JP2001213887A - Optically active 2-(hydroxycarbonyl)ethyl-3- amino-3-(hydroxycarbonyl)propylphosphinic acid and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new optically active 2-(hydroxycarbonyl)ethyl-3- amino-3-(hydroxycarbonyl)propylphosphinic acid which is useful as a physiologically active substance and its intermediate raw material. SOLUTION: This aminophosphinic acid represented by the general formula (1) (C* is an asymmetric carbon atom).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel optically active aminophosphinic acid derivative useful as a raw material for a physiologically active substance and an intermediate thereof, and a method for producing the same.

[0002]

2. Description of the Related Art Conventionally, the following general formula (3):

[0003]

[Chemical 3]

(In the formula, R represents a methyl group or a hydroxyl group.)
The aminophosphinic acid derivative and the aminophosphonic acid derivative represented by are known as physiologically active substances. For example, D-2-amino-5-phosphonopentanoic acid in which R is a hydroxyl group and n=3 and D-2-amino-7-phosphonoheptanoic acid in which R is a hydroxyl group and n=5 are very physiologically active. Is high,
It is a selective NMDA antagonist and has an antiepileptic drug action.
It is known that R is a hydroxyl group, n=2 L-2-amino-4-phosphonobutanoic acid is an agonist of metabolic glutamic acid, R is a methyl group, and n=2 phosphonotricin inhibits glutamine synthase. ing. Further, the following general formulas (4), (5) and (6):

[0005]

[Chemical 4]

[0006]

[Chemical 5]

[0007]

[Chemical 6]

(In the formula, A and B are alkylene groups having 1 to 6 carbon atoms, ortho-, meta-, para-CH ₂ C ₆ H ₄ C
_{H 2, CH 2 CH 2 OCH} 2 CH 2, CH = CHCH 2 or C
Shows the H ₂ CH = CHCH _2. Y is COOH, PO(O
H) ₂ is shown. The phosphorus-containing amino acid represented by the formula (1) is of interest as an inhibitor of purine nucleoside phosphorylase in human erythrocytes, or as a GABA _b receptor agonist or antagonist. (JLKelley e a., J.Me
d.Chem., 1995,38,1005-1014,W.Frorestl a.,J.Med.Che
m., 1995, 38, 3297-3312, 3313-3331).

It is also known that certain phosphorus-containing amino acids have a pharmacological action on neurological diseases such as Alzheimer's disease and epilepsy. recent years,
The proportion of optically active drugs in the marketed drugs tends to increase year by year, and in the last five years, the ratio of optically active drugs has risen to 39%.

Optically active substances are required not only in pharmaceuticals but also in fields related to physiological activity. Many physiologically active substances are contained in physiologically active substances, and two optically active enantiomers are used for their physiological activities. One reason is that they may have different intensities or may have completely different physiological activities. For example, as seen with phosphinothricin, the herbicidal effect of the L form is twice that of the racemate. In addition, it is known that in the barbituric acid derivative having a butyl group and a phenyl group as substituents, the R-form has analgesic and hypnotic actions, while the S-form exhibits convulsive action.

[0011]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted extensive studies on a novel optically active aminophosphinic acid, and as a result, the optically active 2-aminophosphinic acid represented by the general formula (1) is obtained.
(Hydroxycarbonyl)ethyl-3-amino-3-
We have found (hydroxycarbonyl)propylphosphinic acid. That is, the object of the present invention is to provide a novel optically active aminophosphinic acid and a method for producing the same.

[0012]

The aminophosphinic acid to be provided by the present invention is represented by the following general formula (1):

[0013]

[Chemical 7]

2-(hydroxycarbonyl)ethyl-3-(wherein C ^* represents an asymmetric carbon atom)
The structural feature is that it is amino-3-(hydroxycarbonyl)propylphosphinic acid. Further, the manufacturing method thereof is represented by the following general formula (2):

[0015]

[Chemical 8]

