DESC:Field of Invention

The present invention relates to a process for the preparation of Dolutegravir and its novel intermediates or pharmaceutically acceptable salts thereof. The present invention provides novel intermediates, which may be useful for the preparation of Dolutegravir or its pharmaceutically acceptable salts thereof. The process of invention by using novel intermediate is very simple cost effective and may be employed at commercial scale. The product obtained by using novel intermediate yield the Dolutegravir of purity more than 98 %, when measured by HPLC.

Background of the invention

Dolutegravir is an approved drug for the treatment of HIV infection. Dolutegravir is an integrase inhibitor and marketed as Tivicay by GlaxoSmithKline.

Dolutegravir is chemically known as (4R, 12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3 ,4,6,8, 12,12a-hexahydro-2H-pyrido[ 1 ',2':4,5]pyrazino[2,1-b] [1 ,3]oxazine-9-carboxamide,compound of Formula I

Formula-I
Dolutegravir or its salt thereof with its processes are disclosed in US Patent No. 8,129,385. Other processes for the preparation of dolutegravir are also disclosed in International patent application publications 2010/011812, 2010/068253 and 2010/011819 and European patent application 2412709.

The (4R,11aS)-N-(2,4-difluorobenzyl)-6-(benzyloxy)-2,3,4,4a,5,7,11,11a-octahydro-4-methyl-5,7-dioxopyrano[3,2-b]quinolizine-8-carboxamide, compound of formula-II is a key intermediate for the preparation of Dolutegravir.

Formula-II
While working on the process development of Dolutegravir the present inventors found that the benzyl protected Dolutegravir produced according to the prior art procedures involves multiple steps of synthesis, which results in to low yields. Therefore, there is a need to develop a simple and industrially feasible process for the preparation of Dolutegravir and intermediates thereof, or a pharmaceutically acceptable salt thereof.

According to the present invention benzyl protected Dolutegravir can be obtained in higher yields and process involves less number of reaction steps than the processes known in the art.

A novel processes for the preparation of benzyl protected Dolutegravir using novel intermediate has been developed. The instant process is simple, inexpensive and reproducible and is well suited on an industrial scale. Thus, an object of the present invention is to provide a novel processes for preparing dolutegravir by using novel intermediate.
Summary of the Invention

The present invention provides a process for the preparation of Dolutegravir intermediates or pharmaceutically acceptable salt thereof.

In an aspect, the present invention is to provide a process for the preparation of Dolutegravir, compound of Formula I

Formula-I
or a pharmaceutically acceptable salt thereof,
the process includes the step of ;
a) reacting dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate, with ammonium acetate in a alcoholic solvent to obtain dimethyl-3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2,5-dicarboxylate,

b) condensing dimethyl-3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2,5-dicarboxylate with (2,4-difluorophenyl)methanamine to obtain methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2-carboxylate,

c) contacting methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2-carboxylate with 2-bromoethane-1,1-diolpresence of base in aprotic solventto obtain methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-1-(2,2-dihydroxyethyl)-4-oxopyridine-2-carboxylate,

d) cyclizing methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-1-(2,2-dihydroxyethyl)-4-oxopyridine-2-carboxylate to benzyl protected Dolutegravir, with (S)-3-aminobutan-1-ol and formic acid,

e) reducing benzyl protected Dolutegravir with Palladium on carbon in alcoholic solvent to obtain Dolutegravir or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention is to provide methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2-carboxylate compound of formula-V,

Formula V
or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention is to provide methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-1-(2,2-dihydroxyethyl)-4-oxopyridine-2-carboxylate compound of formula-VI,

Formula VI
or a pharmaceutically acceptable salt thereof.

In an aspect, the present invention is to provide Dolutegravir Sodium has purity more than 98 % when measured by HPLC.

Description of the Invention

For purposes of the present invention, the following terms are defined below.

The Dolutegravir and its intermediates of the invention may be prepared/used as free bases or as a salts.

The pharmaceutically acceptable salt or M+ refers to salts is selected from the group comprising alkali metal salts and alkaline-earth metal salts, wherein alkali metal salts is selected from sodium, lithium, potassium salts and alkaline-earth metal salts selected from calcium, magnesium salts and ammonium salts.

