Indian Patents. 251515:PROCESS FOR PREPARATION OF ATOVAQUONE AND NOVEL INTERMEDIATES THEREOF

Title of Invention	PROCESS FOR PREPARATION OF ATOVAQUONE AND NOVEL INTERMEDIATES THEREOF
Abstract	Disclosed herein is novel process of Atovaquone, which process includes reacting 1,4-naphthoquione with trans-4-(4-chlorophenyl) cyclohexane carboxyane carboxylic acid followed by halogenation to obtain dihalo-compound, further dehydrohalogenation of dihalo-compound to obtain monohalogeno-compound, and hydrolysis of the monolageno-compound to obtain Atovquone.

Full Text	FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 PROVISIONAL SPECIFICATION (See section 10 and rulel3) 1. TITLE OF THE INVENTION: "Process for preparation of Atovaquone and novel intermediates thereof. 2. APPLICANT (a) NAME: IPCA LABORATORIES LIMITED (b) NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention. Technical field of invention: The present invention relates to a process for preparation of Atovaquone in better yield and high purity, which is a useful medicine for the treatment and prophylaxis of Pneomcystis carinii infections. It also relates to new intermediates useful in the preparation of Atovaquone. Background of invention: Atovaquone, chemical name being trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone, is a hydroxy-1,4-naphtoquinone., an analog of ubiquinone, with antipneumocystic activity. Atovaquone is potently active (in animals and in vitro) against Pneumocystis carinii, Plasmodia, and tachyzoite and cyst forms of Toxoplasma gondii. Its inhibitory effect in sensitive parasites, Atovaquone can act by selectively affecting mitochondrial electron transport and parallel processes such as ATP and pyrimidine biosynthesis. Atovaquone is the trans-isomer of 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone whose synthesis, activity and uses are disclosed in the patent Nos. US5053432 and EP0362996. Although various synthetic methodologies are disclosed in said references, a decarboxylative condensation process, as shown in scheme 1, is practically used in these disclosures which are analogous to the methods disclosed in Journal of American Chem. Society, 1948, yielding the condensation product in nearly 1 to 6% only. Using the process of '432 patent the reported yield of Atovaquone is very low in the range of 3-5%. Therefore there is a need in the art to have alternative process to improve the yield of Atovaquone. 2 Therefore the object of this invention is to develop alternative processes for the synthesis of Atovaquone, more specifically in its trans isomer form and ensuring better isomeric separation on large scale production. Summary of the invention: The present inventors had discovered that the prior art processes present substantial difficulties in producing Atovaquone in a consistent and reliable manner in satisfactory yields. The invention, therefore, aims to provide a new process for making Atovaquone. In accordance with one aspect, the invention provides a process for preparation of Atovaquone, which process includes reacting 1,4-naphthoquinone with trans-4-(4-chlorophenyl)cyclohexane carboxylic acid followed by chlorination and hydrolysis according to scheme 2. 3 Scheme 2 O Formula I (70%) The intermediate compound of formula III is novel and forms part of the present invention and sought patent protection. The intermediate compound of Formula II in substantially pure trans-form is also not known and forms part of the present invention. Detailed description of the invention^ Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows. Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any 4 general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. "Atovaquone" is a free species of fra«5-2-(4-chlorophenyl)cyclohexyl)-3-hydroxy-1,4-naphthoquinone has the trans geometry. It has the formula: Atovaquone Formula I The inventors of the present invention had found that the use of 2-chloro-l,4-naphthoquinone in the condensation reaction with fran5-4-(4-chlorophenyl)cyclohexane carboxylic acid does not provide a reliable, consistent methodology to prepare Atovaquone due to poor yield in the range of 3-5%. The required trans-isomer of intermediate compound of Formula IV (scheme 1), according to reported processes, is isolated in nearly 5-7% yield which is present in a large junk of impurities and cis-isomer (formula IV) making it difficult to purify. The present inventors, on exploring various process alternatives, for a reliable process solution have found that the use of unsubstituted 1,4-naphthoquinone in the condensation reaction provides a significantly better yield in the condensation reaction and permits reliable isolation of trans-isomer, which can be further converted to Atovaquone. The process of the present invention is represented in scheme 2. Thus, according to the present invention, there is provided a process for preparation of Atovaquone, said process comprises the steps of 5 a) reacting the 1,4-naphthoquinone with 4-(4-chlorophenyl)cyclohexane carboxylic acid, preferably in trans-isomer form in presence of a metal nitrate and a persulphate reagent in an aqueous and/or organic solvent to obtain the compound of Formula II; b) chlorinating compound of formula II to form a compound of Formula III; c) subjecting compound of formula III to dehydrohalogenation reaction to obtain a