JP3489319B2 - Carboxylic acid derivatives, their production and use - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a carboxylic acid derivative, a method for producing the same, and a method for producing racemic or optically active threo-3- (3,4-dihydroxyphenyl) serine using the derivative.

[0002]

BACKGROUND OF THE INVENTION Threo-3- (3,4-dihydroxyphenyl) serine (hereinafter abbreviated as threo DOPS) has a pharmacological activity on the circulatory system or central nervous system. The use as a peripheral orthostatic hypotensive agent, antidepressant, therapeutic agent for Parkinson's disease, etc. is known, and conventionally, threo DOPS has been produced by a method of condensing glycine with benzaldehyde (for example, , Chem. Ber., 52, 1734 (1919)). Also, the L-
The body was manufactured by optical resolution of a threo DOPS derivative.

However, in the conventional production method, an excessive amount of expensive benzaldehydes is used, and when the product becomes a mixture of a threo body and an erythro body, a separation operation is required when an optically active body is required. Further, there is a problem that the enantiomer of the target compound is by-produced in the same amount as the target compound.

[0004]

[Means for Solving the Problems] In order to solve such a problem, as a result of extensive studies, a racemic or optically active carboxylic acid derivative represented by the following general formula (2) is reacted with an azide agent. To obtain a racemic or optically active carboxylic acid derivative represented by the following general formula (1), and by reducing and deprotecting the derivative (1), racemic or optically active threo-3- (3,4-dihydroxy). The inventors have found that phenyl) serine can be obtained, and completed the present invention.

That is, the present invention is based on the general formula (1) (In the formula, R ¹ and R ² each represent a hydroxyl-protecting group,
R ³ represents a protecting group for carboxylic acid. ), A racemic or optically active carboxylic acid derivative, a method for producing the same, and a corresponding racemic or optically active threo-3 using the derivative.
-(3,4-dihydroxyphenyl) serine is provided.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. The racemic or optically active carboxylic acid derivative represented by the general formula (1), which is the compound of the present invention, has the corresponding general formula (2) (In the formula, R ⁴ represents a lower alkyl group or a phenyl group. Here, the lower alkyl group may be substituted with a halogen atom, a lower alkoxy group, or a halogenated lower alkyl group. , Halogen atom,
It may be substituted with a nitro group, a lower alkyl group, a lower alkoxy group or a halogenated lower alkyl group.
R ¹ , R ² and R ³ have the same meanings as described above. ) Is obtained by reacting a racemic or optically active carboxylic acid derivative represented by (4) with an azide agent. Here, the racemic or optically active carboxylic acid derivative represented by the general formula (2) as the raw material is represented by the general formula (3) (Wherein R ¹ , R ² and R ³ have the same meanings as described above) and a racemic or optically active dihydroxycarboxylic acid derivative represented by the general formula (4) (In the formula, R ⁴ has the same meaning as described above, and X represents a halogen atom.)
It is obtained by reacting in the presence of a basic substance.

In the racemic or optically active dihydroxycarboxylic acid derivative represented by the general formula (3), R ¹ , R
² represents a hydroxyl-protecting group, for example, an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group, a benzyl group, a naphthylmethyl group, etc. And an aralkyl group having 7 to 11 carbon atoms, an allyl group, and the like. In addition, for R ¹ and R ^{2 as a} whole, for example, a methylene group, a 2-propylidene group, a 2-butylidene group, a cyclohexylidene group, a benzylidene group, a naphthylmethylene group, or another alkyl group having 1 to 6 carbon atoms, and 6 to 10 carbon atoms. Examples thereof include a methylene group and the like, which may be substituted with the aryl group and the like. R ³ represents a protecting group for carboxylic acid, for example, a C 1-6 alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group, a carbon group such as a benzyl group and a naphthylmethyl group. Number 7 ~
Examples thereof include aryl groups having 6 to 10 carbon atoms such as 11 alkyl groups, allyl groups, phenyl groups, tolyl groups, and aryl groups such as naphthyl groups.

In the sulfonic acid halide represented by the general formula (4), R ⁴ represents a lower alkyl group or a phenyl group. Here, the lower alkyl group may be substituted with a halogen atom, a lower alkoxy group, or a halogenated lower alkyl group, and specifically, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, Ethyl group, propyl group, butyl group, t-butyl group, methoxy group, ethoxy group, propoxy group, monochloromethyl group,
Examples thereof include a dichloromethyl group, a trichloromethyl group, a fluoromethyl group and a trifluoromethyl group, and the number and position of these substituents are not particularly limited. Also, R
The phenyl group of ⁴ may be substituted with a halogen atom, a nitro group, a lower alkyl group, a lower alkoxy group or a halogenated lower alkyl group, and specific examples thereof include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. , Nitro group, methyl group, ethyl group, propyl group, butyl group, t-butyl group, methoxy group, ethoxy group, propoxy group, monochloromethyl group, dichloromethyl group, trichloromethyl group,
Examples thereof include a fluoromethyl group and a trifluoromethyl group, and the number and position of these substituents are not particularly limited. Further, in the sulfonic acid halide represented by the general formula (4), examples of the halogen atom of X include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the basic substance used in the above reaction include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. , Triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N,
N-dimethylaminopyridine, 2-picoline, 3-picoline, 4-picoline, 5-ethyl-2-methylpyridine, N-methylimidazole, DBU, 1,4-diazabicyclo [2,2,2] octane, etc. Organic bases are mentioned. The amount used is usually 1 to 50 relative to the racemic or optically active dihydroxycarboxylic acid derivative (3).
The molar ratio is twice, preferably 1 to 10 times. The amount of the sulfonic acid halide used is usually 1 to 20 relative to the racemic or optically active dihydroxycarboxylic acid derivative (3).
It is a double mole, preferably 1 to 2 moles.

The above-mentioned reaction can be carried out in the presence or absence of a solvent, and the solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include dichloromethane, chloroform, carbon tetrachloride and mono. Halogenated hydrocarbons such as chlorobenzene, diethyl ether, methyl t
Examples include ethers such as butyl ether, amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, and the like, or a mixture thereof.
The amount of solvent is not particularly limited. The reaction temperature is generally -50 to 150 ° C, preferably -20 to 80 ° C,
The reaction time is not particularly limited, and the end point may be the disappearance of the starting compound (3) or the termination of the decrease.

