JPH0940621A - Optically active indanylmethylamine derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new derivative by using mandelic acid as a reagent for optical resolution, useful as an intermediate for producing a medicine, having high safety and high purity in high yield, efficiently and industrially usefully. SOLUTION: This compound of formula I (R is a lower alkyl) e.g. (+)-[2-[(4- chlorphenyl)sulfonylaminomethyl]-indan-5-yl]sodium salt.1/4 hydrate, etc.} is obtained by reacting a racemic modification of an indanylmethylamine derivative of formula II with optically active mandelic acid [e.g. S-(+)-mandelic acid, etc.] to give a pair of diastereomer salts, fractionating and crystallizing the salts and eliminating mandelic acid in the presence of a base (e.g. sodium carbonate, etc.).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to the following general formula (I) useful as an intermediate for the production of pharmaceuticals.

[0002]

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The present invention relates to a novel optically active indanylmethylamine derivative represented by the formula (wherein R represents a lower alkyl group) and a method for producing the same.

[0004]

PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION International Patent Publication WO92 / 15558 describes an indane derivative useful as a thromboxane A ₂ antagonist. The present invention provides an intermediate for producing the optically active indane derivative described in the publication and a production method thereof.

[0005]

Means for Solving the Problems The inventors of the present invention have the general formula (II)

[0006]

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In order to optically resolve the racemate of the indanylmethylamine derivative represented by the formula (wherein R has the same meaning as described above), optically active tartaric acid, dibenzoyltartaric acid, naproxen, N are used as resolving agents. -Acetyltryptophan, N-acetylglutamic acid, N-acetylvaline, N-acetylleucine, N-acetylcysteine,
Although N-protected amino acids such as N-benzoylglutamic acid were used, no sufficient effect was obtained. As a result of further studies by the present inventors, the present invention has been completed by using an optically active mandelic acid as a resolving agent for optical resolution.
That is, an optically active mandelic acid is allowed to act on an indanylmethylamine derivative to form a pair of diastereomeric salts, these diastereomeric salts are separated, and the mandelic acid is eliminated in the presence of a base to obtain an optically active compound. The inventors have found that an indanylmethylamine derivative can be efficiently produced, and completed the present invention.

That is, the present invention relates to an optically active indanylmethylamine derivative represented by the general formula (I). Also,
In the present invention, a racemate of an indanylmethylamine derivative represented by the general formula (II) is reacted with an optically active mandelic acid to form a pair of diastereomeric salts, and the salt is fractionally crystallized and then in the presence of a base. The present invention relates to a method for producing an optically active indanylmethylamine derivative represented by the general formula (I), which comprises removing mandelic acid.

In the present invention, the "lower alkyl group" means an alkyl group having 1 to 4 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-
Butyl group, isobutyl group, sec-butyl group, tert
-Butyl group.

The racemate (II) of the indanylmethylamine derivative used as a raw material in the present invention can be produced, for example, by the following method.

[0011]

[Chemical 6]

(In the formula, R has the same meaning as described above.) That is, 2-indanyl acetic acid (III) was converted to α-halo-α-methylthioacetic acid alkyl ester according to the method described in International Publication WO92 / 15558. Condensation (Friedel-Crafts reaction), followed by reduction with zinc in acetic acid to give compound (IV), which was added to a trialkylamine such as triethylamine with diphenylphosphoryl azide and benzyl alcohol according to a known method. The compound (II) can be produced by performing the Curtius rearrangement reaction and further deprotecting the N-substituent by catalytic reduction.

Compound (II) can also be produced by the following method.

[0014]

[Chemical 7]

(In the formula, R has the same meaning as described above.) That is, 2-indanylmethylamine (V) obtained from 2-indanylacetic acid by a known method, for example, Curtius rearrangement of acyl azide, is converted into methyl formate, N-formylated with a formate such as ethyl formate to give a compound (V
I). Then, in the presence of a Lewis acid such as aluminum chloride, titanium tetrachloride or tin tetrachloride, (VI) and α-halo-
The α-methylthioacetic acid alkyl ester is condensed (Friedel-Crafts reaction), and subsequently reduced with zinc in acetic acid to produce a compound (VII). The compound (II) can be converted to the compound (II) by treating with an acid such as dilute hydrochloric acid or dilute sulfuric acid to eliminate the N-formyl group.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION In one embodiment of the optical resolution of the present invention, compound (II) is dissolved in a solvent which does not influence the reaction, such as water, an alcohol solvent, an ether solvent, etc. Add mandelic acid and heat to dissolve and react. When the reaction mixture is then cooled, one of the diastereomeric salts preferentially crystallizes out. After separating the crystallized product, an alkali such as potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate is added, and an ether solvent such as ethyl acetate, ether or tetrahydrofuran, a halogen solvent such as methylene chloride or chloroform, etc. By adding the organic solvent of
The optically active indanylmethylamine derivative produced at the same time as the preferentially crystallized salt is decomposed can be extracted into the organic layer. Decomposition and extraction can also be performed separately. One of the optically active indanylmethylamine derivatives (I) is obtained by drying this extract and distilling off the solvent according to a conventional method. The liquid remaining after the separation of the crystallized substance contains a large amount of the other diastereomeric salt formed, so alkali such as potassium hydroxide or sodium hydroxide is added to this liquid to decompose the diastereomeric salt. After that, by extracting with an organic solvent and distilling off the solvent, a residue containing a large amount of an optically active substance having an optical activity opposite to that of the optically active substance obtained from the precipitate is obtained. The other optically active indanylmethylamine derivative (I) can be obtained by reacting this residue with mandelic acid having an optical activity opposite to that of the above residue in the same manner as in the above-mentioned method.

The thus obtained optically active indanylmethylamine derivative (I) is condensed with a sulfonating agent such as a halogenated benzene sulfonic acid derivative by a conventional method, and if necessary, further hydrolyzed with an ester group. Thromboxane A described in International Patent Publication WO92 / 15558 by decomposing and converting to carboxylic acid
₂ It can be led to an optically active indane derivative having an antagonistic action.

[0018]

The present invention will be described in more detail with reference to the following examples, which should not be construed as limiting the invention.

Example 1 (+)-[2-[(4-chlorophenyl) sulfonylaminomethyl] indan-5-yl] acetic acid sodium salt
Production of 1/4 hydrate

Step 1 Preparation of (+)-(2-aminomethylindan-5-yl) acetic acid ethyl ester

(±)-(2-aminomethylindan-5
-Yl) Acetic acid ethyl ester hydrochloride (50 g) was dissolved in 300 ml of water, and 190 ml of 1N aqueous sodium hydroxide solution was added. This was extracted with 250 ml of ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
To the residue 500 ml of water and (S)-(+)-mandelic acid 2
8 g was added and dissolved by heating. The reaction solution was allowed to cool and the precipitated crystals were collected by filtration, then recrystallized from water to give the title compound (S)-(+).
12 g of mandelate salt are obtained. Yield 17%. Melting point: 145 to 146 ° C. [α] D = + 38 ° (c = 0.5, MeOH)

50 ml of water and 100 mg of potassium carbonate were added to 280 mg of the salt of the title compound and extracted with 25 ml of chloroform.
The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (160 mg) as a colorless oil. 94% yield. The enantiomeric excess is H
It was calculated by PLC. [Α] D = + 6 ° (c = 0.8, CH ₂ Cl ₂ ) enantiomeric excess: 99.5% ee ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t), 1.25 (2H, brs), 2.
47〜2.69 (3H, m), 2.78 (2H, d), 3.03 (1H, dd), 3.07 (1H, dd),
3.56 (2H, s), 4.14 (2H, q), 7.04 (1H, d), 7.12 (1H, s), 7.14 (1
H, d)

Step 2 Preparation of (+)-[2-[(4-chlorophenyl) sulfonylaminomethyl] indan-5-yl] acetic acid ethyl ester.

6.8 g of potassium carbonate was dissolved in 50 ml of water, and (S)-(+) of ethyl ester of (+)-(2-aminomethylindan-5-yl) acetic acid obtained in step 1 was obtained.
-9.5 g of mandelate salt was dissolved in this aqueous solution and further ethyl acetate was added. While stirring this solution vigorously, 5.2 g of parachlorobenzenesulfonyl chloride was added and the mixture was stirred at room temperature for 1 hour.
Stir for hours. After the reaction, the organic layer was separated, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in that order, dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (chloroform).
After being purified by the above method, it was recrystallized from a mixed solution of hexane and ethyl acetate to obtain 9.1 g of the title compound. 90% yield. Melting point: 92.5 ° C. MS (m / z): 407 (M ⁺ ) [α] D = + 14.8 ° (c = 0.5, MeOH) Enantiomeric excess: 99.5% ee

Step 3 (+)-[2-[(4-chlorophenyl) sulfonylaminomethyl] indan-5-yl] acetic acid sodium salt
Production of 1/4 hydrate

(+)-[2-[(4-
Chlorophenyl) sulfonylaminomethyl] indan-
9.0 g of 5-yl] acetic acid ethyl ester was suspended in 50 ml of a 1N sodium hydroxide aqueous solution and stirred at 60 ° C. for 1 hour. 50 ml of 1N hydrochloric acid was added to the reaction solution and allowed to cool. The precipitated crystals were collected by filtration and recrystallized from 50% ethanol to obtain (+)-
8.1 g of [2-[(4-chlorophenyl) sulfonylaminomethyl] indan-5-yl] acetic acid was obtained. Yield 9
6%. Melting point: 166.5 to 167.5 ° C MS (m / z): 379 (M ⁺ ) [α] D = + 12.9 ° (c = 0.5, MeOH)

8.0 g of the obtained (+)-[2-[(4-chlorophenyl) sulfonylaminomethyl] indan-5-yl] acetic acid was dissolved in 144 ml of ethanol, and 1.77 g of anhydrous sodium carbonate was added and heated. Dissolved. The solution was allowed to cool, and the obtained precipitated crystals were collected by filtration to give the title compound (7.0 g). Yield 83%. Melting point: 264 to 266 ° C. [α] D = + 12.9 ° (c = 2.6, MeOH) Enantiomeric excess: 99.5% ee

Example 2 (-)-[2-[(4-chlorophenyl) sulfonylaminomethyl] indan-5-yl] acetic acid sodium salt
Production of 1/4 hydrate

Step 1 Preparation of (-)-(2-aminomethylindan-5-yl) acetic acid ethyl ester

140 ml of a 1N aqueous sodium hydroxide solution was added to the filtrate obtained by filtering the precipitated crystals in the step 1 of Example 1.
It was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 350 ml of water and 20 g of (R)-(-)-mandelic acid were added to the residue and dissolved by heating. The reaction solution was allowed to cool, the precipitated crystals were collected by filtration, and then recrystallized from water to give (R)-(-)-mandelate salt of the title compound (10 g).
I got Yield 14%. Melting point: 145 to 146 ° C. [α] D = −35 ° (c = 0.5, MeOH)

According to the same manner as in Step 1 of Example 1, 172 mg of the title compound was obtained as a colorless oil from the obtained salt of the title compound. 95% yield. [Α] D = −7 ° (c = 0.8, CH ₂ Cl ₂ ) enantiomeric excess: 99.5% ee

Step 2 Preparation of (-)-[2-[(4-chlorophenyl) sulfonylaminomethyl] indan-5-yl] acetic acid ethyl ester.

8.0 g of potassium carbonate was dissolved in 55 ml of water, and (R)-(-) of ethyl ester of (-)-(2-aminomethylindan-5-yl) acetic acid obtained in step 1 was obtained.
11 g of mandelate salt was dissolved in this aqueous solution and further ethyl acetate was added. While vigorously stirring this solution, 6.6 g of parachlorobenzenesulfonyl chloride was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the organic layer was separated, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in that order, dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform) and then recrystallized from a mixed solution of hexane and ethyl acetate to obtain 10.2 g of the title compound. Yield 87%. Melting point: 93 ° C. MS (m / z): 407 (M ⁺ ) [α] D = -13.0 ° (c = 1.45, MeOH) Enantiomeric excess: 99.5% ee

Step 3 (-)-[2-[(4-chlorophenyl) sulfonylaminomethyl] indan-5-yl] acetic acid sodium salt.
Production of 1/4 hydrate

(-)-[2-[(4-
Chlorophenyl) sulfonylaminomethyl] indan-
10.0 g of 5-yl] acetic acid ethyl ester was suspended in 50 ml of a 1N sodium hydroxide aqueous solution and stirred at 60 ° C. for 1 hour. 50 ml of 1N hydrochloric acid was added to the reaction solution, the mixture was allowed to cool, and the precipitated crystals were collected by filtration and recrystallized from 50% ethanol to give (-)-
9.1 g of [2-[(4-chlorophenyl) sulfonylaminomethyl] indan-5-yl] acetic acid was obtained. Yield 9
8%. Melting point: 166.5 to 167.5 ° C MS (m / z): 379 (M ⁺ ) [α] D = -10.3 ° (c = 0.5, MeOH)

9.0 g of the obtained (-)-[2-[(4-chlorophenyl) sulfonylaminomethyl] indan-5-yl] acetic acid was dissolved in 162 ml of ethanol, and 1.99 g of anhydrous sodium carbonate was added and heated. Dissolved. The solution was allowed to cool, and the obtained precipitated crystals were collected by filtration to give the title compound (9.1 g). Yield 96%. Melting point: 264 to 266 ° C. [α] D = −12.9 ° (c = 2.5, MeOH) Enantiomeric excess: 99.5% ee

[0037]

Comparative Example Using other resolving agents according to the examples (±)
The optical resolution of-(2-aminomethylindan-5-yl) acetic acid ethyl ester hydrochloride was carried out, and [2-[(4-
Chlorophenyl) sulfonylaminomethyl] indan-
HPLC after conversion to 5-yl] acetic acid ethyl ester
Was calculated by

Comparative Example 1 (±)-(2-Aminomethylindan-5-yl) acetic acid ethyl ester hydrochloride (1 g) was dissolved in 1N aqueous sodium hydroxide solution (5.6 ml) and extracted with ethyl acetate (50 ml). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml of ethanol, and 854 mg of naproxen was added and dissolved by heating. The reaction solution was allowed to cool, the precipitated crystals were collected by filtration, and dried under reduced pressure to obtain 749 mg of naproxen salt. This salt was dissolved in 2.4 ml of 5% aqueous potassium carbonate solution, 2.4 ml of ethyl acetate and p-chlorobenzenesulfonyl chloride were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, the organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform), [2-
178 mg of [(4-chlorophenyl) sulfonylaminomethyl] indan-5-yl] acetic acid ethyl ester were obtained. Enantiomeric excess was calculated by HPLC. [Α] D = 0.0 ° (c = 0.5, MeOH) Enantiomeric excess: 0% ee

Comparative Example 2 (±)-(2-Aminomethylindan-5-yl) acetic acid ethyl ester hydrochloride (1 g) was dissolved in 1N aqueous sodium hydroxide solution (5.6 ml) and extracted with ethyl acetate (50 ml). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml of ethanol, and 701 mg of N-acetyl-L-glutamic acid was added and dissolved by heating. The reaction solution was allowed to cool and the precipitated crystals were collected by filtration and dried under reduced pressure to give 773 mg of N-acetyl-L-glutamic acid salt. This salt was dissolved in 2.6 ml of a 5% aqueous potassium carbonate solution, 2.6 ml of ethyl acetate and p-chlorobenzenesulfonyl chloride were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, the organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform) to give [2-[(4-chlorophenyl) sulfonylaminomethyl] indane-5-.
173 mg of yl] acetic acid ethyl ester was obtained. Enantiomeric excess was calculated by HPLC. [Α] D = −2.0 ° (c = 0.5, MeOH) Enantiomeric excess: 15.0% ee

According to Comparative Examples 1 and 2, optically active tartaric acid, dibenzoyltartaric acid, N-acetyltryptophan, N-acetylvaline, N-acetylleucine, N-acetylcysteine and N-benzoylglutamic acid were used as resolving agents. Optical resolution is performed using [2-[(4-chlorophenyl) sulfonylaminomethyl] indan-5-
When the enantiomeric excess is calculated by derivatizing ethyl] acetic acid ethyl ester, the enantiomeric excess is 1.5
It was ~ 8.0% ee, and sufficient results could not be obtained.

[0041]

INDUSTRIAL APPLICABILITY According to the method of the present invention, an optically active indanylmethylamine derivative can be efficiently produced with high purity and high yield, and since it is highly safe, it is an industrially useful production method. .

Claims (2)

[Claims] 1. A compound of the general formula (I) (In the formula, R represents a lower alkyl group.) An optically active indanylmethylamine derivative. 2. A compound of the general formula (II) (In the formula, R represents a lower alkyl group.) The racemate of the indanylmethylamine derivative represented by the formula (1) is reacted with an optically active mandelic acid to give a pair of diastereomeric salts. Of the general formula (I), characterized in that mandelic acid is eliminated in the presence of a base. (In the formula, R has the same meaning as described above.) A method for producing an optically active indanylmethylamine derivative.