SU1574167A3 - Method of obtaining arylalkanic acids - Google Patents

Abstract

This invention relates to the preparation of α-aryl-alkanoic acids of the formula AR-CH (R) -COOH, where AR is methoxynaphthyl, possibly substituted by bromine

RC ₁ -C ₄ -alkyl, which are used as anti-inflammatory and analgesic agents. The purpose of the invention is to conduct the process stereoselectively. Receiving lead by rearrangement of ketals in the aquatic environment in one stage at 90-100 ° C and RH 3.6-5.9 in the presence of buffer - K ₂ HPO ₄ / KH ₂ PO ₄ or KH ₂ PO ₄ / NAOH. THE METHOD ALLOWS TO RECEIVE STEREOISOMERS WITH A HIGHER CONTENT OF ONE OF THEM, WHICH CONTRIBUTES TO MORE SIMPLE THEIR SEPARATION.

Description

This invention relates to a new process for the preparation of o-arylalkanoic acids of general formula.

Cg-sn-soi

. -and,

where Ar is methoxynaphthyl, possibly substituted by bromine; R -. - alkyl, representing a large class of compounds, most of which are used as anti-inflammatory and pain relievers.

The aim of the invention is to conduct the process stereoselectively. (

Examples 1-11 illustrate the preparation of the starting compounds.

Example 1. Catalysis of 2- -bromo-1- (6-methoxy-2-naphthyl) -propan-1-one with 2 (B), 3 (I) -dihydroxy-dimethyl ether L (+) - butane acid - dimethyl tartrate.

A mixture of 2-bromo-1- (6-methoxy-2-naphthyl) propan-1-one (1.465; 0.005 mol), L (+) - dimethyl tartrate (7.5 g), three-1 m-methyl methane (2 , 5 rj 0.236 mol) and trifluoromethanes 0,0 phosphates (0.075 g; 0.0005 mol) are stirred while stirring at 50 ° C for 60 hours. The reaction mixture is poured into J 0% aqueous sodium carbonate and extracted with dichloromethane. The organic phase is washed with water and dried over sodium sulfate. Evaporation of the plant under reduced pressure affords the raw material, which is purified by chromatography in a column (silica gel, eluent of hexin: diethyl ether 8: 2).

A mixture of two diastereoisomers of 2- (1-bromoethyl) -2- (b-methoxy--2-naphtyp) -1, 3-dioxolane-4 (R), 5 (R) dimethyl ester (1) and ( 2)

cl

four

S

|

about

dicarboxylic acid (0.9 g,

0,002 mol) in the ratio (1) :( 2) 1: 1

(determined by n-NMR 200 MHz).

Diastereoisomer 1. (PRS).

4H-NMR (200 MHz, CBC13-tetramethylsilane) 8, h / tys: 1.68 (d, 3H, J 7.5 Hz) 3.54 (s, 3H H 3.90 (s, 3H J 4.08 (s, 3HX 4.48 (q, H, J 7.5 Hz); 4.94 (2H, ABq, i-5 26.8, J 7.2 Hz) 7.1-8 , 0 (6H, aromatic protons).

Diastereoisomer 2 (RRR).

4B-NMR (2.00 MHz, CDCl1-tetramethylsilane) 8, h / th. :; I, 64 (d, 3N, J 7.5 Hz) -, 3.58 (s, 3N); 3.89 (s, 3N); 4.08 (s, 3N); 4.50 (q, 1H, J 7.5 Hz); 4.89 (2H, ABq, AND 36.3. J 6.3 Hz); 7.1-8.0 (6H, aromatic protons).

Example 2. Preparation of a di- stereomeric mixture of 2- (1-bromoethyl) -2 -2 (6-methoxy-2 naphthyl) -1,3-dioxolane-4 (R), 5 (R) dicarboxylic acid in a ratio of 1 :one

&

n

p-soon

CH-CH3

Igp ir

CH3-0

A mixture of two diastereoisomers of 2- - (1-bromoethyl) -2- (6-methoxy-2-naphthyl -1, 3-dioxolan-4 (R), 5 (R) -diethyl ether (3) and (4) dicarboxylic acid (21.18 g | 0.014 mol) in the ratio (3) :( 4) 1: 1, caustic soda (3.52 g, 0.088 mol), dimethoxyethane (35 ml) and water (35 ml) is kept under stirring , at room temperature for 2 hours, the reaction mixture is diluted with water and extracted with diethyl ether. The aqueous phase is acidified with hydrogen chloride and extracted with diethyl ether. The organic phase is washed with water and dried with sodium sulfate. This pressure has two diastereoisomers of 2- (1-bromo-ethyl) -2- (b-methoxy-2-naphthyl) -1, 3- - (dioxolane) -4 (R), 5 (V.) -dicarboxylic acid ( 5) and (6) (16 g 0.0367 mole yield 85.5%) in the ratio (5) g (6) 1: 1 (determined by 1H-NMR 200 MHz).