After completion of the reaction, the reaction solution is poured into water, and the organic layer is separated or extracted with a usual extraction solvent such as toluene, ethyl acetate, diethyl ether and dichloromethane, and the organic layer is separated and concentrated to give racemic or An optically active carboxylic acid derivative (2) can be obtained. If necessary, it can be purified by a usual method such as column chromatography or recrystallization.
Specific examples of the carboxylic acid derivative (2) include 2-benzenesulfonylamino-3-hydroxy-
Methyl 3- (3,4-dimethoxyphenyl) propanoate, 2-benzenesulfonylamino-3-hydroxy-
Methyl 3- [3,4-bis (2-propoxy) phenyl] propanoate, 2-benzenesulfonylamino-3-hydroxy-3- (3,4-methylenedioxyphenyl)
Methyl propanoate, 2-benzenesulfonylamino-3
Methyl 2-hydroxy-3- [3,4- (2-propylidenedioxy) phenyl] propanoate, methyl 2-benzenesulfonylamino-3-hydroxy-3- (3,4-cyclohexylidenedioxyphenyl) propanoate Two
-Benzenesulfonylamino-3-hydroxy-3-
Methyl [3,4- (2,2,2-trichloroethylidenedioxy) phenyl] propanoate, methyl 2-benzenesulfonylamino-3-hydroxy-3- (3,4-benzylidenedioxyphenyl) propanoate, 2 -Benzenesulfonylamino-3-hydroxy-3- (3,4-
Methyl dibenzyloxyphenyl) propanoate, 2-benzenesulfonylamino-3-hydroxy-3- (3,3
Ethyl 4-dimethoxyphenyl) propanoate, 2-benzenesulfonylamino-3-hydroxy-3- (3,4
-Ethyl diethoxyphenyl) propanoate, 2-benzenesulfonylamino-3-hydroxy-3- [3,4-
Ethyl bis (2-propoxy) phenyl] propanoate,
2-benzenesulfonylamino-3-hydroxy-3-
Ethyl (3,4-methylenedioxyphenyl) propanoate, 2-benzenesulfonylamino-3-hydroxy-
Ethyl 3- [3,4- (2-propylidenedioxy) phenyl] propanoate, Ethyl 2-benzenesulfonylamino-3-hydroxy-3- (3,4-cyclohexylidenedioxyphenyl) propanoate, 2- Benzenesulfonylamino-3-hydroxy-3- [3,4-
Ethyl (2,2,2-trichloroethylidenedioxy) phenyl] propanoate, ethyl 2-benzenesulfonylamino-3-hydroxy-3- (3,4-benzylidenedioxyphenyl) propanoate, 2-benzenesulfonylamino- Ethyl 3-hydroxy-3- (3,4-dibenzyloxyphenyl) propanoate, benzyl 2-benzenesulfonylamino-3-hydroxy-3- (3,4-dimethoxyphenyl) propanoate, 2-benzenesulfonylamino- Benzyl 3-hydroxy-3- [3,4-bis (2-propoxy) phenyl] propanoate, 2
-Benzenesulfonylamino-3-hydroxy-3-
Benzyl (3,4-methylenedioxyphenyl) propanoate, 2-benzenesulfonylamino-3-hydroxy-3- [3,4- (2-propylidenedioxy) phenyl] propanoate benzyl, 2-benzenesulfonylamino Benzyl-3-hydroxy-3- (3,4-cyclohexylidenedioxyphenyl) propanoate, 2-benzenesulfonylamino-3-hydroxy-3- [3,4-
Benzyl (2,2,2-trichloroethylidenedioxy) phenyl] propanoate, benzyl 2-benzenesulfonylamino-3-hydroxy-3- (3,4-benzylidenedioxyphenyl) propanoate, 2-benzenesulfonylamino- Benzyl 3-hydroxy-3- (3,4-dibenzyloxyphenyl) propanoate, 2- (4-
Methylbenzenesulfonyl) amino-3-hydroxy-
Methyl 3- (3,4-dimethoxyphenyl) propanoate, 2- (4-methylbenzenesulfonyl) amino-3
-Hydroxy-3- [3,4-bis (2-propoxy)
Phenyl] propanoate methyl, 2- (4-methylbenzenesulfonyl) amino-3-hydroxy-3- (3,4
-Methylenedioxyphenyl) propanoate methyl, 2-
Methyl (4-methylbenzenesulfonyl) amino-3-hydroxy-3- [3,4- (2-propylidenedioxy) phenyl] propanoate, 2- (4-methylbenzenesulfonyl) amino-3-hydroxy-3 -(3,4-
Methyl cyclohexylidenedioxyphenyl) propanoate, 2- (4-methylbenzenesulfonyl) amino-3
Methyl -hydroxy-3- [3,4- (2,2,2-trichloroethylidenedioxy) phenyl] propanoate,
Methyl 2- (4-methylbenzenesulfonyl) amino-3-hydroxy-3- (3,4-benzylidenedioxyphenyl) propanoate, 2- (4-methylbenzenesulfonyl) amino-3-hydroxy-3- (3 , 4-Dibenzyloxyphenyl) propanoate, 2- (4-
Methylbenzenesulfonyl) amino-3-hydroxy-
Ethyl 3- (3,4-dimethoxyphenyl) propanoate, 2- (4-methylbenzenesulfonyl) amino-3
Ethyl 3-hydroxy-3- (3,4-diethoxyphenyl) propanoate, 2- (4-methylbenzenesulfonyl) amino-3-hydroxy-3- [3,4-bis (2
-Propoxy) phenyl] ethyl propanoate, 2- (4
-Methylbenzenesulfonyl) amino-3-hydroxy-3- (3,4-methylenedioxyphenyl) propanoate ethyl, 2- (4-methylbenzenesulfonyl) amino-3-hydroxy-3- [3,4- ( 2-propylidenedioxy) phenyl] ethyl propanoate, 2- (4-
Methylbenzenesulfonyl) amino-3-hydroxy-
3- (3,4-cyclohexylidenedioxyphenyl)
Ethyl propanoate, 2- (4-methylbenzenesulfonyl) amino-3-hydroxy-3- [3,4- (2,
Ethyl 2,2-trichloroethylidenedioxy) phenyl] propanoate, ethyl 2- (4-methylbenzenesulfonyl) amino-3-hydroxy-3- (3,4-benzylidenedioxyphenyl) propanoate, 2- (4 −
Methylbenzenesulfonyl) amino-3-hydroxy-
Ethyl 3- (3,4-dibenzyloxyphenyl) propanoate, benzyl 2- (4-methylbenzenesulfonyl) amino-3-hydroxy-3- (3,4-dimethoxyphenyl) propanoate, 2- (4- Benzyl methylbenzenesulfonyl) amino-3-hydroxy-3- [3,4-bis (2-propoxy) phenyl] propanoate,
2- (4-methylbenzenesulfonyl) amino-3-hydroxy-3- (3,4-methylenedioxyphenyl)
Benzyl propanoate, 2- (4-methylbenzenesulfonyl) amino-3-hydroxy-3- [3,4- (2-
Benzylpropylidenedioxy) phenyl] propanoate, 2- (4-methylbenzenesulfonyl) amino-3
Benzyl 3-hydroxy-3- (3,4-cyclohexylidenedioxyphenyl) propanoate, 2- (4-methylbenzenesulfonyl) amino-3-hydroxy-3-
Benzyl [3,4- (2,2,2-trichloroethylidenedioxy) phenyl] propanoate, 2- (4-methylbenzenesulfonyl) amino-3-hydroxy-3-
Benzyl (3,4-benzylidenedioxyphenyl) propanoate, benzyl 2- (4-methylbenzenesulfonyl) amino-3-hydroxy-3- (3,4-dibenzyloxyphenyl) propanoate, 2- (4- Nitrobenzenesulfonyl) amino-3-hydroxy-3- (3,3
Methyl 4-dimethoxyphenyl) propanoate, 2- (4
Methyl -nitrobenzenesulfonyl) amino-3-hydroxy-3- [3,4-bis (2-propoxy) phenyl] propanoate, 2- (4-nitrobenzenesulfonyl) amino-3-hydroxy-3- (3,4- Methylenedioxyphenyl) propanoate, 2- (4-nitrobenzenesulfonyl) amino-3-hydroxy-3-
Methyl [3,4- (2-propylidenedioxy) phenyl] propanoate, methyl 2- (4-nitrobenzenesulfonyl) amino-3-hydroxy-3- (3,4-cyclohexylidenedioxyphenyl) propanoate, 2-
Methyl (4-nitrobenzenesulfonyl) amino-3-hydroxy-3- [3,4- (2,2,2-trichloroethylidenedioxy) phenyl] propanoate, 2- (4
-Nitrobenzenesulfonyl) amino-3-hydroxy-3- (3,4-benzylidenedioxyphenyl) propanoate methyl, 2- (4-nitrobenzenesulfonyl)
Methyl amino-3-hydroxy-3- (3,4-dibenzyloxyphenyl) propanoate, 2- (4-nitrobenzenesulfonyl) amino-3-hydroxy-3-
Ethyl (3,4-dimethoxyphenyl) propanoate, 2
Ethyl-(4-nitrobenzenesulfonyl) amino-3-hydroxy-3- (3,4-diethoxyphenyl) propanoate, 2- (4-nitrobenzenesulfonyl) amino-3-hydroxy-3- [3,4-bis Ethyl (2-propoxy) phenyl] propanoate, 2- (4-nitrobenzenesulfonyl) amino-3-hydroxy-3-
Ethyl (3,4-methylenedioxyphenyl) propanoate, 2- (4-nitrobenzenesulfonyl) amino-3
Ethyl -hydroxy-3- [3,4- (2-propylidenedioxy) phenyl] propanoate, 2- (4-nitrobenzenesulfonyl) amino-3-hydroxy-3-
Ethyl (3,4-cyclohexylidenedioxyphenyl) propanoate, 2- (4-nitrobenzenesulfonyl)
Amino-3-hydroxy-3- [3,4- (2,2,2
-Ethyl trichloroethylidene dioxy) phenyl] propanoate, ethyl 2- (4-nitrobenzenesulfonyl) amino-3-hydroxy-3- (3,4-benzylidenedioxyphenyl) propanoate, 2- (4-nitrobenzenesulfonyl) Amino-3-hydroxy-3-
Ethyl (3,4-dibenzyloxyphenyl) propanoate, 2- (4-nitrobenzenesulfonyl) amino-3
Benzyl 3-hydroxy-3- (3,4-dimethoxyphenyl) propanoate, 2- (4-nitrobenzenesulfonyl) amino-3-hydroxy-3- [3,4-bis (2
-Propoxy) phenyl] benzyl benzyl propanoate, 2-
Benzyl (4-nitrobenzenesulfonyl) amino-3-hydroxy-3- (3,4-methylenedioxyphenyl) propanoate, 2- (4-nitrobenzenesulfonyl) amino-3-hydroxy-3- [3,4- ( 2-propylidenedioxy) phenyl] benzyl propanoate,
Benzyl 2- (4-nitrobenzenesulfonyl) amino-3-hydroxy-3- (3,4-cyclohexylidenedioxyphenyl) propanoate, 2- (4-nitrobenzenesulfonyl) amino-3-hydroxy-3- [3,3
Benzyl 4- (2,2,2-trichloroethylidenedioxy) phenyl] propanoate, 2- (4-nitrobenzenesulfonyl) amino-3-hydroxy-3- (3,4
-Benzylidenedioxyphenyl) benzyl benzyl propanoate, 2- (4-nitrobenzenesulfonyl) amino-3
Examples thereof include benzyl 3-hydroxy-3- (3,4-dibenzyloxyphenyl) propanoate.

