Title of Invention	A PROCESS FOR THE MANUFACTURE OF 6-METHOXY-8-[4-AMINO-1-METHYLBUTYLAMINO]QUINOLINE(PRIMAQUINE)AND ITS ACID ADDITION SALTS
Abstract	This invention discloses a process for the manufacture of 6-methoxy-8-[4-amino-1-methylbutylamino]quinoline(primaquine)which is an anti-malarial drug,more particularly for the redical cure of vivax malaria.It is also known as curative agent for relapsing vivax malaria.This invention further disclosess to a process for preparation of acid addition salts of 6-methoxy-8-[4-amino-1-methylbutylamino]quinoline(primaquine).

Title of Invention

A PROCESS FOR THE MANUFACTURE OF 6-METHOXY-8-[4-AMINO-1-METHYLBUTYLAMINO]QUINOLINE(PRIMAQUINE)AND ITS ACID ADDITION SALTS

Abstract

This invention discloses a process for the manufacture of 6-methoxy-8-[4-amino-1-methylbutylamino]quinoline(primaquine)which is an anti-malarial drug,more particularly for the redical cure of vivax malaria.It is also known as curative agent for relapsing vivax malaria.This invention further disclosess to a process for preparation of acid addition salts of 6-methoxy-8-[4-amino-1-methylbutylamino]quinoline(primaquine).

