FI88500C - Process for the preparation of 1- (p-chlorobenzoyl) -5-methoxy-2-methylindo-3-acetic acid carboxymethyl ester - Google Patents

Description

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Process for the preparation of 1- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid carboxymethyl ester The present invention relates to a process for the preparation of 1- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid carboxymethyl ester, hereinafter referred to as acacetine. Acetazine of structural formula (I) can be used as an anti-inflammatory drug.

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h, co'? indole-3-acetic acid (II), hereinafter referred to as indomethacin.

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(II) The alkali metal salt of indomethacin is reacted with benzyl bromoacetic acid to give the benzyl ester of acetazine, from which the benzyl group is removed by catalytic reduction. In this case, a deslorine compound and a trivalent acid are formed as by-products. Acetazine also always contains indomethacin-35 as an impurity which is difficult to remove by recrystallization.

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FI 78467 discloses an improved process for the preparation of acetazine from indomethacin and tert-butyl chloroacetate in Ν, Ν-dimethylformamide in the presence of potassium fluoride. Tert-butyl chloroacetate is prepared from mono-chloroacetic acid and isobutylene. The resulting acetazine tert-butyl ester is crystallized from a mixture of benzene and n-hexane. The tert-butyl protecting group of acemethacin tert-butyl ester is removed with, for example, trifluoroacetic acid or formic acid and the crude product is recrystallized from benzene or a mixture of acetone and n-hexane.

The process described uses tert-butyl ester, which has to be prepared in diethyl ether from monochloroacetic acid and isobutylene gas (Chemical Abstracts 56,5968), which forms an explosive mixture with moisture in air. The handling of diethyl ether and isobutylene is cumbersome on an industrial scale and poses occupational safety risks.

Deprotection of the tert-butyl group is accomplished under acidic conditions, with acacetazine readily partially hydrolyzed to indomethacin. This is a particular problem on an industrial scale, where considerably longer reaction times have to be used than on a laboratory scale. In addition, the benzene used in the crystallizations is known to be a carcinogen which poses a significant occupational safety risk.

Based on our studies, the method according to patent FI 78467 left 0.8-1% unreacted acetazine tert-butyl ester in the product and the yield was about 92%.

? In addition, both acetazine tert-butyl ester and acacetazine will have to be recrystallized in the process of this patent.

3. This invention is based on the application of phenyl protection of carboxylic acids used in peptide synthesis (Houben-Weyl, Methoden den organischen Chemie, Band 15, Teil 1. p. 402) in the preparation of acacetine. Indomethacin is reacted with phenyl bromoacetate to give the phenyl ester of acacetazine from which the phenyl protecting group is removed with hydrogen peroxide. This method does not have the disadvantages of the previous methods. The reactions take place in good yield under mild conditions. Deprotection 10 is performed with hydrogen peroxide at about pH 8, thus avoiding possible ester degradation, i.e. hydrolysis of acacetazine to indomethacin. The raw materials used in the reaction are cheap; the phenyl bromoacetate used as a starting material can be purchased or also easily prepared by a known method.

It is surprising that the removal of the phenyl protecting group is already possible at about pH 8, although according to the literature in peptide synthesis it is done at pH 10.

The process according to the invention is characterized in that a compound of formula (III), X-CH 2 CO 2 - (3) (III), wherein X is a halogen atom, is reacted with indomethacin of formula (II) at 30 ° C-O- · ChjCooh 35 (II) c- 3 5 at 0 ° C to 150 ° C with a reaction time of 10 minutes to a few hours to give the phenylacetazine phenyl ester of formula (IV).

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The phenyl protecting group is removed from the phenyl ester of the acacetazine by treatment with hydrogen peroxide or sodium hypochlorite at a temperature between 0 'and 50 ° C for 10 minutes to a few hours to give pure acacetazine (I).

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In the compound of formula (III), X is a halogen atom: chlorine, iodine, fluorine or bromine. The compound of formula (III) phenyl haloacetate can either be purchased or easily prepared in a known manner from, for example, bromoacetic acid and phenol * in xylene.

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In preparing acacetazine by the process of the invention, indomethacin (II) and phenyl haloacetate (III), most preferably phenyl bromine or phenyl chloroacetate, are first reacted in a solvent in the presence of an early metal carbonate or alkali metal bicarbonate or a tertiary amine, most preferably potassium carbonate. The preferred solvent is N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, methyl ethyl ketone or the like.

1 ° The reaction is most preferably allowed to proceed from room temperature to 150 ° C, most preferably at 30 ° C, for a reaction time of 10 minutes to several hours. The phenyl protecting group of the phenylester of the azacetazine thus obtained is removed with hydrogen peroxide in a solvent such as isopropanol, N, N-dimethylformamide, tetrahydrofuran or the like in the presence of a base such as morpholine or triethylamine, most preferably triethylamine. The reaction is allowed to proceed from 0 ° C to 50 ° C, most preferably at 35 ° C, for a reaction time of 10 minutes to a few hours.

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The process according to the invention for the preparation of acetazine is industrially well-functioning and economical, the yields of the process are good and the conditions are mild. The acacetazine prepared by the process of the invention is pure and thus does not require recrystallization.

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The following examples illustrate the invention.

Example 1

Dissolve 150 g of indomethacin in 500 ml of N, N-dimethylformoid. 48 g of potassium carbonate and 95 g of phenyl bromoacetate are added to the solution. Heat the mixture to 30 ° C with stirring for 2 hours. 630 ml of toluene and 530 ml of water are added to the mixture. The layers are separated and the solvent is distilled off from the toluene layer. The residue is crystallized by heating and cooling from 2500 ml of isopropanol. The precipitate is filtered off, washed with chilled isopropanol and dried. The yield of acemethacin phenyl ester is 200 g (97% of theory) and the m.p. 102-104 ° C.

Example 2

The phenyl ester of acemethacin can be prepared by the method and amounts of Example 1 using N-methylpyrrolidone instead of N, N-dimethyl-n-formamide. The yield is then 198 g (96% of theory) and the m.p. 101-103 ° C.

Example 3 s 120 g of indomethacin are dissolved in 430 ml of N, N-dimethylformamide. 36 g of potassium carbonate and 61 g of phenyl chloroacetate are added to the solution. Heat the mixture to 30 ° C with stirring for 2 hours. 600 ml of toluene and 500 ml of water are added to the mixture. The layers are separated and the solvent is distilled off from the toluene layer in vacuo. The residue is crystallized by heating from 2000 ml of isopropanol. The precipitate is filtered off, washed with chilled isopropanol and dried. The yield of acemethacin phenyl ester is 153 g (93% of theory) and the m.p. 102-104 ° C.

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Example 4

Acetazetine phenyl ester can be prepared by the method and amounts of Example 1 using 58 g of triethylamine instead of potassium carbonate as base 5. The yield is then 185 kg (90% of theory) and the m.p. 101-102 ° C.

Example 5 1 ° 120 g of phenylacetazine phenyl ester are slurried in a mixture of 820 ml of isopropanol and 70 ml of water. 22 g of an aqueous hydrogen peroxide solution (50% concentration) are added to the mixture. 46 g of triethylamine are added to the reaction mixture at 30-35 ° C, maintaining the pH at 6.5-8.5. Stir at the reaction temperature for 4 hours. The mixture is cooled to 20 ° C and adjusted to pH 3.0 with hydrochloric acid. The mixture is cooled and the crystallized precipitate is filtered off, washed with chilled isopropanol and dried at 70-75 ° C. The yield of asemethacin is 96 g (95% of theory) and the m.p. 150-151 ° C. Content of the substance 99.4% (HPLC; area%).

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Example 6

Acetazine can be prepared by the method and amounts of Example 5 using a base instead of triethylamine as the base. The yield is then 88 g (88% of theory) and the m.p. 149-150 ° C.

Claims (6)

A process for the preparation of 1- (p-chloro-benzoyl) -5-methoxy-2-methyl-indole-3-acetic acid carboxymethyl ester of the formula (I) wherein Cl 0 CO χώτ *, CH 2 -CO-CH reacting a compound of formula (III) X-CH 2 CO 2 - (1) wherein X is a halogen atom with 1- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3- with acetic acid, at a temperature between CO 2 10 ° C and 150 ° C to give 1- (p-chlorobenzoyl) -5-methoxy compound of formula (IV). 2-Methyl-indole-3-acetic acid phenylcarboxymethyl ester, CJ O CO WVch, HjC-O * ^ W-O-CH, .C «hQ (IV) 9. S 5 G O and the phenyl protecting group are removed from the phenylcarboxymethyl ester of 1- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid by treatment with hydrogen peroxide at a temperature between 0 ° C and * 50 ° C. 5 2. A compound according to claim 1, which comprises chlorine or bromine. Process according to Claim 1, characterized in that X is chlorine or bromine. Process according to Claim 1 or 2, characterized in that the reaction between 1- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid and phenylhaloacetate is carried out in N, N-dimethylformamide, In Ν-dimethylacetamide, N-methylpyrrolidone or methyl ethyl ketone. 15 Process according to one of Claims 1 to 3, characterized in that the reaction between 1- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid and phenylhaloacetate is carried out with potassium carbonate, sodium carbonate, potassium hydrogen carbonate or triethylamine. acid. Process according to one of Claims 1 to 4, characterized in that the removal of the phenyl group takes place in isopropanol, Ν, Ν-dimethylformamide or tetrahydrofuran. Process according to one of Claims 1 to 5, characterized in that triethylamine or morpholine is used as the base in the removal of the phenyl group. ίο b 8 5 Ο ϋ l.Forfarande för framställning av l- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid carboxymethyl ester with the formula (I) Cl φ CO, nbr, (i> HjC-lr ^ NtHj-CO-CHj-COOH can be converted to the halogen atom of formula (III) X-CH2CO2 (III) halogen, 1- (p-chlorobenzoyl) -5-methoxy-2- methylindole-3-acetic acid from formula (II) JÖÖC "'<«> CH, C00M at a temperature of 0 * C and 150 * C, color of 1- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3 -Atixyl phenylcarboxymethyl ester of formula (IV) Cl 0 CO MjC-O 2 H 2 -O-CH 7 -CCOCH 4 (IV) ^ <nr VW w V- / O varefter 1- (p-chlorobenzoyl) - 5 -methoxy-2-methylindole-3-acetyl-cyano phenylcarboxymethyl esters of phenylcarboxyl groups of the genome after treatment with sulfur peroxide at temperatures between 0 * C and 50 * C 5 3. A compound according to claims 1 or 2, which can be reacted with 1- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid and phenyl haloacetate to give Ν, Ν-dimethylformamide, N, N-dimer. -ethylacetamide, N-methylpyrrolidone or methyl ethyl ketone. 15 4. For example, a mixture of potassium carbonate, sodium carbonate, potassium carbonate or triethylamine is used. 2Π 5. A compound according to claims 1-4, which comprises the phenyl group of isopropanol, N, N-dimethylformamide or tetrahydrofuran. 1 6. A preferred embodiment of claims 1-5, which comprises the use of triphylamine or a morpholine base.