JPH03190843A - 2-halogeno-3-oxo-3-phenylpropionic acid derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A 2-halogeno-3-oxo-3-phenylpropionic acid derivative of formula I (ring A is phenyl which may be substituted; X is halogen; R is lower alkyl). EXAMPLE:2-Chloro-3-oxo-3-(4-methoxyphenyl)propionic acid methyl ester. USE:Useful as an intermediate for synthesizing drugs. The employment of the compound of formula I as the intermediate raw material gives optically active trans-3-phenylglycidic acid ester compounds which are useful as raw materials for synthesizing diltiazem hydrochloride useful as a coronary vasodilator and other drug compounds. PREPARATION:An acetophenone compound of formula II is reacted with a di-low alkyl carbonate in the presence of a base and the prepared 3-oxo-3- phenylpropionic acid derivative of formula III is halogenated to obtain the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel 2-halogeno-3-oxo-3-phenylpropionic acid derivative useful as a pharmaceutical synthesis intermediate and a method for producing the same.

(Prior Art) Optically active trans-3-phenylglycidate ester compounds are important compounds as raw materials for the synthesis of diltiazem hydrochloride, which is useful as a coronary vasodilator, and various other pharmaceutical compounds. - A method of producing a racemic form of glycidic acid (methoxyphenyl) or its alkali metal salt by optically resolving it with optically active amines and then esterifying it (JP-A No. 61-145160, No. 6O-137)
75) is known.

(Problems to be Solved) The present invention provides optically active 3
- It is an object of the present invention to provide a new synthetic intermediate for efficiently producing phenylgrid acid ester compounds and a method for producing the same.

(Means for Solving the Problems) The present invention relates to a 2-halogen compound represented by the general formula (wherein the ring is an optionally substituted phenyl group, -3-oxo-3-phenylpropionic acid derivatives.

As an example of the compound of the present invention, in general formula (1),
Examples include compounds in which Ring A is a phenyl group which may have a substituent selected from a lower alkyl group, a lower alkoxy group, and a halogen atom, X is a halogen atom, and R is a straight chain or branched lower alkyl group, More specifically, the ring is a phenyl group, 4-methylphenyl group, 4-methoxyphenyl group, or 4-chlorophenyl group, X is a chlorine atom, a bromine atom, an iodine atom, R is a methyl group, an ethyl group, an isopropyl group, L -Methyl group and the like.

The 2-halogeno-3-oxo-3-phenylpropionic acid derivative (1) of the present invention is obtained by combining an acetophenone compound represented by the general formula (wherein, ring A has the same meaning as above) in the presence of a base. A 3-oxo-3-phenylpropionic acid derivative represented by the general formula (wherein the ring and R have the same meanings as above) is produced by reacting with a di-lower alkyl carbonate, and then halogenated. It can be manufactured by

The reaction between the acetophenone compound (II) and the di-lower alkyl carbonate can be suitably carried out in a solvent in the presence of a base. Examples of the di-lower alkyl carbonate include dimethyl carbonate and diethyl carbonate, and the amount used thereof is preferably about 2 to 7 mol per 1 mol of compound [■]. On the other hand, as a base,
Examples include alkali metals such as the metal sodium chloride and alkali metal hydrides such as sodium hydride, and the amount used is approximately 0.8 to 1.2 per mole of the compound [■].
Preferably it is in moles.

? Each category includes ethers such as tetrahydrofuran, dioxane, and dimethoxyethane, and aromatic hydrocarbons such as toluene, xylene, and ethylbenzene.

This reaction is preferably carried out by dispersing a base in a solvent, adding di-lower alkyl carbonate, and then adding compound (II). The reaction preferably proceeds under heat, especially at about 70-90°C.

The 3-oxo-3-phenylpropionic acid derivative (III) thus obtained can be suitably halogenated by reacting it with a halogenating agent in a solvent.

Examples of the halogenating agent include sulfuryl chloride, sulfuryl fluorochloride, cupric chloride, N-chlorosuccinimide, 2-bromo-2-cyano-N, N-dimethylacetamide, trifluoromethanesulfonyl chloride, bromine,
N-bromosacudiimide, tetra-n-butylammonium iodotetrachloride, pyridinium hydropromide perbromide, and the like can be suitably used.

The amount of these halogenating agents used is preferably about 0.9 to 1.1 mol per 1 mol of compound [■].

As the tIJ medium, halogenated hydrocarbons such as carbon tetrachloride, chloroborum, dimethyl chloride, and dimethyl ethane, ethers such as tetrahydrofuran, dioxane, and dimethoxyethane, and aromatic hydrocarbons such as toluene, xylene, and ethylbenzene are preferably used. I can do it.

The reaction can be suitably carried out at room temperature or under heating,
In particular, it is preferred to carry out at a temperature of about 40 to 100°C.

(Example) (1-a) 30.7 g of sodium and 30 g of toluene
After heating to 93°C, the mixture was allowed to cool while stirring vigorously to form a sodium sandwich. A solution of 300 g of dimethyl carbonate in 600 m2 of toluene was added thereto, and a solution of 1.00 g of p-methoxyacetophenone in 250 mE of toluene was added dropwise at 84 to 86°C over a period of 2 hours and 15 minutes. After the dropwise addition, the mixture was heated and stirred at 82 to 83°C for 1.5 hours, then the solvent was distilled off, 12 pieces of isopropyl ether were added to the residue, and the crystals were collected by filtration. Washed with. The crystals were added to an ice-ethyl acetate mixture containing 100 g of acetic acid, and extracted with ethyl acetate.

The extract was washed with 5% sodium hydrogen carbonate, washed with water, dried, and the solvent was distilled off to give 3-oxo3-(4-
Methoxyphenyl)propionate methyl ester 131
．． ．． 6 g were obtained as an oil.

Yield: 94.9% T R (liquid): 3625-3450.
1740.1665 cm-'NMRδ(CDCl3
)43.74(3+1.S), 3.87(311,s
) 3.95 (2+1.s ), 6.94 (211,
d, 9.2Hz), 7.92(2+1.d, 9
．． 211z ) (1-b) Sodium hydride (60χ oil suspension) =
7 2.7 g was suspended in 25 ml of tetrahydrofuran,
Add 5.0 g of p-methoxyacetophenone to this,
At 5°C, 6.0 g of dimethyl carbonate was added over 10 minutes. After refluxing for 6 hours, the same procedure as in (1-a) below was carried out to obtain 6.3 g of 3-oxo-3-(4-methoxyphenyl)propionate methyl ester as an oil.

Yield: 91.3% (2) 131 g of 3-oxo-3-(4-methoxyphenyl)propionic acid methyl ester obtained in (1) above was dissolved in 1.32 terachloromethane, and 85 g of thionyl chloride was dissolved. was added dropwise over a period of 1 hour at 45-50°C. After dropping, stir at the same temperature for 1 hour, cool, wash with water,
After drying, the solvent was distilled off and the resulting oily residue was distilled under reduced pressure to obtain 2-chloro-3-oxo-
140 g of 3-(4-methoxyphenyl)propionic acid methyl ester was obtained.

Yield: 92.1% b, p, 143.5-145°C/0.3 mm1
1gJR (Ifquid): 1750 16
60 cm-'NMRδ(CDCl1): 3.82(
311,s ), 3.88(3H,s )5.91(2
11,s) + 6.96(211,d, 9.0
JIz) + 7.97 ('21Ld, 9.0
) Reference example (11N, N'-dibenzoyl-L-cystine 1
．． 614 g, 237 mg of lithium borohydride in a suspension of 16 m of tetrahydrofuran, 357 mg of tert-butanol and 20 m2 of tetrahydrofuran under an argon atmosphere! The solution was added and refluxed for 1 hour. Then, a solution of 728 mg of 2chloro-3-oxo-3-(4-methoxyphenyl)propionic acid methyl ester in 10 mA of tetrahydrofuran was added at -65 to -To'C,
The mixture was stirred at the same temperature for 1 hour. After the reaction, 1 (1% hydrochloric acid was added to the reaction solution for decomposition, then 5% sodium bicarbonate aqueous solution was added to adjust the pH to 9-10, and the mixture was extracted with ethyl ether. The extract was washed with water and dried. After that, the solvent was distilled off, and 740 mg of the yellow oily residue obtained was purified by silica gel column chromatography (solvent: hexane: ethyl acetate - 3:1) to obtain 2-chloro-3-hydroxy-3. (4-methoxyphenyl) propionic acid methyl ester threo(2R,33) form and erythro(
660 mg of a mixture of 2S, 3S) bodies was obtained as colorless crystals.

IR (eyequid): 34B0.1750.1
610.1515°1250, 1+75.1030.8
30cm NMRδ (CDCh): (threo body) 2.89 (ill, d, 3.911z
), 3゜67(311,s )+3.80(31
1,s), 4.42(ill,d, 6.8Hz >
, 5.08 (III, dd, 3.9 and 6.
8+1z)6.89(211,d,8.8+1z)
, 7.30 (211, d, 8.811z) (erythro body) 2.89 (III, d, 4.6 Hz) +
3°80 (611, s), 4.35 (III, d,
8.111z), 5.00 (III, dd, 4.
6 and 8.111z), 6.9H211,d
,8.8Hz)+7.32(211,d,8.8H
z) (2) The crystals obtained in (1) above were dissolved in methanol 16m
A solution of 153 mg of sodium methoxide in 5 ml of methanol was added to the solution dissolved in 1 at 0°C, stirred at the same temperature for 90 minutes, and then stirred at room temperature for 10 minutes. Then, water was added to the reaction solution, and the mixture was extracted with ethyl ether. After washing the extract with saturated brine and drying, the solvent was distilled off. The resulting oily residue was purified by silica gel column chromatography (solvent: hexane: ethyl acetate = 3:1) to obtain 506 mg of (2R,3S)-3-(4-methoxyphenyl)glycid acid methyl ester. Obtained.

(a)": --143,3° (C=0.30, m/-l) (optical purity: 82%; from HPLC) IR (Nujol): 2920.1730
．． 1615.1520゜1440, 1250.1030
．． 840c+n-'NMRδ (CDCl3): 3.
50 (III, d, 1.8 Hz).

3, BO (311, s ) + 3.81 (311, s
)+4.04(II(,dl,8Hz),6.8
7 (21Ld, 9.0 Hz), 7.20 (21
1, d, 9.011z) Mass (E I ): 20B (M) (Effects of the Invention) According to the method of the present invention, acetophenone compound (II)
The target compound CI'l can be produced in high yield from.

11 In addition, the object compound (1) of the present invention can be produced extremely easily and efficiently by asymmetric reduction using a metal hydride in the presence of an optically active amino acid derivative and a lower aliphatic alcohol, followed by intramolecular ring closure. It can be optically active 3-phenyl glycidate ester compounds.

2 March 7, 1991

Claims (2)

[Claims] (1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (However, ring A is an optionally substituted phenyl group, X is a halogen atom, and R is a lower alkyl group.) 2-halogeno-3-oxo-3-phenylpropionic acid derivative. (2) General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [II] (However, ring A represents an optionally substituted phenyl group.) In the presence of a base, di-lower By reacting with an alkyl carbonate, 3-oxo compound represented by the general formula ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ [III] (However, R represents a lower alkyl group, and ring A has the same meaning as above.) A general formula characterized by producing a -3-phenylpropionic acid derivative and then halogenating it ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [I] (However, X represents a halogen atom, ring A and R represents the same meaning as above.) A method for producing a 2-halogeno-3-oxo-3-phenylpropionic acid derivative.