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] "A process for the manufacture of 6-methoxy-8-[4-amino-l-methylbutylaminojquinoline (Primaquine) and its acid addition salts" (a) IPCA LABORATORIES LIMITED (b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of this invention and the manner in which it is to be performed: Technical filed of the invention: This invention relates to a process for the manufacture of 6-methoxy-8-[4-amino-l-methylbutylaminojquinoline (primaquine) which is an anti-malarial drug more particularly for the radical cure of vivax malaria. It is also known as curative agent for relapsing vivax malaria. This invention further relates to process for preparation of acid addition salts of 6-methoxy-8-[4-amino-1 -methylbutylamino]quinoline (primaquine). Background and Prior art: 6-methoxy -8-[4-amino-l-methylbutylamino]quinoline, commonly known as primaquine, was first described in the "Journal of American Chemical Society" vol. 68, 1526 (1946). The method detailed in this paper for the preparation of primaquine involves the condensation of 8-amino-6-methoxyquinoline (1.0 mole) of Formula (I) with 4-bromo-l -phthalimido pentane (1.1 mole) of Formula (II) in presence of absolute alcohol at a temperature of 75 to 80° C for a period of 60 hours. The final product is extracted with ether. After drying and removal of solvent the phthalimido intermediate of Formula (III) is distilled under pressure less than 0.5 mm Hg in nitrogen atmosphere. The intermediate of the Formula (III) is converted into its free base and then to its acid addition salts. Further, Journal of American Chemical Society, Vol. 77, 1955, 4816-4823 describes the process which comprises condensation of 8-amino-6-methoxy quinoline (2.0 moles) of Formula (I) with 4-bromo-l-phthalimidopentane (1.0 mole) of Formula (II) in absolute alcohol at a temperature 75 to 80° C for a period of 72 hours. After cooling the reaction mass, ether is added. The hydrobromide salt of unreacted 8-amino-6-methoxyquinoline is filtered off. The filtrate is dried and concentrated to give dark brown residue. This dark brown residue is dissolved in alcohol, decolorized and isolated as phthalimido product of Formula (III) in 40 -50 % yield after crystallization. The phthalimido compound of Formula (III) is hydrolysed by refluxing with calculated amount of hydrazine hydrate for 2.0 hours. The hydrolysis method of phthalimido compound of Formula (III) is documented in Journal of Chemical society (1926), 2348. Primaquine base obtained after hydrolysis of phthalimido compound is converted into its diphosphate salt by adding alcoholic solution of calculated amount of 85% phosphoric acid. GB 695159 describes a process for preparation of primaquine in which 1,4-dibromopentane is treated with an alkali metal phathalimide in an organic non-hydroxylic solvent, acetone at 45 - 65° C. Further N-bromo alkyl phthalimide is treated with 6-methoxy 8-aminoquinoline and splitting the phthalyl hydrazide from the product by treatment with hydrazine hydrate. These products are isolated as salts such as hydrochloride, semioxalate, and diphosphate. The process for synthesis of 8-amino-6-methoxy quinoline from 6-methoxy-8-nitro-quinoline is very well documented in Chemistry of Synthetic Antimalarials Part II 611-614. The synthesis of 6-methoxy-8-nitroquinoline is reported in Organic synthesis Collective Volume III, 568 and 661. The preparation of intermediate of Formula (II) i.e. 4-bromo-l-phthalimidopentane from 2-methyl tetrahydrofuran is detailed in Organic Synthesis, Collective Volume I, 119; Journal of Chemical Society (1929), 2959 and Journal of American Chemical Society Vol. 77, (1955), 4816-4823. The drawback of the prior art is product contaminated with high levels of impurities, poor isolated yields and difficulties in isolation of the final product. Another drawback is the use of excess 1.0 mole of 8-amino-6-methoxy quinoline which needs to be recovered and recycled to makes process economically acceptable. Objectives The main objective of the present invention is to provide a simple, economical and environmental friendly process for the preparation of 6- methoxy-8-[4-amino-l -methyl -butyl amino] quinoline [primaquine] and its acid addition salts of high quality. The further objective of the present invention is to avoid the excess use of the 8-amino-6-methoxy quinoline. This modification reduces the impurities level substantially and also avoids the recovery and recyclability of the said intermediate of the Formula I. Another objective of the present invention is to reduce the time cycle by avoiding the extraction and tedious high vacuum distillation procedures to remove the phthalimido intermediate and therefore significantly improving the capacity utilization. Summary of the invention This invention relates to a process for the manufacture of 6-methoxy-8-[4-amino-l-methylbutylamino]quinoline (primaquine) which is an anti-malarial drug, more particularly for the radical cure of vivax malaria. It is also known as curative agent for relapsing vivax malaria. This invention further relates to a process for preparation of acid addition salts of 6-methoxy-8-[4-amino-1 -methylbutylamino]quinoline (primaquine). Detailed description of the invention The present invention relates to a process for preparation of 6-methoxy-8-[4-amino-l-methylbutylamino] quinoline (Primaquine). The above said process comprises condensation of 8-amino-6-methoxyquinoline of the Formula (I) with 4-bromo-l-phthalimidopentane of the Formula (II) in presence of organic bases (such as triethylamine, diisopropylamine) at a temperature of 110-115° C to give 6-methoxy-8-[4-amino-l-methylbutylamino]quinoline of Formula (III). The reaction is carried out between 8-amino-6-methoxyquinoline and 4-bromo-l-phthalimidopentane in the molar ratio of 1.1 to 3.5 preferably 2.5 to 3.0 in the presence of organic base in a molar ratio from 1.1 to 4.0 mole at a temperature ranging from 100-150°C preferably between 115 to 125° C for a period of 20-25 hours. Triethylamine base acts as a catalyst/driving force for completing the reaction thereby increasing the yield and purity of the final product. It also acts as acid scavenger for the gaseous by-product hydrogen bromide generated from the reaction to form triethylamine salt. The excess use of the expensive 8-amino-6-methoxy quinoline and the absence of triethylamine in the reaction as in prior art results in impurity generation due to the slow rate of reaction which leads to incomplete reaction. This necessitates further purification to obtain the final product. The higher yield and purity resulting from the use of triethylamine in the absence of any solvent constitutes a considerable technical advance with respect the process described in the prior art. The phthalimido compound of Formula (III) is reacted with hydrazine hydrate for 2.0 hours and the resultant free base i.e. 6-methoxy-8-[4-amino-l-methylbutyl-amino]quinoline of the Formula (IV) is extracted with ethyl acetate and the drug is obtained as diphosphate salt by adding an alcoholic solution of 85 % of phosphoric acid to the alcoholic solution of the free base under stirring. The salt falls down as an orange crystalline product 4-bromo-1 -phthalimidopentane (!!) 