FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFIC A TION
(See section 10 and rule 13)
Title of the invention
"A NOVEL PROCESSES FOR PREPARING LIRANAFTATE"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada. Navi Mumbai Maharashtra, India. Pin Code: 400705

I. The following specification particularly describes the invention and the manner in which it is to be performed.

A NOVEL PROCESSES FOR PREPARING LIRANAFTATE
FIELD OF THE INVENTION:
The present invention provides 0- 5, 6, 7, 8-tetrahydronaphthalen-2-yl 6-methoxypyridin-2-ylcarbamothioate (TMC) compound of structural formula II and O- 5, 6, 7, 8-tetrahydronaphthalen-2-yl 6-chloropyridin-2-ylcarbamothioate (TCC) compound of structural formula III useful as intermediates for the preparation of liranaftate compound of structural formula I. The present invention also provides processes for preparing these intermediates and a process for preparing liranaftate compound of structural formula I.

BACKGROUND OF THE INVENTION:
Liranaftate is chemically O- 5. 6, 7, 8-tetrahydro-2-napthyl N-(6-methoxy-2-pyridyl)-N-methylthiocarbamate and is known from US Patent No. 4,554,012 and is represented by compound of structural formula I.


The proprietary name of liranaftate is "ZEFNART". It is being used as an antifungal and antibacterial agent and is indicated for the treatment of tinea pedis.
U.S. Patent nos. 4.826,859 and 4,621.090 described two processes for the preparing liranaftate compound of structural formula I. First, the Hranaftate compound of structural formula I is formed by reacting 5, 6. 7, 8-tetrahydronaphthalen-2-ol compound of structural formula IV with 3-methoxyphenyl (methyl) carbamothioic chloride compound of structural formula V in the presence of anhydrous potassium carbonate in acetone solvent as showed below in scheme I.

And second, the liranaftate compound of structural formula I is formed by reacting 0-5,6,7,8-tetrahydronaphthalen-2-yl carbonochloridothioate compound of structural formula VI with 3-methoxy-N-methylbenzenamine compound of structural formula VII in the presence of anhydrous potassium carbonate in acetone solvent as showed below in scheme II.

U.S. Patent Publication No. 2009/0247762 described another method for the preparation of liranaftate compound of structural formula I, which involves reacting sodium 6-methoxy-2-methylaminopyridine dithiocarbamate compound of structural formula VIII with 5, 6, 7, 8-tetrahydronaphthalen-2-ol compound of structural formula IV in presence of base as showed below in scheme III.


Japanese patent No.62061967, JP 62048667 and International patent application WO 2007/010744 also described various methods for the preparation of liranaftate compound of structural formula 1.
The processes described in the above publications are long, and result in low chemical yields, making their application in the industry very hard. There is a need in the art for a new process for preparing liranaftate compound of structural formula I and its intermediates.
SUMMARY OF THE INVENTION:
One of the embodiments of the invention provides O- 5, 6, 7, 8-tetrahydronaphthalen-2-yl 6-methoxypyridin-2-ylcarbamothioate (TMC) compound of structural formula II and O- 5, 6, 7, 8-tetrahydronaphthalen-2-yl 6-chloropyridin-2-ylcarbamothioate (TCC) compound of structural formula III useful as intermediates for the preparation of liranaftate compound of structural formula I.

Another embodiment of the invention provides a process for preparing liranaftate compound of structural formula I comprising alkylating a compound of structural formula II with an alkylating agent.


Another embodiment of the invention provides a compound of structural formula IX, useful for the preparation of liranaftate compound of structural formula I.

wherein X is methoxy group, halogen atom, nitro group or any other group which can be
converted into methoxy group.
Another embodiment of the invention provides a process for preparing compounds of structural formula II, III and IX.
Another embodiment of the invention provides a process for preparing compound of structural formula IX comprising the steps of:
a. reacting a compound of structural formula XI with a compound of structural formula XII to get a compound of formula IX and,

wherein X is methoxy group, halogen atom, nitro group or any other group which can be converted into methoxy group.


b. isolating a compound of structural formula IX.
Another embodiment of the invention provides a process for preparing compound of structural formula IX comprising the steps of:
a. reacting a compound of formula XIII with a compound of formula XIV to get a
compound of formula IX and.

wherein X and R are as defined above. b. isolating a compound of structural formula IX.
Another embodiment of the invention provides a process for preparing liranaftate compound of structural formula I. which comprises the steps of
a. alkylating a compound of structural formula IX to get a compound of structural formula X and


b. when X is not a methoxy group then converting a compound of structural formula X into Iiranaftate compound of structural formula I.

