Form 2
The patents Act, 1970,
(39 of 1970),
The patents rule, 2003, Complete specification See section 10 rule 13
Title of invention : A NOVEL PROCESS FOR MANUFACTURE OF INDOXACARB
Name of applicant : CHEMINOVA INDIA LTD.
Nationality : INDIAN

ADDRESS: KESHAVA, 7TH FLOOR, BANDRA KURLA
COMPLEX, BANDRA (EAST), MUMBAI-400051
The following specification particularly describes the invention and the manner in which it is to be performed

A NOVEL PROCESS FOR MANUFACTURE OF INDOXACARB FIELD OF INVENTION
The invention relates to an improved process for manufacture of Arthropodicidal Oxadiazines, particularly lndoxacarb[l], by a novel Carbmethoxylation process of the Intermediate Urea derivative[ll] having a chiral centre(*), using Methyl Chloroformate.

The invention relates particularly to a suitable solvent which is safe and convenient for large scale manufacturing process.
BACKGROUND OF THE INVENTION
It is known that Oxadiazine compound of formula[l] known as Indoxacarb is effective in controlling harmful arthropods, particularly Lepidoptera insects in crops. This is disclosed in patent WO 9211249, USP 5462938 etc. Indoxacarb exists in two chiral forms, [S] and [R]. Only [S] form is active towards controlling the insects. Industrially the synthesis is done using a chiral catalyst and an enantiomeric ratio of 75:25 [S:R] is obtained, Though the chiral isomers can be obtained in pure form by crystallization the inactive isomer [R] is not possible to be racemised and hence not economically viable to adopt separation. The patents disclose a manufacturing method which is by another route involving phosgene usage and catalytic hydrogenolysis which the authors of this invention did not find suitable due to techno commercial reasons; mainly use of poisonous phosgene and exorbitant cost of catalyst Pd/C used for hydrogenolysis.
Patent WO 9211249 by DUPONT mentions the carbmethoxylation process of the urea derivative of oxadiazine with Methyl Chloroformate using Sodium hydride as a base, in DMF solvent. However the patent does not give details of the conditions of the process or the results. The authors of this invention also found that the method given in the patent does not work satisfactorily.
The patent IN241255 is an improvement of the above process using a mixed solvent comprising Toluene and Monoglyme in varying ratio of solvents .It is claimed that the chiral ratios do not change under different solvent ratios.
However the authors of this invention found that the above process given in IN 241255 suffers from various deficiencies such as use of large quantity of mixed solvent fire hazards resulting from use of Sodium Hydride and solvents with low flash points, like Toluene-4.4°c,Monoglyme-4.5°c etc.

Our research on this process has resulted in the present invention of use of two solvents, one with higher flash point and the other a nonflammable one. The solvents are Methylene dichloride[MDC] which is nonflammable and Acetonitrile [AN] with flash point-12.8°C. These solvents in various mixtures or Acetonitrile as a single solvent can be used . The solvent MDC gives the additional advantage in work up and product isolation. Mono Chloro benzene is also usable in place of MDC.
Our finding is also that the chiral ratios are fixed at the intermediate stage and it does not change under the carbmethoxylation reaction conditions. In other words racemisation does not occur during reaction.
SUMMARY OF THE INVENTION
The existing practices in the industry for manufacture of Indoxacarb is clumsy in terms of solvent choice. Solvents like Dimethyl formamide[DMF] is high boiling, water soluble, difficult to recover etc .Use of mixed solvents like Toluene mixed with Monoglyme etc. Poses it's own problems in a manufacturing plant. Also use of large quantities of solvents is undesirable in industry. Our research was focused on finding a single solvent with high flash point, in which the reaction could be done and work up of the reaction mass also could be done in the same solvent. In the above mentioned patents, the reaction solvent mixture has to be recovered and new water immiscible solvent has to be used for work up and isolation of the product, which is inconvenient as an industrial practice .
Our experiments led us to the selection of two solvents, Methylene di Chloride[CH2CI2]and Acetonitrile as a mixture in any ratio as suitable solvents for the reaction. The reaction mass can be worked up in the same solvent for recovery of the product. Thus, an easy to operate and convenient process for Carbmethoxylation to make Indoxacarb is developed.
Methylene Chloride is a unique solvent for this reaction due to it's low boiling point, immiscible with water and it's general non reactivity to nucleophiles unlike other halo compounds. A small quantity of Acetonitrile added to MDC offers a smooth reaction. The reaction takes place in Acetonitrile alone as solvent but with more quantity for solubility.Mono chloro benzene is also a good solvent in place of MDC,it's only disadvantage being higher boiling point.
The reaction condition has no effect on the chirality of the molecule and the same chiral ratio of starting intermediate is retained. The chiral ratio of starting intermediate and resulting Indoxacarb is normally same as 76/24 of S/R forms.
The reagent used are industrial grade Methyl chloro formate of purity 98% min., paraffin coated NaH having 65 % purity etc. The reaction is carried out at -15°c to +30 °c preferably 0 to +5°c.

EXAMPLES:
Following are examples given to illustrate the invention and not limiting of the disclosure in any way whatsoever.
Example-1
In an RB flask having agitator and cooling system,118 gms Methyl -7-chloro-2,5-dihydro-2-[[[(4-trifluoro methoxy) phenyl]amino]carbonyl3-indeno[1,2-e][1,3,4]oxadiazine-4a(3H) carboxylate (II) analysing 76% S-isomer was reacted with 20 gms sodium hydride[NaH] 60% purity in 600 ml Methylene dichloride[MDC] solvent and 60 ml Acetonitrile solvent at 0°C and further reacted at same temperature with 48 gms Methyl chloroformate [MCF].The reaction is completed in one hr, monitored by GC till <2% starting material is left. The reaction mass is brought to 30°C and neutralized with Acetic acid , salt is filtered & concentrated to get a semisolid mass resulting in 91% yield and 94% purity of Indoxacarb. The chiral purity remained same 76% S-isomer.
Example-2
In an RB flask having agitator and cooling system, 141 gms Methyl -7-chloro-2,5-dihydro-2-[[[(4-trifluoro methoxy) phenyl]amino]carbonyi]-indeno[1,2-e][1,3,4]oxadiazine-4a(3H) carboxylate (II) analysing 76% S-isomer was reacted with 21 gms sodium hydride[NaH] 60% purity in 570 ml Acetonitrile and 30 ml Methylene dichloride[MDC] at -10°C and further reacted at 15°C to 20°C with 57 gms Methyl chloroformate[MCF]The reaction is completed in one hr, monitored by GC till <2% starting material is unreacted. . The reaction mass is brought to 30°C and neutralized with Acetic acid , salt is filtered & concentrated to get a semisolid mass resulting in 95% yield and 95% purity of Indoxacarb. The chiral purity remained same 76% S-isomer.
Example-3
In an RB flask having agitator and cooling system,141 gms Methyl -7-chloro-2,5-dihydro-2-[[[(4-trifluoro methoxy) phenyl]amino]carbonyl]-indeno[1,2-e][1,3,4]oxadiazine-4a(3H) carboxylate (II) analysing 76% S-isomer was reacted with 22 gms sodium hydride[NaH] 60% purity in 250 ml Methylene dichloride[MDC] solvent mixed with 250 ml Acetonitrile], at 0°C and further reacted at 0°C to 15°C with 57 gms Methyl chloroformate[MCF].The reaction is completed in one hr.monitored by hplc till <2% starting material is unreacted. The reaction mass is brought to room temp, of about 30°C.Excess NaH is destroyed using glacial Acetic acid. The mass is washed with water .layer separated and concentrated to get a semisolid mass resulting in 94% yield and 95.2% purity of Indoxacarb. The chiral purity remained same 76% S-isomer.

Example-4
In an RB flask having agitator and cooling system, 141 gms Methyl -7-chloro-2,5-dihydro-2-[[[(4-trifluoro methoxy) phenyl]amino]carbonyl]-indeno[1,2-e][1,3,4]oxadiazine-4a(3H) carboxylate (II) analysing 76% S-isomer was reacted with 22 gms sodium hydride[NaH] 60% purity in 1570 ml Acetonitrile at 15 °C and further reacted at 15°C to 20°C with 57 gms Methyl chloroformate[MCF].The reaction completed in Two hrs, monitored by GC till <2% starting material. The reaction mass is brought to 30°C and neutralized with Acetic acid , solvent is distilled out & worked up to isolate the product .resulted 95% yield and 95% purity of Indoxacarb. The chiral purity remained same 76% S-isomer.
CLAIMS:
Our claims through this invention are;
1. A process for the N-Carbo methoxylation of intermediate [II] using Methyl chloro formate and Sodium hydride in a solvent system, of Methylene dichloride and Acetonitrile as a mixture in varying ratios, at a temperature of -0°C to 30°C resulting in lndoxacarb[l]

2. A process as claimed in claim-1 where in the solvent Methylene dichloride is spiked with 5-10% by volume Acetonitrile.
3. A process as claimed in claim-1 where in the solvent Acetonitrile is spiked with 10% Methylene di chloride.
4. A process as claimed in claim -1 where in 50/50mixture of Methylene dichloride and Acetonitrile is used.
5. A process as claimed in claim-1 where in solvent ratio varying from 10% to 90 % Methylene di chloride and rest Acetonitrile and vice a versaje 10% to 90% Acetonitrile and rest Methylene dichloride is used.
6. A process as claimed in claim-1 where in the solvent Acetonitrile alone is used.
7. A process as claimed in claim-1 where in Mono chloro benzene in combination with Acetonitrile is used as a solvent.