6-methoxy-8-(4-phtha!imido-1-m ethylbutylamino)quinoline (III) The starting material of Formula (I) i.e. 8-amino-6-methoxy quinoline used in this invention is prepared by the process disclosed in Organic synthesis Collective Volume III, 568 and 661. The starting intermediate of Formula (II) i.e. 4-bromo-l-phthalimidopentane is prepared according to the process disclosed in Journal of American Chemical Society Vol. 77, (1955), 4816-4823. 6-methoxy-8-[4-amino-1-methylbu tyiamino]quinoline (IV) The following examples illustrate the process of the invention in greater details and are in no way limiting the scope of the invention. Experimental Example 1 6-methoxy-8-[4-phthalimido-l-methylbutylamino]quinoline A mixture of 8-amino-6-methoxy quinoline (lOOgms), 4-bromo-l-phthalimidopentane (300gms) and triethylamine (104.0gms) is heated with stirring for 20-25hrs at a temperature of 110 tol 15°C. The reaction mixture is cooled and 500ml of acetone added to separate the hydrobromide salt of triethylamine by filtration. Then the acetone is distilled out from the filtrate to get the oily mass. Methanol (1000ml) is added to oily mass and cooled to 10-15°C. Sulphuric acid is added drop wise to the reaction mass to precipitate the product of Formula III as a sulphate salt. The above salt is dissolved in water (500ml) and basified with ammonium hydroxide (300ml) solution and the liberated quinoline base of Formula (III) is extracted with ethyl acetate (400 X 2). After complete removal of ethyl acetate, the phthalimido intermediate of quinoline base of Formula (III) is isolated as oil. The product was identified by elementary analysis, IR and NMR. After precipitating the phthalimido quinoline as a sulphate salt, the excess 4-bromo-l-phthalimidopentane remains in the mother liquor, can be easily recycled. The yield of the product is 180gms (% yield is 80%). Purity - 98.0 % (by HPLC analysis). Example 2 6-methoxy-8-[4-phthalimido-l- methylbutyIaminojquinoline(primaquine)diphosphate The above phthalimido intermediate of quinoline base (lOOgms) of Formula (III) is dissolved in ethanol (1000ml), 220 gms of hydrazine hydrate is added to the reaction mass. The reaction mixture is refluxed for 2.0 hours, cooled to room temperature and filtered to remove the by product generated during the reaction. Ethanol is recovered from the filtrate, and 6-methoxy-8-[4-amino-l-methylbutylamino]quinoline base isolated as an oil. The above base is diluted with ethanol (500ml). The reaction mixture is heated to 55-60°C and phosphoric acid (lOOgms) added. The reaction mixture is then refluxed for 1.0 to 2.0 hours, cooled to room temperature to get the desired diphosphate salt of Formula (IV). The yield of the product is 105gms (% yield is 90%). Purity - 99.0 % (based on HPLC analysis) M.P: 198-200°C. We claim 1. A process for the manufacture of 6-methoxy-8-[4-amino-methylbutylamino]quinoline (Primaquine) of Formula IV, and its acid addition salts, wherein the said process comprising: a) heating a mixture of 8-amino-6-methoxyquinoline of Formula (I) and 4-bromo-l-phthalimidopentane of Formula (II) in presence of an organic base at a temperature ranging from about 100 to 150° C for a period of 20 hours or more, b) adding an organic solvent to the said reaction mixture to precipitate the by¬product hydrobromide salt of organic base and removing it by filtration, c) concentrating said filtrate and dissolving the residue in an alcohol, treating with sulfuric acid to precipitate sulphate salt of product of Formula III, e) Dissolving said precipitate of Formula III in water and treating with ammonium hydroxide to form a phthalimido-compound of Formula III, f) treating said phthalimido-intermediate of Formula (III) with hydrazine hydrate to form a reaction mass containing the 6-methoxy-8-[4-amino-l-methylbutylaminojquinoline base of Formula (IV) and g) isolating said primaquine of formula IV from said reaction medium. 2. A process for the manufacture of 6-methoxy-8-[4-amino-methylbutylamino]quinoline {Primaquine) as claimed in claim 1(a) wherein condensation of 8-amino-6-methoxy quinoline with 4-bromo-l-phthalimidopentane in presence of organic bases such as triethylamine, diisopropylamine and more particularly triethylamine. 3. A process for the manufacture of 6-methoxy-8-[4-amino-methylbutylamino]quinoline {Primaquine) as claimed in claim 1 (a) wherein condensation of 8-amino-6-methoxy quinoline of Formula (I) with 4-bromo-l-phthalimidopentane (II) is in a molar ratio ofl.lto3.5 4. The process as claimed in claim 1 (a) wherein condensation of 8-amino-6-methoxy quinoline of Formula (I) with 4-bromo-l-phthalimidopentane (II) is in a molar ratio of2.5to3.0 5. Process for the manufacture of 6-methoxy-8- [4-amino-methylbutylarnino] quinoline {Primaquine) as claimed in claim 1 (a) wherein the molar ratio of the organic base is in the range of l.lto 4.0 moles relative to 8-amino-6-methoxy quinoline. 6. A process for the manufacture of 6-methoxy-8-[4-amino-methylbutylamino]quinoline {Primaquine) as claimed in claim 1 (a) wherein the molar ratio of the organic base is 2.5 to 3.0 relative to 8-amino-6-methoxy quinoline. 7. A process for the manufacture of 6-methoxy-8-[4-amino-methylbutylamino]quinoline (Primaquine) as claimed in claim 1 (a) wherein the reaction mixture is heated to a temperature ranging from 100-150°C for a period of 20-25hrs. 8. A process for the manufacture of 6-methoxy-8-[4-amino-methylbutylamino]quinoline {Primaquine) as claimed in claim 1 (a) wherein the reaction mixture is heated to a temperature ranging from 110-125°C for a period of 20-25hrs. 9. A process for the manufacture of 6-methoxy-8-[4-aminomethylbutylamino]quinoline {Primaquine) as claimed in claim 1 (b) wherein the said organic solvent is acetone. 10. A process for the manufacture of 6-methoxy-8-[4-aminomethylbutylamino]quinoline {Primaquine) as claimed in claim 1(c) wherein the said alcohol used to dissolve oily mass is ethanol. • 11. A process for the manufacture of 6-methoxy-8-[4-aminomethylbutylamino]quinoline {Primaquine) as claimed in claim 1 wherein the above said quinoline base is further treated with phosphoric acid in ethanol at 55-60°C to obtain the diphosphate salt. 12. A process for the manufacture of 6-methoxy-8-[4-aminomethylbutylamino]quinoline {Primaquine) and its acid addition salts as substantially described herein with reference to the aforesaid examples 1 to 2. Dated this 20th day of Feb 2004 Dr. Gopakumar G. Nair Agent for the Applicant