Another embodiment of the invention provides a process for preparing liranaftate compound of structural formula I. which comprises the steps of
a. reacting a compound of structural formula XV with methanol to get a compound of structural formula I and

b. isolating liranaftate compound of structural formula I.
Another embodiment of the invention provides compounds of structural formula II, III, IX, X
and XV with the proviso that X is not a methoxy group.


Another embodiment of the invention provides a process for preparing liranaftate compound of structural formula 1. which comprises the steps of
a. reacting a compound of structural formula XVI with a compound of structural formula XIV to get a compound of formula X and

wherein X and R are as defined above b. when X is not a methoxy group then converting a compound of structural formula X into liranaftate compound of structural formula 1.
Another embodiment of the invention provides a process for preparing liranaftate compound of structural formula 1. which comprises the steps of
a. reacting a compound of structural formula XVII with a compound of structural formula XII to get a compound of structural formula X and


wherein X, R and R1as defined above b. when X is not a methoxy group then converting a compound of structural formula X into liranaftate compound of structural formula I.
DETAIL DESCRIPTION OF THE INVENTION:
The reaction of compound of structural formula XI with a compound of structural formula XII may be carried out in presence of inorganic base in a polar aprotic solvent at a temperature in the range of 10°C to 50°C for period of 30 minutes to 8 hours to get compound of structural formula
IX.
The examples of polar aprotic solvent may include ethyl acetate, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide or mixture(s)
thereof.
The examples of inorganic base may include alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali earth metal hydroxide such as calcium hydroxide, magnesium hydroxide, alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, alkali earth metal carbonate such as calcium carbonate, magnesium carbonate, alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate.
The compound of structural formula IX may be isolated from the reaction mixture by diluting the reaction mixture with ether solvents, separating organic layer, washing organic layer with water and then distilling ether solvents from the organic layer under reduced pressure.

The examples of ether solvents may include but not limited to tetrahydrofuran, 2-methyl tetrahydrofuran. 1, 4-dioxane, methyl tertiary butyl ether, diethyl ether, diisobutyl ether, di-n-butyl ether, di-n-propyl ether, diisopropyl ether or mixture(s) thereof.
The compound of structural formula IX may also be prepared by reacting compound of structural formula XIII with compound of structural formula XIV in presence of inorganic base in a polar aprotic solvent at a temperature in the range of 10°C to 50°C for period of 30 minutes to 8 hours to get compound of structural formula IX.
The alkylation of compound of structural formula IX may be carried out by treating a compound of structural formula IX with alkylating agent at a temperature in the range of 0°C to 15°C for a period of 3 hours to 16 hours to get a compound of structural formula X.
The alkylating agent may include but not limited to dimethyl sulfate, trimethyl phosphate or methyl iodide.
The alkylation of compound of structural formula XIX may be carried out in the presence of phase transfer catalyst in aromatic hydrocarbon solvents.
The examples of phase transfer catalyst may include but not limited to tetraethylammonium p-
toluenesulfonate, letrapropylammonium trifluoromethanesulfonate, tetraphenylphosphonium
hexafluoroantimonate, cetylpyridinium bromide, triphenylmethyl triphenylphosponium chloride,
benzyltriethylammonium chloride, benzyltrimethylammonium chloride,
benzyltriphenylphosphonium chloride, benzytri butyl ammonium chloride,
butyltriethylammonium bromide, butyltriphenylphosphonium bromide, cetyltrimethyl
ammonium bromide, cetyltrimethyl ammonium chloride, ethyltriphenylphosphonium bromide.
ethyltriphenylphosphonium iodide, methyltrioctylammonhim bromide,
methyltriphenylphosphonium bromide, rnethyltriphenylphosphonium iodide,
phenyltrimethylammonium chloride, tetrabutylammonium hydroxide, tetrabutylammonium perchlorate, tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate, tetrabutylammonium iodide, tetrabutylammonium tetrafluoroborate. tetrabutylammonium

thiocyanate. letraethylammonium hydroxide, tetraethylammonium iodide, tetraethylammonium
bromide, tetramethylammonium chloride, tetramethylammonium iodide, tetramethylammonium
chloride, tetraoctylammonium bromide, tetraphenylphosphonium bromide,
tetrapropylammonium hydroxide, tetrapropylammonium bromide or tributylmethylammonium chloride.
The examples of aromatic hydrocarbon solvents may include but not limited to benzene, toluene, cresol or xylene.
The compound of structural formula X may be isolated by quenching the reaction mixture with water followed by the separation of an organic layer.
The organic layer containing the compound of structural formula X may be washed with IN HC1 solution and an aqueous solution of sodium bicarbonate.
The aqueous solution of sodium bicarbonate may have concentration in the range of 5% weight / weight to 10% weight / weight.
The organic layer containing the compound of structural formula X may be concentrate under reduced pressure to get a compound of structural formula X.
The compound of structural formula X may also be prepared by reacting compound of structural formula XVI with compound of structural formula XIV in presence of inorganic base in a polar aprotic solvent at a temperature in the range of 10°C to 50°C for period of 30 minutes to 8 hours to get compound of structural formula X.
The compound of structural formula X may also be prepared by reacting compound of structural formula XVIIcompound of structural formula XII in presence of inorganic base in a polar aprotic solvent at a temperature in the range of 10°C to 50°C for period of 30 minutes to 8 hours
to get compound of structural formula X.

The compound of structural formula X may be converted into liranaftate compound of structural formula I by treating compound of structural formula X with methoxylating agent in an alcohol solvent at a temperature in the range of 20 to 600 for a period of 30 minutes to 8 hours to get liranaftate compound of structural formula I.
The methoxylating agent may include but not limited to sodium methoxide or potassium methoxide.
The examples of alcohol solvents may include but not limited to methanol, ethanol, propanol, butanol, isobutanol. penlanol. isopropanol or mixture(s) thereof.
The liranaftate compound of structural formula I may be isolated by neutralizing the reaction mixture with acetic acid, concentrating the reaction mixture under reduced pressure and then washed with water to get liranaftate compound of structural formula I.
The liranaftate compound of structural formula I may be dried at a temperature in the range of 40°C to 50°C for a period of 2 to 6 hours.
The 0-5, 6, 7, 8-tetrahydronaphtha!en-2-yl 6-methoxypyridin-2-ylcarbamothioate compound of structural formula 11 may be converted into liranaftate compound of structural formula I by treating 0-5. 6. 7. 8-tetrahydronaphthalen-2-yl 6-methoxypyridin-2-yIcarbamothioate compound of structural formula II with alkylating agent at a temperature in the range of 0°C to 15°C for a period of 3 hours to 16 hours in the presence of phase transfer catalyst in an aromatic hydrocarbon solvents to get liranaftate compound of structural formula I.
The 0- 5. 6, 7. 8-tetrahydronaphthalen-2-yl 6-chloropyridin-2-yl (methyl) carbamothioate compound of structural formula XV may be converted into liranaftate compound of structural formula I by treating 0-5, 6, 7. 8-tetrahydronaphthalen-2-yl 6-chloropyridin-2-yl (methyl) carbamothioate compound of structural formula XV with methoxylating agent in an alcoholic solvent at a temperature in the range of 20 to 60°C for a period of 30 minutes to 8 hours to get liranaftate compound of structural formula I.

EXAMPLE:
In the following examples, the preferred embodiment of the present invention is described only by way of illustrating the processes of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of liranaftate compound of structural formula I.
Stage A: Preparation of O - 5. 6, 7, 8-tetrahydronaphthalen-2-yl 6-chloropyridin-2-
ylcarbamothioate compound of structural formula III.
A solution of sodium 6-chloropyridin-2-ylcarbamodithioate (30gm) in dimethylformamide
(600ml) was added 5, 6, 7. 8-tetrahydronaphthalen-2-ol (19.6gm), potassium carbonate (18.2gm)
and stirred for 10 minutes at 20-25°C. The resulting reaction mixture was cooled to 10°C and
stirred for 1 hour then the reaction mixture was diluted with diethyl ether (300ml) and ether layer
was separated, washed with water (50ml) and concentrated under reduced pressure to get title
compound.
Yield: 42.2gm
Purity: 99.7% (By HPLC)
Stage B: Preparation of 0-5, 6, 7, 8-tetrahydronaphthalen-2-yl 6-chloropyridin-2-yl (methyl) carbamothioate compound of structural formula XV.
A solution of 0-5, 6. 7, 8-tetrahydronaphthalen-2-yl 6-chloropyridin-2-ylcarbamothioate compound of structural formula III (30gm) in toluene (500ml) was added tetrabutyl ammonium bromide (11gm)and sodium hydroxide solution (20%, 120.5ml) at 0-5°C. The resulting reaction mixture was stirred for 30 minutes at 5-10°C and then sodium hydroxide solution (50%, 100ml) and dimethyl sulphate (22.6gm) was added at 5-10°C. The resulting reaction mixture was stirred 14 hours at 5-10°C and then it was quenched with water (200ml). The organic layer was separated and washed with hydrochloric acid solution (1N,9ml); sodium bicarbonate solution (8% weight/weight. 90ml) and water (90ml). The organic layer was dried over anhydrous sodium sulphate (l0gm)nd concentrated under reduced pressure to get title compound. Yield: 28.7gm Purity: 99.8% (By HPLC)

Stage C: Preparation of liranaftate compound of structural formula I.
A solution of 0- 5, 6, 7, 8-tetrahydronaphthalen-2-yl 6-chloropyridin-2-yl (methyl)
carbamothioate compound of structural formula XV (25gm) in methanol (250ml) was added
sodium methoxide (8gm) and stirred for 6 hours at 50°C. The reaction mixture was cooled to
25°C and neutralized with acetic acid (15ml). The resulting reaction mixture was concentrated
under reduced pressure, washed with water (50ml) and dried at 45°C for 3 hours to get title
compound.
Yield: 24.6gm
Purity: 99.9% (By HPLC)
Example 2: Preparation of liranaftate compound of structural formula I
A solution of 0-5, 6, 7, 8-tetrahydronaphthalen-2-y] 6-methoxypyridin-2-ylcarbamothioate compound of structural formula II (30gm) in toluene (500ml) was added tetrabutyl ammonium bromide (11gm) and sodium hydroxide solution (20%, 120.5ml) at 0-5°C. The resulting reaction mixture was stirred for 30 minutes at 5-10°C and then sodium hydroxide solution (50%, 100ml) and dimethyl sulphate (22.6gm) was added at 5-10°C. The resulting reaction mixture was stirred 14 hours at 5-10°C and then it was quenched with water (200ml). The organic layer was separated and washed with hydrochloric acid solution (IN, 90ml); sodium bicarbonate solution (8% weight/weight, 90ml) and water (90ml). The organic layer was dried over anhydrous sodium sulphate (10gm) and concentrated under reduced pressure to get title compound. Yield:31.3gm Purity: 99.9% (By HPLC)

WE CLAIM:
1. A process for preparing liranaftate compound of structural formula I comprising alkylating a compound of structural formula II with an alkylating agent.

2. The process according to claim no. 1 wherein alkylating agent may be selected from the group comprising of dimethyl sulfate, trimethyl phosphate or methyl iodide.
3. The compounds of structural formula II, III and IX useful for the preparation of liranaftate compound of structural formula I.

wherein X is methoxy group, halogen atom, nitro group or any other group which can be converted into methoxy group.
4. A process for preparing compound of structural formula IX comprising the steps of:

a. reacting a compound of structural formula XI with a compound of structural formula XII to get a compound of formula IX and,

wherein X is methoxy group, halogen atom, nitro group or any other group which can be
converted into methoxy group.

b. isolating a compound of structural formula IX.
5. A process for preparing compound of structural formula IX comprising the steps of:
a. reacting a compound of formula XIII with a compound of formula XIV to get a
compound of formula IX and,

wherein X and R are as defined above in claim no. 4. b. isolating a compound of structural formula IX.

6. A process for preparing liranaftate compound of structural formula I, which comprises the steps of
a. alkylating a compound of structural formula IX to get a compound of structural formula X and

b. when X is not a methoxy group then converting a compound of structural formula X into liranaftate compound of structural formula I.

7. A process for preparing liranaftate compound of structural formula I, which comprises the steps of
a. reacting a compound of structural formula XV with methanol to get a compound of structural formula I and

b. isolating liranaftate compound of structural formula I-8. A compounds of structural formula II, III, IX, X or XV.


wherein X is halogen atom, nitro group or any other group which can be converted into methoxy group.
9. A process for preparing liranaftate compound of structural formula I, which comprises the steps of
c. reacting a compound of structural formula XVI with a compound of structural formula XIV to get a compound of formula X and

wherein X and R are as defined above in claim no. 4. d. when X is not a methoxy group then converting a compound of structural formula X into liranaftate compound of structural formula I.
10. A process for preparing liranaftate compound of structural formula I, which comprises the steps of

a. reacting a compound of structural formula XVII with a compound of structural formula
XII toget a compound of structural formula X and

wherein X. R and R1as defined above in claim no. 4. b. when X is not a methoxy group then converting a compound of structural formula X into liranaftate compound of structural formula I.