compound of Formula IV; and d) converting the monochloro-compound of Formula IV into Atovaquone . In the process step (a), preferably, the metal nitrate is silver nitrate and the persulphate is ammoniumpersulphate. The solvent for the reaction can be chosen from any inert solvent, preferably selected from polar protic and polar aprotic solvent. The aqueous solvent is water or water containing organic solvents. Preferably it is a mixture of water and acetonitrile. The reaction can be carried out optionally in presence of a catalyst, preferably a phase-transfer catalyst. After the completion of first step reaction (a) preferably the product of formula II is isolated in its trans-form and used in the step b). In the process of step b) the chlorination of step of product of formula II is carried out in presence of a chlorinating agent. Preferably the chlorination is effected by passing chlorine gas in presence of compound of formula II in glacial acetic acid or in any conventional solvent to obtain compound of formula III. The dehydrohalogenation of compound III in step c) is effected by treatment with an acid or base. Preferably, dehydrohalogenation is carried out by treating it with sodium acetate in glacial acetic acid to obtain compound of formula IV. The hydrolysis of compound of formula IV into Atovaquone is carried out in a conventional manner by reacting it with a base like potassium hydroxide or sodium hydroxide in a solvent, which is preferably an alcohol. 6 Effect of the invention: The invention provides better yield of compound of formula II in the condensation reaction in the order of about 12-17% isolated yield. The reaction product analysis shows nearly 30 - 45% or more of trans product (formula II) in the reaction as compared to 15-17 % in the reported processes, which gives an isolated yield of compound IV in nearly 5-7% only. Thus the yield of the required trans-isomer is improved to a great extent by the practice of the present invention. The isolated compound of formula II in substantially pure trans-form is not made available in literature and also forms part of the present invention. The following examples are presented to illustrate the working of the present invention, but are not limiting the scope of the individual embodiments presented. Example 1 Preparation of 2-[4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone (Formula II) To a stirred solution of Silver nitrate 17.5 gm (0.104 moles ) dissolved in 100 ml water, 50 gm (0.209 moles) trans-4-(4-chlorophenyl)cyclohexane carboxylic acid was added. To this solution acetonitrile 250 ml was added and under stirring heated to reflux and 33.1 gm (0.209 gm) 1,4-naphthoquinone was added. 120 gm (0.525 mole) Ammonium persulfate dissolved in 400 ml water was added dropwise to the stirred solution and continued reflux for 2 hours. The reaction solution then cooled to 0-5 degree Celsius and extracted with methylene chloride. The organic layer was first washed with water followed by washing with 10% sodium carbonate aqueous solution, further with water till the pH is neutral. The organic layer was distilled to eliminate methylene chloride and was stirred in acetonitrile and filtered. The solid obtained was crystallized from acetonitrile to obtain 15 gm (20% yield). M.P. 146-149 (uncorrected), 'H NMR (400MHZ), 8H (d6-CDC13) 8.07-8.14(2H, m, Naphth), 7.65-7.74(4H, m, Naphth), 7.27-7.30(2H, d, arom.), 7.07-7.19(2H, d, arom.), 6.80(1H, s, naphtho.), 2.8-3.01 (1H, tt, CH), 2.54-2.58(lH, tt, CH-), 1.25-2.03(8H, multi, CH2) 7 Example 2 o Preparation of 2-[4-(4-chlorophenyl)cyclohexyl]-2,3-dichloro-2,3-dihydro-l ,4-naphthoquinone (Formula III) 10 gm of compound of formula II of example 1 2-[4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone was added to 50 ml glacial acetic acid and to this soltuion chlorine gas was passed at about 20 degrees. The reaction mass was then quenched into water and filtered. The product was dried at 30 degree to obtain 11.5 gm (95% yield) compound of formula III. ]H NMR (400MHz), 8H (d6-CDC13) 8.13(2H, m, Naphth), 7.82-7.89(2H, m, Naphth), 7.0-7.30(4H, m, arom.), 4.90-5.0(lH), 2.67 (1H, tt, CH), 2.49(1H, m, CH-), 1.2-2.0(8H, multi, CH2) Example 3 Preparation of 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l ,4-naphthoquinone (Formula IV) 10 gm of 2-[4-(4-chlorophenyl)cyclohexyl]-2,3-dichloro-2,3-dihydro-l ,4-naphthoquinone (formula III) obtained in example 2 was suspended in glacial acetic acid (80 ml) and 2.9 gm anhydrous sodium acetate was added to the mixture. The mixture was heated to reflux for 1 hour and then cooled and water was added to the mixture. The precipitated product was filtered of and recrystallized from acetonitrile to obtain 6.5 gm (70% yield) of compound IV. Example 4 Preparation of Atovaquone 6.0 gm of 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l,4-naphthoquinone (formula IV) obtained in example 3 was suspended in 120 ml methanol and 6.0 gm sodium hydroxide dissolved in 60 ml water was added drop-wise under heating over a period of 20 minutes. 8 Further, it was refluxed for 45 minutes and cooled to 0-5 degrees and filtered. The filtrate was neutralized with 50% aqueous hydrochloric acid to precipitate the product. The precipitated product was filtered, and recrystallized from acetonitrile to obtain 4 gm (70% yield) Atovaquone. Dated this 19th day of 2007 9

