JP2001294577A - Method for producing optically active imidazolidin-2-ones - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method enabling objective optically active imidazolidin-2-ones to be obtained in better chemical and asymmetric yields than conventional method without using metal which is disadvantageous in the aspect of waste disposal. SOLUTION: This method for producing optically active imidazolidin-2-ones represented by general formula (3) is to react a compound represented by general formula (1) with a hydroxy compound in the presence of optically active alkaloids and in the presence or absence of a basic compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing optically active imidazolidine-2-ones in which a cyclic acid anhydride is opened with an alcohol.

[0002]

2. Description of the Related Art Optically active imidazolidine-2-one derivatives are extremely important compounds as synthetic intermediates such as d-biotin (vitamin H). Many methods for producing the compound are known, and a method for reacting a cyclic acid anhydride according to the present invention with an alcohol to open the ring to obtain an optically active compound is also known. For example, Bull. Chem. Soc. Jp
n, 1993, 66 , 2128, the method using alkaloids and dialkyl zinc, and J. Org. Chem. 1998, 63, 11
A method using the optically active titanate compound described in No. 90 is known. However, the resulting imidazolidine-2
The optical purity of the -one derivative was not always sufficient. In addition, in any case, at least one equivalent of an organic metal or a metal alkoxide is required relative to the acid anhydride as a raw material. Therefore, from the viewpoint of economy and waste treatment, a production method which is not necessarily industrially satisfactory. It was hard to say.

[0003]

DISCLOSURE OF THE INVENTION The present invention relates to an optically active imidazolin-2-one having improved chemical and asymmetric yields without using metals which are disadvantageous in terms of waste disposal. It is an object of the present invention to provide a production method capable of obtaining such a product.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have reached the present invention. That is, the present invention relates to the general formula (1) (In the formula, R ¹ represents an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent.) A cyclic acid anhydride represented by the following general formula (2): R ² OH (2) wherein R ² is an alkyl group optionally substituted with an alkoxy group, a phenoxy group, a dialkylamino group or a halogen atom; An aralkyl group optionally substituted with an alkoxy group, a phenoxy group, a nitro group or a halogen atom; or an aryl group optionally substituted with an alkyl group, an alkoxy group, a nitro group or a halogen atom). General formula (3) in which a hydroxy compound is reacted in the presence of an optically active alkaloid in the presence or absence of a basic compound (Wherein, R ¹ and R ² have the same meaning as described above.) The present invention provides a method for producing an optically active imidazolidine-2-one represented by the formula:

[0005]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. In the cyclic acid anhydride represented by the general formula (1), the alkyl group which may have a substituent of R ¹ has 1 carbon atom.
And 10 to 10 alkyl groups, which may be linear, branched or cyclic, and examples of the substituent include a halogen atom and an alkoxy group. Examples of the alkyl group which may have a substituent include, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group,
Isopropyl, t-butyl, isoamyl, cyclopentyl, cyclohexyl, cycloheptyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, 1-chloroethyl, 2-chloroethyl, 1,2- Examples thereof include a dichloroethyl group, a 2,2,2-trichloroethyl group, a methoxymethyl group, and a 2-methoxyethyl group. Examples of the aralkyl group optionally having a substituent of R ¹ include a benzyl group, a 1-phenethyl group, a 2-phenethyl group, an α-naphthylmethyl group, a β-naphthylmethyl group, and the like. In which the aromatic ring is substituted with a halogen atom, the above-mentioned alkyl group, or the like. The number and position of the substituents that substitute these aromatic rings are not particularly limited. Examples of the aryl group for R ¹ include a phenyl group, a naphthyl group,
Examples thereof include an anthranyl group and a phenanthryl group, and those in which these aromatic rings are substituted with a halogen atom, the above-mentioned alkyl group and the like. The number and position of the substituents that substitute these aromatic rings are not particularly limited.

Specific examples of the cyclic acid anhydride represented by the general formula (1) include, for example, 4,6-dimethyl-2,4,4
6,3a, 6a-pentahydro-4,6-diaza-2-
Oxapentalene-1,3,5-trione, 4,6-bisbenzyl-2,4,6,3a, 6a-pentahydro-
4,6-diaza-2-oxapentalene-1,3,5-
Trione, 4,6-diphenyl-2,4,6,3a, 6
a-pentahydro-4,6-diaza-2-oxapentalene-1,3,5-trione and the like.

The hydroxy compound represented by the general formula (2) used in the present invention includes an alkyl alcohol, an aralkyl alcohol and an aryl alcohol which may have a substituent. Specifically, for example, methyl alcohol, ethyl alcohol, n-propyl alcohol, i-propyl alcohol, n-butyl alcohol, s-butyl alcohol, t-butyl alcohol, n
-Pentyl alcohol, neopentyl alcohol, amyl alcohol, hexyl alcohol, octyl alcohol, 2-methoxyethanol, 2-phenoxyethanol, 2- (dimethylamino) ethanol, 2-chloroethanol, benzyl alcohol, 2-methylbenzyl alcohol, 4- Methylbenzyl alcohol, 2-methoxybenzyl alcohol, 4-methoxybenzyl alcohol, 2-phenoxybenzyl alcohol, 4-phenoxybenzyl alcohol, 4-nitrobenzyl alcohol, 4-chlorobenzyl alcohol, phenol, 2-
Examples include methylphenol, 4-methylphenol, 2-methoxyphenol, 4-methoxyphenol, 4-nitrophenol, 4-chlorophenol and the like.

In such a hydroxy compound (2),
Primary alcohols and benzyl alcohols are preferred in terms of reaction rate.

The amount of the hydroxy compound (2) used is usually 1 equivalent or more based on the cyclic acid anhydride (1), and may be used in excess if necessary, or used as a solvent. Generally, unreacted raw materials after the completion of the reaction can also be recovered by an operation such as distillation.

[0010] The present invention is carried out in the presence of optically active alkaloids. Examples of such optically active alkaloids include quinine, epiquinine, cinchonine, cinchonidine and the like. Particularly, quinine is preferred in that the optical purity of the product is increased.

The amount of the optically active alkaloids to be used is not particularly limited, but is usually 0.1 to 1.0 with respect to the cyclic acid anhydride (1).
About 001 to 100 mol%, preferably 0.01 to 50
It is about mol%.

The present invention is carried out in the presence or absence of a basic compound, and specific examples of the basic compound include:
For example, inorganic carbonates such as lithium carbonate, potassium carbonate, sodium carbonate, lithium hydrogen carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, ammonium carbonate, magnesium carbonate, etc., triethylamine, ethyldiisopropylamine, pyridine, 1,2,2,6 6-pentamethylpiperidine, 2-methyl-5-ethylpyridine, 2,6
Organic bases such as -dichloropyridine, picoline and N-methylimidazole, and especially 1,2,2,6,6
The use of -pentamethylpiperidine is preferred in that the chemical yield can be improved while maintaining high optical purity of the product.

The amount of the basic compound used is not particularly limited, but is usually about 0.1 to 10 mol times, preferably about 0.1 to 2 mol times, relative to the cyclic acid anhydride (1).

When the basic compound is used in the present invention, the desired optically active imidazolidine-2-ones (3) can be advantageously obtained even if the amount of the optically active alkaloids used is small.

When reacting the cyclic acid anhydride (1) with the hydroxy compound (2) in the presence or absence of a basic compound in the presence of an optically active alkaloid,
Usually, it is carried out under an atmosphere of an inert gas such as argon or nitrogen. The reaction can be carried out under normal pressure, increased pressure or reduced pressure.

The reaction can be carried out without a solvent or in a solvent.
Halogenated hydrocarbons such as chloroform, 1,2-dichloroethane, carbon tetrachloride, hexane, heptane, octane,
Aliphatic hydrocarbons such as nonane, benzene, toluene, xylene, aromatic hydrocarbons such as chlorobenzene,
Examples thereof include ether solvents such as diethyl ether and tetrahydrofuran, and mixed solvents of two or more kinds of solvents arbitrarily selected from these.

The reaction temperature is not particularly limited, but is preferably in the range of -80 to 100 ° C, particularly preferably in the range of -60 to 50 ° C.

The optically active imidazolidine-2-ones (3) produced by the above reaction can be washed with water or acidic water to remove basic substances, and if necessary, distilled and recrystallized. , Etc., can be easily separated from the reaction mixture. In addition, a strong base can be added to the aqueous phase obtained by washing to release alkaloids and organic bases, which can be recovered.

[0019]

According to the present invention, the optically active imidazolidine-2-ones (3) can be obtained with good optical purity and chemical yield, which is advantageous as an industrial production method.

[0020]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 Cis-4,6-bisbenzyl-2,4,6,3a, 6a-pentahydro-4,
199 mg (0.60 mmol) of 6-diaza-2-oxapentalene-1,3,5-trione was charged, 5 ml of toluene was added, and the mixture was cooled to -50 ° C. Furthermore, quinine 212.7mg (0.66
mmol), methanol (53.1 mg, 1.7 mmol) was added dropwise, and the mixture was stirred at the same temperature for 21 hours. The reaction mixture was quenched with 2N hydrochloric acid and extracted with diethyl ether.
After the organic phase was washed with a saturated saline solution, quantitative analysis by HPLC (internal standard: diisopropyl phthalate) was carried out. As a result, (4S, 5R) -1,3-bisbenzyl- obtained was obtained.
The yield of 2-oxo-5- (methoxycarbonyl) imidazolidin-4-carboxylic acid was 49.1%. Furthermore, optically active HPLC (SUMICHIRAL OA-
It was 73.3% ee when the optical purity was measured by 3300).

Example 2 In a 20 mL eggplant-shaped flask purged with nitrogen, cis-4,6-bisbenzyl-2,4,6,3a, 6a-pentahydro-4,
199 mg (0.6 mmol) of 6-diaza-2-oxapentalene-1,3,5-trione was charged, and 2.5 mL of toluene and 2.5 mL of carbon tetrachloride were added, followed by cooling to −20 ° C. Further, 213.9 mg (0.66 mmol) of quinine was charged, 64.0 mg (0.6 mmol) of benzyl alcohol was added dropwise, and the mixture was stirred at the same temperature for 16 hours. The reaction mixture was treated as in Example 1, (4
S, 5R) -1,3-Bisbenzyl-2-oxo-5-
(Methoxycarbonyl) imidazolidine-4-carboxylic acid was obtained at a yield of 76.8%. The optical purity of the product was 73.6% ee.

Example 3 In the same manner as in Example 2 except that cinchonidine was used instead of quinine, (4S, 5R)
-1,3-Bisbenzyl-2-oxo-5- (methoxycarbonyl) imidazolidine-4-carboxylic acid in a yield of 8
1.4%. The optical purity of the product was 25.9% ee.

Example 4 Cis-4,6-bisbenzyl-2,4,6,3a, 6a-pentahydro-4,
After 202 mg (0.60 mmol) of 6-diaza-2-oxapentalene-1,3,5-trione was charged, 5 ml of toluene was added, and the mixture was cooled to -50 ° C. Furthermore, 19.3mg of quinine (0.06m
mol) and 106.0 mg (0.68 mmol) of 1,2,2,6,6-pentamethylpiperidine, and 55.0 mg of methanol
(1.7 mmol) was added dropwise, and the mixture was stirred at the same temperature for 21 hours. The reaction mixture was treated as in Example 1 and (4S, 5R)-
1,3-Bisbenzyl-2-oxo-5- (methoxycarbonyl) imidazolidin-4-carboxylic acid was obtained in a yield of 96.0.
%. The optical purity of the product was 59.8% ee.

Claims (6)

[Claims] 1. The general formula (1) (Wherein, R ¹ represents an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent.) Cyclic acid anhydride and general formula (2) R ² OH (2) (wherein, R ² is an alkyl group optionally substituted by an alkoxy group, a phenoxy group, a dialkylamino group or a halogen atom; an alkyl group, an alkoxy group Or an aralkyl group optionally substituted with a phenoxy group, a nitro group or a halogen atom; or an aryl group optionally substituted with an alkyl group, an alkoxy group, a nitro group or a halogen atom). A compound represented by the general formula (3), wherein the compound is reacted in the presence of an optically active alkaloid in the presence or absence of a basic compound. (Wherein R ¹ and R ² have the same meanings as described above.) A method for producing an optically active imidazolidine-2-one represented by the formula: 2. A compound represented by the general formula (1):
The method according to claim 1, wherein R ¹ is a benzyl group which may have a substituent. 3. A compound represented by the general formula (1):
The method according to claim 1, wherein R ¹ is a benzyl group. 4. The method according to claim 1, wherein the optically active alkaloid is quinine. 5. The production method according to claim 1, wherein the basic compound is a tertiary organic base. 6. The method according to claim 1, wherein the basic compound is a piperidine derivative.