(Wherein R ¹ represents a linear or branched alkyl group having 1 to 6 carbon atoms, and the alkyl group is a halogen, a hydroxy group, an alkoxy group having 1 to 3 carbon atoms, a phenyl group, It may be substituted with a phenoxy group or a thienyl group, and the phenyl group and the phenoxy group have 1 to 3 carbon atoms.
May be substituted with an alkyl group, a hydroxy group, a nitro group, an amino group, a halogen, or an alkoxy group having 1 to 3 carbon atoms. ), a racemic mixture of 2-(hydroxycarbonyl)ethyl-3-(N-acyl)amino-3-(hydroxycarbonyl)propylphosphinic acid and penicillin amidase are contacted for enzymatic resolution. Characterize. The term “enzyme resolution” as used herein means to selectively hydrolyze only the N-acyl group of L-form.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION The optically active aminophosphinic acid of the present invention is 2-(hydroxycarbonyl)ethyl-3-amino-(hydroxycarbonyl)propylphosphinic acid represented by the general formula (1). 2-(hydroxycarbonyl)ethyl of the general formula (1) of the invention
Since 3-amino-3-(hydroxycarbonyl)propylphosphinic acid has an amphoteric property, it can form an acid addition salt and a salt with a base.

Examples of such acid addition salts include pharmaceutically acceptable salts of the compounds with hydrohalic acid, sulfuric acid or phosphoric acid, for example, hydrochlorides, hydrosulfides, sulfates, aliphatic or aromatic salts. Examples thereof include pharmaceutically acceptable salts with sulfonic acid and N-substituted sulfamic acid, such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, N-cyclohexylsulfamate and the like. On the other hand, as the salt with a base, for example, a pharmaceutically acceptable base and the 2-
(Hydroxycarbonyl)ethyl-3-amino-3-
(Hydroxycarbonyl)propylphosphinic acid salts, for example, non-toxic metal salts derived from metals of group Ia, group Ib, group IIb, and such metal salts include
Examples thereof include alkali metal salts such as sodium and potassium, and alkaline earth metal salts such as calcium and magnesium. In addition, salts with ammonia, organic amines, ammonium bases and organic amines are also acceptable.

Next, the manufacturing method of the present invention will be described. The optically active 2 represented by the general formula (1) of the present invention
-(Hydroxycarbonyl)ethyl-3-amino-3-
The method for producing (hydroxycarbonyl)propylphosphinic acid is as follows: 2-(hydroxycarbonyl)ethyl-3-(N-acyl)amino-3-represented by the general formula (2).
A racemic mixture of (hydroxycarbonyl)propylphosphinic acid and penicillin amidase are brought into contact with each other to enzymatically separate the mixture, and L-2-(hydroxycarbonyl)ethyl-3-amino-3-(hydroxycarbonyl)propylphosphinic acid and D A major characteristic is to obtain 2-(hydroxycarbonyl)ethyl-3-(N-acyl)amino-3-(hydroxycarbonyl)propylphosphinic acid.

<2-(hydroxycarbonyl)ethyl-
Preparation of 3-(N-acyl)amino-3-(hydroxycarbonyl)propylphosphinic acid> 2-(hydroxycarbonyl) represented by the above general formula (2) as a raw material of the present invention
In the formula of ethyl-3-(N-acyl)amino-3-(hydroxycarbonyl)propylphosphinic acid, R ¹ represents a linear or branched alkyl group having 1 to 6 carbon atoms, and the alkyl group is halogen. , A hydroxy group, an alkoxy group having 1 to 3 carbon atoms, a phenyl group, a phenoxy group or a thienyl group may be substituted, and the phenyl group and the phenoxy group are an alkyl group having 1 to 3 carbon atoms, a hydroxy group, a nitro group, It may be substituted with an amino group, a halogen or an alkoxy group having 1 to 3 carbon atoms. Specific examples of R ¹ include a methyl group, a butyl group, a chloromethyl group, a benzyl group, a phenoxymethyl group, a 2-methylbenzyl group,
4-nitrobenzyl group, 4-hydroxybenzyl group, 4
-Aminobenzyl group, thienyl-(2)-4-chlorobenzyl group, 4-methoxybenzyl group and the like can be mentioned, and of these, a benzyl group is preferable.

2-(hydroxycarbonyl)ethyl-3, which is a racemate corresponding to the optically active substance of the above-mentioned general formula (1).
As a method for producing -amino-3-(hydroxycarbonyl)propylphosphinic acid, it can be produced by a method developed by the present inventors and a patent pending, for example, as follows. That is, the following general formula (7):

[0022]

[Chemical 9]

A phosphinic acid derivative having a vinyl group represented by the formula (wherein R is a lower alkyl group having 1 to 5 carbon atoms) and the following general formula (8):

[0024]

[Chemical 10]

(Wherein R is as defined above) is reacted with an acetamidomalonic acid ester to give the following general formula (9):

[0026]

[Chemical 11]

A phosphinic acid amide derivative represented by the formula (wherein R is as defined above) is obtained, and then hydrolyzed under acidic condition to give the following general formula (10):

[0028]

[Chemical formula 12]

2-(hydroxycarbonyl) represented by
Ethyl-3-amino-3-(hydroxycarbonyl)propylphosphinic acid racemate is obtained. There is no particular limitation on the method for producing 2-(hydroxycarbonyl)ethyl-3-(N-acyl)amino-3-(hydroxycarbonyl)propylphosphinic acid represented by the general formula (2), and any known method is known. Can be used. For example, the following general formula (11):

[0030]

[Chemical 13]

It can be easily obtained by reacting the above compound (10) with a halogenated acetyl compound represented by the formula (wherein R ¹ has the same meaning as above and X represents a halogen atom).

<Penicillin Amidase> The penicillin amidase used in the present invention is an enzyme that splits penicillin into 6-aminopenicillic acid, and is an E. coli produced from a prokaryote, for example, Escherichia coli. C. The number is 3.5.1.11. Penicillin amidase can be used as a free water-soluble enzyme, for example, as a freeze-dried product or a water-insoluble immobilized enzyme. In addition, penicillin amidase is 2-(hydroxycarbonyl)ethyl-3-(N-acyl)amino-3.
It has a very wide range of substrate specificity for -(hydroxycarbonyl)propylphosphinic acid, and only different L-groups act on the L-form, for example, 2-(hydroxycarbonyl)ethyl-3-(N-phenyl). In the case of acetyl)amino-3-(hydroxycarbonyl)propylphosphinic acid, an enzyme having a specific activity of about 10 ⁵ to 10 ⁶ U/g is used.

<Reaction conditions> The above-mentioned general formula (2) as a raw material
2-(hydroxycarbonyl)ethyl-3-
(N-acyl)amino-3-(hydroxycarbonyl)
The propylphosphinic acid concentration is between 0.1 mol/l and the solubility limit of the aqueous reaction solvent medium or the aqueous organic reaction solvent medium. As the aqueous organic reaction solvent medium, for example, a mixed solvent of water and a lower alcohol such as methanol or ethanol is used. The reaction temperature is usually 10-
The reaction time is 60°C, preferably 15 to 40°C.
Usually 2 to 120 hours, depending on the enzyme activity and the concentration of the substrate,
It is preferably 15 hours or more. The penicillin amidase used in the present invention is sufficiently active at pH 5.0 to 8.5, and the optimum pH is around 7 to 8. The reaction can be carried out in the absence of a buffer or using a commonly used buffer such as a phosphate buffer.

In such a reaction, it is advantageous to immobilize penicillin amidase for reuse of the enzyme, and the reaction can be performed using a column type or batch type reaction vessel. This enzyme resolution can be easily followed analytically by a known method. For example, the progress of the reaction can be traced by quantitatively analyzing the free carboxylic acid. After completion of the reaction, for example, the immobilized penicillin amidase can be removed from the reaction system by filtration, and the immobilized penicillin amidase can be reused by washing with water or the like.

Post-treatment of the reaction mixture by enzymatic resolution is carried out, for example, by the following three methods to give the desired optically active 2-(hydroxycarbonyl)ethyl-3-amino-
Optical isomers of 3-(hydroxycarbonyl)propylphosphinic acid can be obtained. 1. After acidifying the reaction system with an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or acetic acid, the mixture was evaporated and concentrated, and D-2-(hydroxycarbonyl)ethyl-3-(N-phenylacetyl) was added.
Amino-3-(hydroxycarbonyl)propylphosphinic acid and free carboxylic acid are extracted with an organic solvent such as ethanol, and the residue is L-2-(hydroxycarbonyl)ethyl-3-amino-3-(hydroxycarbonyl)propyl. Phosphinic acid is obtained.

2. Column chromatography is carried out using an H ⁺ type strongly acidic cation exchanger. As the mobile phase, D-2-(hydroxycarbonyl)ethyl-3-(N-acyl)amino-3-(hydroxycarbonyl)propylphosphinic acid and free carboxylic acid were first flowed out by sequentially flowing water, Then, L-2-(hydroxycarbonyl)ethyl-3-amino-3-(hydroxycarbonyl)propylphosphinic acid is eluted.

3. An acid is added to the reaction system to make it acidic, and then column chromatography treatment is carried out using an H ⁺ type strongly acidic cation exchanger. As a mobile phase, D-2-(hydroxycarbonyl)ethyl-3-by flowing water
(N-acyl)amino-3-(hydroxycarbonyl)
Propylphosphinic acid and free carboxylic acid flow out, and then L-2-(hydroxycarbonyl)ethyl-3-amino-3-(hydroxycarbonyl)propylphosphinic acid flows out by flowing an acidic aqueous solution.

In the present invention, if desired, D-
A mixture of 2-(hydroxycarbonyl)ethyl-3-(N-acyl)amino-3-(hydroxycarbonyl)propylphosphinic acid and a carboxylic acid is extracted with an organic solvent such as ethanol to form a D-2- (Hydroxycarbonyl)ethyl-3-(N-acetyl)amino-3-(hydroxycarbonyl)propylphosphinic acid can be isolated.

D-2-(hydroxycarbonyl)ethyl-3-(N-acetyl)amino-3-(hydroxycarbonyl)propylphosphinic acid is usually used for 1 to 20 hours, preferably under reflux with an acid such as hydrochloric acid. By reacting for 10 hours or more and deacylating, the target D-2 can be obtained.
-(Hydroxycarbonyl)ethyl-3-amino-3-
(Hydroxycarbonyl)propylphosphinic acid can be obtained.

Further, D-2-(hydroxycarbonyl)ethyl-3-amino-3-(hydroxycarbonyl)propylphosphinic acid and L-2-(hydroxycarbonyl)ethyl-3-amino-3-(hydroxycarbonyl)propyl. Phosphinic acid can be isolated as a crystalline substance by treating with propylene oxide in an ethanol solution or an aqueous ethanol solution, or by column chromatography using an H ⁺ -type cation exchange resin.

[0041]

[Preparation of 2-(hydroxycarbonyl)ethyl-3-(N-phenylacetyl)amino-3-(hydroxycarbonyl)propylphosphinic acid]

<Preparation of ethyl-2-(hydroxycarbonyl)ethylvinylphosphinic acid> Ammonium phosphite 4.0 g
(0.048 mol), hexamethyldisilazane 15 ml
(0.07 mol) was charged into a reaction vessel and reacted at 120 to 130° C. for 2 hours under an argon atmosphere. The reaction vessel was then cooled and 5.3 ml of ethyl acrylate (0.
(048 mol) is slowly added dropwise to the reaction vessel, and 40 to 50
The reaction was carried out at a temperature of °C for 2 hours. Next, 21 ml (0.24 mol) of 1,2-dibromoethane was added to the reaction vessel, and the mixture was further reacted at 120°C for 2 hours. Then, after vacuum-drying to remove impurities, ethanol was added to the residue and further reaction was carried out under reflux. After completion of the reaction, filtration and drying were carried out. Then, 40 ml of triethylorthoformic acid was added to the residue.
(0.24 mol) was added, the reaction was carried out under reflux, and after completion of the reaction, distillation was carried out to obtain 3.5 g of the desired product (yield 35%).

Identification data Boiling point: 125-129° C. 3 mmHg Elemental analysis; Actual value C; 49.14%, H; 7.97% Calculated value C ₉ H ₁₇ O ₄ PC; 49.09%, H; 7 0.78% ¹ H-NMR (CDCl ₃ , δ, ppm); 1.25 (t, 3H),
1.34 (t, 3H), 2.07 (m, 2H), 2.60
(M, 2H), 4.03 (m, 2H), 4.15 (m, 2)
H), 6.00 to 6.50 (m, 3H) ³¹ P-NMR (δ, ppm); 41.3

<2-(hydroxycarbonyl)ethyl-
Preparation of 3-amino-3-(hydroxycarbonyl)propylphosphinic acid>Ethyl-2-(hydroxycarbonyl)ethylvinylphosphinic acid 7.47 obtained above
g (0.034 mol), diethyl acetamide malonic acid 6.78 g (0.031 mol), potassium carbonate 8.6
g, 20 ml of tetrahydrofuran and 0.5 g of tetrabutylammonium bromide were charged into a reaction vessel, reacted for 12 hours at room temperature with stirring, and after the reaction was completed, it was filtered and dried. Next, 70 ml of 6N hydrochloric acid was added to the residue, and the mixture was reacted under reflux for 15 hours. After the reaction was completed, ether was added to wash, and then concentrated. Furthermore, the residue was purified by column chromatography to give 5.3 g of the desired product (yield 7
1.0%) was obtained.

Identification data Melting point: 205 to 207° C. Elemental analysis; Actual value C; 33.83%, H; 6.07% Calculated value C ₇ H ₁₄ NO ₆ P.1/2H ₂ O C; 33.88 %, H; 6.09% ¹ H-NMR (D ₂ O+DCl, δ, ppm); 1.70 (m, 2
H), 1.88 (m, 4H), 2.36 (dt, 2H, _JPH
12 Hz), 3.92 (t, 1H) ³¹ P-NMR (δ, ppm); 55.0 (D ₂ O+DCl, pH<1), 4
4.0 (D ₂ O+NaOD, pH=10)

<2-(hydroxycarbonyl)ethyl-
Preparation of 3-(N-phenylacetyl)amino-3-(hydroxycarbonyl)propylphosphinic acid> A solution of 4.6 ml (0.036 mol) of phenylacetyl chloride in 5 ml of dioxane and a 50% KOH aqueous solution were added as above. In a solution of 6.9 g of racemic isomer of 2-(hydroxycarbonyl)ethyl-3-amino-3-(hydroxycarbonyl)propylphosphinic acid obtained in (3) in 30 ml of water at a temperature of 0 to 5°C, pH was adjusted. It was added at the same time while maintaining at 9.5. After completion of the reaction, the pH was adjusted to 5, neutralized and extracted with ether. Then, the aqueous layer is added with 6N hydrochloric acid to p.
After adjusting to H1 and removing water by decantation,
An oily substance was obtained, the oily substance was dissolved in ethanol, the ethanol insoluble matter was filtered off, and the filtrate was concentrated. The residue was recrystallized with a mixed solution of hexane:acetone=10:1 to obtain 8.2 g of the desired product (yield 79%).

Identification data Melting point: 127-129° C. ¹ H-NMR (CD ₃ OD, δ, ppm); 1.80 (m, 2H),
2.00 (m, 4H), 2.55 (m, 2H), 4.66
(T, 1H) ³¹ P-NMR (CD ₃ OD, δ, ppm); 53.4

(Example 1) <Preparation of D-2-(hydroxycarbonyl)ethyl-3-amino-3-(hydroxycarbonyl)propylphosphinic acid> 2-(hydroxycarbonyl)ethyl-3-obtained above (N-phenylacetyl)amino-3
7.15 g (0.02 mol) of a racemic mixture of -(hydroxycarbonyl)propylphosphinic acid was dissolved in 70 ml of water, and the pH was adjusted to 7.5 with a 1N aqueous potassium hydroxide solution. Immobilized penicillin amylase 7-10
g (10 ⁵ to 10 ⁶ U/g) was added to the reaction mixture at a temperature of 20 to
The reaction was carried out at 25° C. for 25 hours with stirring. After the reaction,
The penicillin amylase was removed by filtration.

Then, the aqueous layer was concentrated to 20 ml, the pH was adjusted to 2 by adding hydrochloric acid, and the mixture was passed through an H-type cation exchange resin (3×30 cm), and water was used as an outflow solution.
The acidic ninhydrin-negative fraction was collected and concentrated to give D-2-(hydroxycarbonyl)ethyl-3-(N-phenylacetyl)amino-3-(hydroxycarbonyl)propylphosphinic acid. Then, 3 g of the obtained D-2-(hydroxycarbonyl)ethyl-3-(N-phenylacetyl)amino-3-(hydroxycarbonyl)propylphosphinic acid was dissolved in 30 ml of concentrated hydrochloric acid and reacted under reflux for 10 hours. Let
Then, the solution was concentrated, water and ether were added to the residue, and after stirring well, the aqueous phase was concentrated. Further, excess propylene oxide and a solution of water:ethanol=1:7 were added to the residue, and the formed crystal product was filtered and dried to give D-2-
(Hydroxycarbonyl)ethyl-3-amino-3-
(Hydroxycarbonyl)propylphosphinic acid 1.7
g (yield 71.0%) was obtained.

Identification data Melting point: 194 to 195° C. Elemental analysis: Actual value C; 34.08%, H; 6.12% Calculated value C ₇ H ₁₄ NO ₆ P.1/2H ₂ O C; 33.88 %, H; 6.09% ¹ H-NMR (D ₂ O+DCl, δ, ppm); 1.70 (m, 2
H), 1.88 (m, 4H), 2.36 (dt, 2H),
3.92 (t, 1H) ³¹ P-NMR (δ, ppm); 55.0 (D ₂ O+DCl, pH<1), 4
4.0 (D ₂ O+NaOD, pH=10) [α] ²⁵ _D −22.9° (C 1.3, 6N HCl) [α] ²⁵ _D −13.5° (C 1.2, H ₂ O)

<Preparation of L-2-(hydroxycarbonyl)ethyl-3-amino-3-(hydroxycarbonyl)propylphosphinic acid> Next, 0.7 to 1.0 N hydrochloric acid was added to the D-form of the N-phenylacetyl form. Flow through the column and collect the ninhydrin-positive fractions,
Concentrated. Further, a solution of water:ethanol=1:7 was added to the concentrate, and excess propylene oxide was further added. Then, the crystallized substance was collected and dried to obtain 1.3 g of L-2-(hydroxycarbonyl)ethyl-3-amino-3-(hydroxycarbonyl)propylphosphinic acid (yield 54.
4%) was obtained.

Identification data Melting point: 184-187° C. Elemental analysis: Theoretical value C; 33.36%, H; 6.04% Calculated value C ₇ H ₁₄ NO ₆ P·1/2H ₂ O C; 33.88 %, H; 6.09% ¹ H-NMR (D ₂ O+DCl, δ, ppm); 1.70 (m, 2
H), 1.88 (m, 4H), 2.36 (dt, 2H),
3.92 (t, 1H) ³¹ P-NMR (δ, ppm); 55.0 (D ₂ O+DCl, pH<1), 4
4.0 (D ₂ O+NaOD, pH=10) [α] ²⁷ _D +24.5° (C 1.1, 6N HCl) [α] ²⁸ _D +12.5° (C 1.2, H ₂ O) )

[0052]

As described above, the optically active 2 of the present invention is used.
-(Hydroxycarbonyl)ethyl-3-amino-3-
(Hydroxycarbonyl)propylphosphinic acid is a novel aminophosphinic acid derivative useful as a raw material for physiologically active substances and intermediates thereof, and according to the production method of the present invention, the compound can be produced by an industrially advantageous method. Can be easily obtained.

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Roshiko Lyukov Fyodorovna Russian Federation, Moscow, Noginsk District, Chernogarovka 142432 (72) Inventor Saratovskiy Irina Wassilyevna Russian Federation, Noginsk District, Moscow, Chernogalovka 142432 (72) Inventor Zefirov Nikolai Serafimovich Russian Federation, Moscow Oblast, Noginsk District, Chernogalovka 142432 F-term (reference) 4B064 AE63 BB05 BB16 BC03 BH01 BH03 BH04 CA21 CB05 CC03 CD15 ACD02 CD11 AB84 AB99 AC10 AC50 AC81 AD32

Claims (3)

[Claims] 1. The following general formula (1): (In the formula, C ^* represents an asymmetric carbon atom.) An optically active 2-(hydroxycarbonyl)ethyl-3-amino-3-(hydroxycarbonyl)propylphosphinic acid. 2. The following general formula (2): (In the formula, R ¹ represents a linear or branched alkyl group having 1 to 6 carbon atoms, and the alkyl group is a halogen, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, a phenyl group, a phenoxy group or It may be substituted with a thienyl group, and the phenyl group and the phenoxy group may be substituted with an alkyl group having 1 to 3 carbon atoms, a hydroxy group, a nitro group, an amino group, a halogen or an alkoxy group having 1 to 3 carbon atoms. The racemic mixture of 2-(hydroxycarbonyl)ethyl-3-(N-acyl)amino-3-(hydroxycarbonyl)propylphosphinic acid represented by the formula (1) and penicillin amidase are contacted for enzymatic resolution, Then, the reaction solution was passed through an H ⁺ type cation exchange resin to give L-2.
-(Hydroxycarbonyl)ethyl-3-amino-3-
(Hydroxycarbonyl)propylphosphinic acid and D
The optically active 2- according to claim 1, wherein 2-(hydroxycarbonyl)ethyl-3-(N-acyl)amino-3-(hydroxycarbonyl)propylphosphinic acid is obtained.
(Hydroxycarbonyl)ethyl-3-amino-3-
A method for producing a precursor of (hydroxycarbonyl)propylphosphinic acid. 3. D-2-(hydroxycarbonyl)ethyl-3-(N-acyl)amino-3-(hydroxycarbonyl)propylphosphinic acid is deacylated to obtain D-2.
-(Hydroxycarbonyl)ethyl-3-amino-3-
The method for producing optically active 2-(hydroxycarbonyl)ethyl-3-amino-3-(hydroxycarbonyl)propylphosphinic acid according to claim 1, wherein (hydroxycarbonyl)propylphosphinic acid is obtained.