CN101830850B

CN101830850B - Efficient preparation method of (1'S)-homophenylalanine carboxylic ester-benzoazepine-bis chiral compound

Info

Publication number: CN101830850B
Application number: CN 200910266548
Authority: CN
Inventors: 杨登贵; 胡衍毅; 胡林
Original assignee: Wisdom Pharmaceutical Co Ltd
Current assignee: Jiangsu Huiju Pharmaceutical Co ltd
Priority date: 2009-12-29
Filing date: 2009-12-29
Publication date: 2013-07-10
Anticipated expiration: 2029-12-29
Also published as: CN101830850A

Abstract

The invention provides an efficient preparation method of a diastereoisomer (3S, 1'S) type [compound (I)] and (3R, 1'S) type [compound (II)] homophenylalanine carboxylic ester-benzoazepine compound. The preparation method comprises the following steps of: (1) separating a (3R, 1'S) type in a diastereoisomer (3R, 1'S)/(3S, 1'S) type of a 3-[(1'S)-homophenylalanine carboxylic ester]-benzoazepine compound by utilizing a carboxylate crystallization and induction mode and then obtaining a (3R, 1'S) type homophenylalanine carboxylic ester-benzoazepine compound through an esterification reaction; (2) carrying out highly (absolutely) selective (no racemization) epimerization on the separated 3R-[(1'S)-homophenylalanine carboxylate]-benzoazepine compound in a buffer system the pH of which is 5-6 to obtain a (3S, 1'S) type carboxylic acid (carboxylate) compound; and then obtaining a (3S, 1'S) type homophenylalanine carboxylic ester-benzoazepine compound through an esterification reaction.

Description

(1'S)-high efficiency preparation method of homophenylalanine carboxylic ester-benzazepine-both hands compound

Technical field

The present invention relates to following both hands compound:

(1 ' S)-homophenylalanine carboxylic ester-benzazepine-both hands compound (I) and high efficiency preparation method (II).

Wherein R represents C ₁～C ₄Alkyl

Background technology

3S-[(1 ' S)-homophenylalanine carboxylic ester]-benzazepine compounds (I) is the important source material that can be used for preparing angiotensin-converting enzyme (ACE) inhibitor class medicine, for example can be directly used in to make benazepril hydrochloride (Benazepril.HCl).

Report among existing literature such as the patent CN1266136C, only can isolate S, S type homophenylalanine carboxylic ester-benzazepine compounds (I) is by the mensuration of high performance liquid chromatography (HPLC): compound (I) wherein

Diastereomer (ratio S) is＞99.0: 1.0 for S, S/R,

And wherein enantiomorph (ratio R) is＞99.5: 0.5 for S, S/R.

The present invention points out a kind of than above-mentioned document (patent) milder, more efficient methods on operational condition, not only can obtain S respectively, S type and R, S type homophenylalanine carboxylic ester-benzazepine compounds (I) and (II), and the mensuration by high performance liquid chromatography (HPLC), compound (I) and chemical purity (II) all can be greater than 99.5%.

In addition, the compound that the present invention prepares (I) is by the mensuration of high performance liquid chromatography (HPLC): wherein

Diastereomer (ratio S) is＞99.5: 0.5 for S, S/R,

And wherein enantiomorph (ratio R) is＞99.9: 0.1 for S, S/R, does not almost have racemic compound R, and the R type generates.

Summary of the invention

The objective of the invention is to prove a kind of efficient production (1 ' S)-homophenylalanine carboxylic ester-benzazepine compounds (I) and method (II).

Make the key intermediate-compound (X) ((X) being compound (I) and mixture (II)) of benazepril hydrochloride (Benazepril.HCl), can use document Tetrahedron:Asymmetry 14 (2003) 2239-2246 and Molecules 2006,11,641-648 makes, perhaps can referenced patent US4575503, US4410520, the similar approach that provides of US4473575, US2002183515, US2003055245 makes.

Preparation compound (I): at first, the mode that compound (X) utilizes crystallization to induce can obtain a part of S earlier, S type carbonate (I), crystalline mother solution (III) concentrates back aqueous sodium hydroxide solution hydrolysis, after crystallization, can obtain R, S type carboxylic acid sodium salt compound (IV), compound (IV) carries out epimerization [highly selective (no racemization) epimerization] reaction of height (definitely) selectivity (no racemization) in the buffer system of pH=5～6 then, obtain S, S type carboxylic acid cpd (V), and almost there is not racemic compound R, the R type generates, compound (V) carries out esterification again after crystallization, can obtain required S, S type carbonate (I).

Preparation compound (II): if the aforementioned compound that obtains (IV) is directly carried out esterification after crystallization, can obtain another kind of both hands compound, i.e. R, S type carbonate (II).

Description of drawings

Below in conjunction with accompanying drawing the specific embodiment of the present invention is described in further detail:

Fig. 1 has illustrated preparation compound (I): compound (X) utilizes crystallization mode to obtain a part of S earlier, S type carbonate (I), crystalline mother solution (III) is induced to split two diastereomers by the crystallization of carboxylic acid sodium salt compound and is obtained R, S carboxylic acid sodium salt compound (IV), compound in buffer system (IV) has significantly improved required S by the effective epimerization of gentleness, the content of S type carboxylic acid cpd (V), and almost there is not racemization (no R, the generation of R type enantiomer product), compound (V) carries out esterification can obtain compound (I) again after crystallization then.

Fig. 2 has illustrated preparation compound (II): compound (IV) carries out esterification can get compound (II) after crystallization.

Embodiment

Can understand the present invention more specifically by the following examples, but it is to illustrate rather than limit the scope of the invention.

Embodiment 1

The mode that compound (X) utilizes crystallization to induce obtains a part of S earlier, behind the S type carbonate (I), (the 3S that obtains after crystalline mother solution is concentrated, 1 ' S)/(3R, 1 ' S) mixture (III) 25.0g is dissolved in the ethanol of 25mL, under the condition of nitrogen, add water 50mL, 30% aqueous sodium hydroxide solution 6.9g successively in reaction mixture, open stirring, oil bath is heated to 65 ± 3 ℃, keeps 1 hour to dissolving fully, after high performance liquid chromatography (HPLC) detection analytical reaction are qualified, add toluene extracting twice (12.5mL * 2), toluene layer is discarded; With the ice-water bath decrease temperature crystalline of the water layer after the layering second time, filter, can get the white weight in wet base product of 16.1g after the flushing of filter cake water, get (the 3R of 11.3g after the oven dry, 1 ' S) type carboxylic acid sodium salt compound (IV) is by the mensuration of high performance liquid chromatography (HPLC): compound (IV) wherein

Diastereomer (3R, 1 ' S): (3S, 1 ' S) ratio is 98.5: 1.5 mixture,

If this mixture can obtain by recrystallize in the system of ethanol and aqueous sodium hydroxide solution

(3R, 1 ' S): (3S, 1 ' S) ratio is＞99.5: 0.5 mixture to diastereomer.

Embodiment 2

Under the condition of nitrogen, successively with (3R, 1 ' S) type carboxylic acid sodium salt compound (IV) 11.3g, toluene 80mL and acetic acid 2.3g join in the reaction flask, open stirring, and oil bath is heated to 110 ± 3 ℃, in buffer system, refluxed 20 hours, be cooled to 20 ℃, filter the wet product of 15.8g light yellow solid, dry 10.0g (3S, 1 ' S) type carboxylic acid cpd (V) is by the mensuration of high performance liquid chromatography (HPLC): compound (V) wherein

Diastereomer (3S, 1 ' S): (3R, 1 ' S) ratio is 95.4: 4.6 mixture,

And wherein enantiomorph (3S, 1 ' S): (3R, 1 ' R) ratio is＞99.9: 0.1 mixture, does not almost have racemic compound R, the R type generates.

Embodiment 3

With 10.0g (3S, the similar approach that 1 ' S) type carboxylic acid cpd (V) provides with US4575503 prepares and obtains (3S, behind 1 ' S) the type carbonate (I), add the ethyl acetate of 25mL and the octane of 35mL and do recrystallization, get 6.5g (3S after the crystalline solid drying, 1 ' S) type carbonate (I), productive rate is 60.0%.

Mensuration by high performance liquid chromatography (HPLC): compound (I) wherein

Diastereomer (3S, 1 ' S): (3R, 1 ' S) ratio is＞99.5: 0.5 mixture,

And wherein enantiomorph (3S, 1 ' S): (3R, 1 ' R) ratio is＞99.9: 0.1 mixture.

The feature of compound (I) is as follows: 125 ℃ of mp; [α] ²⁰-184.07 ° (c=10, THF).

Embodiment 4

With 10.0g (3R, the similar approach that 1 ' S) type carboxylic acid sodium salt compound (IV) provides with US4575503 prepares and obtains (3R, behind 1 ' S) the type carbonate (II), add the ethyl acetate of 25mL and the octane of 35mL and do recrystallization, get 7.0g (3R after the crystalline solid drying, 1 ' S) type carbonate (II), productive rate is 65.0%.

Mensuration by high performance liquid chromatography (HPLC): wherein

(3R, 1 ' S): (3S, 1 ' S) ratio is＞99.5: 0.5 mixture to diastereomer.

The feature of compound (II) is as follows: mp 88-89 ℃; [α] ²⁰+ 171.68 ° (c=10, THF).

Claims

One kind prepare (1 ' S)-homophenylalanine carboxylic ester-benzazepine-both hands compound (I) and method (II),

Wherein: R represents C ₁～C ₄Alkyl;

This method comprises the following steps:

The first step: the mode that compound (X) utilizes crystallization to induce obtains a part of S earlier, S type carbonate (I),

Wherein: R represents C ₁～C ₄Alkyl;

Second step: crystalline mother solution (III) concentrates the back and uses the aqueous sodium hydroxide solution hydrolysis, obtains R through crystallization, S type carboxylic acid sodium salt compound (IV),

Wherein: R represents C ₁～C ₄Alkyl;

The 3rd step: compound (IV) carries out the epimerization reaction of highly selective, no racemization in the buffer system of pH=5～6, obtain S, S type carboxylic acid and S, and S type carboxylic acid salt mixture (V), and almost do not have racemic compound R, the R type generates,

The 4th step: compound (V) carries out esterification again after crystallization, obtains required S, S type carbonate (I);

The 5th step: compound (IV) directly carries out esterification through crystallization, obtains R, S type carbonate (II).