FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the Invention:
PROCESS FOR PREAPARTION OF CHLOROQUINE AND DERIVATIVES
THERE OF
Applicant Name and Address: Bioxera Pharma Research LLP
An Indian Company having registered address of
4A, 5A Ground floor, Plot 17-B, Botawala Building,
Sitaladevi Temple Road, Mahim (W),
Mumbai-400016,
Maharashtra,
India.
The following specification particularly describes the invention and the manner in which it to be performed

FIELD OF THE INVENTION
New process for preparation of Hydroxychloroquine (1).
The present invention relates to a process for the preparation of hydroxychloroquine which is
therapeutically effective as an anti-malarial drug.

BACKGROUND OF THE INVENTION
The Chloroquine and its derivative viz. hydroxychloroquine which is chemically known as 2-[[4-[7-chloro-4-quinolinyl]amino]pentyl]-ethylamino]ethanol and has a structure of the formula (1) are used for treatment of malaria worldwide. Besides, they are used to treat rheumatoid arthritis and cutaneous lupus erythematosus (LE) and rashes associated with systemic lupus erythematosus (SLE), Recently they are also used in some photosensitivity disorders and occasionally in other inflammatory skin conditions. Further, they have been also shown anti-HIV activity.
Hydroxychloroquine was first disclosed in US Patent No. 2,546,658 (hereafter US'658). This US patent discloses a process for preparing hydroxychloroquine diphosphate, which involves reacting 4,7-diehloroquinoline with Nf-ethyl-N!-P-hydroxyethyl-l,4-pentadiamine in the presence of potassium iodide (KI) and phenol at a temperature of 125°C to 130°C for 18 hours or more thereby prepare crude hydroxychloroquine to which diphosphate is then attached to obtain hydroxychloroquine diphosphate with a yield of 35% which on further hydrolysis yields desired product.
US Patent No. 5,314,894 discloses a process for preparing (S)-(+)-hydroxychloroquine wherein 4,7-dichloroquinoline and (S)-N'-ethyl-N'-β-hydroxyethyl-l,4-pentadiamine with N,N -diisopropylethylamine were heated at reflux for 48 hours to obtain (S)-(+)-hydroxychloroquine with a yield of 46%.

Further, CA Patent No. 2,561,987 teaches a process for preparing hydroxychloroquine, which involves reacting 4,7-dichloroquinoline with N'-ethyl-Nf-p-hydroxyethyl-l,4-pentadiamine at a temperature of 120°C to 130°C for 20 to 24 hours, and introducing a protective group, as illustrated below, to the reaction product so as to facilitate the removal of impurities, followed by hydrolysis of the protective group to obtain a desired product hydroxychloroquine.
However, with currently known methods of preparing hydroxychloroquine and its acid addition salts, there is a difficulty in elimination of undesirable byproducts upon the preparation of acid addition salts, due to using a toxic solvent such as phenol or a reagent such as N,N-diisopropylethylamine, which has a high boiling point and a structure similar to that of the final product. Particularly, a long reaction time at high temperatures may result in increased production costs and buildup of byproducts, for which a higher-efficiency synthesis method of hydroxychloroquine and disulfate is required in related industrial fields.
To this end, there is a need for the development of a novel method of synthesizing hydroxychloroquine, which is capable of overcoming a variety of problems and disadvantages as discussed above and is capable of providing a desired product with higher purity and yield.
The present invention is intended to provide a novel method for preparing hydroxychloroquine, which is capable of inhibiting the formation of byproducts and decreasing production costs by significantly decreasing a reaction temperature and a reaction time, using Lewis acids salts of H+, Li+, Na+, K+, (Rb+, Cs+), Mg2+, Ca2+, Sr2*, (Ba2+), Ti4+, Zr4*, Cr3*, Cr6*, MoO3+, Mn2+, Mn3+, Fe3+, Co3+, Al3+, Si4+, CO2, Fe2+, Co2+, Ni2+, Cu2+9 Zn2+, (Pb2+), Cu+, Ag+, Au+, Cd2+, Hg+, Hg2+, CH3Hg+ and likes with or without solvent & ligands to produce the hydroxychloroquine.
OBJECTS OF THE PRESENT INVENTION
The primary object of the present invention is to provide efficient, economic and industrially viable process for the preparation of the Chloroquine and its derivative viz. hydroxychloroquine.

DETAILED DESCRIPTION OF THE INVENTION
In one of the embodiments of the invention, there is provided a novel process for the preparation of Chloroquine comprising reacting 4,7-dichloroquinoline with N,N-diethylpentane-l,4-diamine in the presence of lewis acid and optionally with or without solvent to provide Chloroquine.
The whole process can be represented by the following reaction scheme-1.
Scheme-1

According to another embodiment of the present invention, Chloroquine may be further purified either by acid-base treatment, or solvent crystallization.
The lewis acid used in the said conversion is a salt selected from H+ Li+, Na+, K+, (Rb+, Cs+), Mg2+, Ca2+, Sr2*, (Ba2+), Ti4+, Zr4*, Cr3*, Cr6*, Mo03+, Mn2+, Mn3+, Fe3+, Co3+, Al3+, Si4+, C02, Fe2+, Co2+, Ni2+, Cu2+, Zn2+, (Pb2+), Cu+, Ag+, Au+, Cd2+, Hg+, Hg2+, CH3Hg+.
The suitable solvent(s) used in said conversion is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but not limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers such as but not limited to tetrahydrofuran, 1,4-dioxane and the like; substituted cyclic ethers such as but not limited to 2-methyl tetrahydrofuran and the like; alcohols such as but not limited to methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, n-pentanol, ethylene glycol, diethylene glycol and the like; esters; ketones such as but not limited to

acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; dialkylsulfoxides such as but limited to dimethyl sulfoxide; dialkylacetamides such as but not limited to N,N,-dimethyl acetamide; nitriles such as but not limited to acetonitrile, and propionitrile; ionic liquids, hexamethylphosphorous triamide, hexamethylphosphoramide and water or mixtures thereof. The said conversion is carried out at temperature in the range of 25°C to 150°C. Preferably, the reaction is carried out at temperature in the range of 80°C to 130°C.
According to another embodiment of the present invention, there is provided a process for the preparation of Hydroxychloroquine comprising reacting the 4,7-dichloroquinoline and 2-(N-(4-aminopentyl)-N-ethylamino)ethanol diamine in the presence of lewis acid and optionally in a suitable solvent to provide Hydroxychloroquine.
The whole process can be represented by the following reaction Scheme-2.
Scheme-2

Hie lewis acid used m the said conversion is a salt of selected from H+, Li+, Na+, K+, (Rb+, Cs+), Mg2+, Ca2+, Si2*, (Ba2+), Ti4+, Zr4*, Cr3+, Cr6*, Mo03+, Mn2+, Mn3+, Fe3+, Co3+, Al3+, Si4+, C02, Fe2+, Co2+, Ni2+, Cu2+, Zn2+, (Pb2+), Cu+, Ag+, Au+, Cd2+, Hg+, Hg2+, CH3Hg+.
The suitable solvents) used in the said conversion is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but not limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers such as but not limited to tetrahydrofiiran, 1,4-dioxane and the like; substituted cyclic ethers such as but not limited to 2-methyl tetrahydrofiiran and the like; alcohols such as but not

limited to methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, n-peotanol, ethylene glycol, diethylene glycol and the like; esters; ketones such as but not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; dialkylsulfoxides such as but limited to dimethyl sulfoxide; dialkylacetamides such as but not limited to N,N,-dimethyl acetamide; nitriles such as but not limited to acetonitrile, and propionitrile; ionic liquids, hexamethylphosphorous triamide, hexamethylphosphoramide and water or mixtures thereof. The step (a) is carried out at temperature in the range of 25°C to 150°C. Preferably, the reaction is carried out at temperature in the range of 80°C to 130°C.
The Chloroquine & Hydroxychloroquine prepared by the processes of present invention was later converted to the sulfate salts using the processes disclosed in prior art methods.
The purity of Chloroquine & Hydroxychloroquine salts obtained by the process is greater than about 99% as measured by HPLC.
BEST MODE OR EXAMPLES FOR WORKING OF THE INVENTION
The present invention is described in the examples given below; further these are provided
only to illustrate the invention and therefore should not be construed to limit the scope of the
invention.
EXAMPLE-1
PREPARATION OF HYDROXYCHLOROQUINE

5g of 4,7-dichloroquinoline and 7.3 g (1.0 eq) 2-(N-(4-aminopentyl)-N-ethylamino)ethanol were heated under nitrogen atmosphere in presence of 1.5g ferric chloride at 100°C to 110°C for about 15 hours. After completion of reaction, the contents were cooled to ambient temperature and work up using acid base extractive work up in dichloromethane (DCM). The DCM layer was evaporated and swapped with 20 mL acetone. Finally 20 mL acetone was added and slight excess sulfuric acid was added. The product was filtered and dried to 9.4 g of dried compound.

EXAMPLE-2
PREPARATION OF HYDROXYCHLOROQUINE

5g of 4,7-diehloroquinoline and 7.3 g (1.0 eq) 2-(N-(4-aminopentyl)-N-ethylamino)ethanol were heated under nitrogen atmosphere in presence of 1.5g zinc chloride and 0.1 equivalent proline at 100°C to 110°C for about 5-7 hours. After completion of reaction, the contents were cooled to ambient temperature and work up using acid base extractive work up in dichloromethane (DCM). The DCM layer was evaporated and swapped with 20 mL acetone. Finally 20 mL acetone was added and slight excess sulfuric acid was added. The product was filtered and dried to 9,4 g (85% yield) of dried compound, EXAMPLE-3 PREPARATION OF HYDROXYCHLOROQUINE

5g of 4,7-dichloroquinoline and 7.3 g (1.0 eq) 2-(N-(4-aminopentyl)-N-ethylamino)ethanol were heated under nitrogen atmosphere in presence of 1.5g zinc chloride at 100°C to 110°C for about 15 hours. After completion of reaction, the contents were cooled to ambient temperature and work up using acid base extractive work up in dichloromethane (DCM). The DCM layer was evaporated and swapped with ethyl acetate. The hydroxychloroquine base was isolated from ethyl acetate and sulfuric acid salt was prepared using process disclosed in the prior art. The product was filtered and dried to 9.4 g (85% yield) of dried compound.

We Claim
1. A process for the preparation of Chloroquine, comprising reacting 4,7-dichloroquinoline with N,N-diethylpentane-1,4-diamine in the presence of chloride salt of ferric or zinc as lewis acid and optionally with or without solvent to provide Chloroquine.
2. A process for the preparation of Hydroxychloroquine comprising reacting the 4,7-dichloroquinoline and 2-(N-(4-aminopentyl)-N-ethylamino)ethanol diamine in the presence of chloride salt of ferric or zinc as lewis acid and optionally with or without solvent to provide Hydroxychloroquine.