Full Text

FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"Process for preparation of Atovaquone and novel intermediates thereof.

2. APPLICANT
(a) NAME: IPCA LABORATORIES LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai - 400 067,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention.

Technical field of invention:
The present invention relates to a process for preparation of Atovaquone in better yield and high purity, which is a useful medicine for the treatment and prophylaxis of Pneomcystis carinii infections. It also relates to new intermediates useful in the preparation of Atovaquone.
Background of invention:
Atovaquone, chemical name being trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone, is a hydroxy-1,4-naphtoquinone., an analog of ubiquinone, with antipneumocystic activity. Atovaquone is potently active (in animals and in vitro) against Pneumocystis carinii, Plasmodia, and tachyzoite and cyst forms of Toxoplasma gondii. Its inhibitory effect in sensitive parasites, Atovaquone can act by selectively affecting mitochondrial electron transport and parallel processes such as ATP and pyrimidine biosynthesis.
Atovaquone is the trans-isomer of 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone whose synthesis, activity and uses are disclosed in the patent Nos. US5053432 and EP0362996. Although various synthetic methodologies are disclosed in said references, a decarboxylative condensation process, as shown in scheme 1, is practically used in these disclosures which are analogous to the methods disclosed in Journal of American Chem. Society, 1948, yielding the condensation product in nearly 1 to 6% only. Using the process of '432 patent the reported yield of Atovaquone is very low in the range of 3-5%. Therefore there is a need in the art to have alternative process to improve the yield of Atovaquone.
2

Therefore the object of this invention is to develop alternative processes for the synthesis of Atovaquone, more specifically in its trans isomer form and ensuring better isomeric separation on large scale production.
Summary of the invention:
The present inventors had discovered that the prior art processes present substantial difficulties in producing Atovaquone in a consistent and reliable manner in satisfactory yields. The invention, therefore, aims to provide a new process for making Atovaquone. In accordance with one aspect, the invention provides a process for preparation of Atovaquone, which process includes reacting 1,4-naphthoquinone with trans-4-(4-chlorophenyl)cyclohexane carboxylic acid followed by chlorination and hydrolysis according to scheme 2.