In an aspect of the present invention provides a process for the preparation of Dolutegravir, compound of Formula I

Formula-I
or a pharmaceutically acceptable salt thereof,
the process includes step of ;
a) reacting dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate, compound of formula-III ,

Formula-III
with ammonium acetate in alcoholic solvent to obtain dimethyl 3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2,5-dicarboxylate, compound of formula-IV,

Formula-IV
b) condensing compound of formula-IV with (2,4-difluorophenyl)methanamine in alcoholic solvent to obtain methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2-carboxylate compound of formula-V,

Formula-V
c) contacting compound of formula-V with 2-bromoethane-1,1-diolpresence of base in aprotic solvent to obtain methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-1-(2,2-dihydroxyethyl)-4-oxopyridine-2-carboxylate compound of formula-VI,

Formula-VI
d) cyclizing compound of formula-VI to benzyl protected Dolutegravir, compound of formula-II with (S)-3-aminobutan-1-ol and formic acid,

Formula-II
e) reducing compound of formula-II with palladium on carbon in alcoholic solvent to obtain Dolutegravir or a pharmaceutically acceptable salt thereof.

The step (a) of present invention involves the reacting dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate with ammonium acetate in the alcoholic solvent at temperature in between range of 60°C to 65°C for 6 hours, wherein alcoholic solvent is selected from group comprises one or more of methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, propylene glycol, water and mixtures thereof. After completion of reaction, alcoholic solvent distill off under reduced pressure, followed by addition of water. Reaction mass is extracted in ethyl acetate, followed by distilled off organic layer to get the dimethyl 3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2,5-dicarboxylate.

The step (b) of present invention involves the addition of 2,4-difluoro benzyl amine in the alcoholic solution of dimethyl 3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2,5-dicarboxylate, followed by refluxing to about 5 to 6 hours. After completion of reaction, alcoholic solvent distill off under reduced pressure, followed by addition of water. Reaction mass is extracted in ethyl acetate, followed by distilled off organic layer to get the methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2-carboxylate.

The step (c) of present invention involves the contacting methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2-carboxylate with 2-bromoethane-1,1-diolin in presence of base in aprotic solvent, followed by stirring the reaction mixture for the period of 5 hours to 6 hours. After completion of reaction, water is added to get precipitate the solid, which is subsequently, filtered to get methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-1-(2,2-dihydroxyethyl)-4-oxo pyridine-2-carboxylate.

Aprotic solvent is selected from the group comprising one or more of N,N-dimethylformamide; N,N-diethylformamide; dimethyl sulfoxide; hexamethylphosphoramide; dimethylpropylene urea; sulpholane; N-methyl-2-pyrrolidone, tetrahydrofuran and mixture thereof.

The bases used is selected from the group comprising one or more of organic base such as dimethylamine, diethylamine or triethylamine and ammonia. Inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide and potassium t-butoxide.

The step (d) of present invention involves the cyclizing methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-1-(2,2-dihydroxyethyl)-4-oxopyridine-2-carboxylate with (R)-3-aminobutan-1-oland formic acid. The reaction mixture heated at temperature in between range of 80°C to 90°C for 2 hour. Water was added after completion of reaction and compound is extracted in dichloromethane, followed by removal of dichloromethane under vacuum and obtained mass is treated with methyl tert-butyl ether and filtered to get benzyl protected Dolutegravir.

The step (e) of present invention involves the dissolving benzyl protected Dolutegravir in alcoholic solvent, followed by treatment with 5% palladium carbon 50% wet in presence of hydrogen.

After completion of the reaction, the reaction mixture is filtered and alcoholic solvent is distilled off to get the Dolutegravir or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention is to provide methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2-carboxylate compound of formula-V,

Formula V
or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention is to provide methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-1-(2,2-dihydroxyethyl)-4-oxopyridine-2-carboxylate compound of formula-VI,

Formula VI
or a pharmaceutically acceptable salt thereof.

The resultant compound of formula II is useful for the preparation of Dolutegravir or a pharmaceutically acceptable salt thereof. The process of Dolutegravir or a pharmaceutically acceptable salt thereof is schematically presented in the following scheme 1:

Scheme-1
The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

EXAMPLES

Example 1: Preparation of dimethyl 3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2,5-dicarboxylate

Charged dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (10.0 gm) and ammonium acetate (6 gm) in methanol (50 ml). The reaction mixture was refluxed at temperature range of 60°C to 65°C for 6 hour. After completion of reaction, methanol was distilled off under reduced pressure, followed by addition of water. Reaction mass was then extracted in ethyl acetate. Finally, Ethyl acetate layer was distilled off to get the title compound
Yield: 8.0 gm
HPLC Purity: 98 %

Example 2: Preparation of methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2-carboxylate

Charged 2, 4-difluoro benzyl amine (4.5gm) into the methanolicsolution (50 mL) of dimethyl 3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2,5-dicarboxylate(10.0 gm). The reaction mixture was refluxed for 5 to 6 hour. After completion of reaction, methanol was distilled off. Added water (100 ml) and extracted with ethyl acetate (100 ml). Ethyl acetate layer was distilled off to get title compound.
Yield: 11.0 gm
HPLC Purity: 98 %

Example 3: Preparation of methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-1-(2,2-dihydroxyethyl)-4-oxopyridine-2-carboxylate

Charged methyl-5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-4-oxo pyridine-2-carboxylate (10.0 gm) and 2-bromoethane-1,1-diol(4.0 gm) in dimethylformamide solvent (25 ml), followed by addition of potassium carbonate. The reaction mixture was stirred for 5 hour to 6 hour. After completion of reaction, water (100 ml) was added in to the reaction mixture. The precipitated solid was filtered to get the titled compound.
Yield: 10.0 gm
HPLC Purity: 99 %

Example 4: Preparation of benzyl protected Dolutegravir

Charged methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-1-(2,2-dihydroxy ethyl)-4-oxopyridine-2-carboxylate (10.0 gm) in formic acid (20 ml), followed by addition of (R)-3-aminobutan-1-ol(2.0 gm). The reaction mixture was heated to temperature range 80°C to 90°C for 2 hour. After completion of reaction, water was added into the reaction mixture, followed by extraction in dichloromethane. The dichloromethane was distilled off under vacuum and residue was treated with methyl tert-butyl ether (100 ml). Precipitate solid was filtered to get the titled compound.
Yield: 9.0 gm
HPLC Purity: 98 %

Example 5: Preparation of Dolutegravir Base

Charged benzyl protected dolutegravir(10.0 gm) in methanol (50 mL), followed by treatment with 5% palladium carbon, 50% wet (1.0 gm) in presence of hydrogen. After completion of the reaction, the reaction mixture was filtered out. The methanol was distilled out under vacuum to get the titled compound.
Yield: 7.5 gm
HPLC Purity: 99 %

Example 6: Preparation of Dolutegravir Sodium

Charged Dolutegravir base (10. gm) in methanol (50 ml), followed by addition of sodium hydroxide (1.0 gm). The reaction mixture was stirred for 6 hours. The precipitated solid material was filtered and washed with methanol to get the titled compound.
Yield: 11.0 gm
HPLC Purity: 99 %
,CLAIMS:1. A process for the preparation of Dolutegravir, compound of Formula I

Formula-I
or a pharmaceutically acceptable salt thereof, the process comprises the step of;
a) reacting dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate, formula-III

Formula-III
with ammonium acetate in the alcoholic solvent to obtain dimethyl 3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2,5-dicarboxylate, formula-IV,

Formula-IV
b) condensing dimethyl 3-(benzyloxy)-1,4-dihydro-4-oxopyridine-2,5-dicarboxylate,
compound of formula-IV with (2,4-difluorophenyl)methanamine in the alcoholic solvent to obtain methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-4-oxo pyridine-2-carboxylate formula-V,

Formula-V
c) contacting methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-4
oxopyridine-2-carboxylate of formula-V with 2-bromoethane-1,1-diol presence of base in aprotic solvent to obtain methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-1-(2,2-dihydroxyethyl)-4-oxopyridine-2-carboxylate of formula-VI,

Formula-VI
d) cyclizing methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-1-
(2,2-dihydroxyethyl)-4-oxopyridine-2-carboxylate of formula-VI to benzyl protected Dolutegravir of formula-II with (S)-3-aminobutan-1-ol and formic acid,

Formula-II
e) reducing benzyl protected Dolutegravir, formula-II with Palladium on carbon
(Pd/C) in alcoholic solvent to obtain Dolutegravir or a pharmaceutically acceptable salt thereof.

2. The process of claim 1, wherein alcoholic solvent is selected from group comprises one or more of methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, propylene glycol, water and mixtures thereof.

3. The process of claim 1, wherein aprotic solvent is selected from the group comprising one or more of N,N-dimethylformamide; N,N-diethylformamide; dimethyl sulfoxide; hexamethylphosphoramide; dimethylpropylene urea; sulpholane; N-methyl-2-pyrrolidone, tetrahydrofuran and mixture thereof.

4. The process of claim 1, wherein base is selected from the one or more ammonia, dimethylamine, diethylamine, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide and potassium t-butoxide.

5. The process of claim 1, wherein Dolutegravir or a pharmaceutically acceptable salt thereof has purity more than 98%, when measured by HPLC.

6. A methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-4-oxo pyridine-2-carboxylate compound of formula-V,

Formula V
or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6, wherein compound of formula-V has purity more than 90%, when measured by HPLC.

8. A methyl 5-(2,4-difluorobenzylcarbamoyl)-3-(benzyloxy)-1,4-dihydro-1-(2,2-dihydroxy ethyl)-4-oxopyridine-2-carboxylate compound of formula-VI,

Formula VI
or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8, wherein compound of formula-VI has purity more than 90%, when measured by HPLC.