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10; rule 13]
"A process for the manufacture of 6-methoxy-8-[4-amino-l-methylbutylaminojquinoline (Primaquine) and its acid addition salts"
(a) IPCA LABORATORIES LIMITED
(b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956
The following specification describes the nature of this invention and the manner in which it is to be performed:

Technical filed of the invention:
This invention relates to a process for the manufacture of 6-methoxy-8-[4-amino-l-methylbutylaminojquinoline (primaquine) which is an anti-malarial drug more particularly for the radical cure of vivax malaria. It is also known as curative agent for relapsing vivax malaria.
This invention further relates to process for preparation of acid addition salts of 6-methoxy-8-[4-amino-1 -methylbutylamino]quinoline (primaquine).
Background and Prior art:
6-methoxy -8-[4-amino-l-methylbutylamino]quinoline, commonly known as primaquine, was first described in the "Journal of American Chemical Society" vol. 68, 1526 (1946). The method detailed in this paper for the preparation of primaquine involves the condensation of 8-amino-6-methoxyquinoline (1.0 mole) of Formula (I) with 4-bromo-l -phthalimido pentane (1.1 mole) of Formula (II) in presence of absolute alcohol at a temperature of 75 to 80° C for a period of 60 hours. The final product is extracted with ether. After drying and removal of solvent the phthalimido intermediate of Formula (III) is distilled under pressure less than 0.5 mm Hg in nitrogen atmosphere. The intermediate of the Formula (III) is converted into its free base and then to its acid addition salts.
Further, Journal of American Chemical Society, Vol. 77, 1955, 4816-4823 describes the process which comprises condensation of 8-amino-6-methoxy quinoline (2.0 moles) of Formula (I) with 4-bromo-l-phthalimidopentane (1.0 mole) of Formula (II) in absolute alcohol at a temperature 75 to 80° C for a period of 72 hours. After cooling the reaction mass, ether is added. The hydrobromide salt of unreacted 8-amino-6-methoxyquinoline is filtered off. The filtrate is dried and concentrated to give dark brown residue. This dark brown residue is dissolved in alcohol, decolorized and isolated as phthalimido product of Formula (III) in 40 -50 % yield after crystallization. The phthalimido compound of Formula (III) is hydrolysed by refluxing with calculated amount of hydrazine hydrate for 2.0 hours. The hydrolysis method of phthalimido compound of Formula (III) is documented in Journal of Chemical society (1926), 2348. Primaquine base obtained after hydrolysis of phthalimido compound is converted into its diphosphate salt by adding alcoholic solution of calculated amount of 85% phosphoric acid.
GB 695159 describes a process for preparation of primaquine in which 1,4-dibromopentane is treated with an alkali metal phathalimide in an organic non-hydroxylic solvent, acetone at 45 - 65° C. Further N-bromo alkyl phthalimide is treated with 6-methoxy 8-aminoquinoline and splitting the phthalyl hydrazide from the product by treatment with hydrazine hydrate. These products are isolated as salts such as hydrochloride, semioxalate, and diphosphate.

The process for synthesis of 8-amino-6-methoxy quinoline from 6-methoxy-8-nitro-quinoline is very well documented in Chemistry of Synthetic Antimalarials Part II 611-614. The synthesis of 6-methoxy-8-nitroquinoline is reported in Organic synthesis Collective Volume III, 568 and 661.
The preparation of intermediate of Formula (II) i.e. 4-bromo-l-phthalimidopentane from 2-methyl tetrahydrofuran is detailed in Organic Synthesis, Collective Volume I, 119; Journal of Chemical Society (1929), 2959 and Journal of American Chemical Society Vol. 77, (1955), 4816-4823.
The drawback of the prior art is product contaminated with high levels of impurities, poor isolated yields and difficulties in isolation of the final product. Another drawback is the use of excess 1.0 mole of 8-amino-6-methoxy quinoline which needs to be recovered and recycled to makes process economically acceptable.
Objectives
The main objective of the present invention is to provide a simple, economical and environmental friendly process for the preparation of 6- methoxy-8-[4-amino-l -methyl -butyl amino] quinoline [primaquine] and its acid addition salts of high quality.
The further objective of the present invention is to avoid the excess use of the 8-amino-6-methoxy quinoline. This modification reduces the impurities level substantially and also avoids the recovery and recyclability of the said intermediate of the Formula I.
Another objective of the present invention is to reduce the time cycle by avoiding the extraction and tedious high vacuum distillation procedures to remove the phthalimido intermediate and therefore significantly improving the capacity utilization.
Summary of the invention
This invention relates to a process for the manufacture of 6-methoxy-8-[4-amino-l-methylbutylamino]quinoline (primaquine) which is an anti-malarial drug, more particularly for the radical cure of vivax malaria. It is also known as curative agent for relapsing vivax malaria.
This invention further relates to a process for preparation of acid addition salts of 6-methoxy-8-[4-amino-1 -methylbutylamino]quinoline (primaquine).

