KR840000605B1 - Process for the preparation of 2-amino-3-(alkyl-thiobenzoul)phenylacetic acids - Google Patents

Abstract

The title compds. I (R=H, lower alkyl; R1=H, lower alkyl, metal cation; R2=H, halo, lower alkyl, alkoxy; Am=NH2, MeNH, Me2N), useful as analgesics, inflammation inhibitors, and blood platelet aggregation inhibitors, were prepd. Thus, 5.2g 7-(4-methylthiobenzoyl) indolin-2-on and 75mL 3N-NaOH were refluxed for 20 hrs. to give 4.9g sodium 2-amino-3-(4-methylthiobenzoyl)-phenylacetate monohydrate.

Description

Method for preparing 2-amino-3- (alkylthiobenzoyl) -phenylacetic acid derivative

The present invention relates to the preparation of 2-amino-3- (alkylthiobenzoyl) phenyl acetic acid of the following general formula (I), alkyl esters thereof and metal salts which are useful as anti-inflammatory agents, analgesics and platelet aggregation inhibitors.

In the above formula

R is hydrogen or lower alkyl,

R ¹ is hydrogen, lower alkyl or a pharmaceutically acceptable metal cation,

R ² is hydrogen, halogen, lower alkyl or lower alkoxy,

Am is primary amino (-NH ₂ ), methylamino or dimethylamino. 2-amino-3- (5 and 6) benzoylphenyl acetic acid having benzoyl moieties substituted with lower alkyl, halogen, nitro and trifluoromethyl and methods for their preparation are described in US Pat. No. 4,045,576. However, the compound of the present invention cannot be prepared by this method.

Anti-inflammatory action is Sansilio, L. This can be seen by analyzing experimental animals using a modification of F. Evansblue kerazinan pleural effusion test.

[See: Sancilio, L. F., J. Pharmacol. Exp. Ther. 168,199-204 (1969)]

The action of the compound of general formula (I) as a platelet aggregation inhibitor is shown by the platelet aggregation reduction test described by Bonn and Evans et al. See Born, J. phys. 162, 67-68P (1962) and Evans et al. J. of Expt. Med. 128, 877-894 (1968). Two hours after oral administration of test drug to rats, blood is collected from retro and platelet-rich plasma is obtained. Collagen is added to the platelet-rich plasma to induce platelet aggregation, and the control and drug treated samples are compared.

The compound of general formula (I) is supposed to act as an analgesic agent as measured by the Bradykinan Analgesic Action Assay modified by Sancilio et al. See Dickerson et al, Life Sci 4, 2063-2069 (1965) and Sancilio and Cheung, Fed. Proc. 35,774 (1976).

As used herein, "lower alkyl" is a straight and branched chain radical having up to 6 carbon atoms, preferably up to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, amyl , Isoamyl and hexyl. "Lower alkoxy" means -0-lower alkyl.

"Halogen" means Cl, F, Br, and I.

Pharmaceutically nontoxic salts include its sodium, potassium, calcium, magnesium, zinc, copper salts and hydrates.

Intermediate is a 7- (S-lower alkylthio benzoyl) indolin-2-temperature novel compound of formula (II):

In the above formula

R, R ¹ and R ² are as described above.

Fluorobenzoyl indolin-2-silver used as starting material to prepare the compounds of the present invention can be prepared by several methods described in US Pat. No. 4,045,576. One method involves reacting 2-amino-4'-halobenzoylbenzophenone with ethyl methylthio acetate, tert-BuOCl and Et ₃ N to give 7- (halobenzoyl) -3-methylthioindolin-2-one. Obtained and then reduced with raninickel to produce 7- (halobenzoyl) -3-indolin-2-one. A variation of this method uses tin powder in alcohol and concentrated hydrochloric acid in place of raninickel. The following scheme illustrates the preparation of 7- (fluorobenzoyl) -indolin-2-one used to prepare the compounds of the present invention.

The compounds of the present invention react fluoro benzoylindole-2-one with alkali metal alkylsulfides and then acid hydrolyze to yield 7- (alkylthiobenzoyl) indolin-2-ones and then hydrolyze with alkali metal bases. To give the alkali metal salt of 2-amino-3- (alkylthiobenzoyl) phenylacetic acid. The following scheme shows the process for preparing the alkali metal salt of the compound of general formula (I).

In order to obtain free acid (R ¹ = H) from the alkali metal salt, acetic acid is carefully added to the aqueous solution of the salt to precipitate the free acid, which is then separated by filtration and washed with water to dry.

In order to obtain esters in which R ¹ is lower alkyl, the alkali metal salt is treated with lower alkyl iodide in a suitable solvent such as anhydrous dimethylformamide. Water is added and then the ester is extracted from the mixture with a suitable solvent such as diethyl ether, dried over sodium sulfate and the solvent is evaporated off.

Compounds of formula (I) wherein Am is dimethylamino form 2-aminophenyl acetic acid esters of formula (I) wherein Am is -NH ₂ in a solvent such as acetonitrile under mildly acidic conditions provided by using glacial acetic acid. Prepared by reaction with aldehyde and sodium cyanoborohydride.

The reaction conditions used to prepare the starting material fluoro benzoyl indolin-2-one are described in more detail in the preparation examples below.

[Production Example 1]

7- (4-fluorobenzoyl) -3-methylthioindolin-2-one

42.2 g (0.196 mole) of 2-amino-4'-fluorobenzophenone are dissolved in 2 l of methylene chloride, cooled to -65 ° C and then 26.5 g (0.198 mole) of ethylmethylthio acetate are added. A solution of 23.0 g (0.21 mol) of 95% tertiary butoxychloride dissolved in 50 ml of methylene chloride is added dropwise and the temperature is kept below -65 ° C. After 1 min 22.2 g (2.22 mole) triethyl amine was added dropwise and warmed to room temperature. The solution is concentrated to 700 ml and washed with water. The organic solution is concentrated and the residue is dissolved in 400 ml of methanol containing 30 ml of concentrated hydrochloric acid. The mixture is heated to reflux for 1 hour, cooled, left overnight and the crystals collected and washed with methanol to yield 31.4 g of a pale yellow solid.

Melting Point: 165-167.5 ° C. Yield 53%

Assay: C ₁₆ H ₁₂ NO ₂ FS

Calculated Value: C63.77, H4.01, N4.65

Found: 63.58, 4.11, 4.67

[Production Example 2]

Equivalent molar amount in place of 2-amino-4'-fluorobenzophenone

2-amino-4'-fluoro-4-methylbenzophenone,

2-amino-4'-fluoro-5-methylbenzophenone,

2-amino-4'-fluoro-6-methylbenzophenone,

2-amino-4'-fluoro-4-chlorobenzophenone,

2-amino-4'-fluoro-5-chlorobenzophenone,

2-amino-4'-fluoro-6-chlorobenzophenone,

Using 2-amino-4'-fluoro-5-methoxybenzophenone

7- (4-fluorobenzoyl) -4-methyl-3-methylthioindolin-2-one,

7- (4-fluorobenzoyl) -5-methyl-3-methylthioindolin-2-one,

7- (4-fluorobenzoyl) -6-methyl-3-methylthioindolin-2-one,

7- (4-fluorobenzoyl) -4-chloro-3-methylthioindolin-2-one,

7- (4-chlorobenzoyl) -5-chloro-3-methylthioindolin-2-one,

7- (4-fluorobenzoyl) -6-chloro-3-methylthioindolin-2-one,

7- (4-fluorobenzoyl) -5-methoxy-3-methylthioindolin-2-one is obtained.

[Manufacture example 3]

7- (2-fluorobenzoyl) -3-methylthioindolin-2-one

86 g (0.4 mole) of 2-amino-2'-fluorobenzophenone is dissolved in 3 l of methylene chloride, cooled to -65 ° C, and 54 g (0.4 mole) of ethyl methylthioacetate is added. A solution of 46 g (0.42 mol) of 95% tert-butoxy-chloride dissolved in 100 ml of methylene chloride was added dropwise and the temperature was kept below -65 ° C. After 1 hour, 41 g (0.4 mol) of triethylamine was added dropwise and warmed to room temperature. The solution is concentrated to about 1400 ml and washed with water. The organic solution is concentrated and the residue is dissolved in 800 ml of methanol containing 600 ml of concentrated hydrochloric acid. The mixture is heated to reflux for 1 hour and then cooled. The mixture was left overnight and the crystals were combined and recrystallized with 20% aqueous ethanol to give 66 g of pale yellow acicular crystals (melting points 147 to 148.5 ° C).

Yield: 55%

Assay: C ₁₆ H ₁₂ NO ₂ FS

Calculated Value: C63.77, .H4.01 N4.65

Found: 63.97, 4.19, 4.66

[Production Example 4]

7- (3-fluorobenzoyl) -3-methylthioin using equimolar amount of 2-amino-3'-fluorobenzophenone instead of 2-amino-2'-fluorobenzophenone by the method of Preparation Example 3 Obtain dolan-2-one.

Production Example 5

40.0 g (0.133 mole) of 7- (4-fluorobenzoyl) -3-methylthio indolin-2-one and 40.0 g (0.34 mole) of tin powder were added to 1 l of 95% ethanol at reflux. After heating, 100 ml of concentrated hydrochloric acid is added. The mixture is heated for 6 hours and filtered while warming. The filtrate is cooled and the precipitates are combined and recrystallized from isopropyl alcohol to give 24.5 g of off-white needle crystal (melting point 185 ° to 187.0 ° C). Yield 72%

Analysis: C ₁₅ H ₁₀ NO ₂ F

Calculation: C70.58, H3.95, N5.49

Found: 70.80 4.12, 5.51

[Manufacture example 6]

Equivalent molar amount instead of 7- (4-fluorobenzoyl) -3-methylthioindolin-2-one by the method of Preparation Example 5.

7- (4-fluorobenzoyl) -4-methyl-3-methylthioindolin-2-one,

7- (4-fluorobenzoyl) -5-methyl-3-methylthioindolin-2-one,

7- (4-fluorobenzoyl) -6-methyl-3-methylthioindolin-2-one,

(7- (4-fluorobenzoyl) -4-chloro-3-methylthioindolin-2-one,

7- (4-fluorobenzoyl) -5-chloro-3-methylthioindolin-2-one,

7- (4-fluorobenzoyl) -6-chloro-3-methylthioindolin-2-one,

Using 7- (4-fluorobenzoyl) -5-methoxy-3-methylthioindolin-2-one

7- (4-fluorobenzoyl) -4-methylindolin-2-one,

7- (4-fluorobenzoyl) -5-methylindolin-2-one,

7- (4-fluorobenzoyl) -6-methylindolin-2-one,

7- (4-fluorobenzoyl) -4-chloroindolin-2-one,

7- (4-fluorobenzoyl) -5-chloroindolin-2-one,

7- (4-fluorobenzoyl) -6-chloroindolin-2-one,

7- (4-fluorobenzoyl) -5-methoxyindolin-2-one is obtained.

[Manufacture example 7]

7- (2-fluorobenzoyl) -indolin-2-one

60 g (0.2 mole) of 7- (2-fluorobenzoyl) -3-methylthioindolin-2-one and 60 g (0.5 mole) of tin powder were added to 1 l of 95% ethanol and heated to reflux. Then 150 ml of concentrated hydrochloric acid are added. The precipitates are combined by heating for 18 hours, cooling the mixture and inclining the slurry from the remaining tin and then filtering. The filter cake was recrystallized twice with anhydrous ethanol to give 31 g of white needle crystals.

Melting Point: 209-210 ℃

Yield: 60%

Analysis: C ₁₅ H ₁₀ NO ₂ F

Calculation: C70.58 H3.95 N5.49

Found: 70.31 4.08 5.56

[Manufacture example 8]

A molar amount of 7- (3-fluorobenzoyl) -3-methylthioindolin-2-one was substituted for 7- (2-fluorobenzoyl) -3-methyl thioindolin-2-one by the method of Preparation Example 7. To give 7- (3-fluorobenzoyl) indolin-2-one.

[Manufacture example 9]

In the method of Preparation Example 1, 7- (4-fluorobenzoyl) -3-methylindolin-2-one is obtained using an equimolar amount of ethyl α- (methylthio) propionate instead of ethyl methylthioacetate.

Preparation Example 10

7- (4-fluorobenzoyl) -3-methylindolin using an equimolar amount of 7- (4-fluorobenzoyl) -3-methyl-3-methylthioidolin-2-one by the method of Preparation Example 5. To obtain 2-one.

The novel intermediates and reaction conditions used to prepare the compounds of the present invention are detailed in the Examples below.

Example 1

7- (4-methylthiobenzoyl) indolin-2-one

Sodium methyl mercaptide solution prepared by reacting 400 ml of 3N sodium hydroxide with 24 g (0.5 mol) of methyl sulfide was mixed with 25.5 g (0.1 mol) of 7- (4-fluorobenzoyl) indolin-2-one. do. The mixture is refluxed for 1.5 hours, cooled and acidified. (Note: A large amount of methyl sulfide is rapidly generated.) The resulting precipitate is collected and recrystallized twice with benzene to give 17.8 g of yellow crystals.

Melting Point: 167.0 ~ 169.0 ℃

Yield 70%

Analysis: C ₁₆ H ₁₃ NO ₂ S

Calculation: C67.82, H4.63, N4.94

Found: 67.65 4.63 4.91

Example 2

Equivalent molar amount instead of 7- (4-fluorobenzoyl) indolin-2-one by the method of Example 1

7- (4-fluorobenzoyl) -4-methylindolin-2-one,

7- (4-fluorobenzoyl) -5-methylindolin-2-one,

7- (4-fluorobenzoyl) -6-methylindolin-2one,

7- (4-fluorobenzoyl) -4-chloroindolin-2-one,

7- (4-fluorobenzoyl) -5-chloroindolin-2-one,

7- (4-fluorobenzoyl) -6-chloroindolin-2-one,

7- (4-fluorobenzoyl) -5-methoxyindolin-2-one,

7- (2-fluorobenzoyl) indolin-2-one,

Using 7- (3-fluorobenzoyl) indolin-2-one

7- (4-methylthiobenzoyl) -4-methylindolin-2-one,

7- (4-methylthiobenzoyl) -5-methylindolin-2-one,

7- (4-methylthiobenzoyl) -6-methylindolin-2-one,

7- (4-methylthiobenzoyl) -4-chloroindolin-2-one,

7- (4-methylthiobenzoyl) -5-chloroindolin-2-one,

7- (4-methylthiobenzoyl) -6-chloroindolin-2-one,

7- (4-methylthiobenzoyl) -5-methoxyindolin-2-one,

7- (2-methylthiobenzoyl) indolin-2-one,

7- (3-methylthiobenzoyl) indolin-2-one is obtained.

Example 3

Example 1 7- (4-ethylthiobenzoyl) indoline using equimolar amounts of sodium ethyl mercaptide, sodium isopropyl mercaptide, sodium-n-butylmercaptide instead of sodium methyl mercaptide 2-one, 7- (4-isopropylthiobenzoyl) indolin-2-one, 7- (4-n-butylthiobenzoyl) indolin-2-one is obtained.

Example 4

Sodium 2-amino-3- (4-methylthiobenzoyl) -phenylacetic acid monohydrate

5.2 g (0.018 mol) of (7-4-methylthiobenzoyl) indolin-2-one was added to 75 ml of 3N sodium hydroxide and the mixture was heated to reflux for 20 hours. Cooling of the red solution forms a yellow precipitate. The precipitates are combined by filtration, washed with a small amount of cold water and ground with tetrahydrofuran. The precipitate was isolated by filtration again, dried and recrystallized with 95% ethanol to give 4.9 g of light brown needles.

Melting Point: 244 ~ 247 ℃

Yield 83%

Assay: C ₁₆ H ₁₆ NO ₄ SNa

Calculated Value: C56.30, H4.72, N4.10

Found: 56.38, 4.62, 4.17

Example 5

Equivalent molar amount instead of 7- (4-methylthiobenzoyl) indolin-2-one by the method of Example 4.

7- (4-methylthiobenzoyl) -4-methylindolin-2-one,

7- (4-methylthiobenzoyl) -5-methylindolin-2-one,

7- (4-methylthiobenzoyl) -6-methylindolin-2-one,

7- (4-methylthiobenzoyl) -4-chloroindolin-2-one,

7- (4-methylthiobenzoyl) -5-chloroindolin-2-one,

7- (4-methylthiobenzoyl) -6-chloroindolin-2-one,

7- (4-methylthiobenzoyl) -5-methoxyindolin-5-one,

7- (2-methylthiobenzoyl) indolin-2-one,

7- (3-methylthiobenzoyl) indolin-2-one,

7- (4-ethylthiobenzoyl) indolin-2-one,

7- (4-isopropylthiobenzoyl) indolin-2-one,

Using 7- (4-n-butylthiobenzoyl) indolin-2-one

Sodium 2-amino-3- (4-methylthiobenzoyl) -6-methylphenyl acetic acid,

Sodium 2-amino-3- (4-methylthiobenzoyl) -5-methylphenyl acetic acid,

Sodium 2-amino-3- (4-methylthiobenzoyl) -4-methylphenylacetic acid,

Sodium 2-amino-3- (4-methylthiobenzoyl) -6-chlorophenylacetic acid,

Sodium 2-amino-3- (4-methylthiobenzoyl) -5-chlorophenylacetic acid

Sodium 2-amino-3- (4-methylthiobenzoyl) -4-chlorophenylacetic acid,

Sodium 2-amino-3- (4-methylthiobenzoyl) -5-methoxyphenylacetic acid,

Sodium 2-amino-3- (2-methylthiobenzoyl) -phenylacetic acid,

Sodium 2-amino-3- (3-methylthiobenzoyl) -phenylacetic acid,

Sodium 2-amino-3- (4-ethylthiobenzoyl) -phenylacetic acid,

Sodium 2-amino-3- (4-n-butylthiobenzoyl) -phenylacetic acid,

Sodium 2-amino-3- (4-isopropylthiobenzoyl) -phenylacetic acid is obtained.

Example 6

7- (4-methylthiobenzoyl) -3-methylindolin-2-one

By the method of Example 1, the title compound is obtained using 7- (4-fluorobenzoyl-3-methyl) indolin-2-one instead of 7- (4-fluorobenzoyl) indolin-2-one. .

Example 7

Sodium 2-amino-3- (4-methylthiobenzoyl) -α-methyl phenylacetic acid

A solution of 7- (4-methylthiobenzoyl) -3-methyl-indolin-2-one suspended in sodium hydroxide is refluxed under nitrogen atmosphere, water is removed under vacuum, and the product is separated by polishing with an organic solvent. .

Example 8

Ethyl 2-amino-3- (4-methylthiobenzoyl) phenylacetate

7 g (0.05 mol) of sodium 2-amino-3- (4-methylthiobenzoyl) phenyl acetic acid monohydrate are dissolved in 150 ml of dimethylformamide and the solution is treated with 33 g of ethyl iodide. The solution is stirred at room temperature for 2.5 hours, added to water and the mixture is extracted several times with benzene. The benzene extracts were combined, washed with diluted base and water, hayed over sodium sulfate and concentrated to afford the title compound.

Formulation and Administration

The present invention provides a composition containing the compound of the present invention as an active ingredient. An effective amount of a pharmaceutically active compound can be administered orally to a living body in a variety of ways, namely in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions, or in some cases, intravenously in the form of sterile solutions. In the compositions of the present invention the active ingredient is added to a suitable carrier, ie a pharmaceutical carrier. Suitable pharmaceutical carriers useful in formulating the compositions of the present invention are starch, gelatin, glucose, magnesium carbonate, lactose, malt and the like and suitable liquid pharmaceutical carriers are ethyl alcohol, propylene glycol, glycerin, glucose syrup and the like. .

Pharmaceutically active compounds may advantageously be administered in a unit dose of 0.1 to 150 mg, and the unit dose may be administered once or several times a day, or divided into several daily doses. The daily dose is between 0.3 and 450 mg and the optimal unit dose is estimated to be between 5 and 25 mg.

The fact that the active ingredient constitutes an effective amount, i.e. the fact that a suitable effective amount corresponds to the amount of active ingredient obtained from the amount used, is necessary. The exact personal dose and daily dose are determined according to standard medical principles under the prescription of a physician or veterinarian.

The active compounds of the present invention can be mixed with other pharmacologically active compounds or buffers, antacids, and the proportion of active ingredient in the composition can vary widely.

The following example relates to a composition according to the invention.

1. Capsule

Capsules containing 5 mg, 25 mg and 50 mg of active ingredient per capsule are prepared. As the content of the active ingredient increases, the amount of lacrose is adjusted.

Representative Encapsulation Mix mg per Capsule Representative Encapsulation Mix mg per Capsule

Active Ingredient 5.0 Starch 129.0

Lacrose 296.7 Magnesium Stearate 4.3

Preferably the capsule preparation containing a large amount of the active ingredient is as follows.

Mg per ingredient capsule mg per ingredient capsule

Active Ingredient 25.0 Magnesium Stearate 4.3

Lacrose 306.5 Total 435.0mg

Starch 99.2

In each case, the active ingredient is uniformly mixed with lacrose, starch and magnesium stearate and then the mixture is filled into capsules.

2. Tablet

Representative tablets containing 5.0 mg of the active ingredient per tablet are as follows. If the concentration of the active ingredient is different, the weight of the dicalcium phosphate is adjusted.

(1) Active Ingredients 5.0 (5) Dicalcium Phosphate 68.0

(2) corn starch 13.6 (6) calcium stearate 0.9

(3) corn starch (paste) 3.4 170.1mg

(4) Lactose 79.2

1,2,4 and 5 of the ingredients are mixed uniformly and 3 is added to water to make a 10% paste. The mixture is kneaded with starch yeast and granulated by passing through 8 mesh sieves. The wet granules are dried and sized to 12 mesh sieves. The dried granules are mixed with calcium stearate and compressed.

3. 2% sterile solution for injection

Active ingredient 20 mg

0.5% weight / volume of preservative (eg chlorobutanol)

Water for injection

After the solution is made, filtered and purified, the vial is filled, sealed and sterilized in an autoclave.

Claims (1)

A process for preparing 2-amino-3- (alkylthiobenzoyl) phenyl acetic acid derivatives of general formula (I), characterized by hydrolysis of a compound of general formula (II) with an alkali-metal base.

Wherein R is hydrogen or lower alkyl, R ¹ is hydrogen, lower alkyl or a pharmaceutically acceptable metal cation, R ² is hydrogen, halogen, lower alkyl or lower alkoxy and Am is primary amino (-NH 2) , Methylamino or dimethylamino.