxolan-4 (S, 5 (K) -di-20-carboxylic acid dimethyl ester)

A solution of 1,1-dimethoxy-2-bromo-1 (6-methoxy-2-naphthyl) propane (11.8 g, 34.8 mmol) in 1,2-dichloroethane (100 ml ) 25 added; 1 to a solution obtained by heating a mixture of 2 (R) dimethyl ester, 3 (R) -dioxycarboxylic borate acid (75 g), thioyl chloride at 95 ° C

+ 73.7 (, chloroform), p 22, Preparation of diaste (100 ml) was added dropwise in an argon atmosphere to a solution obtained by heating at 95 ° C a mixture of dimethyl ether 2 (R), (LC) -dioxybutane-dicarbonate acids (75 g), thionyl chloride (7.5 ml) and methanesulfonic acid (0.37 g, 3.8 mmol). The reaction mixture was heated at 125 ° C for 1 hour; at this time, the distillate was 1,2-dichloroethane. Then the reaction mixture is you; and-; dried in 10% sodium bicarbonate aqueous solution and extracted with dichloromethane. The combined organic extracts were washed with water, dried over sodium sulfate, filtered, and concentrated under vacuum. Purification of the residue using column chromatography (silica gel; eluant dichloromethane: hexane 8: 2) gave a diastereoisomeric mixture of 2- (1-iodoethyl) dimethyl ether -2 - (6-methoxy-2-naphthyl) -I, 3-dioxolane-4 (R), 5 (R) -dicarboxylic acid 25 and 26 (5.29 g, 10 mmol, yield 29%) in a ratio of 1 :one.:

 H-NMR (200 MHz,), Wed (ppm):

Diastereoisomer 25 (RRS): 1.80,

(7.5 ml) and methanesulphonic acid (0.37 g, 30 (ZN, doublet, Hz); 3.44 (ZN, singlet); 3.84 (ZN, singlet); 3.90. (ZN, singlet) ; 4.58 (1H, quartet, Hz); 4.95 (2H, AB-quartet,, 70, V 6 Hz); 7.8-8.0 (6H, multiplet).

Diastereoisomer 26 (RRR): 1.80 (3N, doublet, J = 7 Hz); 3.58 (SA, singlet); 3.84 (SA, singlet); 3.90 (SA, singlet); 4.58 (1H, quartet, Hz); 4.87 (2H, AV-quartet,, 04, 8 Hz); 7.8-8.0 (6H, multiplet).

EXAMPLE 24 Ketalization of DI-- 2-bromo-1- (6-methoxy-2-naphthyl) propan-1-one ethyl ester 2 (R), 3 (R) -dioxybutane dicarboxylic acid ( L {+) 3, 8 mmol). The reaction mixture was heated for 1 hour and 1,2-dichloroethane was distilled off during this time.

Then, the reaction mixture was poured into 10% aqueous sodium bicarbonate solution and extracted with dichloromethane.

The combined organic extracts were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue using column chromatography (silica gel, eluent dichloro35

40

50

methane: hexane 8: 2) received diastereo-45 with diethyl tartrate). an isomeric mixture of 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1, 3-dioxolane-4 (R), 5 (R) -dicarboxylic acid dimethyl ester 1 and 2 ( 7.2 g, 15 mmol, yield 43%) in 1: 1 fusion (determined by H-NMR and zhvd).

PRI me R 23. Preparation of a diastereomeric mixture of 2- (1-iodo-ethyl) -2- (6-methoxy-2-naphthyl) dimethyl ether -1, 3-dioxolane-4 (R), 5 ( K) -carboxylic acid.

A solution of 1, l-dimethoxy-2-yod-l- (6-methoxy-2-naphthyl) propane (13.5 g, 34.8 mmol) in 1,2-dichloroethyl

55

A mixture of 2-br. Ohm-1- (6-methoxy-2-naphthyl) propan-1-one (1.465 g, 0.005 mol) b (+) - diethyl tartrate (10 g), triethyl orthoformate (3 g) and sulfuric acids (1 g) were kept under stirring under a nitrogen atmosphere at 90 ° C for 60 hours. The reaction mixture was poured into a 10% aqueous solution of sodium carbonate and extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. By stripping the solvent under reduced pressure, a crude product was obtained, which was purified by column chromatography (100 ml) dropwise under an argon atmosphere and added to a solution obtained by heating a mixture of dimethyl ether 2 (R), (ZK) -dioxybutane at 95 ° C. dicarboxylic acid (75 g), thionyl chloride (7.5 ml) and methanesulfonic acid (0.37 g, 3.8 mmol). The reaction mixture was heated at 125 ° C for 1 hour; at this time, the distillate was 1,2-dichloroethane. Then the reaction mixture was poured into a 10% aqueous solution of sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were washed with water, dried over sodium sulfate, filtered, and concentrated under vacuum. Purification of the residue using column chromatography (silica gel; eluant dichloromethane: hexane 8: 2) gave a diastereoisomeric mixture of 2- (1-iodoethyl) dimethyl ether -2 - (6-methoxy-2-naphthyl) -I, 3-dioxolane-4 (R), 5 (R) -dicarboxylic acid 25 and 26 (5.29 g, 10 mmol, yield 29%) in a ratio of 1 :one.:

 H-NMR (200 MHz,), Wed (ppm):

Diastereoisomer 25 (RRS): 1.80,

35

40

diethyl tartrate).

