JP2771863B2 - Method for direct resolution of β-hydroxycarboxylic acid derivatives - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention relates to a method for directly resolving β-hydroxycarboxylic acid derivatives.

[Problems to be solved by conventional technology and invention]

β-hydroxycarboxylic acid derivatives are used as raw materials for pharmaceutical intermediates and optically active functional materials. For example, optically active β-hydroxybutyrate is a compound useful as an intermediate of an antibiotic having an active natural β-lactam structure. Are being considered. Optically active β-hydroxybutyrate is also a useful compound as a raw material for ferroelectric liquid crystals. Therefore, providing a method for simply and quickly determining the optical purity of a β-hydroxycarboxylic acid ester is extremely useful for efficacy evaluation and quality control. Until now, methods for determining the optical purity of β-hydroxycarboxylic acid derivatives include (R)-
A method such as MTPA (α-methoxy-α-trifluoromethylphenylacetic acid) ester and HPLC analysis (Noyori et al., J. Amer. Chem. Soc., 109 (19), 5856-8) is known. However, no direct analysis method is known.

[Means for solving the problem]

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, the β-hydroxycarboxylic acid derivative is optically resolved by liquid chromatography or the like using a cellulose derivative as an optically active stationary phase to obtain an optical purity. The present invention has been completed by finding that the determination can be made easily and accurately.

That is, the present invention relates to the general formula (Wherein, R ¹ represents an alkyl group or an unsubstituted or substituted aromatic group, and X represents an alkyloxy group, an aryloxy group, an alkylthio group, an arylthio group, an unsubstituted amino group, a monosubstituted amino group or a disubstituted amino group. Wherein * represents an asymmetric carbon atom.) Β-hydroxycarboxylic acid characterized by optically resolving the enantiomer of the β-hydroxycarboxylic acid derivative represented by the formula (1) using a separating agent containing a cellulose derivative as an active ingredient. The present invention provides a method for directly resolving an acid derivative.

In the general formula (1), the aromatic group represented by R ¹ is preferably an aromatic group having 5 to 14 carbon atoms, and examples thereof include a phenyl group and a naphthyl group. Further, it also contains a heteroaromatic group such as a pyridyl group. Further, as the substituent of the aromatic group, an alkyl group having 1 to 10 carbon atoms, Cl,
Br, halogen such as I, further -CN, -NO _2, -CF _3, alkoxy group. On the other hand, in the general formula (1), R ¹
The alkyl group represented by is preferably an alkyl group having 1 to 20 carbon atoms, and may have a double bond, a phenyl group, or a substituent in the structure.

In the general formula (1), as the alkyloxy group and the alkylthio group represented by X, an alkyloxy group and an alkylthio group having 1 to 10 carbon atoms are preferable, and a double bond, a phenyl group, or a substituent May be provided. Specifically, methoxy, ethoxy, butyloxy, octyloxy, decyloxy, cinnamyloxy, vinyloxy, allyloxy, benzyloxy, methylthio, ethylthio, ethylthio, butylthio, octylthio, decylthio, Examples include a cinnamylthio group, a vinylthio group, an anilthio group, and a benzylthio group.

Further, as the aryloxy group and the arylthio group represented by X, an aryloxy group and an arylthio group having 5 to 14 carbon atoms are preferable, and specifically, a phenyloxy group,
Pyridyloxy group, tolyloxy group, naphthyloxy group, phenylthio group, pyridylthio group, tolylthio group,
Alternatively, a naphthylthio group or the like is exemplified, and these groups may have a substituent.

Further, the monosubstituted amino group represented by X in the general formula (1) includes an alkylamino group and an arylamino group. As the alkylamino group, an alkylamino group having 1 to 10 carbon atoms is preferable, and a double bond,
It may have a phenyl group or a substituent. Specific examples include a methylamino group, an ethylamino group, a butylamino group, a heptylamino group, a decylamino group, a cinnamylamino group, a vinylamino group, an allylamino group, and a benzylamino group. The arylamino group is preferably an arylamino group having 5 to 14 carbon atoms, and examples thereof include a phenylamino group, a pyridylamino group, a tolylamino group, and a naphthylamino group. The disubstituted amino group represented by X in the general formula (1) includes a dialkylamino group,
The alkyl group includes an alkylarylamino group and a diarylamino group. The alkyl group is preferably an alkyl group having 1 to 10 carbon atoms, and the aryl group is preferably an aryl group having 5 to 14 carbon atoms. Specific examples include a dimethylamino group, a methylethylamino group, a benzylphenylamino group, a benzylbutylamino group, an allylmethylamino group, a diphenylamino group, a cinnamylmethylamino group, a naphthylmethylamino group, and a hexitolylamino group. Can be

The separating agent used in the present invention contains a cellulose derivative as an active ingredient.

The term "cellulose derivative" as used in the present invention refers to a cellulose derivative in which some or all, preferably 85% or more, of the hydrogen atoms on the hydroxyl groups of cellulose are replaced with other atomic groups. The atomic group referred to here is the following formula (Wherein, R ² is an aliphatic group having 1 to 3 carbon atoms, 3 carbon atoms)
Or a cycloaliphatic group having from 8 to 8 or an aromatic group or a heteroaromatic group having from 4 to 20 carbon atoms, each of which may have a substituent). Cellulose derivatives can be easily obtained using various known chemical reactions.

These cellulose derivatives improve the pressure resistance of the separating agent,
In order to prevent swelling and shrinkage due to solvent substitution, and to increase the number of theoretical plates, it is preferable to hold the carrier on a carrier. The appropriate size of the carrier varies depending on the size of the column or plate used, but is generally 1 μm to 10 mm, preferably 1 μm to 10 μm.
300 μm. The carrier is preferably porous,
The average pore size is 10 ~ 100μm, preferably 50 ~ 100
00Å. The amount of the cellulose derivative retained is 1 to 100% by weight, preferably 5 to 50% by weight, based on the carrier.

The method for retaining the cellulose derivative on the carrier may be a chemical method or a physical method. As a physical method, the cellulose derivative is dissolved in a soluble solvent, mixed well with the carrier, under reduced pressure or heating, the solvent is distilled off by air flow, or the cellulose derivative is dissolved in the soluble solvent, and the carrier is dissolved. After mixing well, there is also a method in which the solvent is stirred and dispersed in a liquid incompatible with the solvent to diffuse the solvent. When the cellulose derivative held on the carrier is crystallized in this manner, a treatment such as a heat treatment can be performed. or,
It is possible to swell or dissolve the cellulose derivative once by adding a small amount of solvent, and to change the retention state, and eventually the separation ability, by distilling off the solvent again.

The carrier used in the present invention includes a porous organic carrier or a porous inorganic carrier, and is preferably a porous inorganic carrier. Suitable examples of the porous organic carrier include a polymer substance composed of polystyrene, polyacrylamide, polyacrylate, and the like. Suitable examples of the porous inorganic carrier include synthetic or natural substances such as silica, alumina, magnesia, titanium oxide, glass, silicate, and kaolin.Surface treatment is performed to improve the affinity with the cellulose derivative. You may go. Examples of the surface treatment method include a silanization treatment using an organic silane compound, a surface treatment method using plasma polymerization, and the like.

In the present invention, as means for optically resolving the β-hydroxycarboxylic acid derivative using the above separating agent,
There are chromatography methods such as gas chromatography, liquid chromatography, and thin layer chromatography.

There are no particular restrictions on the developing solvent used for liquid chromatography or thin-layer chromatography, except for the liquid that dissolves or reacts with the separating agent. When the separating agent is bound to the carrier by a chemical method or insolubilized by crosslinking, there is no restriction except for the reactive liquid. Needless to say, the separation characteristics of the compound or the chemical isomer change depending on the developing solvent, and it is therefore desirable to consider various developing solvents.

〔Example〕

Hereinafter, the present invention will be described specifically with reference to Examples.
The present invention is not limited by these.

Examples 1 to 3 (2) In, an enantiomer mixture of alkyl β-hydroxybutyrate in which R ³ is an alkyl group (the alkyl group is a methyl group, an ethyl group, or an isopropyl group) was separated by liquid chromatography, and the retention time was determined.

Table 1 shows the conditions of the liquid chromatography and the results.

As a column for liquid chromatography, about 20% by weight of cellulose-3,5-dimethylphenylcarbamate (trade name “OD” manufactured by Daicel Chemical Industries, Ltd.) was supported on diphenyllsilane-treated silica gel. 25cm,
A stainless steel column having an inner diameter of 0.46 cm was used.

The liquid chromatography charts obtained in Examples 1 and 2 are shown in FIGS. 1 and 2, respectively.

[Brief description of the drawings]

1 is a chart of the liquid chromatography obtained in Example 1, and FIG. 2 is a chart of the liquid chromatography obtained in Example 2.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification symbol FI // C07B 57/00 340 C07B 57/00 340 370 370 380 380 C07M 7:00 (58) Field surveyed (Int. Cl. ⁶ , DB name) C07C 69/675 C07C 327/22 C07C 235/04 C07C 67/48 C07C 231/20 C07B 57/00

Claims (1)

(57) [Claims] (1) General formula (Wherein, R ¹ represents an alkyl group or an unsubstituted or substituted aromatic group, and X represents an alkyloxy group, an aryloxy group, an alkylthio group, an arylthio group, an unsubstituted amino group, a monosubstituted amino group or a disubstituted amino group. Wherein * represents an asymmetric carbon atom.) Β-hydroxycarboxylic acid characterized by optically resolving the enantiomer of the β-hydroxycarboxylic acid derivative represented by the formula (1) using a separating agent containing a cellulose derivative as an active ingredient. A direct resolution method for acid derivatives.