Detailed description of the invention
The present invention relates to a process for preparation of 6-methoxy-8-[4-amino-l-methylbutylamino] quinoline (Primaquine). The above said process comprises condensation of 8-amino-6-methoxyquinoline of the Formula (I) with 4-bromo-l-phthalimidopentane of the Formula (II) in presence of organic bases (such as triethylamine, diisopropylamine) at a temperature of 110-115° C to give 6-methoxy-8-[4-amino-l-methylbutylamino]quinoline of Formula (III).

The reaction is carried out between 8-amino-6-methoxyquinoline and 4-bromo-l-phthalimidopentane in the molar ratio of 1.1 to 3.5 preferably 2.5 to 3.0 in the presence of organic base in a molar ratio from 1.1 to 4.0 mole at a temperature ranging from 100-150°C preferably between 115 to 125° C for a period of 20-25 hours.
Triethylamine base acts as a catalyst/driving force for completing the reaction thereby increasing the yield and purity of the final product. It also acts as acid scavenger for the gaseous by-product hydrogen bromide generated from the reaction to form triethylamine salt.
The excess use of the expensive 8-amino-6-methoxy quinoline and the absence of triethylamine in the reaction as in prior art results in impurity generation due to the slow rate of reaction which leads to incomplete reaction. This necessitates further purification to obtain the final product. The higher yield and purity resulting from the use of triethylamine in the absence of any solvent constitutes a considerable technical advance with respect the process described in the prior art.

The phthalimido compound of Formula (III) is reacted with hydrazine hydrate for 2.0 hours and the resultant free base i.e. 6-methoxy-8-[4-amino-l-methylbutyl-amino]quinoline of the Formula (IV) is extracted with ethyl acetate and the drug is obtained as diphosphate salt by adding an alcoholic solution of 85 % of phosphoric acid to the alcoholic solution of the free base under stirring. The salt falls down as an orange crystalline product

4-bromo-1 -phthalimidopentane (!!)

6-methoxy-8-(4-phtha!imido-1-m ethylbutylamino)quinoline
(III)
The starting material of Formula (I) i.e. 8-amino-6-methoxy quinoline used in this invention is prepared by the process disclosed in Organic synthesis Collective Volume III, 568 and 661.

The starting intermediate of Formula (II) i.e. 4-bromo-l-phthalimidopentane is prepared according to the process disclosed in Journal of American Chemical Society Vol. 77, (1955), 4816-4823.

6-methoxy-8-[4-amino-1-methylbu tyiamino]quinoline
(IV)
The following examples illustrate the process of the invention in greater details and are in no way limiting the scope of the invention.
Experimental
Example 1 6-methoxy-8-[4-phthalimido-l-methylbutylamino]quinoline
A mixture of 8-amino-6-methoxy quinoline (lOOgms), 4-bromo-l-phthalimidopentane (300gms) and triethylamine (104.0gms) is heated with stirring for 20-25hrs at a temperature of 110 tol 15°C. The reaction mixture is cooled and 500ml of acetone added to separate the hydrobromide salt of triethylamine by filtration. Then the acetone is distilled out from the filtrate to get the oily mass. Methanol (1000ml) is added to oily mass and cooled to 10-15°C. Sulphuric acid is added drop wise to the reaction mass to precipitate the product of Formula III as a sulphate salt. The above salt is dissolved in water (500ml) and basified with ammonium hydroxide (300ml) solution and the liberated quinoline base of Formula (III) is extracted with ethyl acetate (400 X 2). After complete removal of ethyl acetate, the phthalimido intermediate of quinoline base of Formula (III) is isolated as oil. The product was identified by elementary analysis, IR and NMR. After precipitating the phthalimido quinoline as a sulphate salt, the excess 4-bromo-l-phthalimidopentane remains in the mother liquor, can be easily recycled.