The sample obtained by esterification in diethyl ether with diazomethane.

0

five

0

five

0

five

0

five

gives a mixture of two diastereoisomers 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1, 3-dioxolane-4 (R), 5 (P) -dimethyl ether (1) and (2) dicarboxylic acid in the ratio (J) :( 2) J: 1 (determined by FPLC and H-NMR 200 MHz). Preparative thin layer chromatography (HRP).

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

A mixture of 2-chloro-1- (6-methoxy-2-naphthyl) propan-1-one (} 2.4 g, 0.05 mol). 2 (P), 3 (P) -dimethyl ester of dioxibutic acid (75 g) and trimethoxymethane (25 g} 0.236 mol) is gradually heated to 50 ° C. Trifluoromethanesulfoxyloxy (2.4 g, 0.016 mol) was added to the solution. The reactive mixture is kept under the action of nitrogen at 50 ° C for 45 hours, then it is treated.

Purification of the obtained raw material (19.2 g) by chromatography in a column (silica gel, solvent for elution of hexane: diethyl ether 6: 4) gives a mixture of diastereoisomers (7) and (8) (5.6 g) in the ratio (7) :( 8 ) 52:48 (determined by HPLC).

Diastereoisomer 7 (RRS).

 I-NMR (200 MHz, CBC1e-tetramethylsilane), h / th: 1.49 (d, 3N, 6.65 Hz); 3,48 (з, ЗН); 3.85 (s, 3H); 3.89 (s, 3N); 4.41 (q, 1H, J 6.65 Hz) 5 4.95 (ABq, .2H, - J 6 Hz); 7.1-8.0 (6H, aromatic protons),

Diastereoisomer 8 (FRP).

H-NMR (200 MHz, CDC1} -tetramethyl-silane), S, h / th: 1.47 (d, 3N, J 6.65 Hz) 3.53 (s, 3H) i 3.83 (s , 3H) t 3.89 (s, 3H)} 4.44 (q, lH, 65 Hz), 4, 92 (ABq, 2H, Hz), 7.1-8, O (6H, aromatic protons) ,

Example 4. Preparation of 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -15Z-dioxolane-4 (R), 5 (R) -dicarboxylic acid.

Following the sequence described in Example 2, starting with a mixture of 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1, 3-dioxolane-4 (R), 5 (K) dimethyl ether diastereoisomers dicarboxylic acid (38.4 g4.0.094 mol) in the ratio (7): (8) 1: 1, as determined by NPH) to obtain a mixture of two diastereoisomers (9) and (10) (32.5 g 0.085 mol; 1 yield 90% ) in the ratio (9) :( 10U 1: 1.

515

Liastereomeric ratio is determined by NPH analysis carried out

on the obtained sample by esterification with diazomethane.

Diastereoisomer 9.

4 H-NMR (CBC1e tetramethylsilane) 0, ppm: 1.44 (d, 3N, J 6.85 Hz), 4.42 (q, 1H, J 6.85 Hz); 4.88 (ABq, 2H, J 6 Hz) 7.0-8.0 (6H, aromatic protons); 9.0 (s, 2H).

Diastereoisomer 10.

H-NMR (CDCl j-heterramethylsilane) L f h / th: 1.44 (d, 3N, J 6.85 Hz); 4.2fq, 1H, J 6.85 Hz), 4.82 (ABq, 2H, J 6.7 Hz), 7.0-8.0 (6H, aromatic protons)} 9.0 (s, 2H) .

Example 5. Preparation of 2- (1-bromoethyl) -2- 5-bromo-6-methoxy-2-naphthyl) -, 3-dioxolane-4 (RI, 5 (D) -diethyl dicarboxylic ester.

A solution of bromine (13.42 g; 0.084 mol) in carbon tetrachloride is added dropwise over 1 hour to a solution of two diastereoisomers of 2- (1-bromo-ethyl) -2- (6-methoxy-2-naphthyl) -1 , 3-dioxolane-4 (R), 5 (P.) - diethyl ether (3) and (4) dicarboxylic acid in the ratio (3): (4) 1: 1 (39.48 g, 0.082 mol) in tetrachloride carbon (457 ml), incubated, stirring, at 0 ° C and in an inert atmosphere. The reaction mixture was kept at 0 ° C for 1 hour, then it was poured into a well-mixed 10% aqueous solution of sodium carbonate (500 ml). The organic phase is separated, washed with water (ml) and dried with sodium sulfate. Evaporation of the solvent under reduced pressure gives a diastereomeric mixture of 2- (1-bromoethyl) -2- (5-bromo-6-methoxy--2-naphl) -1.3, dioxolane-4 (R) -diethyl ether (11) and (12) dicarboxylic acid (43.6 g; purity 98%) in the relation (11): (12) 1: 1 (determined by HPLC).

Example 6. Preparation of a 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolan-4 (P.), 5 (R) -N, N diastereomeric mixture , N, N-aMHfla of tetraethyl dicarboxylic acid

(CH3CH2) 2NCO. „H

ss

| Ржожсн2сн3) 2

  V °

I Р U f U I t.ri (.rl-j

l6O Br CH-jO 4

A mixture of two diastereoisomers 2- - (1-bromoethyl) -2- (6-methoxy-2-naphthyl)

0

five

one

0

5 .c

five

0

five

0

0

67 "

-1, 3-dioxolane-4 (R), 5 (K) -dimethyl ether (1) and (2) dicarboxylic acid in the ratio (1) :( 2) 1: 1 (12.5 mol) prepared in a way. described in example 1, diethylamine (27.5 ml) and water (20 ml) were kept under stirring at room temperature for 15 hours. Solvents were removed at room temperature under reduced pressure and diethyl ether (50 ml) was added to the residue . The precipitate is filtered and dried under vacuum. A diastereomeric mixture of 2-0-bromoethyl) -2- (6-methoxy-2-naphthyl) -1, 3-dioxolan-4 (R), 5 (P) -N, N, N, N -amide of tetraethyl is obtained. (13), and (14) dicarboxylic acid (11 mol1, yield 88%) in the ratio (13) :( 14) 1: 1 (H-NMR 200 MHz is determined),

Example 7. Preparation of 2- (1-acetoxy-ether) -2- (5-bromo-6-methoxy-2-naphthyl) -1, 3-dioxolan-4 (R), 5 (R) diastereomeric mixture dimethyl dicarboxylic ester.

2-Acetoxy-1,1-dimethoxy-I- (5-bromo-6-methoxy-2-naphthyl) propane (1.22 g; 3.46 mmol) was added under argon to the solution obtained by heating at 65 ° C of a mixture of 2 (R), 3 (K) -dimethyl dioxyethane dicarboxylic ester (20 g), thionyl chloride (1 ml) and methanesulfonic acid (0.03 g). The reaction mixture is heated at 95 ° C for 30 minutes, then poured into a 10% aqueous solution of sodium bicarbonate and extracted into dichloromethane. The combined organic extracts are washed with water, dried with sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (silica gel, eluent dichloromethane: hexane 9: 1) gives a diastereoisomeric mixture of 2- (1-acetoxy-ethyl-2- (5-bromo-6-methoxy-2-na-ethyl) ) -1, 3-dioxolane-4 (R), 5 (P) -dimethyl ether (15) and (16) dicarboxylic acid (0.7 g ", 1.37 μmol; yield 40%) in a ratio ( 15): (16) 65:35 (determined by H-NMR and NPH). Crystallization of methanol gives a diastereomeric mixture in the ratio (15): (16) 95: 5.

Diastereoisomer 15 (main).

 H-NQR (90 MHz, CDG13-tetramethyl-1 silane) S, h / th: 1.28 (3N, d, J 6 Hz); 1.93 (3N, s); 3.47 (3H, s) k, 3.87 (3H, s) i 4.00 (3H, 4.96 (2H, ABq, J 12.35; J 5.4 Hz); 5.38

(1H, q, J 6 Hz), 7.23-7.30 (5H, aromatic protons).

Diastereoisomer 16 (minor).

H-NMR (90 MHz, CDCl j-tetramethyl silane), h / t: 1.23 (3N, d, J 6 Hz L 2.05 (3H, s) 3.60 (3H, s) 3, 87 (3N, s); 4.00 (3H, s); 4.90 (2H, ABq, J 22.96, J 7 Hz) 5.38 (1H, q, J 6 Gi); 7.23- 8.30 (5H, aromatic protons).

Example 8. Preparation of a diastereoisomeric mixture of 2-0-acetoxyethyl) -2- (6-methoxy-2-naphthyl) -1, 3- -dixolan-4 (K), 5 (E) -dimethyl risher of dicobonic acid .

2-Acetoxy-1,1-dimethoxy-1- (b-metoxy-2-naphthyl) propane (23.5 g, 73.8 mmol) is added under the action of argon to the solution obtained by heating at 65 From a mixture of 2 (R), 3 (PO-dihydroxymethyl ester of ethanedicarboxylic acid (150 g), thionyl chloride (15.6 ml) and methanesulfonic acid (0.8 g} 7.4 mmol). The reaction mixture is heated at 95 ° C for 30 minutes, then it is poured into 10% aqueous sodium bicarbonate solution and extracted with dichloromethane.The combined organic extracts are washed with vodka, dried with sodium sulfate, filtered and concentrated in vacuum.

Purification of the residue by in-column chromatography (silica gel, eluent dichloromethane: hexane 7: 3) gives a 2-P-acetoxyethyl-2-ne-methyl-1, 3-dioxolane-4 diastereoisomeonic mixture ( K), 5 (E) -dimethyl ether (17). And (18) dicarboxylic acid (15 g; 34.7 mmol, j output 47%) O = 7): (1 8) 64:36 (1 H determined -NKR and HPLC).

Diastereoisomer 17 (main).

 H-NMR (90 MHz, CBC13-tetramethylsilane) o, h / thousand: 1.23 (3N, d, J 6 Hz) 1.95 (3H, s); 3.45 (3H, s); 3.83 (3H, s) s 3.88 (3H, s); 4.90 (2H, ABq, J 6.82, J 5.4 Hz); 5.33 (lH, q, J 6 FrOi 7.06-8.00 (6H, aromatic protons).

Diastereoisomer 18 (minor),

CMR (90 MHz, CDC13-tetramethyl-silane) {), h / th: 1.20 (3N, d, J 6 Hz); 2.00 (3N, s) i 3.57 (3H, s); 3.81 (3H, s) i 3.88 (3H, s) J 4.80 (2H, ABq, J 15.54, J 6.6 Hz), 5.33 (1H, q, J 6 Hz) ; 7.06-8.00 (6H, aromatic protons).

Example 9. Preparation of a di- stereoisomeric mixture of 2- (1-hydroxyethyl) -2- (6-methoxy -2 naphthyl) -1, oxolane-4 (R), 5 (K) -dimethyl dicarboxylic ester.

A solution of a diastereoisomeric mixture of 2- (1-acetoxyethyl) -2- (6-methoxy-2- -naphthyl) -1, 3-dioxolane-4 (E), 5 (P) - -dimethyl ether (17) and (18) dicarboxylic acid in the ratio (17):: (18) 1: 1 (, 33 g; 10 mmol) in methanol (20 ml) is added dropwise at room temperature to a solution of sodium hydroxide (4 g; 1000 mmol) in water (40 ml). The reaction mixture is kept at room temperature for 24 hours; then acidified with concentrated hydrochloric acid and extracted with DI-type ether. The combined organic extracts are washed with water, dried with sodium sulfate and filtered. Evaporation of the solvent under reduced pressure gives a diastereomeric mixture of 2- (1-hydroxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolan-4 (R), 5 (R) -dicarboxylic acid ( 3.26 g).

The resulting feedstock is added to a solution of methanesulfonic acid (0.086 g; 0.9 mmol) in methanol (300 ml). The solution was heated under reflux for 2 hours, cooled at room temperature, diluted with dichloromethane (300 ml) and poured into water (100 ml). The organic phase is separated, washed with water and a 2% aqueous solution of sodium bicarbonate, dried with sodium sulfate and filtered. The reaction feed, obtained by evaporation of the solvent under reduced pressure, is crystallized from methanol to obtain a diastereoisomeric mixture of 2- (1-hydroxyethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxolan-4 (S, 5 (K) -DI ethyl ester (19) and (20) jarboxylic acid (3 g, 7.7 mmol, yield 77%) in the ratio (19): (20) 56:44.

Diastereoisomer 1 9 (main).

(H-NMR (90 MHz, SBS13-tetramethylsilane) U, h / th,: 1.06 (3N, d, J b Hz); 3.13 (1H, d, J 7 Hz); 3, 30 (3H, s), 3.83 3H, s); 3.90 (3N, s); 4.16 (IH.dq, JCH-CH 6 Hz, Cn-OY 5 Hz), 5.06 (2H, ABq, J 11.77, J - 4.2 Hz); 7.13-8.00 (6H, aromatic protons).

Diastereoisomer 20 (minor).

 H-NMR (90 MHz, CBC1e-tetramethylsilane) 81, h / t: 1.13 (ZN, d} J 6 Hz)} 3.13 (1H, d, J - 7.5 Hz) 3 56 (3H, s) | 3.82 (3H, s) i 3.90 (3N, в); 4.16 (IH.dq, JCH-CH - 6 Hz, JCH-OH 7.5 Hz); 4.97 (2H, ABq, J 2.94, J 1.5 Hz); 7.13-8.00 (6H, aromatic protons).

Example 10. Preparation of a (4-methylphenylsulphonyloxy) -ethyl -2- (6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (R) -dimethyl ester di-esteroisomer mixture carboxylic acid.

A solution of 1,1-dimethoxy-2- (4-methylphenylsulfonyloxy) -1 - (6-methoxy-2- -naphthyl) propane (15 g $ 34.8 mmol) in 1,2-dichloroethane (100 ml) argon is added dropwise to the solution obtained by heating a mixture of 2 (R), 3 (K) -dihydroxymethyl ester of ethanedicarboxylic acid (75 g), thionyl chloride (7.5 ml) and methanesulfonic acid (0, 37 g1, 3.8 mmol). The reaction mixture is heated at 125 ° C for 1 hour, at which time 1,2-dichloroethane is distilled off. The reaction mixture is then poured into a J0% aqueous solution of sodium bicarbonate and extracted. The combined organic extracts are washed with water, dried with sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography (silica gel, eluent dichloromethane: hexane 8: 2) gives a diastereoisomeric mixture of (4-methylphenylsulphonyl si). Ethyl -2- (6-methoxy-2-na-methyl) -1, 3-dioxolane- 4 (R), 5 (R) -dimethyl ester (21) and (22) of dicarboxylic acid (10.8 gJ 19.81 mmol; yield 57%) in the ratio (21) :( 22) 40: 6 (determined H - NMR and NPH).

Diastereoisomer 22 (main).

1H-NMR, ppm: 1.40 (3N, d, J 6 Hz) -, 2.30 (3H, s) 3.43 (3H, s); 3.81 (3H, s) j 3.90 (3H, s); 4.80 (2H, s), 4.90 (lH, q, J 6 Hz); 6.90- 7.80 (YUN, aromatic protons).

Diastereoisomer 21 (minor).

 H-NMR &, h / th: 1.37 (3N, d, J 6 Hz); 2.26 (2H, s) i 3.43 (3H, s)} 3.83 (3H, s), 4.76 (2H, s) i 4.90 (1H,

0

0 5 0, - 0 5

0

five

710

q, J 6 Hz) 6.90-7.80 (YUN, aromatic protons).

Further purification by column chromatography (silica gel, eluent dichloromethane: hexane 1: 1) gives the pure basic diastereoisomer 22.

Example 11. Griging of diastereoisomeric mixture of 2- (1-methane-sulfonyloxyethyl) -2- (6 methoxy-2-- -naphthyl) -, 3-dioxolane-4 (P), 5 (K) -di dicarboxylic acid methyl ester .

A solution of 1,1-dimethoxy-2-methanesulfonoxy-1- (6-methoxy-2-naphthl) -propane (24 g; 68 mmol) in 1, 2-dichloroeth-not (140 ml) is added dropwise under the action of argon into a solution obtained by heating at 95 ° C a mixture of 2 (R), 3No) -dihydroxymethyl ester of butanediic acid (120 g), thionyl chloride (12 ml) and methanesulfonic acid (0.6 g ; 7.4 mmol); The reaction mixture is heated at 125 ° C for 1 hour, during which time 1,2-dichlorophenol is distilled off. The reaction mixture is then drunk into a 10% aqueous solution of sodium bicarbonate and extracted with dorshortak. The combined organic extracts are washed with water, dried with sodium sulfate, filtered and concentrated in vacuo.

Purification of the residue by column chromatography (silica gel, eluent dichloromethane; hexane 2: 2) gave a 2- (1-methanesulphonyloxyethyl) -2- (6-methoxy-2-naphthyl) -1, 3-dioxolan-4 (2 R), 5CR) -dimethyl ester (23 and (24) dicarboxylic acid (20 g Ј 42.7 mmol; yield 63%) in the ratio (23): (24) 63:37 (determined by H-NMR and NPH). Crystallization methanol gives a diastereoisomeric mixture in the ratio of 23 (RPS): 24 (RRR) 80:20.

Diastereoisomer 23 (RRS).

H-Ya # (90 MHz, CDC13-tetramstilsilane) 8, h / thousand: 1.38 (3N, d, J 6 Hz); 2.93 (3H, s); 3.37 (3H, s); 3.90 (3H, s) "4.30 (1H, q, J 6 Hz); 5.03 (2H, ABq, J 5.09, J 4.2 Hz), 7.06-8.00 (6H, aromatic protons)

Diastereoisomer 24 (PRR).

1 H-NMR (90 MHz, CDCl3-tetramethylsilane) 8, h / th: 1.38 (3N, d, J 6 Hz), 2.93 (2F, s); 3.53 (3H, sV, 3.80 (3H, s), 3.90 (3H, s) ;, 4.80 (1H,

111

q, J 6 Hz) -, 4.97 (2H, ABq, J 11.9 J 6.3 Hz) 1, 7.06-8.00 (6H, aromatic protons).

Example 12. Preparation of 2 (E) -hydroxy-3 (P) -Ј2- (6-methoxy-2-naphthyl) propanol-dimethyl ester of ethane-dicarboxylic acid

СН5СООСЯ3

CH-COOH-CH-CH-OH

coaxially

X

H30

A solution of silver tetrafluoroborate (2.4 rj 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 g). mol, in the ratio 52:48) with stirring at 15 ° C. The reaction mixture is heated to 50 ° C and maintained at this temperature for 16 hours, then cooled to room temperature and filtered. The solution was diluted with dichloromethane (60 ml), washed with water (ml) and dried with sodium sulfate.

Evaporation of the solvent under reduced pressure gives a raw material which, after purification by chromatography in a column (silica gel, solvent for elution of n-heptane: 2: 8 diethyl ether), results in a mixture of two dI-sterile esters A and B (2.9 g 0.0074 mol4 , yield 74%) in the ratio A: B 52:48 (H-NMR determined 200 MHz).

Diastereoisomer A (RRS).

H-NMR (200 MHz, (-tetramethylsilane) S, ppm: 1.62 (d, 3N, J "8 Hz); 3.22 (s, 3H); 3.83 (s, 3H) i 3.92 (s, 3H), 3.21 (d, H, J 7.2 Hz); 3.95 (q, 1H, J 8 Hz) 4.68 (ld, 1H, JC-H -OH 7.2 Hz, JCH-OH 2.47 Hz); 5.37 (d, lH, J 2.47 Hz) 1, 7.1-7.8 (6H, aromatic proton).

Diastereoisomer B (RRR).

 N-YaUR (200 MHz, CDC13-tetramethylsilane) 8, h / thousand: 1.66 (d, 3N), J 9 nOi 3.58 (sf3H); 3.72 (s, 3H) ", 3592 (s, 3H), 3.2.4 (d, lH, J 7.5 Hz) 1, 3.97 (q, IH, J 8 Hz) 4.78 (dd , 1H, JCH-OH 7.6 Hz, JCH-CH Hz); 5.45 (d, lH, J 2.47 Hz) J 7.1-7.8 (6H, aromatic proton).

Example 13. Preparation of 2- (6-methoxy-2-naphthyl) -propanoic acid.

12

five

A mixture of two diastereoisomers of esters A and B (2.2 F; 5.64 mol1, 52:48 ratio) prepared according to Example 12, 1.2 dimethoxyethane (22 ml) and concentrated hydrochloric acid (22 ml) is maintained at 95 ° C within 2 hours. The reaction mixture is cooled at room temperature, diluted with water and extracted with dichloromethane. The organic phase is washed with water and extracted with 10% aqueous sodium bicarbonate solution.

The basic aqueous phase is acidified with concentrated hydrogen chloride and extracted with dichloromethane. The organic phase is washed with water and dried over sodium sulfate. Evaporation of dissolution under reduced pressure 0 Gives the raw material 2- (6 methoxy-2-naphthyl) -propanoic acid. An analogous clean sample is obtained after purification by column chromatography (silica gel, eluant 5 hexane: diethyl ether 7: 3).

N ° 42.2 ° (C 1%, chloroform).

Example 14. Preparation of propanoic acid 2- (6-methoxy-2-naphthyl) -methyl ester from a diastereisomeric mixture of 2- (1-methanesulphonyloxyethyl) -2- (6-methoxy-2-naphthyl) -1, 3-dioxolane-4 (R), 5 (R) -dimethyl dicarboxylic ester in a ratio of 80:20.

A diastereomeric 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 the ratio (23): (24) 80:20 (1 g, 2.13 mmol), methanol (7.5 ml) and water (2.5 ml) are heated in a sealed tube at. 150 ° C for 5 hours. The reaction mixture is cooled at room temperature, diluted with water and extracted with diethyl ether. The combined organic extracts are washed with water, dried, filtered and concentrated in vacuo.

Purification of the residue by column chromatography (silica gel, eluent dichloromethane) gives

2 (6-methoxy-2-naphthyl) propanoic acid methyl ester (0.4 g, 1.64 mmol, 55 yield 77%). M.p. 88 ° C.

WDO, 020 (C J%, chloroform).

 H-NMR (200 MHz) analysis carried out in CDClj using a transfer reagent - europium (III)

0

0

50

1315

(entaFluoropropylhydroxymethylene) -c6-camphorte showed an enantiomeric ratio S (+): R (-) 80: 2

Example 15. Preparation of 2- (6-methoxy-2-naphthyl) -propanoic acid from a diastereomeric mixture of 2 - (- bromoethyl) -2- (6-methoxy-2-naphthyl) -1, 3-dioxolane-4 (R ) 55 (R) -dicarboxylic

ACIDS.

A mixture of two diastereoisomers 2- (1- -bromoethyl) -2- (6-methoxy-2-on Btil) -1, 3-dioxolane-4 (R), 5 (R) -dicarboxylic acid (5) and (6 ) in the ratio (5): (6) 1: 1 (12.75 g; 30 mmol) and an aqueous solution (180 ml) prepared by dissolving (26.1 g) and KFtP04 (5.7 g) in water (384 ml), heated under stirring at 100 ° C for 21 hours. The reaction mixture is cooled at room temperature (pH 3.7), acidified with concentrated HCl to pH 1 and extracted with diethyl ether (ml). The combined organic extracts are washed with water and dried with sodium sulfate. Evaporation of the solvent at reduced pressure gives the raw material of 2- (6-methoxy 2-naphthy) propanoic acid, which is purified by chromatography in a column (silica gel, solvent for hexane eltoration: 1: 1 diethyl ether),

Pure acid (4.83 g; 21 mmol, 70% yield) is obtained with an optical purity of 50% (enantiomeric excess). M.p. 154-155 ° C.

NPH analysis carried out in a known manner (J. Pharm. Sci., 1979, 68,112) showed an enantiomeric ratio of 75:25. The enantiomeric ratio was confirmed by H-NMR (200 MHz) analysis, as described in Example 14.. Example 16. Preparation of 2- (6-methoxy-2-naphthyl) -propionic acid from 2- (1-bromoethyl) -2- (6-methoxy-2-naphl) -1, 3-dioxolane-4 (B .), 5 (R) - -N, N, N, N -amide of tetraethyl dicarboxylic acid.

A mixture of two diastereoisomers 2- (1-bromoethyl) -2- (6-methoxy-2-naphthyl) -1, 3-dioxolane-4 (R), 5 (B) -N, N, N, Nf-amide tetraethyl (13) and (14) dicarboxylic acid in the ratio (13): (14) 1: 1 (1.07 g; 2 mmol) and water (4 ml) is heated with stirring at 100 ° C for 16 h (kis1, lot of pH). After the operations described in example 15 and purification of the chromato 67

14

By column chromatography (silica gel, hexane elution solvent: 1: 1 diethyl ether), pure 2 (b-methoxy-2-naphthyl) -prolanoic acid (0.124, 0.54 mmol, 7% yield) with an optical purity of 40% was obtained. M.p. 55 ° C.

C ° 0 x + 26.4 ° (C 1%. Chloroform)

The enantiomeric ratio of S (+) :( P (-) 70: 30 was confirmed by NPH- and H-NMR analyzes by the method described in example 15.

Example 17. Preparation of 2- (b-methoxy-2-naphthyl) -propionic acid from 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1,3-dioxyl-4 (U , 5 (R-dicarboxylic acid.

A mixture of two diastereoisomers 2- (1-chloroethyl) -2- (6-methoxy-2-naphthyl) -1 -1-dioxolan-4 (K), 5 (R) -dicarboxylic acid (9) and (10) in ratio (9): (10) 1: 1 (24 mmol) and an aqueous solution (168 ml) (14.6 g) and KNa04 (3.19 g) with pH 6.6 are heated under stirring at 98 ° C for 10 h The reaction mixture is cooled at room temperature (pH 5.7), acidified with concentrated HC1 to pH 1 and extracted with diethyl ether (ml). The organic phase is extracted with 10% sodium bicarbonate aqueous solution (ml). The combined aqueous extracts are acidified to pH 1 and extracted with diethyl ether (4 x 90 ml). The combined organic phase is washed with water, dried over sodium sulfate and concentrated in vacuo.

The residue (4.8 g): 1,2-dimethoxy ethane (72 ml) and concentrated HC1 (36 ml) are heated with stirring at 75 ° C for 2 hours.

After treatment of the reaction mixture as in Example 16, and purification by column chromatography (silica gel, elution solvent: diethyl ether 7: 3), pure 2- (6-methoxy-2-naphthyl) propanoic acid with an optical purity of 48% is obtained.

MW ° + 31.6 ° (C 1%, chloroform).

The enantiomeric ratio S (+):: R (-) 74:26 was confirmed by NPH- and H-NMR analyzes carried out according to example 15.

Example 18. A mixture of two diastereoisomers of 2- (1-chloroethyl) -2- (6- -methoxy-2-naphthyl) -1,3-dioxolane -4 (R), 5 (R) -dicarboxylic acid (9)

151

, and (10) in a ratio of (9): (10) 1: 1 (10 mmol) and an aqueous solution (140 ml of KNgP04 (20 g) and sodium hydroxide (1 g) with a pH of 4.9 are boiled in a reverse fridge for 240 hours. The reaction mixture is cooled at room temperature (pH 3.6) and treated in the manner described in example 17,

Pure 2- (6-methoxy-2- -naFtil) propanoic acid is obtained with an optical purity of 62%.

Vlij +40,9 (With 1% chloroform

The enantiomeric ratio of S (+):: R (-) 81:19 is confirmed by NPH- and H-NMR analyzes, carried out as in example 15.

Example 19. A mixture of two 2- (1-bromoethyl) -2- (5-bromo-6-methoxy-2-naphthyl) -1,3-dioxo-4 (R), 5 (K)-dicarboxylic acids (25) and (26) in the ratio (25) :( 26) in S; i (2.52 g; 5 mmol), prepared according to example 2, starting with diastereoisomers 11 and 12, and an aqueous solution (70 ml) of KNa04 (Yu g) and sodium hydroxide (1.4 g) with pK 6 are heated — with

90 ° C for 50 hours. The reaction mixture is cooled at room temperature (pH 5.9) and treated as in Example 15.

Pure 2- (5-bromo-6-metho-xi 2-naphthyl) -propanoic acid (0S83 g, 2.7 mmol, 54% yield) is obtained with an optical purity of 70%. M.p.166-168 С

} + 29.4 ° С (С 0.5%, chloroform).

The enantiomeric ratio of S (+):; R (-) 85; 15 was confirmed by NPH- and H-NMR analyzes in example 15.

 Example 20. A mixture of two diastereoisomers of 2- (1-bromoethyl) -2- (5-bromo-6-methoxy-2-naphthyl) -1,3-dioxolane-4 (R), 5 (H) -dicarboxylic acids (25) and (26) in the ratio (25) :( 26) 1: 1 (2.52 rj 5 mmol) of an aqueous solution (70 ml) g) and sodium hydroxide (0.5 g) with pH 5 , 15 is heated at 90 ° C for 52 hours. The reaction mixture is cooled at room temperature (pH 4.40) and treated by the method of Example 3 5.

Pure 2- (5-bromo-6-methoxy x 2 naphthyl) propanoic acid (0.72 g: 2933 mmol j yield 4.7%) is obtained with

optical purity of 170 ° C

M.p.

4-28 ° C (0.5%, chloroform).

sixteen

0

The enantiomeric ratio of S (+):: R (-) 84:16 is confirmed by NPH- and NNMR-analyzes, as in example 15. Example 21. Preparation of a diastereoisomeric mixture of 2 (K) -hydro-Kcn-3 (R) - 2- (6-methoxy-2-naphthyl) propanoshL-dimethyl butanedicyl ester.

A solution of triethylamine (4.45 g1, 0.044 mol) in dichloromethane (10 ml) is added dropwise at -10 ° C over 5 minutes to a mixture of 2 (R), 3N) -dihydroxydimethyl ether of butanedicolone ( 44.5 g, 0.25 mol) and dichloromethane (90 ml). A solution of 2- (6-methoxy-2-naphthyl) propionyl chloride (5 g; 0.02 mol) is added dropwise to the resulting mixture at -10 ° C over a period of 20 minutes. The reaction mixture was poured into a 10% aqueous solution of sodium bicarbonate (200 ml) and extracted with dichloromethane (100 ml). The organic phase is washed with diluted water and HC1 and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gives a raw diastereoisomeric mixture of 2 (K) -hydroxy-3N) - (6-methoxy-2-naphthyl) -propanoyl1

30-dimethyl ether (A) and (B) butane-di-acid (5.5 g) in the ratio (A): (B) 1: 1 (determined by H-NMR).

The {H-NMR (200 KHz) data is identical to the data for diastereoisomers A and

five

20

In example 12. 1

Crystallization of methanol- induced by the pure crystalline diastereoisomer A gives a pure diastereoisomer A (RRS). Mp. 77-79 ° C.

20

3

IX +73.7 ° C (1% C, chloroform).

Thus, the proposed method allows one to obtain stereoisomers with a higher content of one of them, which makes them easier to separate.

Claims (1)

Invention Formula The method of obtaining about arylalkanoic acids of General Formula Ag-CH-COOH I d where Ar is methoxynaphthyl, possibly substituted by bromine; R - C, (- C 4 -alkyl, by rearrangement of ketels in the aquatic environment at elevated temperatures 17 -1574167J8 re possible in the presence of a buffer, R and K2 are the same or differing in that, hydrox-, each, for the purpose of carrying out the process stereo-C-C-alkoxy or group selectively, as cathels using-ESCN CH}), are the compound of the general formula    - chlorine or bromine, or megStilsulfonyloxy; J With carbon n atoms labeled with zooe daughter are simultaneously in   or S-configurations  Sp-Ri and rearrangement are carried out in one at 90-100 ° C, pH 3.6-5.9, and where Ar and R have the indicated value-Buffer quality used- kgHRO / where AG and 15 UKN (Р04 kln KH4P04 / NaOH. BAT chs H / f