A mixture of 2-br. Ohm-1- (6-methoxy-2-naphthyl) propan-1-one (1.465 g, 0.005 mol) b (+) - diethyl tartrate (10 g), triethyl orthoformate (3 g) and sulfuric acids (1 g) were kept under stirring under a nitrogen atmosphere at 90 ° C for 60 hours. The reaction mixture was poured into a 10% aqueous solution of sodium carbonate and extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. By stripping the solvent under reduced pressure, a crude product was obtained, which was purified by column chromatography.

By graph (silica gel; eluent hexane; diethyl).

A mixture of two diastereoisomers 27 and 28 of 2- (1-bromoethyl) -2- (6-methoxy-2-Iaptil), 3 dioxolan-4 (R), 5 (K) -di-carboxylic acid diethyl ester was obtained. (0.96, 0.002 mol) with a ratio of 1; 1 (determined by H-NMR, 200 MHz).

 H-NMR (CDCl1-TMC) (200 MHz):

Diastereoisomer 27 (RRS), e / (h / npn)), 04 (triplet, 3N, J «7 Hz) | 1.31

(triplet, 3N, Hz); 1.65 (Oak- Years, 3N, 8 Hz) 5 3.92 (double-110 Quartet, 2H, Jn, 3 Hz, Hz); 3.98 (singlet, ZN); 4.3 (quartet, 2H,. Hz); 4.48 (quartet, Ø,, 8 Hz) f, 88 (AB quartet, 2H, 5 Hz); 7.2-2.2 (6H, aromatic protons). , I Diastereoisomer 28 (RRR), (/ (ppm), 09 (triplet, 3N, Hz); 1.62 ((doublet, 3N, 8 Hz); 3,98 (syn-summer, 3N) ; 4.29 (quartet, 2H, J Hz); 4.85 (AB-quartet, 2H, J "6.5 Hz); 7.2-8.2 (6H, aromatic protons).

Example 25. Ketali aci 2-bromo-1-4- (2-methylpropyl) phenyl-Pr07 | pan-1-it is dimethyl ether 2 (R),. 3 (R) -dioxycarbonyl acid (b (+) - dimethyl tartrate),

A mixture of 2-bromo-1- {4- (2-methylpropyl) phenyl propan-1-one (1.345 g, 3.005 mol), b (+) - dimethyl tartrette (7.5 g), trimethyl orthoformate (2.5 g, 0 , 0236 mol) and trifluoromethanesulphonic acid (0.075 g, 0.0005 mol)

lived in mixing and 90 ° C

A mixture of 2-bromo-3-methyl-1- (4 chporphenyl) butan-1-one (1.38 g, 0.005 mol) 2 b (+) - dimethyl tartrate (7.5 g), trimethyl orthoformate (2.5 g, O, 0236 mol) and trifluoromethanesulfonic acid (0.075 g 0.0005 mol) were held under nitrogen with stirring and at 90 ° C for 60 hours. The reaction mixture was poured into a 10% aqueous solution of sodium carbonate and extracted with dichloromethane. The organic phase was washed with water and sodium hydrogen sulfate. By melting the solvent in vacuo a crude product was obtained which was purified by column chromatography (silica gel; eluent hexane: diethyl ether 8: 2). In the atmosphere of nitrogen for 48 h. Reak-40 radiated a mixture of two diastereoisomers

45

The resulting mixture was poured into a 10% aqueous solution of sodium carbonate and extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. By evaporation of the solvent under reduced pressure, a crude product was obtained, which was purified by column chromatography (silica gel; eluent hexane: diethyl ether 8: 2). A mixture of two diastereoisomers 29 and 30 of dimethyl ester of 2- (l-bromo-ethyl) (2-methylpropyl) phenyl 1, 3-dioxolane-4 (R), 5 (R) -dicarbonic acid (0.64 g, 0, 00175 mol) in a 1: 1 ratio (determined using H-5ShR 200.MHz). H-NMR (CBC1-TMS) (200 MHz: Diastereoisomer 29 (RRS), cC (h / mlm); 0.87 (doublet, 6H, 4 Hz); 1.61

50

31 and 32 dimethyl ester 2- (1-bromo 2-methylpropyl) -2- (4-chlorophenyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid (1.09 g, 0 , 0025 mol) in a 1: 1 ratio (determined by H-NMR, 200 MHz).

The proposed method allows to obtain ketals of alpha-substituted ketones of the formula

Ag-CO-CHS b (+) - tartaric acid or D (-) - BHH-acid.

