Indian Patents. 210033:NOVEL METHOD FOR THE SYNTHESIS OF SEMICARBAZONE INTERMEDIATE

Title of Invention	NOVEL METHOD FOR THE SYNTHESIS OF SEMICARBAZONE INTERMEDIATE
Abstract	Novel methodology has been presented towards preparation of carbazates further deployed in preparation of semicarbacones maintaining enantiomeric integrity throughout. These semicarbazones and derivatives thereof are of possess arthropodicida properties.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10: rule 13] Novel method for the synthesis of Semicarbazone intermediate. 1. Gharda Chemicals Limited B-27 & 29 MIDC, Phase I, Dombivli, 421203, Dist. Thane, Maharashtra, India. I An Indian company The following specification particularly describes the nature of this invention and the manner in which it is to be performed : Above patent also describes other method of preparation of semicarbazone intermediate by reaction of semicarbazide with Methyl 5-chloro-2, 3dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate. Preparation of semicarbazide intermediate involves reaction of alkyl-N- aryl carbamate with excess of hydrazine hydrate. However the process needs use of large excess of hydrazine and which makes the process inconvenient for practicing on industrial scale. An alternate semicarbazone synthesis as described in patent WO 98/05656 involves reaction of hydrazone with N-Carboxy alkyl carbonyl chloride of trifluromethoxy aniline. However preparation of carbamoyl chloride intermediate involves use of toxic phosgene and hence involves handling of toxic phosgene. The present invention provides an improved process for economic commercial operation and avoids use of hazardous phosgene as well as eliminates use of excess hydrazine. The present invention provides use of organic bases to increase relative nucleophilicity of the substituted aniline (V), as a convenient method for the synthesis of substituted semicarbazone compounds, which are useful for the preparation of tricyclic oxadiazines having arthropodicidal activity. Compound of formula (VI) is reacted with formaldehyde or its acetal to get compound of formula (VII) by the methods already known in the literature to get compound of formula (VII). Compound (VII) N-carbomethoxylation of compound (VII) using methyl or higher alkyl chloroformate to give N- carbomethoxyiated derivative of formula (I) by the methods already known in the literature. Summary of invention: The present invention pertains to a process for preparing a compound of formula (VI), which is racemic or enantiomerically enriched compound Compound (VI) Where R1 = F, CI or C1-C3 fluroalkoxy. R2 =C1-C3 alkyl linear or branched or Aryl unsubstituted or heterosubstituted R3 = trifluromethoxy/ trfluromethyl / F/CI/Br. R4 = Methyl, Ethyl, Propyl, Butyl, Aryl, substituted aryl or heterocyclic. by reacting compound of formula (IV) where R1 = F, CI or C1-C3 fluroalkoxy R2 = C1-C3 alkyl linear or branched or aryl unsubstituted or hetero substituted R5 - Methyl, Ethyl, Propyl, Butyl, Aryl, substituted aryl or hetero substituted with substituted aniline of formula (V). Compound (V) where R4 = F, CI, C1-C3 Fluroalkoxy In presence of an organic bases selected from secondary amines such as Piperidine, Imidazole (substituted or unsubstituted) as well as tertiary amines such as Trimethyl amine, Triethyl amine, Pyridine (substituted or unsubstituted) etc to give compound of formula (VI). Racemic or enantiomerically enriched compound of formula (IV) in turn can be prepared by reacting compound of formula (II) Compound (II) with compound no.