JPH0692956A - Production of @(3754/24)s)-4-oxocumarone-2-carboxylic acid derivative - Google Patents

Abstract

PURPOSE:To obtain an intermediate for synthesizing chemicals from a useless material, as a raw material in high yield and at low cost by protecting a keto group of a specific optically active compound, epimerizing to be a diastereomer mixture, fractionally recrystallizing, eliminating a protecting group and hydrolyzing. CONSTITUTION:A keto group at the fourth position in an optically active compound of formula I [X is H, halogen or alkyl; R1 is (substituted) phenyl or naphthyl; R2 is alkyl or phenyl; here, R1 and R2 are not the same group at the same time.] is protected and the compound is converted to a compound of formula II (A is O or S; B is CH2CH2 or CH2CH2, etc.). Then, the second position of this compound is epimerized to be a diastereomer mixture of an optically active compound of formula II and that of formula III in the presence of a base. The optically active compound of formula III is isolated by fractional crystallization, eliminating the protecting group and hydrolyzing under dicid condition to obtain the compound of formula IV.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is
(S) -4-oxochroman-2-carboxylic acid derivative, which is a target compound of the method of the present invention, is a compound represented by the above general formula (I). In the present specification, the letters "S" are used, as in the case of the abovementioned indications of the target compounds.
Indicates that it has a three-dimensional configuration. Therefore, this should be displayed in italics, but it is displayed in normal English letters because it is an external character. The following "S", "2"
The same applies to S "and" 4S ").

[0002]

2. Description of the Related Art Conventionally, this general formula has been used.
The compound itself represented by (I) is known, and in particular the following formula (V)

[Chemical 5] , Having strong aldose reductase inhibitory activity and optical activity (2S, 4S,)-6-Fluoro-2 ', 5'-dioxospiro [chroman-4,4'-imidazolidine] -2-carboxamide Is important as a synthetic intermediate. because,
This is because the compound represented by the above formula (V) is extremely useful as an active ingredient of a therapeutic agent for diabetic complications, which is a refractory disease. The (R) -4-oxochroman-2-carboxylic acid derivative, which is an optical isomer of the target compound of the method of the present invention (the letter "R" at the beginning of the description relating to this compound is also a stereoisomer different from the above "S"). It is meant to have a configuration and therefore should be shown in italics,
Since it is an external character, it is displayed in the usual English letters. The following "R",
"2R" and "4R" are the same) were not important.

The final product (S) -4-oxochroman-2-carboxylic acid derivative (I) obtained by the method of the present invention has optical activity and pharmacological activity (2S, 4S,)-6. -
In order to produce fluoro-2 ', 5'-dioxospiro [chroman-4,4'-imidazolidine] -2-carboxamide (V), the presence of potassium cyanide is described as described in JP-A-1-93588. After forming the spirohydantoin ring by utilizing the so-called Bücherer reaction in which the compound (I) (wherein X represents fluorine) is heated below, 2
The carboxylic acid at the position may be amidated.

The compound represented by the formula (I) is disclosed by the present applicant in Japanese Patent Laid-Open No. 63-250373. According to this, the compound represented by the formula (I) is synthesized through the following reaction steps. It

[Chemical 6]

The above-mentioned method disclosed in JP-A-63-250373 is obtained by activating the racemic 4-oxochroman-2-carboxylic acid derivative (Ia ') formed in the reaction process. (S)-(-)-1-Methylbenzylamine reacted with (2R, 4S)-and (2S, 4S)-of 4-oxochroman.
Derivation into a diastereomeric mixture with a 2-carboxamide derivative and fractional recrystallization gave the (2S, 4S) -derivative, which
The S, 4S) -derivative is further acid-hydrolyzed to obtain the final product (S) -4-oxochromancarboxylic acid derivative (I).

[0006]

DISCLOSURE OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION AND OBJECTS OF THE INVENTION As described above, the compound is obtained by reacting a racemic 4-oxochroman-2-carboxylic acid derivative (Ia ') with an optically active amine.
Fractional recrystallization of diastereomeric mixture of (2R, 4S)-and (2S, 4S) -2-carboxamide derivatives of 4-oxochroman
The (2R, 4S) -derivative (II) after obtaining the (2S, 4S))-derivative was of little importance and therefore led to unnecessary consumption of the compound represented by the general formula Ia ′ [above The ratio of the (2R, 4S) -derivative to the (2S, 4S) -derivative in the diastereomeric mixture of is 1: 1, so 50% is wasted].

The present invention has been made in view of the above problems of the prior art, and its object is to start from a (2R, 4S) -derivative, which is a so-called unnecessary substance in the above conventional method. (S) -4- which is an optically active and useful raw material for the synthesis of useful drugs without the need for special reagents, conditions, equipment, etc.
It is to provide a method for producing an oxochroman-2-carboxylic acid derivative in a high yield.

[0008]

[Means and Actions for Solving the Problems] The inventors of the present invention have conducted intensive studies with a focus on economic efficiency including raw material costs, reagent costs, yields, etc., and as a result, (R) -amide derivatives (I
(I) is epimerized to form a diastereomeric mixture of (S) -amide derivative and (R) -amide derivative, and then (S) -amide derivative is obtained by fractional recrystallization, which is acid-hydrolyzed. The target optically active (S) -4-oxochroman-2-
The present invention has been completed by developing a method for producing a carboxylic acid derivative.

That is, according to the present invention, the (R) -amide derivative
The keto group at the 4-position is protected with a diol or dithiol in the presence of an acid catalyst to give a compound of the general formula (III), which is converted to a base such as sodium methoxide, sodium hydride or ethanethiol sodium. In the presence of a salt, the compound represented by the general formula (III) and the general formula (IV) is epi-ized by heating in an aprotic polar solvent such as N, N-dimethylformamide or tetrahydrofuran. Diastereomeric mixture with compound. Furthermore, this was fractionally recrystallized from a solvent such as methanol to obtain a compound (IV), which was subjected to acidic conditions under
For example, if treated in acetic acid / hydrochloric acid-acetic acid, deprotection and hydrolysis are carried out at the same time, and the desired (S) -4-oxochroman-2-carboxylic acid (I) can be obtained in high yield and 99.9%, ee or more. It is obtained with optical purity.

[0010]

EXAMPLES The present invention will be described in more detail and concretely with reference to Examples and Examples. Reference Example 1 (A) (2R) -N-[(S) -α-methyl (benzyl)]-6-fluoro-su
Pyro [chroman-4,2 '-(1', 3'-dithian)]-2-carboxa
Mido (protection at 4-position) (2R) -N-[(S) -α-methyl (benzyl)]-6-fluoro-4-oxochroman-2-carboxamide 8.00 g (25.6 mmol), 1,3-
Propanedithiol 3.32 g (32.8 mmol), boron trifluoride
Diethyl ether complex 5.12 ml (20.5 mmol) in acetic acid 80 ml
Heated at 60 ° C. for 2 hours. 250 ml of water to the reaction mixture
The precipitated crystals were collected by filtration to give 10.2 g (yield 99.0%) of the title compound as colorless needle crystals. Melting point: 142-144 ° C. MS spectrum (EI / DI) m / z: 403 (M ⁺ ), 255 (base peak). ¹ H-NMR spectrum (C ₆ D ₆ ) δppm: 1.24 (3H, d, J _{= 7.3Hz, -CH 3), 1.20} - 1.52 (2H, m, -CH 2 -), 1.87 - 2.04 (2H, m, -CH 2 -), 2.31 - 2.65 (2H, m, -CH 2 -) , 2.32 (1H, dd, J = 11.7Hz, 14.6Hz, C ₃ -H), 3.43 (1H, dd, J = 2.0Hz, 14.6Hz, C ₃ -H), 4.98 (1H, dd, J = 2.0 Hz, 11.7Hz, C ₂ -H), 5.29 (1H, quintet, J = 7.3Hz, N-CH (Me) -Ph), 6.43 (1H, dd, J = 4.9Hz, 9.3Hz, C ₈ -H ), 6.54 (1H, ddd, J = 2.9Hz, 7.8Hz, 9.3Hz, C 7 -
H), 6.71 (1H, d, J = 7.3Hz, -CONH-), 7.02-7.18 (5H, m, -C ₆ H ₅ ), 7.98 (1H, dd, J = 2.9Hz, 9.8Hz, C ₅ -H).

(B) (2R) -N-[(S) -α-methyl (benzyl)]-6
-Fluoro-spiro [chroman-4,2 '-(1', 3'-dithian)]-2
- the epimerization sodium hydride 600mg carboxamide (15mmol, 60% in oil) N, N
-Suspend in 30 ml of dimethylformamide,
(2R) -N-[(S) -α-methyl (benzyl)]-6-fluoro-spiro [chroman-4,2 '-(1', 3'-dithian)] obtained in section (A) -2-
A solution of 6.00 g (15 mmol) of carboxamide in 50 ml of N, N-dimethylformamide was added, and the mixture was heated at 100 ° C. for 1 hour. The reaction mixture was added to 180 ml of ice water, and the precipitated crystals were collected by filtration and dried to give (2R) -N-[(S) -α-methyl (benzyl)]-.
6-Fluoro-spiro [chroman-4,2 '-(1', 3'-dithian)]-
2-Carboxamide and (2S) -N-[(S) -α-methyl (benzyl)]-6-fluoro-spiro [chroman-4,2 '-(1', 3'-dithian)]-2- 5.46 g of a mixture with carboxamide (yield 91.0
%) Obtained. As a result of ¹ H-NMR spectrum analysis of this mixture at 270 MHz, the component ratio of the former to the latter was 1: 1.

(B ') (2R) -N-[(S) -α-methyl (benzyl)]-
6-Fluoro-spiro [chroman-4,2 '-(1', 3'-dithian)]-
2-Carboxamide epiation (alternate method) Sodium hydride 100 mg (2.5 mmol, 60% in oil) was added to N,
The suspension was suspended in 10 ml of N-dimethylformamide, and a solution of 155 mg (2.5 mmol) of ethanethiol in 3 ml of N, N-dimethylformamide was added at 0-5 ° C, followed by stirring for 20 minutes. Then (2R) -N-[(S) -α-methyl (benzyl)] obtained in the above item (A)
-6-Fluoro-spiro [chroman-4,2 '-(1', 3'-dithian)]
-2-Carboxamide 1.00g (2.5mmol) was added, and 100 ℃
Heated for 1 hour. The reaction mixture was added to 20 ml of ice water, and the precipitated crystals were collected by filtration and dried to give (2R) -N-[(S)-
α-Methyl (benzyl)]-6-fluoro-spiro [chroman-4,
2 '-(1', 3'-Dithian)]-2-carboxamide and (2S) -N-
0.92 g (yield 92.0%) of a mixture of [(S) -α-methyl (benzyl)]-6-fluorospiro [chroman-4,2 '-(1', 3'-dithian)]-2-carboxamide Obtained. This mixture at 270MHz
As a result of ¹ H-NMR spectrum analysis, the component ratio of the former and the latter was 1: 1.

(C) (2S) -N-[(S) -α-methyl (benzyl)]-6
-Fluoro-spiro [chroman-4,2 '-(1', 3'-dithian)]-2
-Carboxamide (fractional recrystallization) (2R) -N-[(S) -α-methyl (benzyl)]-6-fluoro-spiro [chroman-4, obtained in (B) or (B ') above. 2 '-(1',
3'-dithian)]-2-carboxamide and (2S) -N-[(S) -α-methyl (benzyl)]-6-fluoro-spiro [chroman-4,2'-
(1 ', 3'-Dithiane)]-2-carboxamide epiated mixture
By recrystallizing 5.46 g three times with methanol, 540 mg (yield 19.8%) of the title compound was obtained as colorless prism crystals. Melting point: 112-113 ° C. MS spectrum (EI / DI) m / z: 403 (M ⁺ ), 255 (base peak). ¹ H-NMR spectrum (C ₆ D ₆ ) δppm: 1.27 (3H, d, J _{= 6.8Hz, -CH 3) 1.24 -} . 1.55 (2H, m, -CH 2 -) 1.88 -. 1.96 (2H, m, -CH 2 -) 2.48 -. 2.68 (2H, m, -CH 2 -) 2.46 (1H, dd, J = 11.7Hz, 14.6Hz, C ₃ -H), 3.52 (1H, dd, J = 2.0Hz, 14.6Hz, C ₃ -H), 4.89 (1H, dd, J = 2.0 Hz, 11.7Hz, C ₂ -H), 5.33 (1H, quintet, J = 6.8Hz, N-CH (Me) -Ph), 6.33 (1H, dd, J = 4.9Hz, 9.3Hz, C ₈ -H ), 6.53 (1H, ddd, J = 2.9Hz, 7.8Hz, 9.3Hz, C 7 -
H), 6.72 (1H, d, J = 6.8Hz, -CONH-), 7.04-7.22 (5H, m, -C ₆ H ₅ ), 7.98 (1H, dd, J = 2.9Hz, 9.77Hz, C ₅ -H).

Example (A) (2R) -N-[(S) -α-methyl (benzyl)]-6-fluoro-su
Pyro [chroman-4,2 '-(1', 3'-dioxolane)]-2-carb
Xamide (protection at 4-position) (2R) -N-[(S) -α-methyl (benzyl)]-6-fluoro-4-oxochroman-2-carboxamide 31.3g (0.10mol), ethylene glycol 31.0g (0.50 mmol) and 1.91 g (10 mmol) of p-toluenesulfonic acid monohydrate in 600 ml of toluene.
It was heated to dissolve in, and refluxed for 3.5 hours while removing water produced by the reaction by azeotropic distillation. Pyridine (10.0 ml) was added, the mixture was cooled to room temperature, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained oil was crystallized by adding diethyl ether to obtain 34.2 g (yield 95.7%) of the title compound as colorless needle crystals. Melting point: 128-129 ° C. MS spectrum (EI / DI) m / z: 357 (M ⁺ ), 209 (base peak). ¹ H-NMR spectrum (C ₆ D ₆ ) δppm: 1.22 (3H, d, J = 6.8Hz, -CH ₃ ), 1.98 (1H, dd, J = 12.2Hz, 13.6Hz, C ₃ -H), 2.57 (1H, dd, J = 2.9Hz, 13.6Hz, C ₃ -H), 3.28 -3.47 (4H, m, -CH ₂ -CH _2- ), 4.89 (1H, dd, J = 2.9Hz, 12.2Hz, C ₂ -H), 5.27 (1H, quinetet, J = 6.8Hz, -N- CH (Me) -P
h), 6.47 (1H, dd, J = 4.4Hz, 8.8Hz, C ₈ -H), 6.61-6.68 (2H, m, C7-H, -CONH-), 7.03-7.16 (5H, m, -C ₆ H1 ₅ ), 7.27 (1H, dd, J = 8.8Hz, 2.9Hz, C ₅ -H).

(B) (2R) -N-[(S) -α-methyl (benzyl)]-6
-Fluoro-spiro [chroman-4,2 '-(1', 3'-dioxola
)]-2-Carboxamide sodium hydride 2.24 g (60% in oil, 56.0 mmol)
Suspended in 100 ml of N, N-dimethylformamide, and added to it (2R) -N-[(S) -α-methyl (benzyl)] obtained in (A) above.
-6-Fluoro-spiro [chroman-4,2 '-(1', 3'-dioxolane)]-2-carboxamide 20.0 g (56 mmol) of N, N-dimethylformamide 80 ml solution was added, and the temperature was 100 ° C for 1 hour. Heated. The reaction mixture was added to 400 ml of ice water, and the precipitated crystals were collected by filtration and dried to give (2R) -N-[(S) -α-methyl.
(Benzyl)]-6-fluorospiro [chroman-4,2 '-(1', 3'-
Dioxolane)]-2-carboxamide and (2S) -N-[(S) -α-
Methyl (benzyl)]-6-fluorospiro [chroman-4,2'-
(1 ', 3'-dioxolane)]-2-carboxamide
19.2 g (yield 96.0%) was obtained. This mixture is ¹ H-at 270 MHz
As a result of NMR spectrum analysis, the component ratio of the former and the latter is 1
: It was 1.

(B ') (2R) -N-[(S) -α-methyl (benzyl)]-
6-Fluoro-spiro [chroman-4,2 '-(1', 3'-dioxola
Epitaxy of 2-carboxamide (another method) 1.73 g (32.0 mmol) of sodium methoxide was suspended in 50 ml of N, N-dimethylformamide, and (2R) -N-[(S)-
α-Methyl (benzyl)]-6-fluoro-spiro [chroman-4,
2 '-(1', 3'-Dioxolane)]-2-carboxamide 10.0 g (3
A solution of 1.9 mol) of N, N-dimethylformamide in 50 ml was added, and the mixture was heated at 100 ° C. for 1 hour. The reaction solution was added to 200 ml of ice water, and the precipitated crystals were collected by filtration and dried (2
R) -N-[(S) -α-Methyl (benzyl)]-6-fluoro-spiro
[Chroman-4,2 '-(1', 3'-dioxolane)]-2-carboxamide and (2S) -N-[(S) -α-methyl (benzyl)]-6-fluorospiro [chroman-4 9.11 g (yield 91.1%) of a mixture with 2,2 ′-(1 ′, 3′-dioxolane)]-2-carboxamide was obtained. As a result of ¹ H-NMR spectrum analysis of this mixture at 270 MHz, the component ratio of the former to the latter was 1: 1.

(C) (2S) -N-[(S) -α-methyl (benzyl)]-6
-Fluoro-spiro [chroman-4,2 '-(1', 3'-dioxola
)]-2-Carboxamide (fractional recrystallization) (2R) -N-[(S) -α-methyl (benzyl)]-6-fluoro-spiro obtained in the above item (B) or (B ') [Chroman-4,2 '-(1',
3'-Dioxolane)]-2-carboxamide and (2S) -N-[(S)-
α-Methyl (benzyl)]-6-fluoro-spiro [chroman-4,
The title compound was obtained as colorless prism crystals by recrystallizing 10.0 g of an epilation mixture of 2 '-(1', 3'-dioxolane)]-2-carboxamide 3 times with methanol (yield 20.6%). . Melting point: 162-164 ° C. MS spectrum (EI / DI) m / z: 357 (M ⁺ ), 209 (base peak). ¹ H-NMR spectrum (C ₆ D ₆ ) δppm: 1.24 (3H, d, J = 6.8Hz, -CH ₃ ), 2.11 (1H, dd, J = 12.2Hz, 13.7Hz, C ₃ -H), 2.66 (1H, dd, J = 2.4Hz, 13.7Hz, C ₃ -H), 3.32 -3.49 (4H, m, -CH ₂ -CH _2- ), 4.80 (1H, dd, J = 2.4Hz, 12.2Hz, C ₂ -H), 5.30 (1H, quintet, J = 6.8Hz, -N- CH (Me) -Ph), 6.37 (1H, dd, J = 4.4Hz, 8.8Hz, C ₈ -H), 6.59-6.67 (2H, m, C ₇ -H, -CONH-), 7.02-7.18 ( 5H, m, -C ₆ H ₅ ), 7.27 (1H, dd, J = 3.4Hz, 8.8Hz, C ₅ -H).

(D) (S) -6-Fluoro-4-oxochroman-2-
Carboxylic acid (deprotected) (2S) -N-[(S) -α-methyl (benzyl)]-6-fluoro-spiro [chroman-4,2 ′-(1 ′) obtained in (C) above. , 3'-Dioxolane)]-2-carboxamide (2.00 g, 56.0 mmol) in acetic acid
Dissolve in 4.0 ml, add 4.0 ml of concentrated hydrochloric acid, and add 30 ml at 25 ℃.
After stirring for 1 minute, the mixture was refluxed for 10 hours. The oily substance obtained by distilling off the solvent under reduced pressure was added to 10 ml of ice water, and the precipitated crystals were collected by filtration to obtain 1.06 g (yield 90.1%) of the title compound as pale yellow prism crystals. Melting point: 175-176 ° C. MS spectrum (EI / DI) m / Z: 210 (M ⁺ ), 165 (base peak). ¹ H-NMR spectrum (DMSO-d ₆ ) δppm: 2.98 (1H, dd, J = 7.3Hz, 17.1Hz, C ₃ -H), 3.12 (1H, dd, J = 5.4Hz, 17.1Hz, C ₃ -H), 5.32 (1H, dd, J = 5.4Hz, 7.3Hz, C _2- H), 7.17 (1H, dd, J = 4.4Hz, 8.8Hz, C ₈ -H), 7.42 (1H, dd, J = 3.4Hz, 8.8Hz, C ₅ -H), 7.47 (1H, dt, J = 3.4Hz, 8.8Hz, C ₈ -H). [Α] _D : + 61.4 ° (c = 1, MeOH). Optical purity: 99.9% ee or more.

Reference Example 2 (2R) -N-[(S) -α-methyl (benzyl)]-6-fluoro-spiro
-[Chroman-4,2 '-(1', 3'-dioxane)]-2-carboxami
De (4th protection) (2R) -N - [( S) -α- (benzyl)] - 6-fluoro-4-Okisokuroman-carboxamide 5.00 g (16.0 mmol), 1,3
Propanediol 6.08 g (79.8 mmol) and p-toluenesulfonic acid monohydrate 910 mg (4.8 mmol) were added to toluene 120 m.
The solution was dissolved in 1 l and refluxed for 6 hours while azeotropically removing water produced by the reaction. Pyridine (1.0 ml) was added to the reaction mixture, which was cooled to room temperature, washed with water, dried over anhydrous sodium sulfate, and the toluene was distilled off under reduced pressure. 3.82 g (yield 64.5%) of the title compound was obtained as prism crystals. Melting point: 157-159 ° C. MS spectrum (EI / DI) m / z: 371 (M ⁺ ), 223 (base peak). ¹ H-NMR spectrum (CDCl ₃ ) δppm: 1.44-1.59, 2.16-2.27 (1H x 2, mx 2, -C _5'- H _2- ), 1.59 (3H, d, J = 7.3Hz, -CH ₃ ), 2.02 (1H, dd, J = 11.7Hz, 14.2Hz, C ₃ -H ), 3.33 (1H, dd, J = 2.9Hz, 14.2Hz, C ₃ -H), 3.87-4.26 (4H, m, -C _{4 '} -H _2- , -C _6' -H _2- ), 4.68 (1H, dd, J = 2.9Hz, 11.7Hz, C ₂ -H), 5.19 (1H, quintet, J = 7.3Hz, N-CH (Me) -Ph), 6.82-6.89 (3H, m, -CONH -, C ₇ -H, C ₈ -H), 7.24-7.41 (6H, m, C ₅ -H, -C ₆ H ₅ ).

Reference Example 3 (2R) -N-[(S) -α-methyl (benzyl)]-6-fluoro-5 ′, 5′-
Dimethyl spiro [chroman-4,2 '- (1', 3'-dioxane)] - 2
-Carboxamide (protection at the 4-position) 2 (R) -N-[(S) -α-methyl (benzyl)]-6-fluoro-4-oxochroman-2-carboxamide 2.00 g (6.39 mmol), 2,2-
Dimethyl-1,3-propanediol 3.32 g (31.9 mmol) and
p-Toluenesulfonic acid monohydrate 240 mg (0.64 mmol)
Was dissolved in 40 ml of toluene, and the mixture was refluxed for 3 hours while azeotropically removing water produced by the reaction. Pyridine in the reaction solution
After adding 1.0 ml and cooling to room temperature, washing with water, drying over anhydrous sodium sulfate, distilling off toluene under reduced pressure, and adding diethyl ether-hexane to the resulting oil to crystallize it to give colorless prism crystals. 2.22 g of compound
(Yield 87.4%) was obtained. Melting point: 149-151 ° C. MS spectrum (EI / DI) m / z: 399 (M ⁺ ), 165 (base peak). ¹ H-NMR spectrum (CDCl ₃ ) δppm: 0.79, 1.35 (3H x 2, sx 2, -CH ₃ x 2), 1.58 (3H, d, J = 6.8Hz, -CH ₃ ), 1.94 (1H, dd, J = 11.7Hz, 14.2Hz, C ₃ -H), 3.28 (1H, dd , J = 2.4Hz, 11.7Hz, C ₃ -H), 3.43, 3.47 (1H x 2, dd x 2, J = 2.9Hz, 11.7Hz, C _{2 '
-H, C 4 '-H),} 3.76, 3.90 (1H x 2, dx 2, J = 11.7Hz, C 2' -H, C 4 '-
H), 4.67 (1H, dd, J = 2.4Hz, 11.7Hz, C ₂ -H), 5.18 (1H, quintet, J = 6.8Hz, N-CH (Me) -Ph), 6.85-7.00 (3H, m, C ₇ -H, C ₈ -H, -CONH-), 7.23-7.45 (6H, m, C ₅ -H, -C ₆ H ₅ ).

[0021]

The compound of interest of the method of the present invention is (S) -4-
Oxochroman-2-carboxylic acid is extremely important as an intermediate for the synthesis of therapeutic drugs for diabetic complications, which are intractable diseases, but its optical isomer, the (R) form, has little significance in obtaining it. According to the conventional method (Japanese Patent Laid-Open No. 63-250373), the desired (S) -form is the (S) -form after activating the racemic 4-oxochroman-2-carboxylic acid.
It was reacted with (-)-1-methylbenzylamine to induce a diastereomeric mixture of (2R, 4S)-and (2S, 4S) -2- derivatives of 4-oxochroman, and (2S, 4S ) -Derivative was obtained and was prepared by acid hydrolysis. In this case, the (2R, 4S) -amide derivative after fractionation by recrystallisation of the (2S, 4S) -amide derivative is of lesser importance and therefore (2R, 4S) -amide derivative in the above diastereomeric mixture.
Depending on the amount ratio of the (4S) -amide derivative, the above synthesis method was not necessarily advantageous (in the above diastereomer mixture, if the component ratio was 1: 1, it was 50%.
Will cause a loss). On the other hand, the method of the present invention starts from a (2R, 4S) -amide derivative, which is considered to be unnecessary in the above-mentioned conventional method, and protects the keto group at the 4-position thereof, followed by epimerization (2R, Diastereomeric mixture of (4S) -form and (2S, 4S) -form (component ratio 1: 1) was obtained, and the desired (2S, 4S) -form was obtained by fractional recrystallization. Deprotection and hydrolysis are carried out by treatment to obtain the desired (S)
It can be made into 4-oxochroman-2-carboxylic acid.
Note that deprotection and hydrolysis can be performed simultaneously by using a mixed solution of acetic acid and hydrochloric acid, and no special reagent or device is required for deprotection. Therefore, since the raw material cost and the reagent cost are relatively low and the yield is good, the present invention has a desired (S) -4-oxochroman-
The present invention provides an industrially suitable method for producing a 2-carboxylic acid derivative.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masato Fukushima, 35, Higashi Sotobori-cho, Higashi-ku, Nagoya-shi, Sanwa Chemical Research Institute (72) Inventor, Kiichi Sawai, 35 Higashi-Tobori-cho, Higashi-ku, Nagoya-shi Sanwa Kagaku Co., Ltd. In the laboratory

Claims (1)

[Claims] 1. A compound represented by the general formula (II): (In the formula, X represents hydrogen, halogen or an alkyl group, and R represents
₁ represents a phenyl group, a substituted phenyl group or a naphthyl group, R ₂ represents an alkyl group or a phenyl group, provided that R 2
₁ and R ₂ do not mean the same group at the same time), and the keto group at the 4-position of the optically active compound is protected to give a compound of the general formula (III) (Wherein X, R ₁ and R ₂ have the meanings given above, A is meant oxygen or sulfur, B is _{-CH 2 CH 2 -, - CH} 2 CH 2 CH 2 - or -
CH ₂ C (CH ₃ ) ₂ CH _2- ), and by converting the 2-position of this compound to epi in the presence of a base to give an optically active compound of formula (III). General formula (IV): (Wherein X, A, B, R ₁ and R ₂ have the above-mentioned meanings) to give a diastereomer mixture with an optically active compound, and then by fractional recrystallization an optically active compound of the formula (IV) Was isolated, deprotected and hydrolyzed under acidic conditions to give a compound of general formula (I) (S) -4-oxochroman-2, which is an optically active compound represented by the formula (wherein X has the above-mentioned meaning).
-Method for producing carboxylic acid derivative.