JP2831808B2 - Optical resolution of racemic β-lactams - Google Patents

Description

The present invention relates to an optical resolution method for stereoisomers of β-lactams (particularly, racemates).

[Problems to be solved by conventional technology and invention]

β-lactams are used for drugs such as antibiotics,
It is an important substance for other pharmaceutical ingredients. The action of drugs on living organisms often differs for each stereoisomer, for example, thalidomide (G. Blaschke, Angew, Chem.
Int. Ed. Engl., 19 , 13 (1980)), its separation is extremely important.

Conventionally, as a method for obtaining a stereoisomer of a β-lactam, an asymmetric synthesis method, a separation method of a racemic diastereomer derivative, a chromatography separation method of a racemate, and the like are known. Among them, the method of separating stereoisomers by the chromatographic separation method is excellent in that stereoisomers with high purity can be obtained, and has the advantage that continuous operation is also possible using the Sobex method. But so far β
-Separation columns used for the separation of racemic lactams as well as for the separation of stereoisomers were not sufficiently effective, and there were not many non-separable β-lactams.

[Means for solving the problem]

The present inventors have conducted intensive studies to solve the above problems,
When a separating agent containing a specific polysaccharide derivative as a main component is used, β-
The inventors have found that stereoisomers of lactams (especially racemates) can be efficiently separated, and have completed the present invention.

That is, in the present invention, a part or all of the hydrogen atoms on the hydroxyl group of cellulose or amylose is represented by the following formula (1) or (2). [Where R is (T-Bu is a tert-butyl group). Wherein the racemic β-lactams represented by the following general formulas (3) to (5) are optically resolved using a separating agent mainly composed of a polysaccharide derivative substituted with an atomic group represented by the following formula: To provide a method for resolving racemic β-lactams.

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are hydrogen atoms, —OCH ₂ OCH ₂ CH ₂ OCH ₃ is a substituent in which at least one combination of R ₁ and R ₂ or R ₃ and R ₄ is different.

Also R ₅ Is shown. ) (In the formula, R ₁ and R ₂ have the same meanings as described above.) (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ have the same meanings as described above.) As described above, β-lactams are obtained by replacing a part or all of the hydrogen atoms on the hydroxyl group of cellulose or amylose. The stereoisomer (especially racemic) is efficiently optically resolved by the separating agent mainly composed of the polysaccharide derivative substituted by the atomic group represented by the above formula (1) or (2).

The polysaccharide in the present invention is cellulose or amylose.

The number average degree of polymerization of these polysaccharides (the average number of pyranose or furanose rings contained in one molecule) is 5 or more, preferably 10 or more, and the upper limit is 2000 or less, preferably 500 or less in terms of ease of handling. preferable.

The introduced atomic group is a compound which reacts with the hydroxyl group of the polysaccharide to form an ester bond or a urethane (carbamate) bond represented by the above formula (1) or (2).

The polysaccharide derivative is synthesized, for example, by the following method.

1) Ester bond The carbonyl group forming the ester derivative of the polysaccharide of the present invention is represented by the above-mentioned general formula (1), and accounts for 30% to 100%, preferably 50% or more, more preferably, of all the hydroxyl groups of the corresponding polysaccharide. Is a compound in which 85% or more forms an ester bond with the carbonyl group.

The synthesis of the ester derivative according to the present invention can be easily obtained by converting the corresponding carboxylic acid into an acid chloride using thionyl chloride, oxalyl chloride or the like, and then reacting the corresponding carboxylic acid with the corresponding polysaccharide in a pyridine solvent.

2) Carbamate bond The carbamoyl group forming the carbamate derivative of the polysaccharide of the present invention is represented by the above-mentioned general formula (2), and accounts for 30% to 100%, preferably 50% or more, of the total hydroxyl groups of the corresponding polysaccharide. Are those in which at least 85% form a urethane bond with the carbamoyl group.

In the synthesis of the carbamate derivative according to the present invention, the usual reaction for producing urethane from alcohol and isocyanate can be applied as it is. For example, it can be obtained by reacting a corresponding isocyanate with a polysaccharide in a suitable solvent using a Lewis base such as a tertiary amine or a Lewis acid such as a tin compound as a catalyst. In addition, the synthesis of isocyanate can be easily obtained, for example, by causing phosgene to act on the amino group of the corresponding aniline derivative.

In order to apply the polysaccharide derivative as a separating agent to a liquid chromatography method, it is convenient to pack the polysaccharide derivative as a powder into a column. The polysaccharide derivative is preferably ground or beaded, and the particles are more preferably porous. Further, it is preferable to support a polysaccharide derivative on a carrier in order to improve the pressure resistance of the separating agent, prevent swelling and shrinkage due to solvent substitution, and improve the number of theoretical plates.

When used as a powder, the size of the particles and the size of the carrier vary depending on the size of the column to be used.
m to 1 mm, preferably 1 μm to 300 μm. The carrier is preferably porous and has an average pore size of 10 mm.
100100 μm, preferably 50Å to 50,000Å.
The amount of the polysaccharide derivative supported on the carrier is 1 to 10 with respect to the carrier.
0% by weight, preferably 5 to 50% by weight.

The method for supporting the polysaccharide derivative on the carrier may be a chemical method or a physical method. As a physical method, the polysaccharide derivative is dissolved in a soluble solvent, mixed well with the carrier, under reduced pressure or heating, a method of distilling off the solvent by air flow, or dissolving the polysaccharide derivative in the soluble solvent, There is also a method of diffusing a soluble solvent by mixing well and then separating it into a solvent insoluble in the polysaccharide derivative. The separating agent thus obtained can be improved in its separating ability by performing an appropriate treatment such as heating, addition of a solvent, and washing.

The carrier to be used 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 silica, alumina, magnesia, glass, kaolin, titanium oxide, silicate, etc., which have an improved affinity with a carbamate derivative or a surface of the carrier itself. May be used in order to improve the characteristics of the above. Examples of the surface treatment method include a silanization treatment with an organic silane compound and a surface treatment method with plasma polymerization.

There are no particular restrictions on the developing solvent used in liquid chromatography, except for those that dissolve or react with the polysaccharide derivative. When the polysaccharide derivative is bound to the carrier by a chemical method or insolubilized by cross-linking, there is no particular limitation except for those reacting therewith.

〔Example〕

Hereinafter, the present invention will be described in detail by examples and comparative examples,
The present invention is not limited to these examples.

Examples 1 to 5 Using the separating agents shown in Table 1, the following separation target substances (racemic mixture) were separated. Table 1 shows the results.

(In the above formula, Ac is an acetyl group, Me is a methyl group,
i-Pr represents an isopropyl group, and + represents a t-butyl group. The separation column used in Example 1 was prepared by dissolving amylose (S) -α-methylbenzylcarbamate in tetrahydrofuran, mixing with diphenylsilane-treated silica gel (Lichrospher Si-1000, manufactured by Merck), and then adding tetrahydrofuran. Filler obtained by distillation under reduced pressure, the inner diameter 0.46 cm, length 25 by a slurry method using methanol
It was prepared by packing in a cm stainless steel column. The separation columns used in Examples 2, 3, 4, and 5 were cellulose 3,5-dimethylphenylcarbamate, cellulose p-methylbenzoate, amylose 3,5-dimethylphenylcarbamate, and amylose pt-butylphenylcarbamate. Each was prepared in the same manner.

For the measurement, JASCO's TRI ROTAR-V type high pressure pump,
The company's UV-100-V UV detector was used.

The capacity ratio (k ₁ ′), separation factor (α) and degree of separation (Rs) in the table are defined by the following equations, respectively.

(If the degree of separation is 1 or more, it indicates almost complete separation)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // C07B 57/00 370 C08B 33/02 C07F 7/18 C07D 205/08 P C08B 3/00 499/00 A 33/02

Claims (1)

(57) [Claims] 1. A method according to claim 1, wherein part or all of the hydrogen atoms on the hydroxyl groups of cellulose or amylose are represented by the following formula (1) or (2): [Where R is (T-Bu is a tert-butyl group). Wherein the racemic β-lactams represented by the following general formulas (3) to (5) are optically resolved using a separating agent mainly composed of a polysaccharide derivative substituted with an atomic group represented by the following formula: Resolution of racemic β-lactams. (Wherein R ₁ , R ₂ , R ₃ and R ₄ are hydrogen atoms, —OCH ₂ OCH ₂ CH ₂ OCH ₃ is a substituent in which at least one combination of R ₁ and R ₂ or R ₃ and R ₄ is different. Is shown. ) (In the formula, R ₁ and R ₂ have the same meanings as described above.) (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ have the same meanings as described above.)