Using L (+) - tartaric or D (-) - tartaric acid as the catalysis agent, the target optically active alpha-arylactivate is selectively obtained as the main isomer.

(doublet, ZN, L-7, GHz); 1.84 (triplet, 1H, Jc (f-CH3 6.4 Hz, JCH-C "Z

7.1 Hz); 2.45 (doublet, 2H, l Hz), 3.53 (singlet, 3N); 3.84 (singlet, ZN); 4.38 (quartet, 1H, l Hz); 4.9 (AB, 2H, J-5.9 Hz); 7-7.4 (AA BB 4H, aromatic protons),

Diastereoisomer 30 (RRR), “(ppm), 0.87 doublet, 6H, 4 Hz); 1.58 (doublet, NN, l Hz); 1.87 (triplet, W, JcH-CHj 6.4 Hz, JcH-CHj 7.1. Hz); 2.53 (doublet, 2H, l Hz); 3.6 (singlet, SN); 3.83 (singlet, ZN) 4.41 (quartet, W, l Hz); 4.85 (AB, m2H, 5 Hz); 7-7.4 (AA vB, 4H, aromatic protons).

EXAMPLE 26. Ketalization (2-bromo-3-methyl-1- (4-chlorophenyl) butan-1-one) 2 (R) dimethyl ether, 3 (R) -dioxy-butanedicarboxylic acid (L (- ) -dimethyl tartrate) o

A mixture of 2-bromo-3-methyl-1- (4 chorphenyl) butan-1-one (1.38 g, 0.005 mol) b (+) - dimethyl tartrate (7.5 g), trimethyl orthoformate (2.5 g , O, 0236 mol) and trifluoromethanesulfonic acid (0.075 g, 0.0005 mol) were held under nitrogen with stirring and at 90 ° C for 60 hours. The reaction mixture was poured into a 10% aqueous solution of sodium carbonate and extracted with dichloromethane. The organic phase was washed with water and sodium hydrogen sulfate. By melting the solvent under vacuum, the crude product was obtained, which was purified by column chromatography (silica gel; eluent hexane: diethyl ether 8: 2). By

31 and 32 dimethyl ester 2- (1-bromo-2-methylpropyl) -2- (4-chlorophenyl) -1,3-dioxolane-4 (R), 5 (R) -dicarboxylic acid (1.09 g, 0 , 0025 mol) in a 1: 1 ratio (determined by H-NMR, 200 MHz).

The proposed method allows to obtain ketals of alpha-substituted ketones of the formula

Ag-CO-CHS b (+) - tartaric acid or D (-) - BHH-acid.

Using L (+) - tartaric or D (-) - tartaric acid as the catalysis agent, the target optically active alpha-arylactivate191431678 is selectively obtained as the main isomer.

This acid, in Examples IA-20, shows that starting from ketals with optically active tartaric acid, arylalkane acids can be obtained

78

20

lots in the form of a mixture enriched with the target isomer, as a rule (+) - isomer:

14 - the ratio of enantiomers S (+): R (-) 80:20 15 - 75:25

16 - I7 - 18 - 19 - 20 70:30 74:26 81:19 85:15 84:16

When using catalytic agents other than tartaric acid in previously known methods, only racemic d-arylalkanoic acids were obtained.

Claims (1)

Invention Formula The method of obtaining optically active ketals of the formula I K, - Om. nl one ° x Ag substituted C-C „-Al - phenyl, with a kil or halogen atom, naphthyl substituted with lower alkyl, lower apkoxy group, or halogen atom; RI is C-C4 alkyl; Rj is the same, hydroxy, / Y –OR4 or N a group where R4 is lower alkyl-, Rj and R are both C, -C-alkyl; . X is a chlorine, iodine or bromine atom, a hydroxy group, a lower acyl-hydroxy group, an A-methyl-phenylsulfonyloxy group or a lower alkylsulfonyloxy group; carbon atoms marked with an asterisk are simultaneously in the R and S configurations, characterized in that g 0 five 0 five 0 0  70:30 74:26 81:19 85:15 84:16 L (+) or P (-) - tartaric acid or its derivative of formula II Rj-CO - CH - CH - CO -Rj I I OH OH where RJ and RJ have the indicated meanings, they are reacted with a ketone of formula III Ar - C - CH - R,, II I O X where Ar, R and X have the indicated meanings, or with a ketal of formula IV R70 OR  Ar CH - R, G X Where Ar, R, and X are as defined, R-7 and Rg-C-C-alkyl, in a current of inert gas in the presence of trifluoromethanesulfonic acid or sulfuric acid and trialkyl orthoformate at 50-90 s in the case of using a ketone of formula III or in the presence of thionyl chloride and methanes of ulfacid at 65 125 ° C in the case of using a catal of formula IV, the desired product of formula I is assigned, where R ,, or is converted into a compound of formula I, where, by the action of a strong base followed by acidification, or the product of formula I, where R. is converted into compound Formula I, where R R, the action of the amine. R,