(lll) using Lewis acids as catalyst Compound (III) where R5 = methyl, ethyl, propyl, butyl, aryl, substituted aryl or heterocyclic Examples: Synthesis of 1-H lndene-2-carboxylic acid,5-chloro-2,3 dihydro-2-hydroxy-1-[[[(4 trifluromethoxy) phenyl] amino] carbonyl] hydrazino Methyl ester (Compound VI) 1. To a RB. flask equipped with an overhead stirrer, reflux condenser under inert atmosphere, charged 37.5 gms (0.1 mole) Phenyl (5-chloro-2, 3-dihydro-2-hydroxy-2-(methoxy carbonyl)-1H-inden-1-ylidene) hydrazine carboxylate (compound IV), 19.47 gms (0.11 m) trifluromethoxy aniline and 2.0 gm piperidine in 200 ml toluene. The slurry was heated to reflux and maintained for 24 hour. Resulting slurry was cooled to 30°c, filtered and isolated 41.17 gm (0.09moles) Compound VI. 2. To a RB. flasks equipped with an overhead stirring, reflux condenser under inert atmosphere, was charged 37.5 gms (0.1 mole) Phenyl (5-chloro-2, 3 dihydro-2-hydroxy-2(methoxy carbonyl)-1 H-inden-1-ylidene) hydrazine carboxylate, 19.47 gms (0.11 m) trifluromethoxy aniline and 0.52 9 pyridine in one liter of toluene. The slurry was heated to reflux and maintained for 24 hour. Resulting slurry cooled to 30°c, filtered and isolated 44.17 gm (0.096mole) Compound VI. 3. To a RB. flask equipped with an overhead stirring, reflux condenser under inert atmosphere, charged 37.5 gm (0.1 mole), Phenyl (5-chloro-2, 3 dihydro-2-hydroxy-2-(methoxy carbonyl)-1 H-inden-1-ylidene) hydrazine carboxylate, 19.47 gms (0.11 m) trifluromethoxy aniline and 5 ml Triethyl amine in one liter of o-Xylene. The slurry was heated to reflux for 20 hour. The resulting slurry after reaction was cooled to 30°c and isolated 42.09 gm (0.092moles) of compound (VI). 4. To a one-liter flask equipped with an overhead stirrer, reflux condenser under inert atmosphere, was charged 60.1g (0.25m) of Methyl-5-chloro-2, 3 dihydro-2-hydroxy-1-oxo. 1 H-inden-2 carboxylate (compound II), 38g of phenyl ester of hydrazine carboxylic acid and 0.05 m PTSA in one liter of toluene. The slurry was heated to reflux and maintained for( 7.0 hour, cooled to 30°c, added 48.6gms of trifluromethoxy aniline & 0.3 gms of Triethyl amine, heated to reflux under reduced pressure for 24 hour. Cooled to 30°c, and isolated 93.9 gm (0.205m) Compound VI in 82.2 % yield. 5. To a RB. flask equipped with an overhead stirrer, reflux condenser under inert atmosphere, charged 57.12 gm (0.2375 m) Methyl-5-chloro-2, 3 dihydro-2-hydroxy-1-oxo. 1 H-inden-2 -carboxylate (compound II), 38gms (0.25 m) phenyl ester of hydrazine carboxylic acid in one liter of methanol followed by addition of 0.05-m PTSA. The slurry "was heated to reflux for 5.0 hrs, added 48.6 gm of trifluromethoxy aniline, 0.30 gm of Pyridine & reflux for 15 to 18 hours. Cooled to 30°C, filtered to give 97.2 gm (0.205m) compound (VI) in 85.3 % yield. 6. To a R.B. flask equipped with an overhead stirrer, reflux condenser, under inert atmosphere, charged 57.12g(0.2375m) Methyl-5-chloro-2, 3dihydro-2-hydroxy-1-oxo-1 Hinden-2-carboxylate(compound II), 38gm(0.25m) phenylester of hydrazine carboxylic acid in 0.5liter Methanol followed by addition of 0.06m PTSA The slurry was heated to reflux for 15-18hrs.Cooled to 30°C and filtered to give 75.6g compound no (IV) which can be further, reacted as per above examples with trifluromethoxy aniline to give compound (VI) We claim 1) A method for preparation of racemic or enantiomerically enriched compound of formula (VI) or mixture thereof ,COOR2 Compound (VI) Where R1 - F, CI or C1-C3 fluroalkoxy. R2 = C1-C3 alkyl linear or branched or Aryl unsubstituted or heterosubstituted. R4 = trifluromethoxy/ trifluromethyl/ F, CI, Br. by reacting racemic or enantiomerically enriched compound of formula (IV) Compound (IV) where R1 = F, CI or C1-C3 fluroalkoxy R2 = C1-C3 alkyl linear or branched or aryl unsubstituted or hetero substituted R5 = Methyl, Ethyl, Propyl, Butyl, Aryl, substituted aryl or hetero substituted with compound of formula (V) Compound (V) using organic bases as catalyst in presence of aromatic hydrocarbons or aliphatic hydroxylic solvents at a temperature of 60 to 150°C. 2) A method as claimed in claim 1, wherein the organic bases are/ selected from pyridine or substituted pyridines, tertiary amines like Triethyl amine, Trimethyl amine etc, secondary amines such as dimethyl amine, diethyl amine, Imidazole or substituted imidazole preferably bases from secondary amines. 3) A method as claimed in claim 1, wherein aromatic hydrocarbons are selected from toluene, xylene isomers and aliphatic hydroxylic solvents selected from methyl alcohol, ethyl alcohol, isopropyl alcohol. 4) A method as claimed in claim 1 is carried out either with or without isolation of compound (IV) to get compound (VI).

