JPH07118277A - Separation of diastereomer - Google Patents

Abstract

PURPOSE:To exclusively separate a diastereomer useful as an intermediate for pharmaceuticals in a high efficiency from plural diastereomers taking advantage of the solubility difference in a range from a weakly acidic state to a weakly alkaline state. CONSTITUTION:Two kinds of diastereomers of a cephemcarboxylic acid ester of the formula I [(n) is 0 or 1; R1 is 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl or (CH2)m-OR2 ((m) is 0 or 1; R2 is 1-6C alkyl or 2-6C alkenyl); C atom labeled with * is a mixture of R- and S-configurations] or the formula II (X is anion of basic or polybasic inorganic or organic acid) are separated into a cephemcarboxylic acid esters of the formula III [C atom labeled with (S) has S-configuration] and the formula IV [C atom labeled with (R) has R- configuration]. The diastereomer is preferably dissolved or dispersed in a buffer solution, water or a mixture of water and a water-soluble organic solvent such as methanol.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for separating diastereomers of cephemcarboxylic acid esters which are useful as intermediates for pharmaceuticals.

[0002]

2. Description of the Related Art A method for separating diastereomers of cephemcarboxylic acid esters is disclosed in JP-A-5-178861.
Issue bulletins are listed.

[0003]

However, in the above method, the two diastereomers are separated by silica gel column chromatography, and therefore the operation is complicated and is not suitable for a large amount of treatment. As another method, a crystallization method using an organic solvent is also mentioned, but the purification efficiency in one operation is poor and it is necessary to repeat the crystallization operation many times.

[0004]

The present inventors have found that the solubility of the two diastereomers of the cephem carboxylic acid ester is greatly different when the weakly acidic to weakly alkaline amino groups are free. The invention was completed. Hereinafter, the present invention will be described in detail.

That is, the present invention provides the following formula (1);

[0006]

[Chemical 5]

Or the following formula (2):

[0008]

[Chemical 6]

The two diastereomers of the cephemcarboxylic acid ester of the above are separated and purified by utilizing the difference in solubility between weakly acidic and weakly alkaline, and the following formula (3);

[0010]

[Chemical 7]

A cephemcarboxylic acid ester of the following formula (4);

[0012]

[Chemical 8]

The present invention relates to a method for separating cefem carboxylic acid ester. In the present invention, a mixture of the above two diastereomers is dissolved or suspended in an organic solvent, a buffer solution or water. Solvents which can be used are, for example, water, alcohols, ethers, esters, ketones and nitrites and mixtures thereof. Preferred solvents include water, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetone, acetonitrile and mixtures thereof.

As the monobasic or polybasic acid represented by HX, an organic acid or an inorganic acid can be used. Examples of the organic acid include benzenesulfonic acid, ethylbenzenesulfonic acid, p-tolylsulfonic acid, ethanesulfonic acid, methanesulfonic acid, acetic acid, propionic acid, tartaric acid and the like. Examples of the inorganic acid include stoichiometric amounts of hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid, sulfuric acid, phosphoric acid and the like.

A basic solution is added to a solution or suspension of a mixture of two diastereomers of this cephemcarboxylic acid ester to adjust the pH to 4.5 to 10, preferably 6.5 to 8.5. The precipitated amino group-free crystals are collected by filtration to obtain a cephemcarboxylic acid ester in which the stereo configuration of the ester is S configuration. Bases that can be used at this time are inorganic and organic bases. For example, as inorganic bases, hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide, and basic inorganic substances such as sodium monohydrogen phosphate can be used. Examples include salt and ammonia. Examples of the organic base include organic amines such as triethylamine, diisopropylamine and cyclohexylamine.

From this filtrate, a cephemcarboxylic acid ester having an ester configuration of R configuration can be obtained.
The method is obtained, for example, by extracting the filtrate with an organic solvent such as ethyl acetate. The solvent that can be used at this time is an organic solvent that does not uniformly mix with water. As an alternative method, a mixture of two diastereomers of the cephemcarboxylic acid ester of formula (1) is suspended in a solvent while leaving the amino group free, and a buffer solution having a weakly acidic to weakly basic pH is added. It is also possible to obtain a cephemcarboxylic acid ester having an ester configuration of S configuration as crystals. The pH of the aqueous solution used at this time is 4.5 to 10, preferably 6.5.
To 8.5. From the crystal filtrate, the ester stereotype is R
A configurational cephem carboxylic acid ester can be obtained.

The amino group-free compound having the S configuration and the R configuration can be easily converted into a salt with an organic acid or an inorganic acid. At this time, a usual organic acid or inorganic acid can be used. Examples of the organic acid include p-tolylsulfonic acid, methanesulfonic acid, acetic acid, propionic acid, tartaric acid and the like. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid, sulfuric acid and the like.

[0018]

EXAMPLE A mixture of two diastereomers (1
35 g (64.3 mmol) of R)-and (1S) -1- (2,2-dimethylpropionyloxy) ethyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate p-tolylsulfonate. Methanol 43
After dissolving in 8 ml, 2494 ml of water was added. The pH was adjusted to 8 by adding a 1 M aqueous sodium hydroxide solution to this solution. The crystals formed were collected by filtration and washed with 10 ml of 15% aqueous methanol (1S) -1- (2,2-dimethylpropionyloxy) ethyl 7-amino-3-methoxymethyl-3.
-Cephem-4-carboxylate 8.42 g (22.
6 mmol) was obtained. 1H-NMR (DMSO-d6) δ 1.13 (s,
9H), 1.45 (d, 3H), 3.18 (s, 3)
H), 3.52 (ABq, 2H), 4.10 (s,
2H), 4.82 (bs, 1H), 5.03 (d,
1H), 6.84 (q, 1H) Further, the total amount of the obtained crystals was dissolved in 43 ml of ethyl acetate, and 5.15 g of p-tolylsulfonic acid monohydrate (27.
(1 mmol) dissolved in 43 ml of ethyl acetate was added dropwise and stirred for 10 minutes. After adding 33 ml of ether and stirring for 30 minutes, the crystals were collected by filtration. The crystals obtained were washed with 33 ml of ethyl acetate and then with 33 ml of ether and dried under reduced pressure to give (1S) -1- (2,2-dimethylpropionyloxy) ethyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate. p-tolyl sulfonate 1
Obtained 1.6 g (66.3%). Melting point 175 ° C (decomposition) 1H-NMR (DMSO-d6) δ 1.15 (s,
9H), 1.48 (d, 3H), 2.29 (s, 3)
H), 3.21 (s, 3H), 3.69 (ABq,
2H), 4.17 (s, 2H), 5.2-5.3.
(M, 2H), 6.88 (q, 1H), 7.11
(D, 2H), 7.48 (d, 2H) (1S) -1- (2,2-dimethylpropionyloxy) ethyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate was filtered off. The resulting filtrate was extracted twice with 14 ml of ethyl acetate, and then the solvent was distilled off.
R) -1- (2,2-Dimethylpropionyloxy) ethyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate 5.68 g (47.5%) was obtained. 1H-NMR (DMSO-d6) δ 1.15 (s,
9H), 1.46 (d, 3H), 3.18 (s, 3)
H), 3.50 (ABq, 2H), 4.10 (s,
2H), 4.81 (bs, 1H), 5.03 (d,
1H), 6.90 (q, 1H) The obtained compound was dissolved in 43 ml of ethyl acetate, and p
-Tolylsulfonic acid monohydrate 5.15 g (27.1 mm)
ol) dissolved in 43 ml of ethyl acetate and added dropwise.
Stir for minutes. The solvent was distilled off and (1R) -1- (2,2-
Dimethylpropionyloxy) ethyl 7-amino-3
8.24 g (47.1%) of -methoxymethyl-3-cephem-4-carboxylate p-tolyl sulfonate were obtained. 1H-NMR (DMSO-d6) δ 1.12 (s,
9H), 1.46 (d, 3H), 2.48 (s, 3)
H), 3.19 (s, 3H), 3.66 (ABq,
2H), 4.15 (s, 2H), 5.2-5.3.
(M, 2H), 6.93 (q, 1H), 7.09
(D, 2H), 7.44 (d, 2H)

[0019]

INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to efficiently obtain, from diastereomers, cephemcarboxylic acid esters useful as intermediates for pharmaceuticals, only isomers having the necessary stereochemistry.

[Procedure amendment]

[Submission date] November 29, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Correction content]

[Claims]

[Chemical 1] Or the following formula (2);

[Chemical 2] The two diastereomers of the cephemcarboxylic acid ester of the above are separated and purified by utilizing the difference in solubility between weakly acidic and weakly alkaline, and the following formula (3);

[Chemical 3] Cefem carboxylic acid ester of the following formula (4);

[Chemical 4] Separating the cephem carboxylic acid ester of.

Claims (1)

[Claims] 1. The following formula (1); Or the following formula (2); The two diastereomers of the cephem carboxylic acid ester of are isolated and purified by utilizing the difference in solubility between weakly acidic and weakly alkaline, and are represented by the following formula (3); Cefem carboxylic acid ester of the following formula (4); Separating the cephem carboxylic acid ester of.