3

Scheme 2
O Formula I (70%)
The intermediate compound of formula III is novel and forms part of the present invention and sought patent protection. The intermediate compound of Formula II in substantially pure trans-form is also not known and forms part of the present invention.
Detailed description of the invention^
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.
Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any
4

general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims.
"Atovaquone" is a free species of fra«5-2-(4-chlorophenyl)cyclohexyl)-3-hydroxy-1,4-naphthoquinone has the trans geometry. It has the formula:

Atovaquone Formula I
The inventors of the present invention had found that the use of 2-chloro-l,4-naphthoquinone in the condensation reaction with fran5-4-(4-chlorophenyl)cyclohexane carboxylic acid does not provide a reliable, consistent methodology to prepare Atovaquone due to poor yield in the range of 3-5%. The required trans-isomer of intermediate compound of Formula IV (scheme 1), according to reported processes, is isolated in nearly 5-7% yield which is present in a large junk of impurities and cis-isomer (formula IV) making it difficult to purify. The present inventors, on exploring various process alternatives, for a reliable process solution have found that the use of unsubstituted 1,4-naphthoquinone in the condensation reaction provides a significantly better yield in the condensation reaction and permits reliable isolation of trans-isomer, which can be further converted to Atovaquone. The process of the present invention is represented in scheme 2.
Thus, according to the present invention, there is provided a process for preparation of Atovaquone, said process comprises the steps of
5

a) reacting the 1,4-naphthoquinone with 4-(4-chlorophenyl)cyclohexane carboxylic acid, preferably in trans-isomer form in presence of a metal nitrate and a persulphate reagent in an aqueous and/or organic solvent to obtain the compound of Formula II;
b) chlorinating compound of formula II to form a compound of Formula III;
c) subjecting compound of formula III to dehydrohalogenation reaction to obtain a compound of Formula IV; and
d) converting the monochloro-compound of Formula IV into Atovaquone .
In the process step (a), preferably, the metal nitrate is silver nitrate and the persulphate is ammoniumpersulphate. The solvent for the reaction can be chosen from any inert solvent, preferably selected from polar protic and polar aprotic solvent. The aqueous solvent is water or water containing organic solvents. Preferably it is a mixture of water and acetonitrile. The reaction can be carried out optionally in presence of a catalyst, preferably a phase-transfer catalyst.
After the completion of first step reaction (a) preferably the product of formula II is isolated in its trans-form and used in the step b).
In the process of step b) the chlorination of step of product of formula II is carried out in presence of a chlorinating agent. Preferably the chlorination is effected by passing chlorine gas in presence of compound of formula II in glacial acetic acid or in any conventional solvent to obtain compound of formula III.
The dehydrohalogenation of compound III in step c) is effected by treatment with an acid or base. Preferably, dehydrohalogenation is carried out by treating it with sodium acetate in glacial acetic acid to obtain compound of formula IV.
The hydrolysis of compound of formula IV into Atovaquone is carried out in a conventional manner by reacting it with a base like potassium hydroxide or sodium hydroxide in a solvent, which is preferably an alcohol.
6

Effect of the invention: The invention provides better yield of compound of formula II in the condensation reaction in the order of about 12-17% isolated yield. The reaction product analysis shows nearly 30 - 45% or more of trans product (formula II) in the reaction as compared to 15-17 % in the reported processes, which gives an isolated yield of compound IV in nearly 5-7% only. Thus the yield of the required trans-isomer is improved to a great extent by the practice of the present invention. The isolated compound of formula II in substantially pure trans-form is not made available in literature and also forms part of the present invention.
The following examples are presented to illustrate the working of the present invention, but are not limiting the scope of the individual embodiments presented.
Example 1
Preparation of 2-[4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone (Formula II)
To a stirred solution of Silver nitrate 17.5 gm (0.104 moles ) dissolved in 100 ml water, 50 gm (0.209 moles) trans-4-(4-chlorophenyl)cyclohexane carboxylic acid was added. To this solution acetonitrile 250 ml was added and under stirring heated to reflux and 33.1 gm (0.209 gm) 1,4-naphthoquinone was added. 120 gm (0.525 mole) Ammonium persulfate dissolved in 400 ml water was added dropwise to the stirred solution and continued reflux for 2 hours. The reaction solution then cooled to 0-5 degree Celsius and extracted with methylene chloride. The organic layer was first washed with water followed by washing with 10% sodium carbonate aqueous solution, further with water till the pH is neutral. The organic layer was distilled to eliminate methylene chloride and was stirred in acetonitrile and filtered. The solid obtained was crystallized from acetonitrile to obtain 15 gm (20% yield). M.P. 146-149 (uncorrected), 'H NMR (400MHZ), 8H (d6-CDC13) 8.07-8.14(2H, m, Naphth), 7.65-7.74(4H, m, Naphth), 7.27-7.30(2H, d, arom.), 7.07-7.19(2H, d, arom.), 6.80(1H, s, naphtho.), 2.8-3.01 (1H, tt, CH), 2.54-2.58(lH, tt, CH-), 1.25-2.03(8H, multi, CH2)
7

