JPH0623153B2 - Process for producing indane derivative and its synthetic intermediate - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for producing an indane derivative useful as a thromboxane A ₂ antagonist and a synthetic intermediate thereof.

(Prior Art) 4-{[2- (benzenesulfonylamino) indane-
5-yl] acetylamino} -n-propionic acid or butyric acid and their benzene ring-substituted compounds or salts thereof are
Thromboxane A ₂ (ThromboxanA _2, hereinafter referred to as TxA ₂₎ is a useful pharmaceutical compound as an antagonist, preparation of the compounds have been variously patent application (EP 03
17321 and Japanese Patent Application No. 63-323884).

The above-mentioned application method describes a method using a thioacetic acid derivative or an oxalic acid derivative as a method for introducing a side chain into the 5-position of the 2-aminoindane skeleton. However, as an industrial production method, the use of a thioacetic acid derivative accompanied by generation of odor must be avoided as much as possible, and as a carbonyl group reduction method using an oxalic acid derivative, catalytic reduction or zinc-acetic acid Although a method by combination is described, it takes a long time to complete the reaction, or some side reactions are involved, and therefore, further improvement of the reduction method has been desired.

(Problems to be Solved by the Invention) The present invention provides a novel production method having improved operability, yield and purity as compared with the above method.

(Means for Solving the Problems) According to the present invention, the general formula (However, R ¹ represents a substituted or unsubstituted phenyl group, a naphthyl group or a sulfur-containing heterocyclic group, and R ² represents a carboxy lower alkyl group or a lower alkoxycarbonyl lower alkyl group.) , (1) General formula (Wherein R ³ represents a protecting group for an amino group) and a 4-oxaloamino acid compound represented by the general formula HOOCCONH-R ² (III) (where the symbols have the same meanings as described above). Alternatively, the compound of general formula (However, the symbols have the same meanings as described above.), And (2) this carbonyl compound (IV) or a salt thereof is reduced to give a general formula (However, the symbols have the same meanings as described above), and (3) the hydroxymethylene compound (V) or a salt thereof and the general formula R ⁴ COOH (VI) (provided that R ⁴ Represents an alkyl group, a phenyl group or a substituted phenyl group.) And a carboxylic acid compound represented by (However, symbols have the same meanings as above.), And then (4) the alkanoyloxymethylene compound (VII) or a salt thereof is reduced to give the general formula (Where the symbols have the same meanings as described above), and (5) after removing the amino-protecting group (R ³ ) from the methylene compound (VIII) or a salt thereof, a compound of the general formula R ¹ SO ₃ H (IX) (where the symbols have the same meanings as described above) and the condensation reaction with a sulfonic acid compound or a reactive derivative thereof, and when R ² is a lower alkoxycarbonyl lower alkyl group, If desired, it can be produced by hydrolysis.

As the amino-protecting group R ³ , a conventional protecting group such as a formyl group, a benzyloxycarbonyl group and a trifluoroacetyl group can be used. Further, preferred examples of the lower alkyl group and the lower alkoxy group for R ² include:
Examples thereof include an alkyl group and an alkoxy group having 1 to 4 carbon atoms, and an ethyl group or a propyl group is particularly preferable as the lower alkyl group. The alkyl group of R ⁴ is not particularly limited in the number of carbon atoms, but when converting the hydroxymethylene compound (V) to the alkanoyloxymethylene compound (VII), an alkyl group having less steric hindrance is preferable. , Ethyl group, propyl group, decyl group, isopropyl group and the like. In addition, R ¹ and R ⁴
As the substituted phenyl group, a chlorophenyl group, a promophenyl group, a methylphenyl group and the like can be preferably used.

The condensation reaction of compound (II) with 4-oxaloamino acid compound (III) or its reactive derivative can be carried out in a suitable solvent in the presence of a Lewis acid catalyst. Examples of the reactive derivative of the compound (III) include corresponding acid halide compounds. Further, 1,2-dichloroethane, methylene chloride and nitrobenzene can be preferably used as the solvent, and aluminum chloride can be preferably used as the Lewis acid catalyst. This reaction is preferably carried out under cooling to room temperature.

The reduction reaction of the carbonyl compound (IV) or a salt thereof can be carried out in the presence of an alkali metal borohydride in a suitable solvent, or by catalytic reduction in the presence of a catalyst. In the former case, it is preferable to use sodium borohydride, potassium borohydride, lithium borohydride or the like as the alkali metal borohydride, and carry out under cooling to room temperature. On the other hand, in the latter case, as a catalyst, for example, Raney nickel, platinum oxide, or 10%
It is preferable to carry out the reaction at room temperature to under heating in a hydrogen atmosphere using a palladium-based catalyst such as palladium-carbon. In any reduction reaction, a lower alkanol, a glycol, a cellosolve, tetrahydrofuran, water or a mixture thereof can be preferably used as a solvent.

The condensation reaction of the hydroxymethylene compound (V) or its salt with the carboxylic acid compound (VI) or its reactive derivative can be carried out in a suitable solvent in the presence of a condensing agent. The reactive derivative of the compound (VI) may be a conventional reactive derivative such as a corresponding acid anhydride or acid halide compound. Further, tetrahydrofuran, chloroform and methylene chloride are used as a solvent, and tri-lower alkylamine, pyridine and 4- are used as a condensing agent.
Dimethylaminopyridine, alkali metal carbonate, N, N '
-Dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole and the like can be preferably used. This reaction is preferably carried out at room temperature to under heating.

The reduction reaction of the alkanoyloxymethylene compound (VII) or a salt thereof can be carried out in the presence of ammonium formate and a catalyst in a suitable solvent. A lower alkanol can be suitably used as the solvent, and a catalyst similar to the above catalytic reduction can be suitably used as the catalyst. This reaction is preferably carried out under a nitrogen stream at room temperature to under heating.

Removal of the amino-protecting group (R ³ ) from the methylene compound (VIII) or a salt thereof includes, for example, hydrolysis, solvolysis,
It can be carried out by a conventional method such as acid treatment or reduction.

The subsequent condensation reaction with the sulfonic acid compound (IX) or its reactive derivative can be carried out in the presence or absence of a condensing agent. Preferable examples of the reactive derivative of the compound (IX) include a conventional reactive derivative such as a corresponding sulfonyl halide compound. As the condensing agent, for example, alkali metal carbonate, alkali metal hydrogen carbonate,
Any conventional one such as tri-lower alkylamine and pyridine can be used. This reaction is preferably carried out in a suitable solvent (eg, water, ethyl acetate) under cooling to heating.

When R ² is a lower alkoxycarbonyl lower alkyl group, hydrolysis can be carried out by, for example, treating with a base or an acid. As the base, for example, an alkali metal hydroxide can be appropriately used, and as the acid, for example, a mineral acid can be appropriately used. This hydrolysis reaction is preferably carried out in a suitable solvent (eg water, lower alkanol) under cooling to heating.

As the salts of the compounds (IV), (V), (VII) and (VIII) in the above reaction, for example, alkali metal salts, alkaline earth metal salts and the like can be used.

Further, the object compound (I) of the present invention includes both two kinds of optical isomers based on an asymmetric carbon atom present at the 2-position of the indane skeleton and a mixture thereof, but all the above reactions involve racemization. Since the reaction proceeds without any reaction, the target compound (I) can be obtained as an optically active substance by using an optically active starting compound.

(Example) Example 1 (1) 3.4 g of sodium borohydride was suspended in 340 ml of ethanol, and 4-[(2-formylaminoindan-5-
Il) oxalylamino] -n-butyric acid methyl ester 80
Gradually add g. Stir for 2 hours at 15-20 ° C. After the reaction is completed, ethanol is distilled off. The residue was dissolved in chloroform, washed and dried, then the solvent was distilled off and 80 g of 4- [2- (2-formylaminoindan-5-yl) -2-hydroxyacetylamino] -n-butyric acid methyl ester was obtained as a viscous oil. Get as a thing.

(2) 80 g of this product is dissolved in 540 ml of tetrahydrofuran, and 34.9 g of triethylamine and 29.4 g of acetic anhydride are added. Then 0.2 g of 4-dimethylaminopyridine is added. 25-30
After stirring at ℃ for 1 hour, 40 ml of methanol is added to decompose excess acetic anhydride. After the solvent was distilled off, the residue was dissolved in chloroform, washed and dried, and then the solvent was distilled off to give 4- [2-acetoxy-2- (2-formylaminoindan-5-yl) acetylamino] -n-butyric acid. 90 g of the methyl ester are obtained as viscous oil.

(3) Dissolve 90 g of this product in 600 ml of methanol, and in a nitrogen stream 10
% 9.6 g of palladium-carbon is added. Next, 60.8 g of ammonium formate is added, and the mixture is stirred at 20 ° C. for 15 hours. After the reaction
The solvent is distilled off. The residue is dissolved in chloroform, washed and dried, and then the solvent is distilled off. The residue is recrystallized from a mixed solution of ethyl acetate-isopropyl ether to obtain 5-9.8 g of 4-[(2-formylaminoindan-5-yl) acetylamino] -n-butyric acid methyl ester.

m. p. 89-93 ° C (4) 56.1 g of this product is dissolved in 1000 ml of methanol, 5% hydrogen chloride-methanol solution is added, and the mixture is stirred at room temperature for 3 days. After the reaction, the solvent was distilled off, the residue was crystallized with an ether-isopropyl alcohol mixed solution, and recrystallized from a methanol-ether mixed solution to give 4-[(2-aminoindan-
5-yl) acetylamino] -n-butyric acid methyl ester hydrochloride (49.5 g) is obtained as colorless needle crystals.

m. p. 200 to 201 ° C. (5) A mixture of 42.5 g of this product, 27.6 g of 4-chlorophenylsulfonyl chloride, 54.4 g of potassium carbonate, 1000 ml of ethyl acetate and 1000 ml of water is stirred at room temperature for 15 minutes. After the reaction, the organic layer was separated, washed and dried, the solvent was distilled off, and recrystallized from a mixed solution of ethyl acetate-n-hexane to give 4-{[2-
57.1 g of [(4-chlorophenyl) sulfonylamino] indan-5-yl] acetylamino} -n-butyric acid methyl ester are obtained.

m. p. 128-129 [deg.] C. (6) To 500 ml of a solution of 50.2 g of this product under stirring at room temperature is added 270 ml of 1N sodium hydroxide aqueous solution, and then the mixture is stirred at the same temperature for 2 hours. After the reaction, under cooling and stirring, 6N
-Adjust the pH to 4 with 44 ml of hydrochloric acid and remove the methanol by distillation to give 10
% Hydrochloric acid to adjust the pH to 1, and extract with a mixed solution of ethyl acetate-tetrahydrofuran. After drying, the solvent was distilled off, the residue was dissolved in 220 ml of tetrahydrofuran, and 600 ml of isopropyl ether was added for crystallization to give 4-{[2-[(4-chlorophenyl) sulfonylamino] indan-5-yl] acetylamino}-. 46.2 g of n-butyric acid are obtained. yield:
95% mp 123.5-125.5 ° C Sodium salt mp 196.1 ° C (decomposition) Example 2 (1) The corresponding starting material compound was treated in the same manner as in Example 1- (2) to give 4-
[2- (2-Formylaminoindan-5-yl) -2- (2-methylpropionyloxy) acetylamino] -n-butyric acid methyl ester is obtained.

(2) This product was treated in the same manner as in Example 1- (3) to give 4-[(2-formylaminoindan-5-yl) acetylamino] -n-.
Butyric acid methyl ester is obtained.

(3) This product was treated in the same manner as in Example 1- (4) to (6), and 4-
{[2-[(4-chlorophenyl) sulfonylamino]]
Indan-5-yl] acetylamino} -n-butyric acid is obtained.

[Preparation of raw material compound] (1) To 124.1 g of 2-aminoindane, 500 ml of ethyl formate was added, and the mixture was refluxed for 23 hours. Excessive formic acid ethyl ester was distilled off, heated and dissolved in ethyl acetate, treated with carbon powder, the solvent was distilled off, and crystallized with n-hexane to obtain 2
-144 g of formylaminoindan are obtained.

mp 74.5-76 ° C. (2) 4- (oxaloamino) -n-butyric acid methyl ester 0.3hydrate 11.67 g was suspended in 100 ml of methylene chloride, and with stirring under ice cooling, 15.23 g of oxalyl chloride in methylene chloride. A 50 ml solution is added dropwise, one drop of dimethylformamide is added, and the mixture is stirred at room temperature for 2.5 hours. After the reaction, the solvent is distilled off to obtain 4- (chlorooxalylamino) -n-butyric acid methyl ester.

50 ml of 1,2-dichloroethane solution of this product is powdered aluminum chloride 32.0 g of 1,2-dichloroethane 50 ml.
The suspension is added dropwise over 10 minutes with cooling and stirring. Then 2
A solution of 6.45 g of formylaminoindan in 50 ml of 1,2-dichloroethane was added dropwise at 5 ° C. or lower over 15 minutes, and the mixture was stirred at room temperature for 2 hours. Ice water and ethyl acetate are added under ice cooling, and ethyl acetate is extracted, washed and dried. After filtration, the solvent was distilled off, the residue was dissolved in ethyl acetate, treated with carbon powder, the solvent was distilled off, and recrystallized from an ethyl acetate-isopropyl ether mixed solution to give 4-[(2-formylaminoindan-5-yl). ) Oxalylamino] -n-butyric acid methyl ester 11.77 g is obtained as colorless prism crystals.

mp 100 to 102 ° C. (Effect of the invention) According to the method of the present invention, when the alkanoyloxymethylene compound (VII) is used as an intermediate, the carbonyl group of the oxalic acid derivative introduced at the 5-position of the 2-aminoindane skeleton is It can be reduced and converted to a methylene group in a short time without involving side reactions. Therefore, according to the present invention, the target compound (I) can be obtained in high yield and high purity without using a sulfur compound, and the operability can be remarkably improved by an industrially advantageous production method. is there.

Claims (4)

[Claims] 1. A general formula (Wherein R ² represents a carboxy lower alkyl group or a lower alkoxycarbonyl lower alkyl group, R ³ represents a protecting group for an amino group, R ⁴ represents an alkyl group, a phenyl group or a substituted phenyl group). Or a general formula characterized by reducing its salt (However, the symbols have the same meanings as described above.) A method for producing a methylene compound or a salt thereof. (2) (1) General formula (However, R ² represents a carboxy lower alkyl group or a lower alkoxycarbonyl lower alkyl group, and R ³ represents a protective group for an amino group.) Or a salt thereof is reduced to give a compound of the general formula (Where the symbols have the same meanings as described above), and (2) the hydroxymethylene compound or salt thereof and the general formula R ⁴ COOH (wherein R ⁴ is an alkyl group or a phenyl group). Or a substituted phenyl group), and a carboxylic acid compound represented by (Where the symbols have the same meanings as described above), and (3) the general formula characterized by reducing the alkanoyloxymethylene compound or a salt thereof. (However, the symbols have the same meanings as described above.) A method for producing a methylene compound or a salt thereof. 3. General formula (Wherein R ² represents a carboxy lower alkyl group or a lower alkoxycarbonyl lower alkyl group, R ³ represents a protecting group for an amino group, R ⁴ represents an alkyl group, a phenyl group or a substituted phenyl group). Alternatively, after reducing the salt thereof, the protecting group (R ³ ) for the amino group is removed, and further the general formula R ¹ SO ₃ H (wherein R ¹ is a substituted or unsubstituted phenyl group, naphthyl group or sulfur-containing heterocyclic group) is used. When the R ² is a lower alkoxycarbonyl lower alkyl group, it is optionally hydrolyzed and, if necessary, the product is General formula characterized by being salt (However, the symbols have the same meanings as described above.) A method for producing an indane derivative or a salt thereof represented by the above. 4. A general formula (Wherein R ² represents a carboxy lower alkyl group or a lower alkoxycarbonyl lower alkyl group, R ³ represents a protecting group for an amino group, R ⁴ represents an alkyl group, a phenyl group or a substituted phenyl group). Or its salt.