JPH07330697A - Production of substituted indan derivative - Google Patents

Abstract

PURPOSE:To obtain a substituted indan derivative of high purity, a synthetic intermediate for, for example, a strong thromboxane A2 antagonist by Hoffmann rearrangement reaction of a specific compound, in a high yield with industrial advantage without use of expensive reagents economically with excellent operability and safety. CONSTITUTION:A compound of formula I (m, n are each 0-3; R1 is H, a lower alkyl; R2 is H, O) is subjected to Hoffmann rearrangement reaction to give this substituted indan derivative, for example, 5-(2-aminomethyl)indanylacetic acid. In the production, the reaction of the compound of formula I is carried out in the presence of an alkali such as sodium hydroxide and a salt of oxo-acid such as sodium hypochlorite.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an intermediate of the formula (II) which is an intermediate for the production of indane derivatives useful as a medicine.

[0002]

[Chemical 3]

(In the formula, m and n each represent a number of 0 to 3, R ₁ is a hydrogen atom or a lower alkyl group, and R ₂ is a hydrogen atom or an oxygen atom.) The present invention relates to a novel method for producing a derivative.

[0004]

BACKGROUND OF THE INVENTION The indane derivative described in International Patent Publication WO92 / 15558 is a pharmaceutical compound useful as a thromboxane A ₂ antagonist, and its production method is disclosed in the publication. There is. According to this, the indane derivative can be produced by a method using the Curtius rearrangement reaction of acyl azide with indan-2-ylalkylcarboxylic acid as a starting material. However, this method is difficult to use industrially because an explosive acyl azide is produced as an intermediate.

On the other hand, JP-A-4-264068 discloses a method for producing a substituted indane derivative from 5-acetyl-2- (acetylaminomethyl) indane by the Wilgerlot reaction and the subsequent hydrolysis reaction. However, the yield was low and it was not industrially satisfactory.

[0006]

[Means for Solving the Problems] The inventors of the present invention have conducted extensive studies in order to solve the above-mentioned problems, and by using a salt of an alkali and an oxo acid, a so-called Hoffman rearrangement reaction is carried out, whereby the indane derivative described in the publication It was found that the substituted indane derivative, which is a production intermediate of, can be obtained safely and economically, and the present production method was completed.

That is, the present invention has the general formula (I)

[0008]

[Chemical 4]

(Wherein m, n, R ₁ and R ₂ have the same meanings as defined above), a Hoffman rearrangement reaction is carried out on the compound represented by the general formula (II).

[0010]

[Chemical 5]

The present invention relates to a process for producing a substituted indane derivative represented by the formula (m, n, R ₁ and R ₂ are as defined above).

In the present invention, when R ₂ is an oxygen atom, this oxygen atom forms a carbonyl group with an adjacent carbon atom. The "lower alkyl group" refers to an alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group,
Examples thereof include an isobutyl group, sec-butyl group and tert-butyl group.

The compound of the general formula (I) used in the production method of the present invention can be produced by appropriately combining known methods. For example, the following reference production method can be mentioned.

Reference Manufacturing Method 1

[0015]

[Chemical 6]

(In the formula, R ₁ has the same meaning as described above, R ₁ 'is a lower alkyl group, and X is a halogen atom.) 2-Indanyl acetic acid (III) is thionyl chloride, phosphorus tribromide, etc. by a conventional method. After being converted into an acid halide (IV) by the halogenating agent of 1), it is reacted with aqueous ammonia to produce 2-indanylacetamide (V). Then, in the presence of a Lewis acid such as aluminum chloride, titanium tetrachloride or tin tetrachloride, 2-indanylacetamide (V) and α-halo-
α-Methylthioacetic acid alkyl ester is condensed (Friedel-Crafts reaction) to give compound (VI), which is subsequently reduced with zinc in acetic acid so that m and n in the general formula (I) are 0.
A compound (Ia) in which R ₂ is a hydrogen atom can be produced. When R ₁ in the compound (Ia) is a lower alkyl group, it can be converted into a hydrogen atom by a hydrolysis reaction.

Reference Manufacturing Method 2

[0018]

[Chemical 7]

(In the formula, R ₁ , R ₁ 'and X have the same meanings as described above.) 2-indanyl acetic acid (III) and α-halo-α-methylthioacetic acid alkyl ester were prepared according to Reference Production Method 1. The compound (VII) is produced by condensation by Friedel-Crafts reaction. Then, the compound (VII) is reduced with zinc in acetic acid to give a compound (VIII), which is converted into an acid halide (IX) with a halogenating agent, and then reacted with aqueous ammonia to produce a compound (Ia). You can

Reference manufacturing method 3

[0021]

[Chemical 8]

(In the formula, R ₁ , R ₁ 'and X have the same meanings as described above.) 2-Indanylacetamide (V) produced in the same manner as in Reference Production Example 1, chloroglyoxylic acid methyl ester, and chloroglyoxyl A compound (Ib) wherein m and n in the general formula (I) are 0 and R ₂ is an oxygen atom can be produced by condensing an oxalic acid ester / acid halide such as acid ethyl ester by Friedel-Crafts reaction. it can. When R ₁ in the compound (Ib) is a lower alkyl group,
It can be converted into a hydrogen atom by a hydrolysis reaction.

The compound represented by the general formula (I) obtained as described above can be converted into the substituted indane derivative (II) by the production method (Hoffmann rearrangement reaction) of the present invention.
This production method is carried out using a salt of an alkali and an oxo acid in a suitable solvent. Compound (I) can be used in the reaction regardless of whether R ₁ in the formula is a hydrogen atom or an alkyl group. However, when R ₁ is an alkyl group, it is converted to a hydrogen atom by a hydrolysis reaction of acid or alkali. Is particularly preferable. As the solvent used in the reaction, water or a mixed solvent of a solvent not involved in the reaction and water is used. Examples of the alkali used in the reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and sodium hydroxide is preferably used. As the salt of oxo acid, hypochlorite such as sodium hypochlorite and potassium hypochlorite, or hypobromite is used.
Furthermore, it is also possible to use bromine instead of the salt of oxo acid. The reaction temperature can be from room temperature to the reflux temperature of the solvent.

According to the present production method, the substituted indane derivative (II) can be obtained in a high yield, and since the amount of impurities is extremely small, it is possible to use it in the next reaction as a reaction mixture or crude crystal as it is. Is advantageous.

The substituted indane derivative (I
For I), for example, the compound described in International Patent Publication WO92 / 15558 can be produced by condensation with a halogenated benzenesulfonic acid derivative or the like. This condensation reaction can be carried out in the presence or absence of a condensing agent. As the condensing agent, any conventional one such as alkali metal carbonate, alkali metal hydrogen carbonate, tri-lower alkylamine, pyridine can be used. This reaction is preferably carried out using a suitable solvent, for example, a hydrocarbon solvent such as toluene.

The compound (I) used in the present invention has an asymmetric carbon atom at the 2-position of the indane skeleton, and there are two optical isomers based on the asymmetric carbon atom. However, this production method does not affect the optical activity. Therefore, the substituted indane derivative (II) corresponding to the optical isomer of the compound (I) can be produced.

[0027]

EXAMPLES The present invention will be described in detail with reference to Production Examples of compounds represented by the general formula (II) by reference examples and Examples, but the present invention is not limited thereto.

Reference Example 1 Preparation of 5- (2-carbamoylmethyl) indanyl acetic acid ethyl ester

Step 1 10.0 g of 2-indanyl acetic acid and 7.1 g of thionyl chloride
And 1 drop of dimethylformamide were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain 9.9 g of 2-indanylacetyl chloride as a yellow oily substance. Yield 99%. NMR (CDCl ₃ ) δ: 2.65 (dd, 2H), 2.91 to 3.23 (m, 5H), 7.
12 to 7.21 (m, 4H)

Step 2 2-indanyl acetyl chloride obtained in Step 1.
Dissolve 9 g in 5 ml of tetrahydrofuran, and under ice cooling 28
% Ammonia water 32 ml. The precipitated crude crystals were collected by filtration and recrystallized from a mixed solution of ethanol and water to obtain 8.72 g of 2-indanylacetamide as colorless crystals.
Yield 89%. Melting point: 148-150 ° C NMR (CDCl ₃ ) δ: 2.38 (d, 2H), 2.65 (dd, 2H), 2.83-2.
99 (m, 1H), 3.16 (dd, 2H), 5.48 (brs, 1H), 5.67 (brs, 1H), 7.1
0 ~ 7.21 (m, 4H)

Step 3 4.0 g of 2-indanyl acetamide obtained in Step 2
Was suspended in 20 ml of 1,2-dichloroethane, and 4.6 g of α-chloro-α-methylthioacetic acid ethyl ester was added,
Under ice cooling, 6.4 ml of tin tetrachloride was added dropwise over 15 minutes,
Stir at room temperature for 1.5 hours. The reaction solution was poured into 100 ml of water and stirred for 5 minutes, the 1,2-dichloroethane layer was separated, and the remaining aqueous layer was extracted with chloroform. The 1,2-dichloroethane layer and the chloroform layer were combined, washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 6.9 g of α- [5- (2-carbamoylmethyl) indanyl] -α-methylthioacetic acid ethyl ester as a pale yellow oily substance. Yield 99%. NMR (CDCl ₃ ) δ: 1.26 (t, 3H), 2.09 (s, 3H), 2.37 (d, 2
H), 2.56 to 2.71 (m, 2H), 2.83 to 3.01 (m, 1H), 3.06 to 3.22 (m,
2H), 4.09 ~ 4.30 (m, 2H), 4.46 (s, 1H), 5.51 (brs, 2H), 7.10
~ 7.34 (m, 3H)

Step 4 6.9 g of 5- (2-carbamoylmethyl) indanylmethylthioacetic acid ethyl ester obtained in Step 3 was added to 20 ml of acetic acid.
Was dissolved in the mixture, 6 g of zinc powder was added with stirring, and the mixture was refluxed for 2 hours. The reaction solution was allowed to cool to room temperature, suction filtered, and the residue was washed with ethyl acetate. The filtrate and the washing solution were combined, concentrated under reduced pressure, 50 ml of water was added, and the mixture was stirred for 20 minutes. The precipitated crude crystals were collected by filtration, washed with water and then recrystallized from a mixed solution of hexane-ethyl acetate to obtain 5- (2-carbamoylmethyl) indanyl acetic acid ethyl ester (4.91 g). Yield 83
%.

Reference Example 2 Preparation of 5- (2-carbamoylmethyl) indanyl acetic acid

Step 1 To 100.4 g of 2-indanyl acetic acid, 95.9 g of α-chloro-α-methylthioacetic acid ethyl ester and 300 ml of 1,2-dichloroethane were added and suspended, and the mixture was cooled to 5 ° C. 82 ml of tin tetrachloride dissolved in 50 ml of 1,2-dichloroethane was added dropwise to this suspension over 30 minutes while keeping the internal temperature at 15 ° C or lower, and the mixture was stirred at room temperature for 40 minutes.
The reaction solution was poured into a solution obtained by adding 600 ml of 1N hydrochloric acid to 400 g of ice and stirred for 5 minutes. The 1,2-dichloroethane layer was separated and the remaining aqueous layer was extracted with 200 ml of dichloromethane.
Combine the 1,2-dichloroethane layer and the dichloromethane layer,
The extract was washed successively with 1N hydrochloric acid and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and α- [5- (2-
176 g of carboxymethyl) indanyl] -α-methylthioacetic acid ethyl ester was obtained as a yellow oil. Yield 99%. NMR (CDCl ₃ ) δ: 1.27 (t, 3H), 2.09 (s, 3H), 2.55 (d, 2
H), 2.54 to 2.71 (m, 2H), 2.85 to 2.93 (m, 1H), 3.11 to 3.19 (m,
2H), 4.13 to 4.27 (m, 2H), 4.47 (s, 1H), 7.14 to 7.30 (m, 3H)

Step 2 176 g of α- [5- (2-carboxymethyl) indanyl] -α-methylthioacetic acid ethyl ester obtained in Step 1
Was dissolved in 350 ml of acetic acid, and zinc powder 112.4 was stirred under stirring.
g and refluxed for 2 hours. After allowing to cool to room temperature, the reaction solution was suction filtered and the residue was washed with ethyl acetate. After the filtrate and the washing solution were combined, the solvent was distilled off and the residue was replaced with 1500 ml of ice water.
Was stirred for 30 minutes. The precipitated crystals were collected by filtration, and 5-
142.8 g of (2-carboxymethyl) indanyl acetic acid ethyl ester was obtained. Yield 97%. Melting point: 54-56 ° C NMR (CDCl ₃ ) δ: 1.25 (t, 3H), 2.54 (d, 2H), 2.60-2.6
8 (m, 2H), 2.84 to 2.95 (m, 1H), 3.10 to 3.19 (m, 2H), 3.57 (s, 2
H), 4.14 (q, 2H), 7.04 to 7.18 (m, 3H)

Step 3 To 139.8 g of 5- (2-carboxymethyl) indanyl acetic acid ethyl ester obtained in Step 2 was added thionyl chloride 4.
6 ml and 0.2 ml of dimethylformamide were added, and the mixture was stirred at room temperature for 2 hours. Toluene (100 ml) was added to the reaction solution and the solvent was evaporated to obtain 5- [2- (chloroformyl) methyl] indanyl acetic acid ethyl ester (148.8 g) as a yellow oil. Yield 99%. MS (m / z): 280,282 (M ⁺ ) NMR (CDCl ₃ ) δ: 1.26 (t, 3H), 2.61 to 2.68 (m, 2H), 2.9
1 to 3.20 (m, 5H), 3.57 (s, 2H), 4.15 (q, 2H), 7.05 to 7.16 (m, 3
H)

Step 4 148.8 g of ethyl 5- [2- (chloroformyl) methyl] indanylacetic acid obtained in Step 3 was added to toluene 5
It was dissolved in 0 ml and added dropwise to a mixed solution of 220 ml of 28% ammonia water and 100 ml of water under ice cooling over 30 minutes while keeping the internal temperature at 15 ° C or lower. The precipitated crystals are collected by filtration,
After washing with water and air-drying, 136.5 g of 5- (2-carbamoylmethyl) indanyl acetic acid ethyl ester was obtained as ocher crystals. Yield 99%. Melting point: 109 to 110 ° C MS (m / z): 261 (M ⁺ ) NMR (CDCl ₃ ) δ: 1.26 (t, 3H), 2.37 (d, 2H), 2.58 to 2.6
8 (m, 4H), 2.87 ~ 2.98 (m, 1H), 3.10 ~ 3.19 (m, 2H), 3.57 (s, 2
H), 4.15 (q, 2H), 5.36 (brs, 2H), 7.04 to 7.16 (m, 3H)

Step 5 134.0 g of ethyl 5- (2-carbamoylmethyl) indanylacetic acid obtained in Step 4 was added to methanol 2
An aqueous solution prepared by dissolving 32.0 g of 96% sodium hydroxide in 270 ml of water was added dropwise to this suspension under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, concentrated hydrochloric acid was added to adjust the pH to 2, and the precipitated crystals were collected by suction filtration,
After washing with water, air-drying and recrystallizing from a methanol-water mixture to give 5- (2-carbamoylmethyl) indanyl acetic acid 8
5.1 g was obtained as colorless crystals. Yield 71%. Melting point: 188 to 191 ° C MS (m / z): 233 (M ⁺ ) NMR (DMSO-d ₆ ) δ: 2.19 (d, 2H), 2.54 to 2.60 (m, 2H),
2.65 ~ 2.75 (m, 1H), 2.78 ~ 3.01 (m, 2H), 3.48 (s, 2H), 6.75
(brs, 1H), 6.97 ~ 7.19 (m, 3H), 7.29 (brs, 1H), 12.22 (brs, 1
H)

Example 1 Preparation of 5- (2-aminomethyl) indanyl acetic acid

[0040]

[Chemical 9]

An aqueous solution prepared by dissolving 630 mg of 96% sodium hydroxide in 20 ml of water was added to 1.0 g of 5- (2-carbamoylmethyl) indanylacetic acid obtained in Reference Example 2 and dissolved. 2.5 g of 12% sodium hypochlorite was added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 50 minutes,
Heat the inner temperature to 90 ° C over an additional 15 minutes to reach an inner temperature of 90
The reaction was carried out at 0 ° C for 20 minutes. The reaction solution is allowed to cool, pH is adjusted to 6.5 with hydrochloric acid, and the precipitated crystals are collected by filtration to give 5-
667 mg of (2-aminomethyl) indanyl acetic acid was obtained as colorless crystals. Yield 76%. Melting point: 224 to 226 ° C MS (m / z): 205 (M ⁺ ) NMR (CD ₃ OD) δ: 2.64 to 2.76 (m, 3H), 2.99 to 3.10 (m, 4)
H), 3.45 (s, 2H), 7.09 ~ 7.16 (m, 3H)

Also, by performing the reaction under the same conditions as above, allowing the reaction solution to cool, and purifying it with an ion exchange resin (trade name: DIAION SK110) using ammonia water as an eluent, 5- (2-Aminomethyl) indanyl acetic acid 6
80 mg could be obtained as colorless crystals. Yield 77% Melting point: 220-223 ° C

Example 2 Production of sodium 5- {2- (4-chlorophenyl) sulfonylaminomethyl} indanylacetate 10.0 g of 5- (2-carbamoylmethyl) indanylacetate obtained in Reference Example 2 was added with 96% hydroxylation. Sodium 6.8
An aqueous solution prepared by dissolving g in 80 ml of water was added and dissolved. Under ice-cooling, 12% sodium hypochlorite (29.3 g) was added, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 50 minutes, and further 1
The internal temperature is heated to 90 ° C over 5 minutes, and the internal temperature is 90 ° C to 10 ° C.
The reaction was carried out at 0 ° C. The reaction mixture was ice-cooled, then 4-chlorobenzenesulfonyl chloride 11.8 g toluene 13 ml.
The solution was added and stirred at room temperature for 20 hours. The reaction solution was adjusted to pH 4 by adding 8 ml of concentrated hydrochloric acid and stirred for 30 minutes. The precipitated crude crystals were collected by suction filtration, washed with water, and then recrystallized from an ethanol-water mixture to give 5- {2- (4-chlorophenyl) sulfonylaminomethyl} indanyl acetic acid 13.
1 g was obtained as colorless crystals. Yield 80%. Melting point: 180 to 182 ° C MS (m / z): 379, 381 (M ⁺ ) NMR (DMSO-d ₆ ) δ: 2.47 to 2.56 (m, 3H), 2.76 to 2.94
(m, 4H), 3.48 (s, 2H), 6.96-7.10 (m, 3H), 7.66 (d, 2H), 7.80
(d, 2H), 7.87 (t, 1H), 12.20 (brs, 1H)

13.1 g of 5- {2- (4-chlorophenyl) sulfonylaminomethyl} indanyl acetic acid was suspended in 30 ml of methanol, and 28 ml of 1N sodium hydroxide solution was added to the suspension, followed by heating. Further, 600 mg of sodium hydrogen carbonate was added little by little under heating and dissolved. 400 mg of coconut husk activated carbon was added to this solution, heated under reflux for 10 minutes, and suction filtered, and the mother liquor was concentrated under reduced pressure. The obtained crude crystals were recrystallized from water and air dried for 24 hours to obtain 12.5 g of sodium 5- {2- (4-chlorophenyl) sulfonylaminomethyl} indanylacetate monohydrate as colorless crystals. Yield 86%. Melting point: 260 ° C. (decomposition) NMR (DMSO-d ₆ ) δ: 2.44 to 2.52 (m, 3H), 2.75 to 2.89
(m, 4H), 3.16 (s, 2H), 6.91-7.01 (m, 3H), 7.64 (d, 2H), 7.80
(d, 2H), 8.13 (brs, 1H)

[0045]

INDUSTRIAL APPLICABILITY According to the method of the present invention, a substituted indane derivative (II) which is a production intermediate for a strong thromboxane A ₂ antagonist or the like can be obtained without carrying out the dangerous Curtius rearrangement reaction of acyl azide. . The method of the present invention has good operability, and since it can be produced in high yield and high purity without using expensive reagents, it is excellent in economical efficiency and safety,
This is an industrially advantageous manufacturing method.

Claims (1)

[Claims] 1. A compound represented by the general formula (I): (In the formula, m and n each represent a number of 0 to 3, R ₁ is a hydrogen atom or a lower alkyl group, and R ₂ is a hydrogen atom or an oxygen atom.) To a compound represented by Hoffmann rearrangement reaction The general formula (II) is characterized in that (In the formula, m, n, R ₁ and R ₂ have the same meanings as described above.) A method for producing a substituted indane derivative.