Single step regioselective cyclization and chlorination of hydroxyamino-N-(2-methylphenyl)acetamide to 5-chloro-7-methylindoline-2,3-dione

Abstract

A one-pot process for the manufacture of 5-chloro-7-methylindoline-2,3-dione starting from 2-hydroxyimino-N-(2-methylphenyl)acetamide via tandem cyclization in sulfuric acid and acetic acid, followed by in-situ chlorination with sulfur dioxide and chlorine gas in high regioselectivity and yield.

Claims

1. A process that reacts 2-hydroxyimino-N-(o-tolyl) acetamide with a mixture of sulfuric acid and acetic acid followed by reaction with sulfur dioxide and chlorine gas to yield 5-chloro-7-methylindoline-2,3-dione.

2. A process according to claim 1 wherein the sulfuric acid is between 18M and 18.4M concentration.

3. A process according to claim 1 wherein the acetic acid is between 17M and 17.4M concentration.

4. A process according to claim 1, wherein the volumetric ratio of sulfuric acid to acetic acid is 2:1.

5. A process according to claim 1, wherein the reaction temperature of the sulfuric acid and acetic acid is between 50 and 60 C.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) Before describing the present invention in detail, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

(2) In accordance with the present invention, there is provided a process to produce, in a highly regiospecific and cost effective manner, the agrochemical intermediate 5-chloro-7-methylindoline-2,3-dione.

(3) In one embodiment of the present invention, a process is described for the preparation of 5-chloro-7-methylindoline-2,3-dione by reacting 1.0 equivalent of 2-hydroxyimino-N-(o-tolyl)acetamide dissolved in 2.0 equivalent of acetic acid with 4.0 equivalent of sulfuric acid at 55 C. followed by addition of 0.3 equivalent sulfur dioxide and 1.5 equivalent chlorine gas and heating the mixture to 65 C. for 2 hours. The reaction mass is added to 10.0 equivalent of ice water, stirred and filtered to yield the desired 5-chloro-7-methylindoline-2,3-dione in high yield and purity.

(4) It will be clear to those skilled in the art that modifications can be made to the process described herein without departing from the inventive concept set forth in our claims below.

(5) ##STR00001##

(6) 70 g of N-(o-tolyl)acetamide is dissolved in 300 ml of acetic acid and this mixture was taken in 500 ml of RBF. This mixture was cooled to 25 C., and 50 g of chlorine purged to mass. Reaction mass was gradually heated to reflux temperature for 2 hr. After completing the reaction acetic acid was distilled out and quenched with water to get 25 g (50% GC yield) of N-(4-chloro-2-methylphenyl)acetamide.

(7) ##STR00002##

(8) 15 g of 2-(hydroxyimino)-N-(o-tolyl)acetamide was dissolved in 150 ml of acetic acid and this mixture was taken in 250 ml of RBF. This mixture was cooled to 25 C., and 50 g of chlorine purged to mass. Reaction mass was gradually heated to reflux temperature for 2 hr, reaction mass was monitored by HPLC, and found formation of more impurities.

(9) ##STR00003##

(10) 29.4 g (0.2 mole) of 7-methyl isatin was dissolved in 2220 ml of acetic acid and this mixture was taken into a kettle and was cooled to 25 C. 28 g of chlorine was purged into the kettle and the reaction mass was slowly heated to reflux condition and maintained for 3 hr. Reaction was monitored by HPLC method, reaction completed with less than 70% of regio-selective product formed.

(11) ##STR00004##

(12) 39.2 g (0.4 mole) of concentrated sulphuric acid was taken into a RBF, heated to 50-60 C. 17.8 g of (0.1 mole) of 2-(hydroxyimino)-N-(o-tolyl)acetamide was dissolved in 20 ml of acetic acid at hot condition and this solution was slowly added to the reaction mass over the period of 20-30 mins. After completion of this stage the mass was cooled to room temperature. 0.03 mole of sulphur dioxide was purged into reaction mass followed by addition of 0.15 mole of chlorine gas into reaction mass. This reaction mixture was heated to 60-65 C. and cooking for 2 hr. After completion of reaction, mass was quenched in ice cool water. The precipitated solid was filtered and dried to yield 15 g (77% of yield) of 5-chloro-7-methylindoline-2,3-dione and 98% regioselectivity.

(13) ##STR00005##

(14) 39.2 g (0.4 mole) of concentrated sulphuric acid was taken into RBF and then heated to 50-60 C. 17.8 g of (0.1 mole) of 2-(hydroxyimino)-N-(o-tolyl)acetamide was added slowly into reaction mass over the period of 20-30 mins. After completion, the mass is cooled to room temperature. Reaction mass became thick and started purging of SO.sub.2 gas followed by Cl.sub.2 gas. There was no reaction observed.