Example 2
o
Preparation of 2-[4-(4-chlorophenyl)cyclohexyl]-2,3-dichloro-2,3-dihydro-l ,4-naphthoquinone (Formula III)
10 gm of compound of formula II of example 1 2-[4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone was added to 50 ml glacial acetic acid and to this soltuion chlorine gas was passed at about 20 degrees. The reaction mass was then quenched into water and filtered. The product was dried at 30 degree to obtain 11.5 gm (95% yield) compound of formula III. ]H NMR (400MHz), 8H (d6-CDC13) 8.13(2H, m, Naphth), 7.82-7.89(2H, m, Naphth), 7.0-7.30(4H, m, arom.), 4.90-5.0(lH), 2.67 (1H, tt, CH), 2.49(1H, m, CH-), 1.2-2.0(8H, multi, CH2)
Example 3
Preparation of 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l ,4-naphthoquinone (Formula
IV)
10 gm of 2-[4-(4-chlorophenyl)cyclohexyl]-2,3-dichloro-2,3-dihydro-l ,4-naphthoquinone (formula III) obtained in example 2 was suspended in glacial acetic acid (80 ml) and 2.9 gm anhydrous sodium acetate was added to the mixture. The mixture was heated to reflux for 1 hour and then cooled and water was added to the mixture. The precipitated product was filtered of and recrystallized from acetonitrile to obtain 6.5 gm (70% yield) of compound IV.
Example 4
Preparation of Atovaquone
6.0 gm of 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l,4-naphthoquinone (formula IV) obtained in example 3 was suspended in 120 ml methanol and 6.0 gm sodium hydroxide dissolved in 60 ml water was added drop-wise under heating over a period of 20 minutes.
8

Further, it was refluxed for 45 minutes and cooled to 0-5 degrees and filtered. The filtrate was neutralized with 50% aqueous hydrochloric acid to precipitate the product. The precipitated product was filtered, and recrystallized from acetonitrile to obtain 4 gm (70% yield) Atovaquone.
Dated this 19th day of 2007

9

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Patent Number

251515

Indian Patent Application Number

760/MUM/2007

PG Journal Number

12/2012

Publication Date

23-Mar-2012

Grant Date

21-Mar-2012

Date of Filing

19-Apr-2007

Name of Patentee

IPCA LABORATORIES LIMITED

Applicant Address

48, KANDIVLI INDUSTRIAL ESTATE, CHARKOP, KANDIVLI (WEST), MUMBAI-400067,

Inventors:

#	Inventor's Name	Inventor's Address
1	KUMAR ASHOK	123/AB, CRD, IPCA LABORATORIES LTD., KANDIVLI INDUSTRIAL ESTATE, CHARKOP, KANDIVLI (WEST), MUMBAI-400067
2	DIKE, SUNEEL YESHWANT	123/AB, CRD, IPCA LABORATORIES LTD., KANDIVLI INDUSTRIAL ESTATE, CHARKOP, KANDIVLI (W), MUMBAI 400067
3	MATHUR, PRAMIL KUMAR	123/AB, CRD, IPCA LABORATORIES LTD., KANDIVLI INDUSTRIAL ESTATE, CHARKOP, KANDIVLI (W), MUMBAI 400067
4	KORE, SWAPNIL SHREEKANT	123/AB, CRD, IPCA LABORATORIES LTD., KANDIVLI INDUSTRIAL ESTATE, CHARKOP, KANDIVLI (W), MUMBAI 400067
5	BUCHUDE, VITTHAL SURYABHAN	123/AB, CRD, IPCA LABORATORIES LTD., KANDIVLI INDUSTRIAL ESTATE, CHARKOP, KANDIVLI (W), MUMBAI 400067

PCT International Classification Number

C07C46/10

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA