Indian Patents. 206244:A PROCESS FOR THE PREPARATION OF 7-CHLORO-4-(5(-N-ETHYL-N-2-HYDROXYETHYLAMINE)-2-PENTYL] AMINOQUINOLINE [HYDROXYCHLOROQUINE] AND ITS ACID ADDITION SALTS

Title of Invention	A PROCESS FOR THE PREPARATION OF 7-CHLORO-4-(5(-N-ETHYL-N-2-HYDROXYETHYLAMINE)-2-PENTYL] AMINOQUINOLINE [HYDROXYCHLOROQUINE] AND ITS ACID ADDITION SALTS
Abstract	A process for the preparation of 7-chloro-4-[5-(N-ethyl-N-2-hydroxyethyl amino)-2-pentyl]aminoquinoline (Hydroxychloroquine - Formula III) and its acid addition salts characterized by using a catalyst potassium iodide, and an inorganic base sodium hydroxide, for 40 to 50 hrs at a temperature ranging from 100 to 150°C comprising the steps of;

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] "A process for the preparation of 7-Chloro-4-(5-(N-ethyl-N-2-hydroxyethylamine)-2-pentyl] aminoquinoline [Hydroxychloroquine] 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: Field of Invention This invention relates to an improved process for the preparation of the title compound, which is useful as an anti-malarial, anti-rheumatic agent, used either as free base or in the form of acid addition salt. Background and prior art Hydroxychloroquine chemically known as 7-chIoro-4-(5-N-ethyl-N-2-hydroxyethylamine)-2-pentyl]aminoquinoline is useful in the treatment of malaria. It is also used in combination with cyclophosphamide and azathioprine in the treatment of rheumatoid arthritis. Racemic hydroxychloroquine which is 7-chloro-4-(5-(N-ethyl-N-2-hydroxyethylamine)-2-pentyfjaminoquinoline, reported in the US patent 2546658 (1951) is sold as Sulfate salt by Sanofi -Winthrop Phramaceuticals under the trade name Plaquenil RTM. Its sulfate is useful as an anti-malarial and also in treating lupus erythematosus and rheumatoid arthritis. Pharmacokinetics of racemic hydroxycholoroquine as studied by S.E Tett et.al., Br. J. Chin Pharamac, 26, 303-313, (1988), is similar to that of chloroquine. H.N Bernstein, Annals of Ophthalmology, 23, 292-296,(1991) presents an analysis of all published cases and FDA reports of retinopathy induced by hydroxychloroquine. In USA, hydroxy chloroquine is preferred to chloroquine because it is significantly less retinotoxic at the current recommended dose (400mg/day according to FDA). 2 US 2546658 discloses the preparation of hydroxy chloroquine and its acid addition salts. In this patent, hydroxychloroquine is prepared by the condensation of 4,7-dichloroquinoline with 5(N-ethyl-N-2-hydroxyethylamino)-2-pentylarnine in presence of phenol at 125-130° C. Another patent R063271 discloses method for synthesis of hydroxychloroquine which comprises the condensation of 7-chloro-2,3-dihydro-4-quinolone with 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine at 130-160° C. GB680225 discloses the preparation of hydroxychloroquine. In this patent, hydroxychloroquine is prepared by the condensation of 4,7-dichloroquinoline with 5(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine in presence of phenol (acid catalyst) at 125-130° C for a period of 18 hrs, followed by treatment with phosphoric acid resulted hydroxychloroquine diphosphate a crude gummy product with a yield of 41.6% . Major drawbacks of the known reported methods results are the formation of high levels of impurities, difficult isolation procedures, and overall poor yield of the final compound. Further drawback of the reported processes in the prior art is the use of stoichiometric amount of phenol in condensation reaction and inherent problems faced in removing the phenol from the reaction mass, after the completion of this reaction. The present invention used the combination of inorganic base and potassium iodide to run the condensation step between 4,7-dichloroquinoline with 5 (N-ethyl-N-2-hydroxyethylamino)-2-penty!amine. This combination drastically increased the yield and purity of the product hydroxychloroquine disulphate. 3 Objective: The main objective of the present invention is to provide a simple, economical, environmental-friendly process for the manufacture of 7-chloro-4-[5-(N-ethyl-N-2-hydroxyethylamino)-2-pentyl]aminoquinoline & its acid addition salts, of high quality. A further objective of the present invention is to avoid the use of phenol. This modification not only reduces the impurity level of the product substantially, but also makes the isolation of the product very easy. This modified process also avoids recovery and recyclability of phenol which is a major requirement of prior art & therefore this invention significantly improves the capacity utilization. Summary of the invention: This invention relates to an improved process for the preparation of 7-chloro-4-[5-(N-ethyl-N-2-hydroxyethylamino)-2-pentyI]aminoquinoline & its acid addition salts which are useful as anti-malarial and anti- rheumatic agents. Detailed description In accordance with the above basic objective of the present invention, there is provided a direct condensation of 4,7-dichloroquinoline of the formula (I) with 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine of the formula (II) in presence of catalytic amount of potassium iodide & organic and inorganic bases' (such as triethyl amine, di-isopropylamine, sodium hydroxide, potassium hydroxide, potassium carbonate, potassium t-butoxide etc) to give corresponding substituted amino quinolines of the formula (III). 4 The cr"Jsnsation reaction is carried out by treating 4,7-dichloroquinoline (I) with 5-(N-ethyl- :-hydroxyethylamino)-2-pentylamine of the formula (II) in the molar ratio of 1.1 to 5.0 preferably 1.7 to 2.0 in presence of catalytic amount of potassium iodide and base in a molar ratio from 0.1 to 1.0 mole preferably 0.2 mole at a temperature ranging from 100 to 150° for a period of 45 to 50 hours. The synthesis of formula (I) i.e. 4,7-dichloroquinoline from m-chloroaniline is well documented in the Prior art (Org Synthesis, Collective Volume 3, 272). The preparation of intermediate of formula (II) 5-(N-ethyl-N-2-hydroxyethyIamino)-2-pentylamine is also reported in the prior art (US 2546658). 5 Experimental: Example 1: A mixture of (lOOgm) of 4,7-dichloroquinoline, (146gm) of 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine, (4.0gm) of potassium iodide & 8.0 gm of sodium hydroxide were heated with stirring for 40 to 50 hours at 110 to 115° C. Then the reaction mixture cooled, methanol (400ml) was added and the reaction mixture was charcolized. The clear filtrate was treated with phosphoric acid (130gm) to give 250gm (yield- 94% & Purity 99% by HPLC) of 7-chloro-4-[5-(N-ethyI-N-2-hydroxyethylamino)-2-pentyl] aminoquinoline diphosphate. The above diphosphate was dissolved in water (500ml), basified with ammonium hydroxide (300ml) solution and the resulting liberated quinoline base was extracted with methylene dichloride (400ml x 2). After complete removal of methylene chloride, the quinoline base was isolated. Melting point is 89 to 91°C. The yield of the product is 130gms (yield -77%) Example 2: 7-chloro-4-r5-(N-ethvl-N-2-hvdroxvethvlamino)-2-pentvl1 aminoquinoline diphosphate. The above quinoline base (lOOgm) was dissolved in methanol (400ml). The reaction mixture was cooled to 5 to 10°C and the phosphoric acid (65gm) was added. The reaction mixture refluxed for 3 to 4 hours to get the desired acid salt of the quinoline base. The yield of the product is 126gms( yield - 80%). Example 3: 7-chloro-4-[5-rN-ethvl-N-2-hvdroxyethvlamino)-2-pentvllaminoquinoline sulphate. 6 The above quinoline base (lOOgm) was dissolved in methanol (400ml). The reaction mixture was cooled to 5 to 10°C. Sulphuric acid (35gm) was added. The reaction mixture refluxed for 3 to 4hours to get the desired acid salt of the quinoline base. The yield of the product is 100gms(Yield - 78% & purity 99.5% by HPLC). Wh th preferred or illustrative emt tustive or limiting of the inve atives, modifications and equ d claims. 7 We claim, 1. A process for the preparation of 7-chloro-4-[5-(N-ethyl-N-2-hydroxyethyl amino)-2-pentyl]aminoquinoline (Hydroxychloroquine - Formula III) and its acid addition salts characterized by using a catalyst potassium iodide, and an inorganic base sodium hydroxide, for 40 to 50 hrs at a temperature ranging from 100 to 150°C comprising the steps of; Formula II a) heating 4,7-dichloroquinoline ( Formula I) with 5-(N-ethyl-N-2-hydroxy-ethylamino) -2-pentylamine ( Formula II) in presence of a catalyst, to obtain a reaction mixture containing the compound 7-chloro-4-[5-(N-ethyl-N-2-hydroxyethyl amino)-2-pentyl] aminoqmnoline; b) cooling the reaction mixture; c) processing the cooled reaction mixture by adding organic solvent like methanol; d) treating said methanol solution with an adsorbant like charcoal and filter; e) treating the clear filtrate with phosphoric acid to obtain 7-chloro-4-[5-(N-ethyl-N-2-hydroxyethylamino)-2-pentyl]-aminoquinoline diphosphate; f) basifying the said diphosphate dissolved in the water, with ammonium hydroxide solution till quinoline base liberated; g) isolating the free quinoline base therefrom by extraction using an organic solvent and evaporating said organic solvent; h) dissolving the said quinoline base in primary and secondary alcohol such as methanol, ethanol and isopropyl alcohol; i) cooling the quinoline base solution to 5 to 10° C; j) adding phosphoric acid or sulphuric acid to said solution; and k) refluxing the reaction mixture for up to 4 hours to get the respective acid addition salts of the hydroxychloroquine base. 2. The process as claimed in claiml, wherein the ratio of 4,7-dichloroquinoline to 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine is 1: 1.46 gm weight by weight. 3. The process as claimed in claiml, wherein the quantity of potassium iodide is 4 % weight by weight of 4,7-dichloroquinoline. 4. The process as claimed in claim 1, wherein the quantity of sodium hydroxide is 8% by weight of 4,7-dichloroquinoline. 5. The process as claimed in claim 1, wherein preferred temperature range is 110 to 115°C. 6. The process as claimed in claim 1, wherein the organic solvent is methanol. 7. The process as claimed in claim 1, wherein the quantity of phosphoric acid in step (e) is 130 % of the 4.7-dichloroquinoline. 8. The process as claimed in claim 1, wherein ratio of quinoline base to methanol is 1 to 4 weight by volume. 9. The process as claimed in claim 1, wherein the quantity of phosphoric acid or sulfuric acid in step (j) is 30 to 35 % weight by weight with reference to the quinoline base. 10. The process as claimed in claim 1, wherein refluxing of quinoline base with phosphoric acid or sulphuric acid is done for 3 to 4 hours. 11. A process for the preparation of 7-chloro-4-[5-(N-ethyl-N-2-hydroxyethylamino)-2-pentyl]aminoquinoline (Hydroxychloroquine) and its acid addition salts as substantially described herein with reference to the foregoing examples 1 to 3. Dated this the 24th day of Nov 2003

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10; rule 13]

"A process for the preparation of 7-Chloro-4-(5-(N-ethyl-N-2-hydroxyethylamine)-2-pentyl] aminoquinoline [Hydroxychloroquine]
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:

Field of Invention
This invention relates to an improved process for the preparation of the title compound, which is useful as an anti-malarial, anti-rheumatic agent, used either as free base or in the form of acid addition salt.
Background and prior art
Hydroxychloroquine chemically known as 7-chIoro-4-(5-N-ethyl-N-2-hydroxyethylamine)-2-pentyl]aminoquinoline is useful in the treatment of malaria. It is also used in combination with cyclophosphamide and azathioprine in the treatment of rheumatoid arthritis.
Racemic hydroxychloroquine which is 7-chloro-4-(5-(N-ethyl-N-2-hydroxyethylamine)-2-pentyfjaminoquinoline, reported in the US patent 2546658 (1951) is sold as Sulfate salt by Sanofi -Winthrop Phramaceuticals under the trade name Plaquenil RTM. Its sulfate is useful as an anti-malarial and also in treating lupus erythematosus and rheumatoid arthritis.
Pharmacokinetics of racemic hydroxycholoroquine as studied by S.E Tett et.al., Br. J. Chin Pharamac, 26, 303-313, (1988), is similar to that of chloroquine. H.N Bernstein, Annals of Ophthalmology, 23, 292-296,(1991) presents an analysis of all published cases and FDA reports of retinopathy induced by hydroxychloroquine. In USA, hydroxy chloroquine is preferred to chloroquine because it is significantly less retinotoxic at the current recommended dose (400mg/day according to FDA).
2

US 2546658 discloses the preparation of hydroxy chloroquine and its acid addition salts. In this patent, hydroxychloroquine is prepared by the condensation of 4,7-dichloroquinoline with 5(N-ethyl-N-2-hydroxyethylamino)-2-pentylarnine in presence of phenol at 125-130° C.
Another patent R063271 discloses method for synthesis of hydroxychloroquine which comprises the condensation of 7-chloro-2,3-dihydro-4-quinolone with 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine at 130-160° C.
GB680225 discloses the preparation of hydroxychloroquine. In this patent, hydroxychloroquine is prepared by the condensation of 4,7-dichloroquinoline with 5(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine in presence of phenol (acid catalyst) at 125-130° C for a period of 18 hrs, followed by treatment with phosphoric acid resulted hydroxychloroquine diphosphate a crude gummy product with a yield of 41.6% .
Major drawbacks of the known reported methods results are the formation of high levels of impurities, difficult isolation procedures, and overall poor yield of the final compound.
Further drawback of the reported processes in the prior art is the use of stoichiometric amount of phenol in condensation reaction and inherent problems faced in removing the phenol from the reaction mass, after the completion of this reaction.
The present invention used the combination of inorganic base and potassium iodide to run the condensation step between 4,7-dichloroquinoline with 5 (N-ethyl-N-2-hydroxyethylamino)-2-penty!amine. This combination drastically increased the yield and purity of the product hydroxychloroquine disulphate.
3

Objective:
The main objective of the present invention is to provide a simple, economical, environmental-friendly process for the manufacture of 7-chloro-4-[5-(N-ethyl-N-2-hydroxyethylamino)-2-pentyl]aminoquinoline & its acid addition salts, of high quality.
A further objective of the present invention is to avoid the use of phenol. This modification not only reduces the impurity level of the product substantially, but also makes the isolation of the product very easy. This modified process also avoids recovery and recyclability of phenol which is a major requirement of prior art & therefore this invention significantly improves the capacity utilization.
Summary of the invention:
This invention relates to an improved process for the preparation of 7-chloro-4-[5-(N-ethyl-N-2-hydroxyethylamino)-2-pentyI]aminoquinoline & its acid addition salts which are useful as anti-malarial and anti- rheumatic agents.
Detailed description
In accordance with the above basic objective of the present invention, there is provided a direct condensation of 4,7-dichloroquinoline of the formula (I) with 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine of the formula (II) in presence of catalytic amount of potassium iodide & organic and inorganic bases' (such as triethyl amine, di-isopropylamine, sodium hydroxide, potassium hydroxide, potassium carbonate, potassium t-butoxide etc) to give corresponding substituted amino quinolines of the formula (III).
4

The cr"Jsnsation reaction is carried out by treating 4,7-dichloroquinoline (I) with 5-(N-ethyl- :-hydroxyethylamino)-2-pentylamine of the formula (II) in the molar ratio of 1.1 to 5.0 preferably 1.7 to 2.0 in presence of catalytic amount of potassium iodide and base in a molar ratio from 0.1 to 1.0 mole preferably 0.2 mole at a temperature ranging from 100 to 150° for a period of 45 to 50 hours.
The synthesis of formula (I) i.e. 4,7-dichloroquinoline from m-chloroaniline is well documented in the Prior art (Org Synthesis, Collective Volume 3, 272). The preparation of intermediate of formula (II) 5-(N-ethyl-N-2-hydroxyethyIamino)-2-pentylamine is also reported in the prior art (US 2546658).
5

Experimental:
Example 1:

A mixture of (lOOgm) of 4,7-dichloroquinoline, (146gm) of 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine, (4.0gm) of potassium iodide & 8.0 gm of sodium hydroxide were heated with stirring for 40 to 50 hours at 110 to 115° C. Then the reaction mixture cooled, methanol (400ml) was added and the reaction mixture was charcolized. The clear filtrate was treated with phosphoric acid (130gm) to give 250gm (yield- 94% & Purity 99% by HPLC) of 7-chloro-4-[5-(N-ethyI-N-2-hydroxyethylamino)-2-pentyl] aminoquinoline diphosphate.
The above diphosphate was dissolved in water (500ml), basified with ammonium hydroxide (300ml) solution and the resulting liberated quinoline base was extracted with methylene dichloride (400ml x 2). After complete removal of methylene chloride, the quinoline base was isolated. Melting point is 89 to 91°C. The yield of the product is 130gms (yield -77%)
Example 2:
7-chloro-4-r5-(N-ethvl-N-2-hvdroxvethvlamino)-2-pentvl1 aminoquinoline diphosphate.
The above quinoline base (lOOgm) was dissolved in methanol (400ml). The reaction mixture was cooled to 5 to 10°C and the phosphoric acid (65gm) was added. The reaction mixture refluxed for 3 to 4 hours to get the desired acid salt of the quinoline base. The yield of the product is 126gms( yield - 80%).
Example 3:
7-chloro-4-[5-rN-ethvl-N-2-hvdroxyethvlamino)-2-pentvllaminoquinoline sulphate.
6

The above quinoline base (lOOgm) was dissolved in methanol (400ml). The reaction mixture was cooled to 5 to 10°C. Sulphuric acid (35gm) was added. The reaction mixture refluxed for 3 to 4hours to get the desired acid salt of the quinoline base. The yield of the product is 100gms(Yield - 78% & purity 99.5% by HPLC).
Wh th preferred or illustrative
emt tustive or limiting of the
inve atives, modifications and
equ d claims.
7

We claim,
1. A process for the preparation of 7-chloro-4-[5-(N-ethyl-N-2-hydroxyethyl amino)-2-pentyl]aminoquinoline (Hydroxychloroquine - Formula III) and its acid addition salts characterized by using a catalyst potassium iodide, and an inorganic base sodium hydroxide, for 40 to 50 hrs at a temperature ranging from 100 to 150°C comprising the steps of;

Formula II
a) heating 4,7-dichloroquinoline ( Formula I) with 5-(N-ethyl-N-2-hydroxy-ethylamino) -2-pentylamine ( Formula II) in presence of a catalyst, to obtain a reaction mixture containing the compound 7-chloro-4-[5-(N-ethyl-N-2-hydroxyethyl amino)-2-pentyl] aminoqmnoline;
b) cooling the reaction mixture;
c) processing the cooled reaction mixture by adding organic solvent like
methanol;
d) treating said methanol solution with an adsorbant like charcoal and filter;
e) treating the clear filtrate with phosphoric acid to obtain 7-chloro-4-[5-(N-ethyl-N-2-hydroxyethylamino)-2-pentyl]-aminoquinoline diphosphate;
f) basifying the said diphosphate dissolved in the water, with ammonium hydroxide solution till quinoline base liberated;
g) isolating the free quinoline base therefrom by extraction using an organic solvent and evaporating said organic solvent;
h) dissolving the said quinoline base in primary and secondary alcohol such as methanol, ethanol and isopropyl alcohol;

i) cooling the quinoline base solution to 5 to 10° C;
j) adding phosphoric acid or sulphuric acid to said solution; and
k) refluxing the reaction mixture for up to 4 hours to get the respective acid
addition salts of the hydroxychloroquine base.
2. The process as claimed in claiml, wherein the ratio of 4,7-dichloroquinoline to 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine is 1: 1.46 gm weight by weight.
3. The process as claimed in claiml, wherein the quantity of potassium iodide is 4 % weight by weight of 4,7-dichloroquinoline.
4. The process as claimed in claim 1, wherein the quantity of sodium hydroxide is 8% by weight of 4,7-dichloroquinoline.
5. The process as claimed in claim 1, wherein preferred temperature range is 110 to 115°C.
6. The process as claimed in claim 1, wherein the organic solvent is methanol.
7. The process as claimed in claim 1, wherein the quantity of phosphoric acid in step (e) is 130 % of the 4.7-dichloroquinoline.
8. The process as claimed in claim 1, wherein ratio of quinoline base to methanol is 1 to 4 weight by volume.
9. The process as claimed in claim 1, wherein the quantity of phosphoric acid or sulfuric acid in step (j) is 30 to 35 % weight by weight with reference to the quinoline base.
10. The process as claimed in claim 1, wherein refluxing of quinoline base with phosphoric acid or sulphuric acid is done for 3 to 4 hours.
11. A process for the preparation of 7-chloro-4-[5-(N-ethyl-N-2-hydroxyethylamino)-2-pentyl]aminoquinoline (Hydroxychloroquine) and its acid addition salts as substantially described herein with reference to the foregoing examples 1 to 3.

Dated this the 24th day of Nov 2003

Documents:

1213-mum-2003- claims.doc

1213-mum-2003-claims.pdf

1213-mum-2003-correspondence(ipo).pdf

1213-mum-2003-correspondence.pdf

1213-mum-2003-description(cancelled).pdf

1213-mum-2003-description(granted).doc

1213-mum-2003-description(granted).pdf

1213-mum-2003-form 1(19-dec-2005).pdf

1213-mum-2003-form 1(19-jan-2005).pdf

1213-mum-2003-form 19.pdf

1213-mum-2003-form 2(granted).doc

1213-mum-2003-form 2(granted).pdf

1213-mum-2003-form 2(title page).pdf

1213-mum-2003-form 26.pdf

1213-mum-2003-form 3.pdf

1213-mum-2003-indian patent specification.pdf

1213-mum-2003-other.pdf

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Patent Number

206244

Indian Patent Application Number

1213/MUM/2003

PG Journal Number

31/2008

Publication Date

01-Aug-2008

Grant Date

19-Apr-2007

Date of Filing

24-Nov-2003

Name of Patentee

M/S. IPCA LABORATORIES LIMITED

Applicant Address

48, KANDIVLI INDUSTRIAL ESTATE, MUMBAI

Inventors:

#	Inventor's Name	Inventor's Address
1	KUMAR ASHOK	B / 203, 204, STERLING CO. HSG. SOC. A2-A3, SUNDARVAN COMPLEX, ANDHERI (WEST), MUMBAI 400053.
2	SINGH DHARMENDRA	BUILDING NO.D/3, A WING, ROOM NO.8, SAHYADRI NAGAR, CHORKOP, KANDIVLI (WEST) MUMBAI 400 067
3	BHISE, SANJAY	A-601, SAI Ashish I, NANCY COLONY, BORIVALI (East), MUMBAI — 400 066
4	JADHAV, ATUL	8, J. M. Pereira Chawl, St. Francis Road, Vile Parle (West), Mumbai—400 056

PCT International Classification Number

A 61 K 31/01

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA