KR860001024B1 - Process for preparing 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indol acetic acid esters - Google Patents

Abstract

Compds. I (R = alkyl, alkenyl, alkoxyalkyl, substd. aryl, aryl, arylalkyl, or cyclo-alkyl) were prepd. Thus, 300 ml dichloromethane was mixed with 10.73g 1-(4-chlorobenzoyl)-5-methoxy-2methyl-3-indole acetic acid and 3.96g 5-methyl-2-mercapto-1,3,4thiadiazole. This mixt. was treated with N,N-dicyclo hexyl carbo diimide and 4- (dimethylamino) pyridine for 6 hr to give 14.02g yellow product.

Description

Method for preparing 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indole acetate ester

The present invention relates to a novel process for preparing 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetic acid ester.

R in the formula (I) represents an alkyl group, an alkenyl group, an alkoxyalkyl group, a substituted aryl group, an aryl group, an arylalkyl group and a cycloalkyl group. Particularly useful among these are p-acetyl aminoferyl, 2-carboxyphenyl, 2-methoxy carbonylphenyl, carboxy methyl and the like.

The compound is a nonsteroidal analgesic anti-inflammatory agent, it is known that the gastrointestinal disorder is greatly reduced compared to the existing 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetic acid.

As a manufacturing method of the compound (I) known so far,

First, the reaction of l- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetic acid with thionyl chloride as described in Spain 341,692, 423,833 and 432,544, U.S. Pat. After obtaining the intermediate, there is a method of preparing compound (I) by adding alcohol thereto, and secondly, 1- (4-chlorobenzoyl) -5-methoxy-2- as described in US Pat. No. 3,770,752 and Belgian Patent 649,169, etc. A method of preparing compound (I) by condensation of methyl-3-indolacetic acid using N, N-dicyclohexylcarbodiimide to obtain an acid anhydride in the form of an acid anhydride is added thereto. . However, in case of the first method, it is necessary to use benzene and thionyl chloride, which are toxic to human body.

In the case of the second method, since the starting material 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indolacetic acid is produced together with the compound (I) in the final step, purification of the final material and recovery of the starting material It is difficult to have a disadvantage in that the yield is lowered.

Therefore, in the present invention, first, 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetic acid and 5-methyl-2-mercapto-1,3,4-thiadiazole are reacted. The disadvantages of the first and second methods are obtained by obtaining the ester (II) as an intermediate and adding the alcohol of the general formula (IV) to the high yield and the reaction solvent using dichloromethane instead of benzene, which is toxic to the human body. Could be removed.

When the content of the present invention is represented by the structural formula as follows.

Non-limiting examples of the invention are as follows.

Example 1

Process for preparing 2 '-(5'-methyl-1', 3 ', 4'-thiadiazolyl-1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-3-indole thioacetate

Attach a thermometer to a 500 ml three-necked flask, add 300 ml of dichloromethane, and add 10.73 g (0.03 mol) of 5-methyl-2-mercapto 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indolacetic acid. 3.96 g (0.03 mol) of -1,3,4-thiadiazole are added and dissolved by stirring.

7.18 g (0.035 mole) of hexyl carbodiimide and a small amount of 4- (dimethylamino) pyridine were added thereto, followed by stirring at the same temperature for 6 hours. The insolubles were removed by filtration and the filtrate was concentrated under reduced pressure to give 14.02 g (yield: 99.0%) of yellow crystals.

IR (KBr) 1740 (CH ₂ CO) cm ^-1

NMR (CDCl ₃ ) 2.38 (s, 3H, CH ₃ ), 2.42 (s, 3H, CH ₃ )

3.8 (s, 3H, OCH ₃ ), 4.3 (s, 2H, CH ₂ CO),

6.5-8.0 (m, 7H, Ar-H) ppm (δ)

Example 2

Preparation of ethyl 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indolyl acetate In a 500 ml three-necked flask, a thermometer and a cooling device were attached, 220 ml of ethyl alcohol was added, and 9.44 g of thioester (II) 0.02 mole) and a small amount of 4- (dimethylamino) pyridine were added and refluxed for 5 hours to react. Then, 250 ml of methyl alcohol was added to the crystal obtained by concentrating under reduced pressure, and stirred for 30 minutes and filtered.

The crystals were again suspended in 200 ml of distilled water, stirred for about 30 minutes, and filtered and dried to obtain 7.43 g of yellow crystals.

(Yield: 96.3%)

Melting Point: 94.6 ℃

IR (KBr) 1725 (CH ₂ CO) cm ^-1

NMR (CDCl ₃ ) 1.3 (t, 3H, CH ₃ ), 2.46 (s, 3H, CH ₃ )

3.6 (s, 2H, OCH ₂ CO), 3.75 (s, 3H, OCH ₃ ),

4.2 (q, 2H, CH ₂ ), 6.5-8.0 (m, 7H, Ar-H) ppm (δ)

Example 3

Preparation of furfuryl 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indolyl acetate 50 ml of dichloromethane was added to a 100 ml three-necked flask, and 2.83 g (0.006 mol) of thioester (II) and 4- 0.06 g (0.0065 mol) of (dimethylamino) pyridine is added to dissolve, and 0.52 ml (0.006) of furfuryl alcohol is added and refluxed for 5 hours. The reaction solution is concentrated under reduced pressure, and the resulting semi-solid substance is dissolved in ethyl alcohol and stirred in a non-bath.

The resulting crystals were filtered, suspended in water, and filtered again to give 1.29 g (49.1%) of pale yellow crystals.

Melting Point: 101 ℃

IR (KBr) 1730 (CH ₂ CO) cm ^-1

NMR (CDCl ₃ ) 2.35 (s, 3H, CH ₃ ), 3.7 (s, 2H, CH ₂ CO),

3.81 (s, 3H, CH ₃ O), 5.1 (s, 2H, OCH ₂ ),

6.4 (m, 2H, CH), 6.74 (m, 1H, OCH =),

6.5-7.8 (m, 3H, Ar-H) ppm (δ)

Example 4

Preparation of 2'-carboxyphenyl 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indolyl acetate After attaching a cooling device to a 500 ml three-necked flask, 220 ml of dichloromethane was added thereto and then thioester (II) 9.44 g (0.02 mol), salicylic acid 3.59 g (0.024) and a small amount of 4- (dimethylamino) pyridine are added and refluxed for 7 hours.

The reaction solution was concentrated under reduced pressure, 200 ml of ethyl alcohol was added thereto, stirred for 1 hour, and filtered. The crystals were suspended in water and stirred for 1 hour, followed by filtration and drying to obtain 4.43 g (yield: 46.3%) of white crystals.

Melting Point: 182.1 ℃

IR (KBr) 1750 (CH ₂ CO) cm ^-1

NMR (CDCl ₃ ) 2.40 (s, 3H, CH ₃ ), 3.83 (s, 3H, OCH ₃ ),

3.96 (s, 2H, CH ₂ CO), 6.8-8.0 (m, 11H, Ar-H) ppm (δ)

Example 5

Preparation of p-acetaminophenyl 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetate

100 ml of dichloromethane was added to a 200 ml three-necked flask, and 3.96 g (0.0084 mol) of thioester (II), 1.3 g (0.0084 mol) of acetaminophen and a small amount of 4- (dimethylamino) pyridine were added and refluxed for 6 hours.

The reaction solution was concentrated under reduced pressure, 50 ml of ethyl alcohol and 50 ml of distilled water were added thereto, stirred for 1 hour, and filtered.

After drying, 1.95 g (yield 47.5%) of pale brown crystals were obtained.

Melting Point: 169.2 ℃

IR (KBr) 1750 (CH ₂ CO) cm ^-1

NMR (CDCl ₃ ) 2.1 (s, 3H, CH ₃ CO), 2.45 (s, 3H, CH ₃ ),

3.85 (s, 5H, CH ₃ CO & OCH ₃ ), 6.5-8.0 (m, 11H, Ar-H) ppm (δ)

Example 6

Preparation of 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetoxyacetic acid To a 200 ml three-necked flask was connected a dry tube and 100 ml of dichloromethane were added. To this was added 2.36 g (0.005 mol) of thioester (II) and 0.38 g (0.005 mol) of glycolic anhydride and a small amount of 4- (dimethylamino) pyridine.

The reaction color was stirred at room temperature for 5 hours and then concentrated under reduced pressure.

50 ml of ethyl acetate is added to the light brown concentrated residue thus obtained, and 30 ml of petroleum ether is added thereto.

After stirring for 30 minutes at room temperature and cooling for 12 hours, 1.08 g of pale yellow crystals were obtained. (Yield: 51.9%)

Melting Point: 151 ℃

IR (KBr) 3110 (OH), 1748 (CH ₂ CO) cm ^-1

NMR (CDCl ₃ ) 2.33 (s, 3H, CH ₃ ), 3.74 (s, 2H, CH ₂ CO),

3.77 (s, 3H, OCH ₃ ), 4.62 (s, 2H, -OCH ₂ CO)

8.67 (s, 1H, COOH), 6.5-7.0 (m, 7H, Ar-H) ppm (δ)

Claims (1)

1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetic acid and 5-methyl-2-mercapto-1,3,4-thiadiazole represented by Structural Formula (III) are reacted. To obtain a thioester of formula (II) to add an alcohol of formula (IV) to prepare a compound of formula (I).

In the above structural formula, R represents an alkyl group, alkenyl group, alkoxyalkyl group, substituted aryl group, aryl group, arylalkyl group and cycloalkyl group.