The carboxylic acid derivative (1) of the present invention has a racemate and an optically active substance, and the present invention includes both the racemate and the optically active substance. Examples of R ¹ , R ² and R ³ in the carboxylic acid derivative (1) include the same ones as described above. Specific examples of the carboxylic acid derivative (1) include 2-azido-
3-hydroxy-3- (3,4-dimethoxyphenyl)
Methyl propanoate, 2-azido-3-hydroxy-3-
Methyl (3,4-diethoxyphenyl) propanoate, 2
-Azido-3-hydroxy-3- [3,4-bis (1-
Methyl propoxy) phenyl] propanoate, methyl 2-azido-3-hydroxy-3- [3,4-bis (2-propoxy) phenyl] propanoate, 2-azido-3-hydroxy-3- (3,4- Methylenedioxyphenyl)
Methyl propanoate, 2-azido-3-hydroxy-3-
Methyl (3,4-ethylidenedioxyphenyl) propanoate, 2-azido-3-hydroxy-3- [3,4-
Methyl (2-propylidenedioxy) phenyl] propanoate, Methyl 2-azido-3-hydroxy-3- (3,4-cyclopentylidenedioxyphenyl) propanoate, 2-Azido-3-hydroxy-3- Methyl (3,4-cyclohexylidenedioxyphenyl) propanoate,
2-azido-3-hydroxy-3- [3,4- (2,
Methyl 2,2-trichloroethylidenedioxy) phenyl] propanoate, 2-azido-3-hydroxy-3-
Methyl (3,4-benzylidenedioxyphenyl) propanoate, 2-azido-3-hydroxy-3- [3,4-
Methyl (1-phenylethylidenedioxy) phenyl] propanoate, 2-azido-3-hydroxy-3- [3,3
Methyl 4- (diphenylmethylenedioxy) phenyl] propanoate, 2-azido-3-hydroxy-3- (3,3
Methyl 4-dibenzyloxyphenyl) propanoate, 2
-Azido-3-hydroxy-3- [3,4-bis (1-
Methyl naphthyloxy) phenyl] propanoate, methyl 2-azido-3-hydroxy-3- [3,4-bis (2-naphthyloxy) phenyl] propanoate, 2-azido-3-hydroxy-3- (3,3 Ethyl 4-dimethoxyphenyl) propanoate, 2-azido-3-hydroxy-
Ethyl 3- (3,4-diethoxyphenyl) propanoate, Ethyl 2-azido-3-hydroxy-3- [3,4-bis (1-propoxy) phenyl] propanoate, 2-
Ethyl azido-3-hydroxy-3- [3,4-bis (2-propoxy) phenyl] propanoate, 2-azido-
Ethyl 3-hydroxy-3- (3,4-methylenedioxyphenyl) propanoate, Ethyl 2-azido-3-hydroxy-3- (3,4-ethylidenedioxyphenyl) propanoate, 2-Azido-3- Hydroxy-3- [3,3
Ethyl 4- (2-propylidenedioxy) phenyl] propanoate, 2-azido-3-hydroxy-3- (3,4
-Ethyl cyclopentylidenedioxyphenyl) propanoate, ethyl 2-azido-3-hydroxy-3- (3,4-cyclohexylidenedioxyphenyl) propanoate, 2-azido-3-hydroxy-3- [3,3 4-
Ethyl (2,2,2-trichloroethylidenedioxy) phenyl] propanoate, 2-azido-3-hydroxy-
Ethyl 3- (3,4-benzylidenedioxyphenyl) propanoate, 2-azido-3-hydroxy-3- [3,3
Ethyl 4- (1-phenylethylidenedioxy) phenyl] propanoate, 2-azido-3-hydroxy-3-
[3,4- (diphenylmethylenedioxy) phenyl]
Ethyl propanoate, 2-azido-3-hydroxy-3-
Ethyl (3,4-dibenzyloxyphenyl) propanoate, ethyl 2-azido-3-hydroxy-3- [3,4-bis (1-naphthyloxy) phenyl] propanoate,
2-azido-3-hydroxy-3- [3,4-bis (2
-Naphthyloxy) phenyl] ethyl propanoate, 2-
Benzyl azido-3-hydroxy-3- (3,4-dimethoxyphenyl) propanoate, benzyl 2-azido-3-hydroxy-3- (3,4-diethoxyphenyl) propanoate, 2-azido-3-hydroxy -3- [3,4
-Ethyl bis (1-propoxy) phenyl] propanoate, benzyl 2-azido-3-hydroxy-3- [3,4-bis (2-propoxy) phenyl] propanoate, 2
Benzyl azido-3-hydroxy-3- (3,4-methylenedioxyphenyl) propanoate, 2-azido-3
Benzyl 3-hydroxy-3- (3,4-ethylidenedioxyphenyl) propanoate, benzyl 2-azido-3-hydroxy-3- [3,4- (2-propylidenedioxy) phenyl] propanoate, 2- Benzyl azido-3-hydroxy-3- (3,4-cyclopentylidenedioxyphenyl) propanoate, benzyl 2-azido-3-hydroxy-3- (3,4-cyclohexylidenedioxyphenyl) propanoate, 2 Benzyl-3-azido-3-hydroxy-3- [3,4- (2,2,2-trichloroethylidenedioxy) phenyl] propanoate, 2-azido-3-hydroxy-3- (3,4-benzylidenedioxy) Phenyl) benzyl propanoate, 2-azido-3-hydroxy-3- [3,4- (1-phenylethylidenedioxy) phenyl] Propane benzyl, 2-azido -
Benzyl 3-hydroxy-3- [3,4- (diphenylmethylenedioxy) phenyl] propanoate, benzyl 2-azido-3-hydroxy-3- (3,4-dibenzyloxyphenyl) propanoate, 2-azide Benzyl-3-hydroxy-3- [3,4-bis (1-naphthyloxy) phenyl] propanoate, 2-azido-3-hydroxy-3- [3,4-bis (2-naphthyloxy) phenyl] propane Benzyl acid and the like can be mentioned.

The racemic or optically active carboxylic acid derivative (1) of the present invention can be produced by reacting the corresponding racemic or optically active carboxylic acid derivative (2) with an azide. Examples of the azide agent used in such a reaction include lithium azide, sodium azide, diphenylphosphoric acid azide and the like. The amount used is usually 1 to 20 mol times, preferably 1 to 2 mol times, of the racemic or optically active carboxylic acid derivative (2).

The reaction is usually carried out in the presence of a solvent, but the solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include halogen such as dichloromethane, chloroform, carbon tetrachloride and monochlorobenzene. Examples thereof include hydrocarbons, ethers such as diethyl ether and methyl t-butyl ether, amides such as dimethylformamide and dimethylacetamide, and nitrites such as acetonitrile. The amount of solvent is not particularly limited. The reaction temperature is generally −30 to 150 ° C., preferably 0 to 80 ° C., and the reaction time is not particularly limited, and the disappearance of the starting compound (2) or the termination of the decrease can be the end point. .

After completion of the reaction, the reaction solution is poured into water and the organic layer is separated or extracted with a usual extraction solvent such as toluene, ethyl acetate, diethyl ether or dichloromethane, and the organic layer is separated and concentrated. The racemic or optically active carboxylic acid derivative (1) can be obtained. If necessary, it can be purified by a usual method such as column chromatography or recrystallization.

The racemic or optically active carboxylic acid derivative (1) thus obtained is subjected to reduction (eg hydrogenation) and deprotection to give the corresponding formula (5). The racemic or optically active threo-3- (3,4-dihydroxyphenyl) serine represented by can be derived. The reduction and deprotection can be carried out according to known methods, for example, the following methods, but are not limited thereto. The order of reduction and deprotection is not particularly limited, and they may be performed simultaneously. First, the reduction hydrogenation reaction will be described.
The azide portion is mixed with a suitable solvent, such as water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, which is used for ordinary hydrogenation reaction, alone or as a mixture, and hydrolyzed in the presence of a noble metal catalyst such as palladium. By doing so, it can be converted into an amino group. Also, conversion to an amino group can be achieved by using triphenylphosphine, hydrogen sulfide, or the like. Next, deprotection of R ¹ and / or R ² will be described. When R ¹ and / or R ² is an alkyl group, and when R ¹ and R ² are linked to form a methylene group, it is treated with a Lewis acid such as aluminum chloride, titanium tetrachloride or boron trifluoride. It can be deprotected. When R ¹ and / or R ² is an aralkyl group and when R ¹ and R ² are a methylene group substituted by an aryl group, hydrogenolysis in the presence of a noble metal catalyst such as palladium is carried out. By doing so, deprotection can be performed. Furthermore, when the carbon connecting R ¹ and R ² is a quaternary carbon substituted with two alkyl groups, it can be deprotected by hydrolysis under acidic conditions. Next, R ³ deprotection will be described. When R ³ is an alkyl group, it can be deprotected by hydrolysis under acidic or basic conditions. When R ³ is an aralkyl group, it can be deprotected by hydrogenolysis in the presence of a noble metal catalyst such as palladium.

[0017]

INDUSTRIAL APPLICABILITY The racemic or optically active carboxylic acid derivative (1) of the present invention is useful as a pharmaceutical intermediate, and can be derived, for example, to the corresponding threo DOPS (5).
In addition, according to the method of the present invention, the compound (1) can be easily obtained from the dihydroxycarboxylic acid derivative (3).

[0018]

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

Reference Example 1 1.4 g of AD-mixβ was added to a mixed solution of 5 ml of t-butyl alcohol and 5 ml of water, and the mixture was stirred at room temperature. The reaction system becomes 2 when the stirring is stopped.
When the layers were separated and the lower layer became yellow, 95 mg (1.0 mmol) of methanesulfonamide and (Z)-
Methyl 3,4-dibenzyloxycinnamate 374mg
(1.0 mmol) was added. The reaction mixture was allowed to stand at room temperature for 3
Stir vigorously for days. Further, with stirring, 1.5 g of sodium sulfite was added over 1 hour. 20 ml of ethyl acetate was added to the reaction mixture for liquid separation, and the aqueous layer was extracted three times with the same amount of ethyl acetate. The organic layers were combined and washed with 2N aqueous potassium hydroxide solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oil obtained is purified by silica gel column chromatography,
(2R, 3R) -2,3-dihydroxy-3- (3,4
Methyl dibenzyloxyphenyl) propanoate 284
mg was obtained. Yield 70%. ¹ H-NMR (CDCl ₃ ) δppm: 2.83 (brs, 2H), 3.61 (s,
3H), 4.39 (d, 1H, J = 4.4 Hz), 4.
73 (d, 1H, J = 4.4 Hz), 5.14 (s, 2
H), 5.15 (s, 2H), 6.79-7.00.
(M, 3H), 7.25 to 7.54 (m, 10H)

Example 1 (2R, 3) under stirring at room temperature
R) -2,3-dihydroxy-3- (3,4-dibenzyloxyphenyl) propanoate methyl 408 mg (1.
0 mmol) to 155 mg of triethylamine (1.5
(mmol) in 5 ml of anhydrous dichloromethane. The reaction solution was cooled in an ice-water bath, and under stirring, 4-nitrobenzenesulfonic acid chloride 222 mg (1.0 mmol)
Was dripped. After stirring at 0-4 ° C. for 3 days, the reaction solution was concentrated under reduced pressure, and the obtained paste was dissolved with ethyl acetate.
The organic layer was washed with 1N hydrochloric acid three times, and with saturated aqueous sodium hydrogen carbonate and saturated brine once each. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain (2R, 3R) -3.
There was obtained 444 mg of methyl 2-hydroxy-2- (4-nitrobenzenesulfonyloxy) -3- (3,4-dibenzyloxyphenyl) propanoate. Yield 75%. ¹ H-NMR (CDCl ₃ ) δppm: 2.83 (brs, 1H), 3.74 (s,
3H), 5.07 (d, 1H, J = 4.8Hz), 5.
14 (d, 1H, J = 4.8 Hz), 5.19 (s, 2
H), 5.20 (s, 2H), 6.79-7.00.
(M, 3H), 7.25-7.54 (m, 10H),
8.11 (d, 2H, J = 8.2Hz), 8.28
(D, 2H, J = 8.2Hz)

(Example 2) (2R, 3
R) -3-Hydroxy-2- (4-nitrobenzenesulfonyloxy) -3- (3,4-dibenzyloxyphenyl) propanoate 594 mg (1.0 mmol)
195 mg (3.0 mmol) of sodium azide was added to a 10 ml solution of N, N-dimethylformamide. The reaction mixture was heated to 55 ° C. and stirred at the same temperature for 16 hours. The reaction mixture was cooled to room temperature, water and diethyl ether were added, and the layers were separated. The aqueous layer was further extracted with diethyl ether, the organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (2S, 3R) -2-azido-3-. There was obtained 390 mg of methyl hydroxy-3- (3,4-dibenzyloxyphenyl) propanoate. Yield 90%. ¹ H-NMR (CDCl ₃ ) δppm: 2.83 (brs, 1H), 3.70 (s,
3H), 4.46 (d, 1H, J = 4.0Hz), 4.
75 (d, 1H, J = 4.0 Hz), 5.41 (s, 2
H), 5.42 (s, 2H), 6.79-7.00.
(M, 3H), 7.25 to 7.54 (m, 10H)

Example 3 A mixed solvent consisting of 8 ml of ethanol, 2 ml of water and 1 ml of concentrated hydrochloric acid was added to an autoclave at room temperature with stirring, and (2S, 3R) -2-azide-3- was added.
Methyl hydroxy-3- (3,4-dibenzyloxyphenyl) propanoate (434 mg, 1.0 mmol) and 5% Pd / C (50 mg) were added thereto, and hydrogen gas was blown thereinto to increase the pressure to 3 atm. Vigorous stirring was continued for 3 hours, the reaction mixture was filtered to remove Pd / C, and then concentrated under reduced pressure.
The crystals obtained were added to 10 ml of 1N-hydrochloric acid water and stirred,
It was hydrolyzed at 60 ° C. for 16 hours. The reaction solution is concentrated under reduced pressure,
Then, the reaction mass was neutralized with 1N sodium hydroxide solution, and the precipitated crystals were collected by filtration to give L-threo-3-.
188 mg of (3,4-dihydroxyphenyl) serine was obtained. Yield 88%. Mp 222 ° C. Optical rotation ^{_{[α] D 20 -37.3 (C}} = 1,1N- hydrochloride)

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI C07C 309/65 C07C 309/65 309/73 309/73 // C07M 7:00 C07M 7:00 (56) Reference US Patent 5516931 (US, A) J.I. Agricultural and Food Chemistry, 1977, Vol. 25, No. 4,692-698 J. Organic Chemistry, 1997, Vol. 62, No. 4,908-915 (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07C 229/00 C07C 227/00 C07C 247/00 C07C 303/00 C07C 309/00 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. A general formula (1) (In the formula, R ¹ and R ² each represent a hydroxyl-protecting group,
R ³ represents a protecting group for carboxylic acid. ) A racemic or optically active carboxylic acid derivative. 2. General formula (2) (In the formula, R ⁴ represents a lower alkyl group or a phenyl group. Here, the lower alkyl group may be substituted with a halogen atom, a lower alkoxy group, or a halogenated lower alkyl group. , Halogen atom,
It may be substituted with a nitro group, a lower alkyl group, a lower alkoxy group or a halogenated lower alkyl group.
R ¹ , R ² and R ³ have the same meanings as described above. ) A racemic or optically active carboxylic acid derivative represented by the formula (4) is reacted with an azide agent, and the corresponding racemic or optically active carboxylic acid derivative represented by the general formula (1) is produced. 3. A racemic or optically active carboxylic acid derivative represented by the general formula (2). 4. General formula (3) (Wherein R ¹ , R ² and R ³ have the same meanings as described above) and a racemic or optically active dihydroxycarboxylic acid derivative represented by the general formula (4) (In the formula, R ⁴ has the same meaning as described above, and X represents a halogen atom.), And the corresponding racemic compound represented by the general formula (2) is reacted with a sulfonic acid halide represented by Alternatively, a method for producing an optically active carboxylic acid derivative. 5. The method according to claim 4, wherein the sulfonic acid halide is p-nitrobenzenesulfonic acid halide. 6. A formula (5) characterized by reducing and deprotecting the racemic or optically active carboxylic acid derivative represented by the general formula (1). A method for producing the corresponding racemic or optically active threo-3- (3,4-dihydroxyphenyl) serine represented by: