FORM 2
The Patent Act 1970,
(39 of 1970)
&
The Patent rule 2003
Complete Specification
(See Section 10 and Rule 13)
1. TITLE OF THE INVENTION
" A PROCESS FOR LARGE SCALE MANUFACTURE OF INDOXACARB"
2. APPLICANT(S)
(a) NAME : GHARDA CHEMICALS LTD
(b) NATIONALITY: INDIAN
(c) ADDRESS: B-27/29, MIDC, PHASE 1, DOMBIVLI.
DIST. THANE, PIN 421 203 MAHARASHTRA INDIA
3. PREAMBLE OF THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION
This invention relates to an improved methodology for N-Carbomethoxylation using sodium hydride particularly of 1,3,4 oxadiazine of formula (II) having increasing ratios of S.R including greater than or equal to 99 % S-isomer to achieve large scale manufacturing process for Oxadiazine of formula (I) with preservation of enantiomeric
integrity through out the stages of conversion and isolation

BACKGROUND OF INVENTION
Arthropodicidal Oxadiazines are disclosed in W09211249. Indoxacarb is one of the important insecticides disclosed in W09211249 which is used for control of lepidoptera insects which creates economic damage to variety of crops. W09211249 also discloses the method of making Indoxacarb having racemic composition of two optically active isomers.
W0952917 discloses preparation of entiomerically enriched Indoxacarb by asymmetric synthetic approach. Asymmetric synthesis of hydroxy indanone intermediate followed by subsequent synthesis of Indoxacarb with retention of enantiomeric excess gives a commercial Indoxacarb having active DPX-KN 128 (S-isomer): inactive DPX-KN 127 (R-isomer) in a ratio of 75 :25.
W09211249 mentions the use of sodium hydride in DMF along with Methyl chloroformate to effect N - carbomethoxylation of penultimate substituted 1,3,4 Oxadiazine without documenting on experimental efficiency of transformation in terms of yield and enantiomer ratio. An attempt to achieve above transformation in our laboratory using DMF as solvent indicates low efficiency due to side reactions and incomplete conversion. The article" Towards the manufacturing of Indoxacarb” by R.Shapiro et al on page178 in Synthesis and chemistry of Agrochemicals VI published by ACS Symposium series 800-
2

edited by Don R Baker and et al also indicates the difficulty experienced in achieving acceptable efficiency in N-Carbomethoxylation of penultimate intermediate.
Review of above prior art indicates the need for further study for N-carbomethoxylation of penultimate 1,3,4 Oxadiazine (II) with varying compositions of S: R enantiomers. Study of compositions of S: R enantiomers in the end product after reaction is essential in terms of commercial application. The difficulty experienced in achieving acceptable efficiency in the N-Carbomethoxylation of penultimate intermediate may be due to various factors such as a) formation of ambident nucleophile, incomplete formation of salt while using sodium hydride and stoicheometry of sodium hydride used b) improper solvolysis of reactant, mass transfer effects and temperature.
We, the inventors hereby are able to develop a commercially feasible as well as commercially verified (in our hands) methodology for N-Carbomethoxylation of 'Oxadiazine'. This methodology is successful across various S: R ratio of the 'Oxadiazine'. The present invention overcomes shortcomings indicated in prior art, as well as effects the N-Carbomethoxylation of penultimate intermediate to commercially acceptable level.
SUMMARY OF THE INVENTION
The present invention pertains to process of N-Carbomethoxylation of 1,3,4-Oxadiazine of formula (II) which are racemic or enantiomerically enriched at chiral center.

COMPOUND (II)
Wherein R1 = F, CI or C1-C3 fluoroalkoxy
R2 = C1-C3 alkyl or branched or Aryl unsubstituted or hetero substituted
R4 = -Trifluoromethoxy Trifluoromethyl, F, CI, Br
3
is reacted with methyl chloro formate in presence of sodium hydride and a judiciously chosen solvent mixture to achieve more than 95% N - Carbomethoxylation to have structure (I) where R3 is C1 to C3 alkvl.


The solvent mixture consists of aliphatic hydrocarbons, aromatic hydrocarbons and ether solvents like Dioxane, Monoglyme, Diglyme and any other open chain or cyclic ethers. The reaction can be carried out at 0°C to ambient temperature. Also stoicheometry of sodium hydride can be in the range of 1 to 3 mole per mole of (II).
Different compositions of (II) subjected for reaction with initial ratio of S-isomer to R-isomer to the end product i.e. N-carbomethoxy Oxadiazine (I) is indicated in the table below:

Initial composition of enantiomers in compound no (II) Final composition of enantiomers in compound no. (I)
S - isomer R - isomer DPX-KN 128 DPX-KN 127
50.0 50.0 50.0 50.0
60.0 40.0 40.0 40.0
75.0 25.0 75.0 25.0
>99.0 1.0 > 99.0 1.0
99 % S- isomer
70.5 g Methyl -7-chloro-2, 5-dihydro-2-[[[(4-trifluoromethoxy) phenyl] amino] carbonyl] -indeno [1,2-e] [1,3,4]-oxadiazine -4a(3H) - carboxylate (II) having 99.3 % s-isomer was reacted with 28.35 g methyl chloro formate in presence of 10.8 g 60% sodium hydride in 500 ml (60:40 V/V) solvent mixture containing toluene and monoglyme at (-10°c). The product 7-Chloro-2,5-dihydro-2-[[(methoxy carbonyl)[4-(trifluoro methoxy) phenyl]amino] carbonyl]-indeno [1,2-e][1,3,4] oxadiazine - 4a (3H)-methyl carboxylate i.e. Indoxacarb (I), isolated in more than 90 % yield, having 99.3 % s-isomer content.
Example 2:
37.56 g Methyl -7-chloro-2, 5-dihydro-2-[[[(4-trifluoromethoxy) phenyl] amino] carbonyl] -indeno [1,2-e] [1,3,4]-oxadiazine -4a(3H) - carboxylate (II) having 75 % s-isomer content was reacted with 22.7 g methyl chloro formate in presence of 9.60 g 60% sodium hydride in 720 ml solvent mixture of (50:50 V/V) toluene and ethylene glycol dimethyl ether at (0°c). The product 7-Chloro-2,5-dihydro-2-[[(methoxy carbonyl)[4-(trifluoro methoxy) phenyl]amino] carbonyl]-indeno [1,2-e][1,3,4] oxadiazine - 4a (3H)-methyl carboxylate i.e. Indoxacarb (I), isolated in more than 90 % yield, having 75 % s-isomer content.
Example 3:
103.3 g Methyl -7-chloro-2, 5-dihydro-2-[[[(4-trifluoromethoxy) phenyl] amino] carbonyl] -indeno [1,2-e] [1,3,4]-oxadiazine -4a(3H) - carboxylate (II) having 60 % s-isomer content was reacted with 41.8 g methyl chloro formate in presence of 15.92 g 60% sodium hydride in 737 ml (70:30 V/V) solvent mixture of toluene and 1,4-Dioxane at (+10°c). The product 7-Chloro-2,5-dihydro-2-[[(methoxy carbonyl)[4-(trifluoro methoxy)
4

phenyl]amino] carbonyl]-indeno [1,2-e][1,3,4] oxadiazine - 4a (3H)-methyl carboxylate i.e. Indoxacarb (I), isolated in more than 90 % yield, having 60 % s-isomer content.
Example 4:
150.3 g Methyl -7-chloro-2, 5-dihydro-2-[[[(4-trifluoromethoxy) phenyl] amino] carbonyl] -indeno [1,2-e] [1,3,4]-oxadiazine -4a(3H) - carboxylate (II) having 50 % s-isomer content was reacted with 60.80 g methyl chloro formate in presence of 23.17 g 60% sodium hydride in 1073 ml (70:30 V/V) solvent mixture of toluene and 1,4-Dioxane at (-10°c). The product 7-Chloro-2,5-dihydro-2-[[(methoxy carbonyl)[4-(trifluoro methoxy) phenyl]amino] carbonyl]-indeno [1,2-e][1,3,4] oxadiazine - 4a (3H)-methyl carboxylate i.e. Indoxacarb (I), isolated in more than 90 % yield, having 50 % s-isomer content
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WE CLAIM
1. A process for preparation of compound (I) having S-isomer content ranging from 50 % to 100 % using sodium hydride and Methyl chloro formate and a judiciously chosen solvent or solvent mixture, at a temperature of -50°C to +50°C.

Wherein R1 = F, CI or C1-C3 fluoroalkoxy
R2 = C1-C3 alkyl or branched or Aryl unsubstituted or hetero substituted
R3 = C1-C3alkyl
R4 = Trifluoromethoxy, trifluoromethyl, F, CI, Br
2. As claimed in claim no 1 the judiciously chosen solvent is an aromatic hydrocarbon with or without alkyl substitution used as such or preferably in mixture with ether solvents, para-dioxane and ethers derived from ethylene glycol or diethylene glycol.
3. As claimed in Claim 1 the said process can be carried out preferably at - 20° to +20°C.
4. A compound of formula containing 99% to100% S-isomer content

Wherein R1 = F, CI or C1-C3 fluroalkoxy
R2 = C1-C3 alkyl or branched or Aryl unsubstituted or hetero substituted
R3 = C1-C3 alkyl
R4 = Trifluoromethoxy, trifluoromethyl, F, CI, Br
6

5. More specifically, a compound of formula containing 99 % to100 % S-isomer content

Dated the 14th Nov 2005

ABSTRACT
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This invention relates to an improved methodology for N-Carbomethoxylation using sodium hydride particularly of 1,3,4 oxadiazine of compound (II) having various ratios of S.R to achieve large scale manufacturing process for Oxadiazine of compound (I) with preservation of enantiomeric integrity through out the stages of conversion and isolation.