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970) COMPLETE SPECIFICATION
[See section 10: rule 13]
Novel method for the synthesis of Semicarbazone intermediate.
1. Gharda Chemicals Limited
B-27 & 29 MIDC, Phase I,
Dombivli, 421203, Dist. Thane,
Maharashtra, India. I
An Indian company
The following specification particularly describes the nature of this invention and the manner in which it is to be performed :

Above patent also describes other method of preparation of semicarbazone intermediate by reaction of semicarbazide with Methyl 5-chloro-2, 3dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate. Preparation of semicarbazide intermediate involves reaction of alkyl-N- aryl carbamate with excess of hydrazine hydrate. However the process needs use of large excess of hydrazine and which makes the process inconvenient for practicing on industrial scale.
An alternate semicarbazone synthesis as described in patent WO 98/05656 involves reaction of hydrazone with N-Carboxy alkyl carbonyl chloride of trifluromethoxy aniline. However preparation of carbamoyl chloride intermediate involves use of toxic phosgene and hence involves handling of toxic phosgene.
The present invention provides an improved process for economic commercial operation and avoids use of hazardous phosgene as well as eliminates use of excess hydrazine. The present invention provides use of organic bases to increase relative nucleophilicity of the substituted aniline (V), as a convenient method for the synthesis of substituted semicarbazone compounds, which are useful for the preparation of tricyclic oxadiazines having arthropodicidal activity.
Compound of formula (VI) is reacted with formaldehyde or its acetal to get compound of formula (VII) by the methods already known in the literature to get compound of formula (VII).

Compound (VII)

N-carbomethoxylation of compound (VII) using methyl or higher alkyl chloroformate to give N- carbomethoxyiated derivative of formula (I) by the methods already known in the literature.

Summary of invention:
The present invention pertains to a process for preparing a compound of formula (VI), which is racemic or enantiomerically enriched compound

Compound (VI)

Where
R1 = F, CI or C1-C3 fluroalkoxy.
R2 =C1-C3 alkyl linear or branched or Aryl unsubstituted or heterosubstituted
R3 = trifluromethoxy/ trfluromethyl / F/CI/Br.
R4 = Methyl, Ethyl, Propyl, Butyl, Aryl, substituted aryl or heterocyclic.
by reacting compound of formula (IV)

where R1 = F, CI or C1-C3 fluroalkoxy
R2 = C1-C3 alkyl linear or branched or aryl unsubstituted or hetero substituted R5 - Methyl, Ethyl, Propyl, Butyl, Aryl, substituted aryl or hetero substituted
with substituted aniline of formula (V).

Compound (V)

where R4 = F, CI, C1-C3 Fluroalkoxy In presence of an organic bases selected from secondary amines such as Piperidine, Imidazole (substituted or unsubstituted) as well as tertiary amines such as Trimethyl amine, Triethyl amine, Pyridine (substituted or unsubstituted) etc to give compound of formula (VI).

Racemic or enantiomerically enriched compound of formula (IV) in turn can be prepared by reacting compound of formula (II)
Compound (II)
with compound no.(lll) using Lewis acids as catalyst
Compound (III)
where R5 = methyl, ethyl, propyl, butyl, aryl, substituted aryl or heterocyclic
Examples:
Synthesis of 1-H lndene-2-carboxylic acid,5-chloro-2,3 dihydro-2-hydroxy-1-[[[(4 trifluromethoxy) phenyl] amino] carbonyl] hydrazino Methyl ester (Compound VI)
1. To a RB. flask equipped with an overhead stirrer, reflux condenser under inert atmosphere, charged 37.5 gms (0.1 mole) Phenyl (5-chloro-2, 3-dihydro-2-hydroxy-2-(methoxy carbonyl)-1H-inden-1-ylidene) hydrazine carboxylate (compound IV), 19.47 gms (0.11 m) trifluromethoxy aniline and 2.0 gm piperidine in 200 ml toluene. The slurry was heated to reflux and maintained for 24 hour. Resulting slurry was cooled to 30°c, filtered and isolated 41.17 gm (0.09moles) Compound VI.
2. To a RB. flasks equipped with an overhead stirring, reflux condenser under inert atmosphere, was charged 37.5 gms (0.1 mole) Phenyl (5-chloro-2, 3 dihydro-2-hydroxy-2(methoxy carbonyl)-1 H-inden-1-ylidene) hydrazine carboxylate, 19.47 gms (0.11 m) trifluromethoxy aniline and 0.52 9 pyridine in one liter of toluene. The slurry was heated to reflux and maintained for 24 hour. Resulting slurry cooled to 30°c, filtered and isolated 44.17 gm (0.096mole) Compound VI.
3. To a RB. flask equipped with an overhead stirring, reflux condenser under inert atmosphere, charged 37.5 gm (0.1 mole), Phenyl (5-chloro-2, 3 dihydro-2-hydroxy-2-(methoxy carbonyl)-1 H-inden-1-ylidene) hydrazine carboxylate, 19.47 gms (0.11 m) trifluromethoxy aniline and 5 ml Triethyl amine in one liter of o-Xylene. The slurry was heated to reflux for 20 hour. The resulting slurry after reaction was cooled to 30°c and isolated 42.09 gm (0.092moles) of compound (VI).

4. To a one-liter flask equipped with an overhead stirrer, reflux condenser under inert atmosphere, was charged 60.1g (0.25m) of Methyl-5-chloro-2, 3 dihydro-2-hydroxy-1-oxo. 1 H-inden-2 carboxylate (compound II), 38g of phenyl ester of hydrazine carboxylic acid and 0.05 m PTSA in one liter of toluene. The slurry was heated to reflux and maintained for( 7.0 hour, cooled to 30°c, added 48.6gms of trifluromethoxy aniline & 0.3 gms of Triethyl amine, heated to reflux under reduced pressure for 24 hour. Cooled to 30°c, and isolated 93.9 gm (0.205m) Compound VI in 82.2 % yield.
5. To a RB. flask equipped with an overhead stirrer, reflux condenser under inert atmosphere, charged 57.12 gm (0.2375 m) Methyl-5-chloro-2, 3 dihydro-2-hydroxy-1-oxo. 1 H-inden-2 -carboxylate (compound II), 38gms (0.25 m) phenyl ester of hydrazine carboxylic acid in one liter of methanol followed by addition of 0.05-m PTSA. The slurry "was heated to reflux for 5.0 hrs, added 48.6 gm of trifluromethoxy aniline, 0.30 gm of Pyridine & reflux for 15 to 18 hours. Cooled to 30°C, filtered to give 97.2 gm (0.205m) compound (VI) in 85.3 % yield.
6. To a R.B. flask equipped with an overhead stirrer, reflux condenser, under inert atmosphere, charged 57.12g(0.2375m) Methyl-5-chloro-2, 3dihydro-2-hydroxy-1-oxo-1 Hinden-2-carboxylate(compound II), 38gm(0.25m) phenylester of hydrazine carboxylic acid in 0.5liter Methanol followed by addition of 0.06m PTSA The slurry was heated to reflux for 15-18hrs.Cooled to 30°C and filtered to give 75.6g compound no (IV) which can be further, reacted as per above examples with trifluromethoxy aniline to give compound (VI)

We claim
1) A method for preparation of racemic or enantiomerically enriched compound of formula (VI) or mixture thereof

,COOR2
Compound (VI)

Where R1 - F, CI or C1-C3 fluroalkoxy.
R2 = C1-C3 alkyl linear or branched or Aryl unsubstituted or heterosubstituted.
R4 = trifluromethoxy/ trifluromethyl/ F, CI, Br. by reacting racemic or enantiomerically enriched compound of formula (IV)

Compound (IV)

where R1 = F, CI or C1-C3 fluroalkoxy
R2 = C1-C3 alkyl linear or branched or aryl unsubstituted or hetero substituted R5 = Methyl, Ethyl, Propyl, Butyl, Aryl, substituted aryl or hetero substituted
with compound of formula (V)
Compound (V)
using organic bases as catalyst in presence of aromatic hydrocarbons or aliphatic hydroxylic solvents at a temperature of 60 to 150°C.
2) A method as claimed in claim 1, wherein the organic bases are/ selected from pyridine or substituted pyridines, tertiary amines like Triethyl amine, Trimethyl amine etc, secondary amines such as dimethyl amine, diethyl amine, Imidazole or substituted imidazole preferably bases from secondary amines.

3) A method as claimed in claim 1, wherein aromatic hydrocarbons are selected from toluene, xylene isomers and aliphatic hydroxylic solvents selected from methyl alcohol, ethyl alcohol, isopropyl alcohol.
4) A method as claimed in claim 1 is carried out either with or without isolation of compound (IV) to get compound (VI).

Documents:

1168-mum-2004-abstract.doc

1168-mum-2004-abstract.pdf

1168-mum-2004-cancelled pages-(29-12-2005).pdf

1168-mum-2004-claims(granted)-(29-12-2005).doc

1168-mum-2004-claims(granted)-(29-12-2005).pdf

1168-mum-2004-claims.doc

1168-mum-2004-claims.pdf

1168-mum-2004-correspondence(29-12-2005).pdf

1168-mum-2004-correspondence(ipo)-(19-01-2006).pdf

1168-mum-2004-correspondence(ipo).pdf

1168-mum-2004-correspondence.pdf

1168-mum-2004-description(granted).doc

1168-mum-2004-description(granted).pdf

1168-mum-2004-form 1-(01-11-2004).pdf

1168-mum-2004-form 1.pdf

1168-mum-2004-form 19-(18-11-2004).pdf

1168-mum-2004-form 2(cancelled).pdf

1168-mum-2004-form 2(granted)-(29-12-2005).doc

1168-mum-2004-form 2(granted)-(29-12-2005).pdf

1168-mum-2004-form 2(granted).doc

1168-mum-2004-form 2(granted).pdf

1168-mum-2004-form 2(title page).pdf

1168-mum-2004-form 3-(01-11-2004).pdf

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Patent Number

210033

Indian Patent Application Number

1168/MUM/2004

PG Journal Number

43/2007

Publication Date

26-Oct-2007

Grant Date

14-Sep-2007

Date of Filing

01-Nov-2004

Name of Patentee

GHARDA CHEMICALS LTD.

Applicant Address

MIDC,B-27/29,Phase l, Dombivli(E)-421203, Dist.Thane

Inventors:

#	Inventor's Name	Inventor's Address
1	PRAMOD RAGHUNATH CHAUDHARI	Gharda Chemicals Ltd, B-27/29 MIDC,Phase l, Dombivli,421 203
2	ANITH VIJAYAN	Gharda Chemicals Ltd, B-27/29 MIDC,Phase l, Dombivli,421 203
3	YASHWANT VASUDEO DHARAP	Gharda Chemicals Ltd, B-27/29 MIDC,Phase l, Dombivli,421 203
4	ASHISH VASUDEO VAIDYA	Gharda Chemicals Ltd, B-27/29 MIDC,Phase l, Dombivli,421 203

PCT International Classification Number

C07C 281/12

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA