JPH0524147B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a method for producing an indane derivative useful as a thromboxane A ₂ antagonist, and an intermediate for its synthesis. (Prior Art) It has been known that [2-(substituted or unsubstituted benzenesulfonylamino ₎ indan-5-yl]acetic acid has an antagonistic effect on thromboxane A ₂ (hereinafter referred to as TxA ₂ ). (Japanese Patent Application Laid-Open No. 63-23853). In addition, as a result of various studies, the present inventors found that a series of compounds in which a lower alkoxycarbonyl (or carboxy)-lower alkylamino group was introduced into the carboxyl group of the indane compound had better TxA ₂ antagonistic properties than the above-mentioned known compounds. We discovered that it has a certain effect and applied for a patent (patent application in 1983).
−289801). (Structure and Effects of the Invention) The present invention relates to a novel method for producing an indane derivative represented by the following general formula () or a salt thereof, which has been found to have excellent TxA ₂ antagonism and has already applied for a patent. (However, R is a phenyl group, a lower alkyl phenyl group, a lower alkoxy phenyl group, a halogenoenyl group, a trifluoromethyl phenyl group, a nitrophenyl group, a naphthyl group, or a thienyl group, and R ² is a hydrogen atom or a lower alkyl group. , ^R3 represents a lower alkoxycarbonyl-lower alkyl group or a carboxy-lower alkyl group.) According to the present invention, the target compound () has the general formula (However, R ¹ is a group represented by the formula -SO ₂ R or a hydrogen atom, Y represents a substituted or unsubstituted phenylmercaptomethylene group, lower alkylmercaptomethylene group, hydroxymethylene group, halogenomethylene group or carbonyl group, R, R ² and R ³ have the same meanings as above.) When the compound represented by or a salt thereof is reduced to convert the group Y into a methylene group, and when R ¹ is a hydrogen atom, the product is It can then be produced by a condensation reaction with a sulfonic acid compound represented by the general formula RSO ₃ H () (wherein the symbols have the same meanings as above) or a reactive derivative thereof. Furthermore, in the target compound (), R ³ is a carboxy lower alkyl group, the target compound () obtained in the ^above reaction is further hydrated. It can also be manufactured by disassembling it. In the above reaction, the raw material compound () is:
Group Y is a lower alkyl group such as phenylmercaptomethylene group, p-tolylmercaptomethylene group, p-chlorophenylmercaptomethylene group, phenylmercaptomethylene group which may be substituted with a halogen atom, methylmercaptomethylene group, ethylmercapto Compounds which are lower alkylmercaptomethylene groups such as methylene group, propylmercaptomethylene group, halogenomethylene group such as hydroxymethylene group, chloromethylene group, and carbonyl group can be suitably used, and the reaction of the sulfonic acid compound () As the derivative, a conventional derivative such as a sulfonyl halide compound can be used as appropriate. The reduction reaction of the starting compound () or its salt can be carried out as appropriate depending on the type of group Y. For example, when the group Y is a carbonyl group, the reduction reaction can be carried out by catalytic reduction in the presence of a catalyst. As the catalyst, it is preferable to use, for example, a Raney nickel, Raney cobalt or palladium catalyst, and a combination with oxalic acid is more preferable. This reaction proceeds suitably in a solvent such as a lower alkanol or hydrous tetrahydrofuran at room temperature to heating. On the other hand, when the group Y is a substituted or unsubstituted phenylmercaptomethylene group, lower alkylmercaptomethylene group, hydroxymethylene group, or halogenomethylene group, the reduction reaction can be carried out by catalytic reduction or, for example, in the presence of heavy metals, acid It can also be processed and implemented. In the former case, the catalytic reduction can be suitably carried out under the same conditions as above, while in the latter case it is preferable to use, for example, zinc, iron, etc. as the heavy metal and an organic acid such as acetic acid or propionic acid as the acid. . This reaction is preferably carried out under cooling to heating, particularly under heating. In any case where the group Y is used, as the salt of the starting compound (), a mineral acid such as a hydrochloride or the like can be appropriately used in the above reaction. The condensation reaction between the above reaction product and the sulfonic acid compound () or its reactive derivative can be carried out in the presence or absence of a deoxidizing agent. As the deoxidizer, any commonly used deoxidizing agent can be used, such as alkali metal carbonate, alkali metal hydrogen carbonate, trialkylamine, pyridine, and the like. This reaction is preferably carried out in a suitable solvent (eg, water, ethyl acetate) under cooling to heating. Moreover, in the target compound () obtained in this way,
The hydrolysis reaction of a compound in which R ³ is a lower alkoxycarbonyl-lower alkyl group is carried out according to a conventional method.
For example, it can be carried out by treatment with an alkaline reagent or an acid. For example, an alkali metal hydroxide can be used as the alkaline reagent, and a mineral acid can be used as the acid. This hydrolysis reaction is preferably carried out in a suitable solvent (eg water, lower alkanol) under cooling to heating. Note that the target compound () of the present invention includes both optical isomers and mixtures thereof based on the asymmetric carbon atom present at the 2-position of the indane skeleton, but all of the above reactions do not involve racemization. Therefore, if an optically active raw material compound is used, the target compound () can also be obtained as an optically active form. Further, according to the present invention, in the general formula (), R is a phenyl group which may be substituted with, for example, a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group or a nitro group,
Any object that is a naphthyl group or a loaded heterocyclic group such as a thienyl group can be prepared. As mentioned above, the object compound of the present invention () or a salt thereof has excellent TxA ₂ antagonistic activity,
Useful as a platelet aggregation inhibitor, for example, for the treatment, mitigation, and prevention of various thromboses and embolisms such as cerebral thrombosis, coronary thrombosis, pulmonary thrombosis, pulmonary embolism, peripheral vascular embolism, and thrombovasculitis. It can be used for. In addition, the target compound () or a salt thereof can also be used for the treatment, alleviation, and prevention of myocardial ischemia, unstable angina, coronary artery spasm, cerebral vasospasm after subarachnoid hemorrhage, cerebral hemorrhage, asthma, and the like. Furthermore, while some conventionally known TxA ₂ antagonists exhibit excellent TxA ₂ antagonistic effects, they also exhibit transient TxA ₂ -like effects, such as platelet aggregation-inducing effects, bronchoconstrictive effects, vasoconstrictive effects, etc. Although some compounds are accompanied by side effects, the target compound (2) of the present invention has the excellent feature of not exhibiting any such TxA _2- like effect either when administered orally or parenterally. Note that the raw material compound () of the present invention is a new compound, and can be produced, for example, as follows. That is, (1)−(i) general formula (However, R ¹¹ represents a group represented by the formula -SO ₂ R or a protecting group for an amino group, and R has the same meaning as above.) Compounds represented by the general formula (However, Y ¹ is a substituted or unsubstituted phenylmercaptomethylene group, a lower alkylmercaptomethylene group, or a carbonyl group, X represents a halogen atom, and R ² and R ³ have the same meanings as above.) (1)-(ii) Compound () and the general formula X-Y ¹ - The general formula obtained by condensation reaction with a compound represented by COOH () (However, the symbol has the same meaning as above) or its reactive derivative (However, the symbols have the same meanings as above.) Compounds represented by or their reactive derivatives and the general formula (However, the symbols have the same meanings as above.) After carrying out a condensation reaction with the amine compound shown by following the conventional method of peptide condensation, (2) If desired, a protective group for the amino group (R ⁽¹¹ ), (3) If Y ¹ is a carbonyl group, it is optionally reduced under mild conditions (e.g., alkali metal borohydride) to convert it into a hydroxymethylene group, and (4) as desired. It can be produced by treating a compound () in which Y ¹ is a hydroxymethylene group with thionyl halide. Example 1 (1) Methyl 4-[(2-aminoindan-5-yl)oxallylamino]-n-butyrate hydrochloride 4.09 g
Add 60 ml of ethyl acetate and 4.98 g of potassium carbonate, add 40 ml of water while stirring under ice cooling, and add dropwise a solution of 2.48 g of 4-chlorophenylsulfonyl chloride in 40 ml of ethyl acetate, and stir at room temperature for 2 hours. After the reaction, the ethyl acetate layer was separated, washed, dried, and filtered, then the solvent was distilled off, and the residue was separated and purified using silica gel column chromatography (solvent: chloroform) to give 4-{[2-[4 -Chlorophyl)sulfonylamino]indan-5-yl]oxalylamino}-methyl n-butyrate 5.67
g is obtained as a pale yellow viscous oil. Yield: 100% MS (m/e): 479 (M ⁺ +H) IRν ^neat _nax (cm ^-1 ): 3280, 1730, 1660 (2) Hydrogenate a solution of 0.60 g of this product in 10 ml of methanol under ice cooling. Add 25 mg of sodium boron and stir for 20 minutes. The solvent was distilled off, water and ethyl acetate were added, and the organic layer was dispersed, washed and dried, and the solvent was distilled off to give 4-{2-[2-[(4-chlorophenyl)sulfonylamino]indan-5- il]-2-
hydroxyacetylamino}-n-methyl acetate
0.58 g is obtained as a colorless oil. Yield: 97% MS (m/e): 481 (M ⁺ +H) IRν ^liquid _nax (cm ^-1 ): 3380, 3275, 1735, 1650 (3) Add 0.32 thionyl chloride to a 10 ml solution of 0.63 g of this product in methylene chloride. ml and stirred at room temperature for 1 hour. The solvent was distilled off, the residue was dissolved in 10 ml of acetic acid, 300 mg of zinc powder was added, and the mixture was stirred at 70°C for 1 hour. After cooling to room temperature and filtering, the solvent was distilled off, ethyl acetate and water were added, and the organic layer was washed.
After drying, the solvent was distilled off and recrystallized from a mixture of ethyl acetate and n-hexane to give 4-{[2-[(4-chlorophenyl)sulfonylamino]indan-5.
-yl]acetylamino}-n-methyl butyrate 450
mg as colorless crystals. Yield: 74% mp 125.5-127°C Example 2 (1) 850 mg of methyl 4-[(2-aminoindan-5-yl)oxarylamino]-n-butyrate hydrochloride was dissolved in 10 ml of methanol, and 10% palladium- Add 425 mg of carbon and subject to catalytic reduction under IR lamp irradiation and hydrogen pressure of 4 atm for 48 hours. After filtering off the catalyst and distilling off the solvent, 20 ml of ethyl acetate, 1.24 g of potassium carbonate and 20 ml of water were added to the residue, and a solution of 633 mg of 4-chlorophenylsulfonyl chloride in 10 ml of ethyl acetate was added dropwise at room temperature, followed by stirring for 1 hour. do. The ethyl acetate layer was separated, washed, dried, and filtered, then the solvent was distilled off, and the residue was separated and purified using silica gel column chromatography (solvent: chloroform:methanol = 99:1) to give 4-{[2 - [(4-
360 mg of methyl chlorophenyl)sulfonylamino]indan-5-yl]acetylamino}-n-butyrate is obtained as colorless prismatic crystals. Yield: 30% mp 128-129℃ IRν ^nujol _nax (cm ^-1 ): 3360, 3280, 1735, 1720, 1650 Furthermore, 4-{2-[2-[(4-chlorophenyl)sulfonylamino]indan-5 −il]
690 mg of methyl-2-hydroxyacetylamino}-n-butyrate are obtained as a colorless oil. Yield: 57% (2) Methyl 4-{2-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]-2-hydroxyacetylamino}-n-butyrate in Example 1-(3 ) in the same way as 4-{2-[2-
Methyl [(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino}-n-butyrate is obtained. Example 3 (1) 502 mg of methyl 4-[(2-aminoindan-5-yl)oxallylamino]-n-butyrate, 8 ml of methanol, 531 mg of oxalic acid, 10% palladium-
Add 250 mg of carbon and hydrogen pressure 4 under IR lamp irradiation.
Subjected to catalytic reduction at atmospheric pressure for 18 hours and further at 3 atmospheres for 9 hours. After removing the catalyst by filtration, the solvent was distilled off, and to the residue was added 10 ml of ethyl acetate, 2.07 g of potassium carbonate, and 10 g of water.
ml of ethyl acetate containing 342 mg of 4-chlorophenylsulfonyl chloride was added dropwise under stirring.
Stir at room temperature for 2 hours. After the reaction, the ethyl acetate layer is separated, washed and dried, and then the solvent is distilled off. The residue was dissolved in ethyl acetate-isopropyl ether-n-
Recrystallize from a hexane mixture to obtain 4-{[2-[(4-
507 mg of methyl chlorophenyli)sulfonylamino]indan-5-yl]acetylamino}-n-butyrate is obtained as colorless crystals. Yield: 74% mp, 125.5-127°C Example 4 (1) 2-aminoindan 13.32g, potassium carbonate
27.64 g of 4-chlorophenylsulfonyl chloride in a mixture of 100 ml of chloroform and 100 ml of water.
Add 21.11 g and stir at room temperature for 30 minutes. After washing and drying the organic layer, the solvent was distilled off and recrystallized from a mixture of ethyl acetate-isopropyl ether-n-hexane to obtain 28.13 g of 2-[(4-chlorophenyl)sulfonylamino]indane as colorless needle-like crystals. . Yield: 91% mp 141-142℃ (2) Methyl 4-(oxaloamino)-n-butyrate 0.3
A solution of 3.67 g of oxalyl chloride in 10 ml of methylene chloride is added dropwise to a mixture of 2.72 g of hydrate, 20 ml of methylene chloride, and 1 drop of dimethylformamide under ice-cooling and stirring, and the mixture is stirred at room temperature for 2.5 hours. After the reaction,
Distill the solvent to give 4-(chlorooxarylamino)
-Methyl n-butyrate is obtained. A solution of this product in 15 ml of 1,2-dichloroethane is added dropwise to a suspension of 5.6 g of powdered aluminum chloride in 10 ml of 1,2-dichloroethane while cooling and stirring. Next, 2.15 g of 2-[(4-chlorophenyl)sulfonylamino]indan 1,2-dichloroethane
Add 55 ml of solution dropwise and stir at room temperature for 2 hours. Add ice water and ethyl acetate under ice cooling, extract with ethyl acetate, wash, and dry. After filtration, the solvent was distilled off, and the residue was separated and purified using a silica gel column (solvent: chloroform) to obtain 4-{[2-[(4-chlorophenyl)sulfonylamino]indan-5.
-yl]oxalylamino}-n-methyl butyrate
Obtain 1.68 g as a pale yellow oil. Yield: 50% (3) This product was treated in the same manner as in Example 1-(2) and (3) to obtain 4-{[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetyl. methyl amino}-n-butyrate is obtained. Example 5 (1) A solution of 3.36 g of phenylthioacetic acid, 30 ml of tetrahydrofuran and 30 ml of methylene chloride was added under ice cooling.
Add 3.24 g of carbonyldiimidazole. 1
After stirring for an hour, 3.07 g of 4-aminobutyric acid methyl ester hydrochloride and then 2.02 g of triethylamine were added, and the mixture was stirred for an additional hour. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent: ethyl acetate:hexane = 2:1), and further crystallized with n-hexane to obtain 4- [(phenylthio)acetylamino]-n-methyl butyrate
4.28 g are obtained as colorless crystals. Yield: 80% mp 38-40℃ MS (m/z): 267 (M ⁺ ) IRν ^nujol _nax (cm ^-1 ): 3300, 1730, 1655, (2) Add 7.38 g of this product to 30 ml of methylene chloride solution. 4.10 g of sulfuryl chloride under ice-cooling under a stream of argon.
Add dropwise 15 ml of methylene chloride solution and stir for 50 minutes. After evaporating the solvent, the residue was dissolved in 30 ml of methylene chloride, 3.54 g of 2-[(4-chlorophenyl)sulfonylamino]indane was added, and stannic chloride was added.
10.42g, nitromethane 4.88g methylene chloride
Add 30 ml of the solution dropwise under cooling, stir at room temperature for 4 hours, and add 30 ml of water under ice cooling. 10% hydrochloric acid was added, the organic layer was separated, and after drying, the solvent was distilled off to give 4-{2-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]-2-(phenylthio). ) Methyl acetylamino}-n-butyrate is obtained as a crude product. (3) Add 0.76g of zinc powder to 50ml of acetic acid solution of this product,
After refluxing and cooling to room temperature, filter. The solvent was distilled off, crystallized from a mixture of isoropyl ether and methanol, and recrystallized from a mixture of ethyl acetate and n-hexane to obtain 4-{[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]. 2.76 g of methyl acetylamino}-n-butyrate are obtained as colorless crystals. Yield: 51% mp 125.5-127°C Example 6 (1) 3-Aminopropionic acid methyl ester hydrochloride was treated in the same manner as in Example 5-(1) to give 3-[(phenylthio)acetylamino]-n - Obtain methyl propionate. mp 62-63℃ (2) This product was treated in the same manner as in Example 5-(2) to obtain 3-
Methyl {2-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]-2-(phenylthio)acetylamino}-n-propionate is obtained as a colorless oil. MS (m/z): 55 = (M ⁺ ) IRν ^nujol _nax (cm ^-1 ): 3280, 1730, 1650, 1320,
1160 (3) This product was treated in the same manner as in Example 5-(3).
{[2-[4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino}-
Methyl n-propionate is obtained as colorless prismatic crystals. mp 150~151℃ IRν ^nujol _nax (cm ^-1 ): 3380, 3160, 1725, 1650,
1325, 1155 Example 7 (1) Methanol solution of 125.5 g of methyl 4-{[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino}-n-butyrate
Add 675 ml of 1N sodium hydroxide aqueous solution to 1250 ml at room temperature with stirring, then add 2
Stir for an hour. After the reaction, the pH was adjusted to 4 with 110 ml of 6N hydrochloric acid under cooling and stirring, and methanol was distilled off.
Add 10% hydrochloric acid to adjust the pH to 1, and extract with a mixture of ethyl acetate and tetrahydrofuran. After drying, the solvent was distilled off, the residue was dissolved in 550 ml of tetrahydrofuran, and 1.5 mL of isopropyl ether was added to crystallize it to give 4-{[2-[4-chlorophenyl].
115.6 g of sulfonylamino]indan-5-yl]acetylamino}-n-butyric acid are obtained. Yield: 95% mp 123.5-125.5°C Sodium salt mp 196.1°C (decomposition) Examples 8-37 Compounds listed in Tables 1-9 below are obtained by treating the corresponding raw material compounds in the same manner as Examples 1-7. .

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[Table] Reference example 1 (1) 124.1g of 2-aminoindan and 500g of ethyl formate
ml and reflux for 23 hours. The solvent was distilled off, the mixture was heated to dissolve in 300 ml of ethyl acetate, 4.5 g of charcoal powder was added, and after filtration, washing, and concentration, the mixture was crystallized with n-hexane to obtain 144 g of 2-formylaminoindan. mp 74.5-76℃ (2) Suspend 64 g of powdered aluminum chloride in 160 ml of 1,2-dichloroethane, and add 39.3 g of ethoxalyl chloride to 60 ml of 1,2-dichloroethane under ice cooling.
ml solution dropwise, then 25.79 g of 2-formylaminoindan 1,2-dichloroethane 10
ml solution was added dropwise for 50 minutes at 0-5°C, and then heated to room temperature for 1
Stir for a further 1 hour at room temperature. After the reaction, add ice water, extract with ethyl acetate, wash,
dry. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (solvent: ethyl acetate:
Separation and purification with n-hexane = 2:1), 5-
Ethoxalyl-2-formylaminoindan
33.4 g are obtained as an oil. IRν ^neat _nax (cm ^-1 ): 3280, 1730, 1680 (3) To a solution of 26.1 g of this product in 200 ml of ethanol, add 200 ml of 1N aqueous sodium hydroxide solution under ice water cooling, and stir at room temperature for 1.5 hours. After reaction, 6N−
Neutralize with hydrochloric acid, distill off the ethanol, adjust the pH to 9 with a saturated aqueous sodium bicarbonate solution, add water,
After washing with ethyl acetate, the aqueous layer was PHed with 6N hydrochloric acid.
1 and filter the precipitated crystals. Furthermore, the aqueous layer was extracted with a tetrahydrofuran-ethyl acetate mixture,
After distilling off the solvent, combine with the crystals obtained earlier, dissolve dimethylformamide, and filter off insoluble matter. The solvent is concentrated, ethyl acetate is added and crystallized to obtain 18.6 g of 5-oxalo-2-formylaminoindan. mp 191-192.5℃ (decomposition) (4) Dissolve 9.32g of this product in a mixed solvent of 80ml of tetrahydrofuran and 30ml of dimethylformamide,
Carbonyldiimidazole under stirring at room temperature.
7.78 g was added thereto for 2 hours, and then 7.99 g of 4-aminobutyric acid methyl ester hydrochloride and 5.26 g of triethylamine were added and stirred for 1.5 hours. After the reaction, the solvent is distilled off, extracted with ethyl acetate, washed and dried. The solvent was distilled off, the residue was separated and purified using silica gel column chromatography (solvent: ethyl acetate), and then recrystallized from an ethyl acetate-isolopyl ether mixture to give 4-[(2-formylaminoindan-5- yl)oxalylamino]-n-
7.3 g of methyl butyrate are obtained as colorless crystals. mp 96-100℃ (5) Add 320 g of 10.4 W/W% hydrogen chloride-methanol to 16.08 g of this product, stir at room temperature for 16 hours, and after distilling off the solvent, add 200 ml of methanol to the pale yellow solid obtained.
dissolve in After charcoal treatment, filtration, and distillation of the solvent, recrystallization from a methanol-isopropyl ether mixture yielded 15.46 g of methyl 4-[(2-aminoindan-5-yl)oxallylamino]-n-butyrate hydrochloride. Obtained as a solid. mp 200-204℃ (decomposition) Reference example 2 (1) Triethylamine was added to a solution of 29.8 g of benzyloxyoxalyl chloride and 21.9 g of 4-aminobutyric acid methyl ester hydrochloride in 140 ml of methylene chloride.
A solution of 30.4 g of methylene chloride in 80 ml is added dropwise and stirred for 1 hour. Then, it is washed, dried, and filtered. The solvent was distilled off, the residue was crystallized from n-hexane, and recrystallized from a mixture of ethyl acetate and n-hexane to give 4-(benzyloxyoxarylamino).
38.0 g of methyl butyrate is obtained as light ocher prism crystals. mp 41-44℃ (2) Dissolve 37.9 g of this product in 360 ml of tetrahydrofuran and subject to catalytic reduction at normal pressure in the presence of 14 g of 10% palladium-carbon. After the contact was removed by filtration, the solvent was distilled off and recrystallized from a mixture of ethyl acetate and n-hexane to obtain 24.9 g of methyl 4-(oxaloamino)butyrate trihydrate as colorless prism crystals. mp 68~72℃

Claims (1)

[Claims] 1. General formula (However, R ¹ is a group represented by the formula -SO ₂ R or a hydrogen atom, R is a phenyl group, lower alkyl phenyl group, lower alkoxy phenyl group, halogenophenyl group, trifluoromethyl phenyl group, nitrophenyl group, naphthyl group) group or thienyl group, R ² is a hydrogen atom or a lower alkyl group, R ³ is a lower alkoxycarbonyl-lower alkyl group or a carboxy-lower alkyl group, Y is a substituted or unsubstituted phenylmercaptomethylene group, a lower alkylmercaptomethylene group, represents a hydroxymethylene group, a halogenomethylene group or a carbonyl group) or a salt thereof is reduced to convert the group Y into a methylene group, and when R ¹ is a hydrogen atom, then the general formula RSO ₃ A general formula characterized by a condensation reaction with a sulfonic acid compound represented by H (however, the symbols have the same meanings as above) or a reactive derivative thereof, and if necessary, converting the product into a salt thereof. (However, the symbols have the same meanings as above.) A method for producing an indane derivative or a salt thereof. 2 General formula (However, R ¹ is a group represented by the formula -SO ₂ R or a hydrogen atom, R is a phenyl group, lower alkyl phenyl group, lower alkoxy phenyl group, halogenophenyl group, trifluoromethyl phenyl group, nitrophenyl group, naphthyl group) group or thienyl group, R ² is a hydrogen atom or a lower alkyl group, R ³² is a lower alkoxycarbonyl-lower alkyl group, Y is a substituted or unsubstituted phenylmercaptomethylene group, a lower alkylmercaptomethylene group, a hydroxymethylene group, a halogenomethylene group or a carbonyl group) or its salt is reduced to convert the group Y into a methylene group, and when R ¹ is a hydrogen atom, then the general formula RSO ₃ H (however, the symbol is (has the same meaning as above.) After a condensation reaction with a sulfonic acid compound or a reactive derivative thereof, the product is hydrolyzed,
If necessary, the general formula is further characterized in that it is a salt thereof. (However, R ³¹ represents a carboxy-lower alkyl group, and R and R ² have the same meanings as above.) A method for producing an indane derivative or a salt thereof. 3 General formula (However, R ¹ is a group represented by the formula -SO ₂ R or a hydrogen atom, R is a phenyl group, lower alkyl phenyl group, lower alkoxy phenyl group, halogenophenyl group, trifluoromethyl phenyl group, nitrophenyl group, naphthyl group) group or thienyl group, R ² is a hydrogen atom or a lower alkyl group, R ³ is a lower alkoxycarbonyl-lower alkyl group or a carboxy-lower alkyl group, Y is a substituted or unsubstituted phenylmercaptomethylene group, a lower alkylmercaptomethylene group, represents a hydroxymethylene group, a halogenomethylene group, or a carbonyl group) or a salt thereof.