The yield of the product is 180gms (% yield is 80%). Purity - 98.0 % (by HPLC analysis).
Example 2
6-methoxy-8-[4-phthalimido-l-
methylbutyIaminojquinoline(primaquine)diphosphate
The above phthalimido intermediate of quinoline base (lOOgms) of Formula (III) is dissolved in ethanol (1000ml), 220 gms of hydrazine hydrate is added to the reaction mass. The reaction mixture is refluxed for 2.0 hours, cooled to room temperature and filtered to remove the by product generated during the reaction. Ethanol is recovered from the filtrate, and 6-methoxy-8-[4-amino-l-methylbutylamino]quinoline base isolated as an oil.
The above base is diluted with ethanol (500ml). The reaction mixture is heated to 55-60°C and phosphoric acid (lOOgms) added. The reaction mixture is then refluxed for 1.0 to 2.0 hours, cooled to room temperature to get the desired diphosphate salt of Formula (IV).
The yield of the product is 105gms (% yield is 90%). Purity - 99.0 % (based on HPLC analysis)
M.P: 198-200°C.

We claim
1. A process for the manufacture of 6-methoxy-8-[4-amino-methylbutylamino]quinoline (Primaquine) of Formula IV, and its acid addition salts, wherein the said process comprising:

a) heating a mixture of 8-amino-6-methoxyquinoline of Formula (I) and 4-bromo-l-phthalimidopentane of Formula (II) in presence of an organic base at a temperature ranging from about 100 to 150° C for a period of 20 hours or more,
b) adding an organic solvent to the said reaction mixture to precipitate the by¬product hydrobromide salt of organic base and removing it by filtration,
c) concentrating said filtrate and dissolving the residue in an alcohol, treating with sulfuric acid to precipitate sulphate salt of product of Formula III,

e) Dissolving said precipitate of Formula III in water and treating with ammonium hydroxide to form a phthalimido-compound of Formula III,
f) treating said phthalimido-intermediate of Formula (III) with hydrazine hydrate to form a reaction mass containing the 6-methoxy-8-[4-amino-l-methylbutylaminojquinoline base of Formula (IV) and
g) isolating said primaquine of formula IV from said reaction medium.

2. A process for the manufacture of 6-methoxy-8-[4-amino-methylbutylamino]quinoline {Primaquine) as claimed in claim 1(a) wherein condensation of 8-amino-6-methoxy quinoline with 4-bromo-l-phthalimidopentane in presence of organic bases such as triethylamine, diisopropylamine and more particularly triethylamine.
3. A process for the manufacture of 6-methoxy-8-[4-amino-methylbutylamino]quinoline {Primaquine) as claimed in claim 1 (a) wherein condensation of 8-amino-6-methoxy quinoline of Formula (I) with 4-bromo-l-phthalimidopentane (II) is in a molar ratio ofl.lto3.5
4. The process as claimed in claim 1 (a) wherein condensation of 8-amino-6-methoxy quinoline of Formula (I) with 4-bromo-l-phthalimidopentane (II) is in a molar ratio of2.5to3.0
5. Process for the manufacture of 6-methoxy-8- [4-amino-methylbutylarnino] quinoline {Primaquine) as claimed in claim 1 (a) wherein the molar ratio of the organic base is in the range of l.lto 4.0 moles relative to 8-amino-6-methoxy quinoline.
6. A process for the manufacture of 6-methoxy-8-[4-amino-methylbutylamino]quinoline {Primaquine) as claimed in claim 1 (a) wherein the molar ratio of the organic base is 2.5 to 3.0 relative to 8-amino-6-methoxy quinoline.
7. A process for the manufacture of 6-methoxy-8-[4-amino-methylbutylamino]quinoline (Primaquine) as claimed in claim 1 (a) wherein the reaction mixture is heated to a temperature ranging from 100-150°C for a period of 20-25hrs.
8. A process for the manufacture of 6-methoxy-8-[4-amino-methylbutylamino]quinoline {Primaquine) as claimed in claim 1 (a) wherein the reaction mixture is heated to a temperature ranging from 110-125°C for a period of 20-25hrs.
9. A process for the manufacture of 6-methoxy-8-[4-aminomethylbutylamino]quinoline {Primaquine) as claimed in claim 1 (b) wherein the said organic solvent is acetone.
10. A process for the manufacture of 6-methoxy-8-[4-aminomethylbutylamino]quinoline
{Primaquine) as claimed in claim 1(c) wherein the said alcohol used to dissolve oily
mass is ethanol.

• 11. A process for the manufacture of 6-methoxy-8-[4-aminomethylbutylamino]quinoline {Primaquine) as claimed in claim 1 wherein the above said quinoline base is further treated with phosphoric acid in ethanol at 55-60°C to obtain the diphosphate salt.
12. A process for the manufacture of 6-methoxy-8-[4-aminomethylbutylamino]quinoline {Primaquine) and its acid addition salts as substantially described herein with reference to the aforesaid examples 1 to 2.
Dated this 20th day of Feb 2004
Dr. Gopakumar G. Nair Agent for the Applicant

Documents:

278-mum-2004-abstract-(05-12-2005).doc

278-mum-2004-abstract-(05-12-2005).pdf

278-mum-2004-cancelled pages(05-12-2005).pdf

278-mum-2004-claims(granted)-(05-12-2005).doc

278-mum-2004-claims(granted)-(05-12-2005).pdf

278-mum-2004-correspondence(5-12-2005).pdf

278-mum-2004-correspondence(ipo)-(17-10-2007).pdf

278-mum-2004-form 1(05-03-2004).pdf

278-mum-2004-form 19(10-09-2004).pdf

278-mum-2004-form 2(granted)-(05-12-2005).doc

278-mum-2004-form 2(granted)-(05-12-2005).pdf

278-mum-2004-form 26(05-12-2005).pdf

278-mum-2004-form 3(05-03-2004).pdf

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Patent Number

211087

Indian Patent Application Number

278/MUM/2004

PG Journal Number

45/2007

Publication Date

09-Nov-2007

Grant Date

17-Oct-2007

Date of Filing

05-Mar-2004

Name of Patentee

M/S. IPCA LABORATORIES LIMITED

Applicant Address

48,KANDIVLI INDUSTRIAL ESTATE, MUMBAI-400 067

Inventors:

#	Inventor's Name	Inventor's Address
1	KUMAR,ASHOK	B/203,204,STERLING CO.HSG.SOC. A2-A3,SUNDARBAN COMPLEX, ANDHERI(W)MUMBAI-400 053
2	VYAS,KETAN DHANSUKHLAL	13/15,TRIVENI APARTMENTS,OPP.KAMATH CLUB,(LOKHANDWALA)OSHIWARA,MUMBAI-400 102
3	NIMBALKAR,MANMOHAN MADHAVRAO	UTKARSH,FLAT NO.46 SAYANI ROAD,KHEDGALLI,PRABHADEVI,MUMBAI-400 025
4	SINGH,DHARMENDRA	BUILDING NO.D/3,'A'WING,ROOM NO.8,SAHYADRI NAGAR,CHARKOP,KANDIVLI(W),MUMBAI-400 067

PCT International Classification Number

C07D215/00 A61K9/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA