JP2000034276A - Method for racemizing optically active n-substituted azetidine-2-carboxylic acid ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a simple method for recemizing an optically active N- substituted azetidine-2-carboxylic acid ester. SOLUTION: The optically active N-substituted azetidine-2-carboxylic acid ester expressed by the formula (R1 is an aryl, a saturated hydrocarbon group or an unsaturated hydrocarbon group; R2 is a saturated hydrocarbon group, an unsaturated hydrocarbon group, an alkyloxycarbonyl, an alkenyloxycarbonyl or sulfonyl) is heated at a temp. of >=100 deg.C or brought into contact with a basic compound selected from alkali metal halides, alkaline earth metal halides, alkali metal alkoxides of an tertiary alcohol and organic amines.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process for the racemization of optically active N-substituted azetidine-2-carboxylic esters.

[0002]

BACKGROUND OF THE INVENTION As described in WO 98/02568, an optically active N-substituted azetidine-2-amine is used.
Carboxylic acid esters are useful intermediates for pharmaceuticals and the like, and are known to be produced by optical resolution of racemic forms of the esters. It is desirable to develop a method for reusing the remaining isomer of the N-substituted azetidine-2-carboxylate after splitting, both economically and in terms of waste reduction.

[0003]

SUMMARY OF THE INVENTION Accordingly, the present inventors
As a result of earnestly studying a racemization method for optically active N-substituted azetidine-2-carboxylic acid esters in order to racemize the other optical isomer remaining without being used and to reuse it, a simple N-substituted azetidine- A racemization method for 2-carboxylic acid esters has been found, and the present invention has been achieved.

[0004]

That is, the present invention provides a compound represented by the following general formula (1): (Wherein * represents an asymmetric carbon atom, R ¹ is an aryl group,
Or a saturated hydrocarbon group or an unsaturated hydrocarbon group optionally substituted with an aryl group, and R ² represents a saturated hydrocarbon group or an unsaturated hydrocarbon group optionally substituted with an aryl group, or An alkyloxycarbonyl group, an alkenyloxycarbonyl group, or a sulfonyl group which may be substituted. ), An optically active N-substituted azetidine-2-carboxylic acid ester represented by the formula:
Heating to 100 ° C. or higher, or contacting with a basic compound selected from alkali metal or alkaline earth metal hydride, tertiary alcohol alkali metal alkoxide or organic amine; The indicated optically active N-substituted azetidine-2-
The present invention provides a method for racemizing carboxylic esters.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. In the optically active N-substituted azetidine-2-carboxylic acid esters represented by the general formula (1), the substituent R
¹ is an aryl group, a saturated hydrocarbon group which may be substituted with an aryl group, or an unsaturated hydrocarbon group.
Examples of the aryl group include a phenyl group and the like, and examples of the saturated hydrocarbon group optionally substituted with the aryl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and a sec- Butyl group,
(Halogen, alkyl, alkyl, such as t-butyl, benzyl, p-methoxybenzyl, o-nitrobenzyl, benzhydryl, triphenylmethyl, etc.
Aralkyl groups which may be substituted with alkoxy or nitro), and unsaturated hydrocarbon groups include, for example, alkenyl groups such as allyl group and 3-butenyl group.

The substituent R ² is a saturated hydrocarbon group which may be substituted with an aryl group, an unsaturated hydrocarbon group, an alkyloxycarbonyl group which may be substituted with an aryl group, or an alkenyloxycarbonyl group. And a sulfonyl group. Examples of the saturated hydrocarbon group which may be substituted with an aryl group include an alkyl group such as a methyl group and an ethyl group, a benzyl group, a p-methoxybenzyl group, an α-phenylethyl group, a β-phenylethyl group, and a phenylpropyl group. And an aralkyl group (which may be substituted with halogen, alkyl, alkoxy or nitro) such as a benzhydryl group and a triphenylmethyl group, and an unsaturated hydrocarbon group includes an alkenyl group such as an allyl group. Examples of the optionally substituted alkyloxycarbonyl group include an aryl group such as a t-butoxycarbonyl group, a trichloroethyloxycarbonyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, and a 2-phenylethyloxycarbonyl group. And an alkyloxycarbonyl group which may be substituted with a halogen atom, an alkyl group, an alkoxy group or a nitro group. Examples of the alkenyloxycarbonyl group include a vinyloxycarbonyl group, an allyloxycarbonyl group, a 1-isopropylallyloxycarbonyl group, and the like. Examples of the sulfonyl group include a benzenesulfonyl group (which may be substituted with alkyl, alkoxy or nitro) such as a benzenesulfonyl group, a p-toluenesulfonyl group, a p-methoxybenzenesulfonyl group, and an o-nitrobenzenesulfonyl group. . One or more of the above-mentioned saturated hydrocarbon groups or unsaturated hydrocarbon groups may be substituted with an alkoxy group, a halogen atom or the like.

[0007] Such a substituent R ² may have an asymmetric carbon atom. Examples of the substituent R ² having an asymmetric carbon atom include (S) -methylbenzyl, (R) -methylbenzyl, (S) -1-phenylpropyl, (R) -1-phenylpropyl, (S) -1- (p-tolyl) ethyl group, (R) -1- (p
-Tolyl) ethyl group, (S) -1- (p-chlorophenyl) ethyl group, (R) -1- (p-chlorophenyl) ethyl group, (S) -1
-(2,4-dichlorophenyl) ethyl group, (R) -1- (2,4-dichlorophenyl) ethyl group, (S) -1- (p-methoxyphenyl) ethyl group, (R) -1- (p -Methoxyphenyl) ethyl group, (S) -1- (4-hydroxyphenyl) ethyl group, (R)-
And a 1- (4-hydroxyphenyl) ethyl group.

Such an optically active N-substituted azetidine-2
Examples of the carboxylic acid esters (1) include N-methylazetidine-2-carboxylic acid methyl ester, N-
Ethyl azetidine-2-carboxylic acid methyl ester, N
-Benzylazetidine-2-carboxylic acid methyl ester, Np-methoxybenzylazetidine-2-carboxylic acid methyl ester, N-[(S) -phenylethyl]
-Azetidine-2-carboxylic acid methyl ester, N-
[(R) -phenylethyl] -azetidine-2-carboxylic acid methyl ester, N-[(S) -phenylpropyl] -azetidine-2-carboxylic acid methyl ester, N
-[(R) -phenylpropyl] -azetidine-2-carboxylic acid methyl ester, N-[(S) -1- (p-tolyl) ethyl] -azetidine-2-carboxylic acid methyl ester, N-[(R ) -1--1- (p-Tolyl) ethyl] -azetidine-2-carboxylic acid methyl ester, N-
[(S) -1- (p-chlorophenyl) ethyl] -azetidine-2-carboxylic acid methyl ester, N-[(R)-
1- (p-chlorophenyl) ethyl] -azetidine-2
-Carboxylic acid methyl ester, N-[(S) -1-
(2,4-dichlorophenyl) ethyl] -azetidine-
2-carboxylic acid methyl ester, N-[(R) -1-
(2,4-dichlorophenyl) ethyl] -azetidine-
2-carboxylic acid methyl ester, N-[(S) -1- (p
-Methoxyphenyl) ethyl] -azetidine-2-carboxylic acid methyl ester, N-[(R) -1- (p-methoxyphenyl) ethyl] -azetidine-2-carboxylic acid methyl ester, N-[(S)- 1- (p-hydroxyphenyl) ethyl] -azetidine-2-carboxylic acid methyl ester, N-[(R) -1- (p-hydroxyphenyl) ethyl] -azetidine-2-carboxylic acid methyl ester, N-β -Phenylethyl azetidine-2-carboxylic acid methyl ester, N-phenylpropyl azetidine-2-carboxylic acid methyl ester, N-benzhydryl azetidine-2-carboxylic acid methyl ester, N-triphenylmethyl azetidine- 2-carboxylic acid methyl ester, N-allylazetidine-2-carboxylic acid methyl ester, Nt-butoxy Carbonyl azetidine-2-
Carboxylic acid methyl ester, N-trichloroethyloxycarbonyl azetidine-2-carboxylic acid methyl ester, N-benzyloxycarbonyl azetidine-2-carboxylic acid methyl ester, Np-methoxybenzyloxycarbonyl azetidine-2-carboxylic acid Acid methyl ester, methyl N-2-phenylethyloxycarbonylazetidine-2-carboxylate, methyl N-vinyloxycarbonylazetidine-2-carboxylate, methyl N-allyloxycarbonylazetidine-2-carboxylate Ester, N-1-isopropylallyloxycarbonylazetidine-2-carboxylic acid methyl ester, N-benzenesulfonylazetidine-2-carboxylic acid methyl ester, Np-toluenesulfonylacetidine-2-cal Acid methyl ester, Np-methoxybenzenesulfonylacetidine-2-carboxylic acid methyl ester, No-nitrobenzenesulfonylacetidine-2-carboxylic acid methyl ester, and the above-mentioned compounds in which the ester substituent is ethyl instead of methyl , N-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, benzyl, p-methoxybenzyl, o-nitrobenzyl, benzhydryl, triphenylmethyl, allyl, compounds corresponding to 3-butenyl and the like. No.

The optically active N-substituted azetidine-2 represented by the general formula (1) used as a raw material of the present invention.
The carboxylic acid ester may be any mixture containing an excess of any of the optical isomers, and the excess is not particularly limited. These raw materials may be purified by distillation, column chromatography, or the like,
It may be an isomer mixture containing an excess of one of the isomers left when a resolution such as a salt resolution method or an enzyme resolution method is performed.

In the racemization method of the present invention, the substituent R ² may be a substituent having an asymmetric carbon atom.
Racemization proceeds with high selectivity on the asymmetric carbon indicated by * in the general formula (1) to produce a diastereomeric mixture. The resulting diastereomer mixture can be separated by a conventional method such as column chromatography or optical resolution using an optically active acid.

The method of racemizing the optically active N-substituted azetidine-2-carboxylic acid ester represented by the general formula (1) is carried out by heating to 100 ° C. or more. It is also possible to use a basic compound. When a basic compound is used, an organic solvent is generally used, and when no basic compound is used, the reaction can be performed without using an organic solvent.

When an organic solvent is used, for example, aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene and chlorobenzene, aliphatic hydrocarbons such as hexane, cyclohexane, heptane and isooctane, and t-butyl Ethers such as methyl ether, isopropyl ether, tetrahydrofuran and dioxane; or alcohols such as methanol, ethanol, isopropanol, n-butanol and t-butanol; or ketones such as acetone and 2-butanone;
Or nitriles such as acetonitrile, or N,
Solvents such as amides such as N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide alone or in a mixture.

The amount of the organic solvent used is usually 100 times by weight or less, preferably 20 times by weight, based on the optically active N-substituted azetidine-2-carboxylic acid ester represented by the general formula (1).
It is not more than 10 times by weight, more preferably not more than 10 times by weight.
The lower limit is not particularly limited.

The optically active N-substituted azetidine-2-carboxylic acid ester represented by the general formula (1) is heated to 100 ° C. or higher, and the temperature is usually about 100 to 300 ° C., preferably 100 to 250 ° C. C., and more preferably about 100 to 200.degree.

In the present invention, the optically active N-substituted azetidine-2-carboxylic acid ester represented by the general formula (1) is a basic compound selected from alkali metal hydrides, tertiary amine alkoxides and organic amines. Racemization can also be achieved by contact with Examples of such basic compounds include alkali or alkaline earth metal hydrides such as sodium hydride, potassium hydride, lithium hydride, calcium hydride, tertiary alcohol alkoxides such as potassium tertiary butoxide, and triethylamine. , Diisopropylethylamine, 1,5-diazabicyclo [4.3.0] non-5
Organic amines such as -ene, 1,8-diazabicyclo [5.4.0] -7-undecene and N-methylmorpholine. These basic compounds may be used alone or in combination of two or more. Particularly, an alkali metal hydride is preferably used.

The amount of the basic compound used is not particularly limited, but is usually 0.01 to 10% based on the optically active N-substituted azetidine-2-carboxylic acid ester (1).
It is about a molar time, preferably about 0.01 to 5 times, and more preferably about 0.1 to 2 times.

When a basic compound is used, the reaction temperature is usually about -20 to 200 ° C, preferably about 0 to 150 ° C, more preferably about 20 to 100 ° C.

The racemized N-substituted azetidine-2-carboxylic acid ester compound obtained according to the present invention is, if necessary, neutralized with acidic water or the like, and then the solvent is distilled off. As can be reused.

[0019]

According to the production method of the present invention, optically active N
-The substituted azetidine-2-carboxylic acid esters (1) can be easily and efficiently racemized.

[0020]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

Example 1 N-[(S) -phenylethyl] -azetidine-2-carboxylic acid methyl ester
9 g (2R form: 2S form = 94: 6) was heated to 170 ° C. and kept at the same temperature for 8 hours. The obtained oil was analyzed by gas chromatography to find that N-[(S)-
[Phenylethyl] -azetidine-2-carboxylic acid methyl ester was obtained in a yield of 71.7%. The diastereomer ratio at that time was 2R form: 2S form = 42: 58.

(Example 2) N-[(S) -phenylethyl] -azetidine-2-carboxylic acid methyl ester
3 g (2R form: 2S form = 92: 8) was heated to 190 ° C. and kept at the same temperature for 10 hours. The obtained oil was analyzed by gas chromatography to find that N-[(S)
-Phenylethyl] -azetidine-2-carboxylic acid methyl ester was obtained in a yield of 70.4%. The diastereomer ratio at that time was 2R form: 2S form = 45: 55.

Example 3 N-[(S) -phenylethyl] -azetidine-2-carboxylic acid methyl ester 1
3.4 g (2R form: 2S form = 93: 7) was heated to 190 ° C. and kept at the same temperature for 10 hours. The resulting oil was analyzed by gas chromatography to find that N-
[(S) -Phenylethyl] -azetidine-2-carboxylic acid methyl ester was obtained at a yield of 73.8%. At that time, the diastereomer ratio was 2R: 2S = 50: 50.
Met.

Example 4 N-[(S) -phenylethyl] -azetidine-2-carboxylic acid methyl ester 2
0.0g (2R form: 2S form = 93: 7)
3.65 g of sodium hydride was added to the solution dissolved in 3.6 g.
g (oil suspension with a content of about 60%) was added at room temperature. This was heated to 80 ° C. and kept at the same temperature for 8 hours. 20 g of water, and then 24.8 g of 35% hydrochloric acid were added to the obtained solution under ice-cooling.
Was added dropwise to adjust the pH to 0.6, and then the oil layer and the aqueous layer were separated.
The aqueous layer was washed with 40 g of toluene, 40 g of toluene was added again, and then 33.9 g of a 20% aqueous sodium hydroxide solution.
Was added dropwise to adjust the pH to 6.3, and then the oil layer and the aqueous layer were separated. After the oil layer was washed with 40 g of water, the solvent was distilled off, and the obtained oil was analyzed by gas chromatography to find N-[(S) -phenylethyl] -azetidine-2.
-Carboxylic acid methyl ester was obtained in a yield of 94.6%.
The diastereomer ratio at that time was 2R form: 2S form = 4
2:58.

Example 5 N-[(S) -phenylethyl] -azetidine-2-carboxylic acid methyl ester
0 g (2R-form: 2S-form = 93: 7) in toluene 25.7
g of sodium hydride (about 60% oil suspension) was added at room temperature to the solution dissolved in g. This is 7
The mixture was heated to 0 ° C. and kept at the same temperature for 10 hours. 7 g of water and then 9.8 g of 35% hydrochloric acid were added dropwise to the resulting solution under ice-cooling to adjust the pH to 1.0, and then the oil layer and the aqueous layer were separated. The aqueous layer was washed with 14 g of toluene, 14 g of toluene was added again, and then 12.0 g of a 20% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 6.1. Then, the oil layer and the aqueous layer were separated. After the oil layer was washed with 14 g of water, the solvent was distilled off, and the obtained oil was analyzed by gas chromatography to find that N-
[(S) -Phenylethyl] -azetidine-2-carboxylic acid methyl ester was obtained in a yield of 96.7%. The diastereomer ratio at that time was 2R form: 2S form = 44: 56
Met.

Example 6 N-[(S) -phenylethyl] -azetidine-2-carboxylic acid methyl ester
0 g (2R-form: 2S-form = 93: 7) in toluene 25.7
g of sodium hydride (about 60% oil suspension) was added at room temperature to the solution dissolved in g. This is 6
The mixture was heated to 0 ° C. and kept at the same temperature for 20 hours. 7 g of water and then 9.8 g of 35% hydrochloric acid were added dropwise to the resulting solution under ice cooling to adjust the pH to 1.1, and then the oil layer and the aqueous layer were separated. The aqueous layer was washed with 14 g of toluene, 14 g of toluene was added again, and then 11.8 g of a 20% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 6.3. Then, the oil layer and the aqueous layer were separated. After the oil layer was washed with 14 g of water, the solvent was distilled off, and the obtained oil was analyzed by gas chromatography to find that N-
[(S) -Phenylethyl] -azetidine-2-carboxylic acid methyl ester was obtained in a yield of 92.7%. The diastereomer ratio at that time was 2R form: 2S form = 44: 56
Met.

Example 7 5.0 g of N-[(S) -phenylethyl] -azetidine-2-carboxylic acid benzyl ester (2R form: 2S form = 100: 0) was added to toluene 2
Sodium hydride 0.74
g (oil suspension with a content of about 60%) was added at room temperature. This was heated to 80 ° C. and kept at the same temperature for 3 hours. 5 g of water and then 2.1 g of 35% hydrochloric acid were added dropwise to the resulting solution under ice cooling to adjust the pH to 6.5, and then the oil layer and the aqueous layer were separated. After the oil layer was washed with 5 g of water, the solvent was distilled off, and the obtained oil was analyzed by gas chromatography to find that N-
[(S) -Phenylethyl] -azetidine-2-carboxylic acid benzyl ester was obtained in a yield of 81.8%. The diastereomer ratio at that time was 2R: 2S = 41: 5
Nine.

Example 8 N-Benzylazetidine-2
-To a solution of 3.0 g of carboxylic acid methyl ester (2R form: 2S form = 100: 0) dissolved in 12.1 g of toluene was added 0.65 g of sodium hydride (oil suspension having a content of about 60%) at room temperature. added. This was heated to 80 ° C. and kept at the same temperature for 3 hours. 10 g of water was added to the obtained solution under ice cooling.
Subsequently, 1.5 g of 35% hydrochloric acid was added dropwise to adjust the pH to 6.5, and then the oil layer and the aqueous layer were separated. After the oil layer was washed with 5 g of water, the solvent was distilled off, and the obtained oil was analyzed by gas chromatography to find N-benzylazetidine-
2-Carboxylic acid methyl ester was obtained in a yield of 75.0%. The diastereomer ratio at that time was 2R form: 2S form = 50: 50.

Example 9 N-[(R) -phenylethyl] -azetidine-2-carboxylic acid methyl ester
0.1g of sodium hydride was added to a solution prepared by dissolving 0 g (purity 0.8 g; 2R-form: 2S-form = 34:66) in a mixed solvent consisting of 15 ml of t-butyl methyl ether and 5 ml of N, N-dimethylformamide. Oil suspension with a content of about 60%) was added at room temperature. It was kept at the same temperature for 5 hours. When the obtained solution was analyzed by gas chromatography, N-[(R) -phenylethyl] -azetidine-2 was obtained.
The diastereomeric ratio of the carboxylic acid methyl ester is 2
R-form: 2S-form = 56:44. Then add this solution to 4
The mixture was heated to 5 ° C. and kept at the same temperature for 3 hours. The diastereomer ratio was 2R form: 2S form = 60: 40.

Example 10 Potassium t-butoxide
In a solution of 0.58 g (5.0 mmol) of dimethyl sulfoxide (DMSO, 10 ml), 1.00 g of N-[(S) -phenylethyl] -azetidine-2- (S) -carboxylic acid methyl ester (4. 53 mmol, 100
% D. e. ) Was added at 26-28 <0> C. After stirring at the same temperature for 30 minutes, the obtained solution was analyzed by gas chromatography, and the diastereomer ratio of N-[(S) -phenylethyl] -azetidine-2-carboxylic acid methyl ester was 2R: 2S Body = 57:43. The mixture was further stirred at the same temperature for 22 hours, but the diastereomer ratio did not change. The solution was further stirred at 50 ° C. for 2 hours, but the diastereomer ratio was 2R form: 2S form = 57: 43, and there was no change.

The N-substituted azetidine-2-carboxylic acid esters obtained in the above Examples can be optically resolved by the following method or the like. (Reference Example 1) N-[(S) -phenylethyl] -azetidine-2-carboxylic acid methyl ester 18.9 g (2R: 2S = 42: 58) obtained in Example 4 was mixed with 9.6 g of toluene. And 2.7 g of methanol, and then heated to 60 ° C. N-[(S)
-Phenylethyl] -azetidine-2-carboxylic acid methyl ester (2R form: 2S form = 0: 100) L-tartrate was added as a very small seed crystal, and then methanol 2
A solution of 13.6 g of L-tartaric acid dissolved in 4.6 g was added to 60
The mixture was added dropwise at 2 ° C. over 2 hours. Subsequently, the solution was cooled to 0 ° C. over 3 hours and kept at the same temperature for 3 hours. Then, the obtained crystals were separated by filtration and N-[(S) -phenylethyl]-
Azetidine-2-carboxylic acid methyl ester (2R form:
L-tartrate salt of 2S form = 0.2: 99.8) was obtained in a yield of 4
Obtained at 8.6%.

Comparative Example 1 N-[(S) -phenylethyl] -azetidine-2-
(S) -Carboxylic acid methyl ester (23.7 mmol
1, 100% d. e. ) In methanol (200 ml) was dissolved in sodium methoxide (0.26 g, 4.8 mmol).
l) was added and refluxed for 24 hours. PH to the reaction mixture
Acetic acid was added until the pH reached 6.5, and the solvent was distilled off. The residue was dissolved in ethyl acetate, washed with water, and the solvent was distilled off under vacuum. As a result, 5.04 g (98.9% de) of the ester was recovered as a pale yellow liquid.

Claims (4)

[Claims] 1. The general formula (1) (Wherein * represents an asymmetric carbon atom, R ¹ is an aryl group,
Or a saturated hydrocarbon group or an unsaturated hydrocarbon group optionally substituted with an aryl group, and R ² represents a saturated hydrocarbon group or an unsaturated hydrocarbon group optionally substituted with an aryl group, or An alkyloxycarbonyl group, an alkenyloxycarbonyl group, or a sulfonyl group which may be substituted. ), An optically active N-substituted azetidine-2-carboxylic acid ester represented by the formula:
Heating to 100 ° C. or higher, or contacting with a basic compound selected from alkali metal or alkaline earth metal hydride, tertiary alcohol alkali metal alkoxide or organic amine; The indicated optically active N-substituted azetidine-2-
Racemization of carboxylic esters. 2. An optically active N-substituted azetidine-2-carboxylic acid ester represented by the general formula (1), wherein both R ¹ and R ² may be substituted with an aryl group, or a saturated hydrocarbon group; 2. An unsaturated hydrocarbon group.
Racemization method described in 1. 3. The racemization method according to claim 1, wherein the temperature of the racemization reaction is 200 ° C. or lower. 4. The racemization method according to claim 1, wherein the basic compound is an alkali metal hydride.