JPS581104B2 - Racemic Kahou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for racemizing optically active amino acid esters.

More specifically, the present invention relates to a novel racemization method for optically active amino acid esters (hereinafter referred to as optically active amino acid esters) represented by the following general formula.

(However, in the formula, R1 represents an alkyl, aralkyl, or aryl group, and R2 represents an alkyl group having 1 to 8 carbon atoms.

) Optically active amino acid esters can serve as intermediates for organic industrial chemicals, agricultural chemicals, and pharmaceuticals, and are also known to be useful as optical resolution agents for racemic acids.

These optically active amino acid esters are usually produced industrially as a racemate, and one useful optically active form can be obtained by optical resolution.

Therefore, by racemizing the remaining optically resolved enantiomers and repeating the resolution, it is possible to convert them into useful optically active forms, making racemization a very important technique.

Furthermore, hydrolysis of optically active amino acid esters yields important α-amino acids.

That is, α-amino acids obtained naturally or by ordinary synthetic methods other than fermentation are racemic, and the remaining enantiomer obtained by optical resolution is esterified. It is also possible to racemize by the method of the present invention and optionally optically resolve in the ester state.

An object of the present invention is to provide an industrially advantageous method for racemizing these optically active amino acid esters.

As a result of intensive research on racemization methods, the present inventors have discovered that an optically active amino acid ester can be easily and quantitatively converted into a racemate by using a catalyst consisting of an alkali metal and a polycyclic aromatic hydrocarbon. The present invention was completed after various studies.

To explain the process of the present invention in more detail, the catalyst used to carry out the racemization is an alkali metal of at least one of lithium, sodium and potassium and at least one of naphthalene, alkylnaphthalene, anthracene, phenanthrene and tetraphenylethylene. 1
It is a complex consisting of various polycyclic aromatic hydrocarbons, and examples include lithium naphthalene, sodium naphthalene, potassium naphthalene, lithium anthracene, sodium anthracene, and potassium anthracene.

Alkali metals and polycyclic aromatic hydrocarbons are known to form soluble colored complexes in the presence of ethers such as dimethyl ether, ethylene glycol dimethyl ether, and tetrahydrofuran (J. Am. Chem.
．． Soc. , 58, 2442 (1936)), such complexes can also be used.

The present inventors have newly discovered that, surprisingly, racemization occurs extremely easily when an optically active amino acid ester is brought into contact with the above catalyst.

That is, by adding the above-mentioned catalyst to an optically active amino acid ester, the reaction can proceed without inhibiting the reaction at a reaction temperature in the range of about -10°C to 150°C, regardless of external pressure.

The optically active amino acid ester used for racemization is represented by the above general formula, and R1 defined in the formula
The alkyl group has 1 to 8 carbon atoms, such as methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, etc.
The alkyl group, an alkyl group substituted with an alkoxycarbonyl group, and an aralkyl group refer to benzyl, phenethyl, naphthylmethyl, naphthylethyl, etc., and an alkyl group having 1 to 4 carbon atoms or an alkoxy group substituted product on the aromatic ring thereof; Aryl groups include phenyl, naphthyl, etc., and their aromatic rings are substituted with alkyl groups or alkoxy groups having 1 to 4 carbon atoms.

R2 represents an alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, butyl, cyclohexyl, and cyclohexylmethyl.

Specific examples include alanine methyl ester, alanine butyl ester, norvaline propyl ester, leucine ethyl ester, β-cyclohexylalanine methyl ester, β-phenylalanine methyl ester, β
-phenylalanine propyl ester, β-3,4-dimethoxyphenylalanine ethyl ester, and the like.

The optically active amino acid ester can be made into a racemic form regardless of the optical purity of the optically active d-form, l-form, or either one.

The process of the invention can be carried out either batchwise or continuously.

The optically active amino acid ester can be added to the reaction vessel together with the catalyst in a single introduction, or if desired, it can be added continuously or intermittently to the reaction vessel as the reaction progresses.

Although the amount of catalyst to be used relative to the optically active amino acid ester is not critical, it is preferable to use any amount of catalyst that will yield a suitable amount of racemic product in a suitable reaction time.

For more economical implementation, 1/1000 to 1/5 mole of catalyst is used per mole of optically active amino acid ester.

More preferably, it is 1/200 to 1/10 mole.

The reaction temperature is approximately -10℃ to 150℃, industrially -10℃
The most suitable temperature range is from 100°C to 100°C; below this temperature, the racemization rate is slow; if the above-mentioned temperature is significantly exceeded, the racemization rate is faster, but it may actually cause decomposition of the optically active amino acid ester and other side effects This is disadvantageous because it causes a reaction.

The reaction proceeds quantitatively even in the absence of a solvent, but if necessary, it is also possible to mix a solvent that does not inhibit the reaction under appropriate reaction conditions.

Racemization can be carried out more safely and reliably under an inert gas atmosphere.

Furthermore, it is better to sufficiently remove moisture from the optically active amino acid ester before contacting it with a catalyst.

The reaction time varies depending on the amount of catalyst used and the reaction temperature, and becomes shorter as the amount of catalyst used increases and the temperature increases.

The progress of the reaction can be determined by measuring the optical rotation of a given concentration or by analyzing it with gas chromatography.

After the reaction is completed, the catalyst is separated and purified.

It is separated and purified by distillation, chromatography, or by an appropriate method such as making a salt with an acid and removing neutral substances and other substances, but since it proceeds quantitatively, a highly pure product can be obtained as it is.

As described in detail, the method of the present invention not only enables racemization, but also allows racemization to be carried out under mild conditions around room temperature using a small amount of catalyst, which is extremely advantageous in terms of operation, equipment, and economy. Amino acid esters can be obtained.

The method of the invention will now be explained by way of examples.

Example 1 L-β-phenylalani was placed in a 100 ml reaction vessel,
After purging with nitrogen, 1.3 g of sodium naphthalene (1:1) was added and stirred at 23°C.

A portion of the reaction solution was sampled at intervals and the optical rotation was measured as shown below.

After the reaction, the catalyst is removed and distilled to give a boiling point of 88-92℃/0
．． 45.3 g of a product with a concentration of 3 mmHg was obtained, and the distilled product was confirmed to be β-phenylalanine methyl ester.

Example 2 After adding L-alanine ethyl ester to a 100 ml reaction vessel, 1.6 g of potassium naphthalene (1:1) was added and stirred at 22°C for 3 hours.

When the catalyst is removed and distilled under reduced pressure, the boiling point is 55-56℃/22
46.2 g of reactant with mmHg was obtained.

The optical rotation was 0° and the infrared spectrum showed it to be alanine ethyl ester.

Example 3 After adding L-leucine ethyl ester to a 25 ml reaction vessel, add 0.8 g of sodium naphthalene (1:1) and heat at 15°C.
The mixture was stirred for 4 hours.

After the reaction, the catalyst is removed and distilled under reduced pressure, resulting in a boiling point of 83-84℃.
/12mmHg racemic leucine ethyl ester 9
．． Example 4 0.8 g of sodium anthracene substituted with diethyl L-aspartate was added to a 25 ml reaction vessel and stirred at 25°C.

When a part of the reaction solution is sampled every time and the optical rotation is measured,
It was as shown below.

After the reaction, the catalyst is removed and distilled under reduced pressure, resulting in a boiling point of 85-86
8.7 g of racemic aspartic acid diethyl ester with a temperature of 0.degree. C./1.0 mmHg was obtained.

Claims (1)

[Scope of Claims] 1. A catalyst comprising a complex consisting of at least one alkali metal among lithium, sodium, and potassium and at least one polycyclic aromatic hydrocarbon among naphthalene, alkylnaphthalene, anthracene, phenanthrene, and tetraphenylethylene. Racemization of an optically active amino acid ester represented by the following general formula, characterized in that it is used as Law.