WO2015019310A1 - Process for the preparation of dolute-gravir and intermediates thereof - Google Patents

Process for the preparation of dolute-gravir and intermediates thereof Download PDF

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WO2015019310A1
WO2015019310A1 PCT/IB2014/063758 IB2014063758W WO2015019310A1 WO 2015019310 A1 WO2015019310 A1 WO 2015019310A1 IB 2014063758 W IB2014063758 W IB 2014063758W WO 2015019310 A1 WO2015019310 A1 WO 2015019310A1
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acid
compound
formula
process according
mixtures
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PCT/IB2014/063758
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Ramesh Dandala
Siva Ram Prasad Vellanki
Madhu Murthy Nadella
Phani Kumar BALUSU
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Mylan Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids

Abstract

The present disclosure relates to processes for the preparation of dolutegravir or of its pharmaceutically acceptable salts. The present disclosure also provides intermediates useful in the synthesis of dolutegravir.

Description

PROCESS FOR THE PREPARATION OF DOLUTE-GRAVIR AND
INTERMEDIATES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. 2612/MUM/2013 filed on date August 07, 2013.
BACKGROUND OF THE INVENTION FIELD OF THE DISCLOSURE
The present disclosure relates to a process for the preparation of dolutegravir or its pharmaceutically acceptable salt using novel intermediates.
DESCRIPTION OF THE RELATED ART
Dolutegravir (DTG, GSK1349572) is an integrase inhibitor being developed for the treatment of human immunodeficiency virus (HIV)-l infection.
TIVICAY® tablets contain dolutegravir sodium, which is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI). Dolutegravir sodium is chemically known as sodium (4R, 12aS)-9-((2,4- difluorobenzyl)carbamoyl)-4-methyl-6, 8-dioxo-3 ,4, 6, 8, 12, 12a-hexahydro-2H- pyrido [ ,2' :4,5] pyrazino[2, 1-b] [l,3]oxazin-7-olate, having the below structure:
Figure imgf000002_0001
Formula-I
PCT Publication No. WO2006116764A1 discloses a process for the preparation of dolutegravir, which is as shown in scheme-I.
Figure imgf000003_0001
F O
Dolutegravir
Scheme-I
The present disclosure provides a novel process for the preparation of dolutegravir or its pharmaceutically acceptable salts that employs novel intermediates.
SUMMARY OF THE DISCLOSURE
A first aspect of the present disclosure is to provide a process for the preparation of dolutegravir or its pharmaceutically acceptable salts.
In one embodiment, the present disclosure provides a process for the preparation of dolutegravir or its pharmaceutically acceptable salts that includes the steps of: a) reacting a compound of Formula 18 with boric acid in presence of acetic anhydride to get a compound of Formula 19;
Figure imgf000004_0001
b) treating the compound of Formula 19 with an acid and optionally catalytic amount of protic acid to get a compound of Formula 20;
Figure imgf000004_0002
c) reacting the compound of Formula 20 with (R)-3-aminobutane-l-ol, followed by cyclization to get a compound of Formula 21;
Figure imgf000004_0003
d) hydrolyzing the compound of Formula 21 with an acid to get a compound of Formula 22;
Figure imgf000004_0004
e) reacting the compound of Formula 22 with 2,4-diflurobenzylamine in presence of a coupling agent to get a compound of Formula 23; and
Figure imgf000005_0001
f) converting the compound of Formula 23 to dolutegravir or its pharmaceutically acceptable salt.
Figure imgf000005_0002
DETAILED DESCRIPTION OF THE DISCLOSURE
It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.
The present invention encompasses novel synthetic schemes for the synthesis of dolutegravir. Within the context of the present invention, novel intermediates are generated as part of the novel synthetic schemes. Together, these schemes and intermediates provide an improved, efficient method for the synthesis of dolutegravir.
More specifically, the present disclosure relates to a process for the preparation of dolutegravir or its pharmaceutically acceptable salts, wherein compound of Formula 18 is reacted with a mixture of boric acid and acetic anhydride to get a compound Formula 19. It is treated with an acid to get a compound of Formula 20. The compound of Formula 20 is reacted with (R)-3-aminobutane-l-ol, followed by cyclization to obtain a compound of Formula 21, which is treated with an acid to produce a compound of Formula 22. The compound of Formula 22 is subjected to condensation reaction with 2,4-diflurobenzylamine to obtain a compound of Formula 23. The compound of Formula 23 is subjected to de- methylation and subsequent salt formation to obtain dolutegravir or a pharmaceutically acceptable salt of dolutegravir.
In one embodiment, the present disclosure provides a process for the preparation of dolutegravir or a pharmaceutically acceptable salt, comprising the steps of: a) reacting a compound of Formula 18 with boric acid in presence of acetic anhydride to get a compound of Formula 19;
Figure imgf000006_0001
b) treating the compound of Formula 19 with an acid and, optionally, a catalytic amount of protic acid to produce a compound of Formula 20;
Figure imgf000006_0002
c) reacting the compound of Formula 20 with (R)-3-aminobutane-l-ol, followed by cyclization to obtain a compound of Formula 21;
Figure imgf000006_0003
d) hydrolyzing the compound of Formula 21 with an acid to get a compound of Formula 22;
Figure imgf000007_0001
e) reacting the compound of Formula 22 with 2,4-diflurobenzylamine in presence of a couplin agent to obtain a compound of Formula 23; and
Figure imgf000007_0002
f) converting the compound of Formula 23 to dolutegravir or a pharmaceutically acceptable salt thereof.
Figure imgf000007_0003
According to the present disclosure, compound of Formula 18 is reacted with a mixture of boric acid and acetic anhydride to obtain compound of Formula 19. The compound of Formula 19 is treated with an acid to generate the aldehyde compound of Formula 20. The aldehyde compound of Formula 20 is reacted with (R)-3-aminobutan-l-ol in a solvent, followed by cyclization to produce compound Formula 21, which is further reacted with an acid in a solvent to get a compound of Formula 22. The compound of Formula 22 is condensed with 2,4- diflurobenzylamine in presence of a coupling agent and a solvent to produce compound of Formula 23. The compound of Formula 23 is subjected de- methylation and subsequent salt formation to obtain dolutegravir or a pharmaceutically acceptable salt of dolutegravir.
Within the context of the present disclosure, the acid employed in step-(b) above may include, as examples, hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, propionic acid, butanoic acid, pivalic acid, pentanoic acid, hexanoic acid, and mixtures thereof. In certain embodiments, it has been found that acetic acid is a particularly useful acid in step-(b). One of skill in the art will recognize numerous well-known weak and strong inorganic and organic acids that may be useful within the context of the present invention.
Within the context of the present disclosure, the protic acid optionally employed in step-(b) may include, as examples, methanesulfonic acid, sulfuric acid, toluene sulfonic acid, hydrochloric acid, and mixtures thereof. In certain embodiments, it has been found that methane sulfonic acid is particularly useful protic acid in step- (b). Additionally, one of skill in the art will recognize that other protic acids may also be useful within the context of the present invention.
Within the context of the present disclosure, the solvent used in step-(c) may include, as examples, dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate, acetone, Ν,Ν-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. It has been found that acetonitrile is a particularly useful solvent for step-(c). Generally, water-miscible solvents are particularly useful for use in step-(c). In some embodiments, the solvent may be removed from the reaction mixture by distillation after completion of the reaction, as disclosed in the examples below. Again, one of skill in the art will recognize numerous additional organic solvents that may be employed as a solvent of step-(c).
Within the context of the present disclosure, the acid employed in step-(d) may include, as examples, hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, propionic acid, butanoic acid, pivalic acid, pentanoic acid, hexanoic acid, methane sulfonic acid, p-toluene sulfonic acid, and mixtures thereof. One of skill in the art will recognize other acids that may be employed in step-(d).
Within the context of the present disclosure, the solvent used in step-(d) may include, as examples, dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate, acetone, Ν,Ν-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. It has been found that dichloromethane is a particularly useful solvent to be employed in step-(d). Generally, the product of this reaction step may be extracted into the solvent, and as such, water immiscible solvents are particularly appropriate for use in step-(d). Again, one of skill in the art will recognize numerous additional organic solvents that may be employed as a solvent of step- (d).
Within the context of the present disclosure, the solvent used in step-(e) may include, as examples, dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate, acetone, Ν,Ν-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. Again, one of skill in the art will recognize numerous additional organic solvents that may be employed as a solvent of step-(e). It has been found that acetonitrile is a particularly useful solvent for step-(e).
According to the present disclosure, the coupling agent employed in step-(e) may include, as examples, carbonyldiimidazole, Ν,Ν'-dicyclohexylcarbodiimide, Ν,Ν'- diisopropylcarbodiimide, and mixtures thereof. One of skill in the art will recognize other mixed anhydride coupling agents that may be useful within the context of the present invention.
In other embodiments, the present disclosure provides novel intermediates of Formulae 19, 20 and 21.
Figure imgf000009_0001
In another embodiment, the compounds of Formulae 19, 20, and 21 can be formed in situ or isolated as intermediates in process to prepare dolutegravir or its pharmaceutically acceptable salts.
Another embodiment of the present disclosure provides a process for the preparation of dolutegravir or a pharmaceutically acceptable salt thereof, which is as shown in scheme-II.
Figure imgf000010_0001
Scheme-II
The present disclosure also relates to a process for the preparation of dolutegravir or a pharmaceutically acceptable salt thereof, wherein compound of Formula 18 is reacted with a mixture of boric acid and acetic anhydride to get a compound of Formula 19. The compound of Formula 19 is, in turn, reacted with 2,4- dflurobenzylamine in the presence of condensing agent to obtain a compound of Formula 24. The compound of Formula 24 is treated with an acid to produce a compound of Formula 25, which is reacted with (R)-3-aminobutane-l-ol, followed by cyclization to get a compound of Formula 23. The compound of Formula 23 is subjected to de-methylation and subsequent salt formation to obtain dolutegravir or pharmaceutically acceptable salts of dolutegravir.
The present disclosure provides a pharmaceutically acceptable salt of dolutegravir. All theoretically possible tautomer, geometrical isomer, optically active compound, and racemate thereof are within the scope of the present invention. Pharmaceutically acceptable salts of dolutegravir include, as basic salts, for example, alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine or procaine salts; aralkyl amine salts such as N,N- dibenzylethylenediamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethyl ammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctyl ammonium salts or tetrabutylammonium salts, and basic amino acid salts such as arginine salts or lysine salts. Acid salts include, for example, mineral acid salts such as hydrochloride, sulfates salts, nitrate salts, phosphates salts, carbonates salts, hydrogencarbonates or perchlorate; organic acid salts such as acetates, propionates, lactates, maleates, fumarates, tararic acid salts, malates, citrates salts, ascorbates, formic acid; sulfonates such as methanesulfonates, isethionates, benzenesulfonates, or p-toluenesulfonates; and acidic amino acid salts such as aspartates or glutamates. In some embodiments, the sodium salt of dolutegravir is particularly useful.
In another embodiment the present disclosure provides a process for the preparation of dolutegravir sodium salt as shown in below scheme-Ill.
Figure imgf000012_0001
Scheme-Ill
The solvents, acids, and protic acids useful within the context of Scheme-II, as disclosed above, may be employed in similar roles within the context of Scheme- Ill.
In another embodiment, the present disclosure provides a process for the preparation of l-(2,2-dimethoxy-ethyl)-3-methoxy-4-oxo-l,4-dihydro-pyridine- 2,5-dicarboxylic acid dimethyl ester (i.e., compound of Formula 18) as shown in below scheme-IV.
Figure imgf000013_0001
Figure imgf000013_0002
Scheme-IV
The solvents, acids, and protic acids useful within the context of Scheme-II, as disclosed above, may be employed in similar roles within the context of Scheme- IV. It has been found that sodium methoxide is particularly useful within the context of Scheme-IV as disclosed above. That exemplary reactant is not limiting, however, in that any metal oxide or LiHMDS (see below) may be used in that step of Scheme-IV.
With all of the reactions disclosed above, one of skill in the art will recognize that the reaction conditions (e.g., reaction time or temperature) may be adjusted to achieve appropriate yield without undertaking undue experimentation and without departing from the scope of the present disclosure.
The dolutegravir and pharmaceutically acceptable salts as synthesized by the methods disclosed herein may be useful in the treatment of individuals infected with the human immunodeficiency virus (HIV), as dolutegravir has been demonstrated to be an effective HIV integrase inhibitor. Dolutegravir may be used singly or in combination with other anti-retroviral agents, such as abacavir, lamivudine, efavirenz, nevirapine, and tipranavir.
The dolutegravir and pharmaceutically acceptable salts thereof may be formulated as a tablet for consumption by patients, where the tablet is formulated having the inactive ingredients of d-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate. That tablet core may, in some embodiments, be coated with a film that includes iron oxide yellow, macrogol/PEG, polyvinyl alcohol part-hydrolyzed, talc, and titanium dioxide.
In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and Formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
Example 1: Preparation of l-(2,2-dimethoxy-ethyl)-3-methoxy-4-oxo-l,4- dihydro-pyridine-2,5-dicarboxylic acid dimethyl ester (Formula 18).
Methyl-4-methoxyacetoacetate (100 gm) was charged followed by slow addition of 1,1-dimethoxy dimethylethanamine (DMF-DMA) (98 gm) at a temperature of 20°C. The reaction content was warmed to 27°C and maintained the reaction mass for 8 hours at the same temperature. The reaction mixture was diluted with methanol (200 mL) and aminoacetaldehyde dimethyl acetal (78.8 gm) was added. The mixture was stirred for 2 hours at a temperature of 20°C, distilled of the solvent and extracted with methylene dichloride. Lithium hexamethyldisilazane (LiHDMS) in THF (tetrahydrofuran) solution (1685 mL) was added slowly followed by gradual addition of dimethyloxalate (202 gm) while maintained the reaction temperature below 4°C. The reaction content was heated to a temperature of 45°C, stirred for 26 hours and then cooled to a temperature of 27°C. The pH of the reaction mixture was adjusted to 3-4 with 2N HC1 solution (615 mL) and the product was extracted with ethyl acetate (1500 mL). The obtained crude product was purified by flash chromatography to get a purified compound of Formula 18 (65 gm). Example 2: Preparation of l-(2,2-dimethoxy-ethyl)-3-methoxy-4-oxo-l,4- dihydro-pyridine-2,5-dicarboxylic acid dimethyl ester (Formula 18).
Methyl 4-chloro-3-oxobutanoate (5 gm) was reacted with 1,1-dimethoxy dimethylethanamine (DMF-DMA) mixture (4.7 gm) at 0°C and further stirred the reaction mass for 2 hours at 0°C. Charged methanol (10 mL) to the reaction mass and amino acetaldehyde dimethyl acetal (3.8 gm) was added at 0°C. Reaction mass further aged at the same temperature for 2 hours and further maintained for 2 hours at 27°C. Dimethyl oxalate (9.8 gm) and sodium methoxide in methanol (15 mL) were added at 20°C, stirred the reaction mass for 16 hours at 42°C. After completion of the reaction, 2N hydrochloric acid was added and compound was extracted into ethylacetate solvent. The solvent was distilled off completely under vacuum to get cyclized chloro intermediate. This compound was converted to a compound of Formula 18 using sodium methoxide in methanol and dimethylsulfoxide.
Example 3: Preparation of l-(2,2-dimethoxy-ethyl)-3-methoxy-4-oxo-l,4- dihydro-pyridine-2,5-dicarboxylic acid dimethyl ester (Formula 18).
Methyl 4-chloro-3-oxobutanoate (5gm) was reacted with 1,1-dimethoxy dimethylethanamine (DMF-DMA) mixture (4.7 gm) at 0°C and further stirred the reaction mass for 2 hours at 0°C. Methanol (10 mL) was charged to the reaction mass and dimethyloxalate (9.8 gm) was added. Sodium methoxide solution (preparation: dissolved sodium (3.6 gm) in methanol 15 mL at 20°C) was added slowly and stirred the reaction mass for 16 hours at 42°C. To the reaction mass methanol (10 mL) and aminoacetaldehyde dimethylacetal (3.8 gm) were added at 0°C, stirred the reaction mass 2 hours at 27°C. Cyclized chloro intermediate was methoxylated by treating the obtained chloro intermediate with sodium methoxide in methanol and dimethylsulfoxide to get pure product of Formula 18.
Example 4: Preparation of 2-ethyl 5-methyl l,4-dihydro-3-methoxy-l-(2,2- dimethoxyethyl)-4-oxopyridine-2,5-dicarboxylate.
Methyl-4-methoxyacetoacetate (100 gm) was charged followed by slow addition of 1,1-dimethoxy dimethylethanamine (DMF-DMA) (98 gm) at a temperature of 20°C. The reaction content was warmed to 27°C and maintained the reaction mass for 8 hours at the same temperature. The reaction mixture was diluted with methanol (200 mL) and aminoacetaldehyde dimethyl acetal (78.8 gm) was added. The mixture was stirred for 2 hours at a temperature of 20°C, distilled of the solvent and extracted with methylene di chloride. THF (1068 mL) was added to the residue and cooled the reaction mass to a temperature of -50°C. LiHDMS (1685 mL) was added slowly followed by ethyl oxalyl chloride in THF (202.9 gm of ethyl oxalyl chloride was dissolved in 365 mL of THF). The reaction content was heated to a temperature of 30°C, stirred for 4 hours, solvent was distilled out completely under vacuum and then cooled to 0°C. The pH of the reaction mixture was adjusted to 3-4 with 2N HC1 solution (615 mL) and the product was extracted with ethyl acetate (1500 mL). The crude product obtained was purified by column chromatography to get a purified compound (42.2 gm).
Example 5: Preparation of l-(2,2-dimethoxy-ethyl)-3-methoxy-4-oxo-l,4- dihydro-pyridine-2,5-dicarboxylic acid dimethyl ester Boron complex (Formula 19).
Boric acid (20.8 gm) was gradually added to acetic anhydride (124 gm) at a temperature of 70°C and stirred for 1 hour. The reaction mixture was heated to 90°C and stirred for 1 hour. The reaction mixture was cooled to 65°C and added a solution of l-(2,2-dimethoxy-ethyl)-3-methoxy-4-oxo-l,4-dihydro-pyridine-2,5- dicarboxylic acid dimethyl ester (100 gm) in toluene (200 mL). The reaction was stirred for 3 hours at the same temperature and water was added to precipitate the title compound. The obtained compound was filtered and washed with water (30 gm).
1H- MR: δ 1.916 (s, 6H), 3.355 (s, 6H), 3.831 (s, 3H), 4.027 (s, 3H), 4.672-4.684 (d, 2H), 4.715-4.727 (d, 1H), 9.063 (s, 1H). Example 6: Preparation of (3S,llaR)-3-methyl-6-(methyloxy)-5,7-dioxo- 2,3,5,7,11, lla-hexahydro[l,3]oxazolo[3,2-a]pyrido[l,2-d]pyrazine-8- carboxylic acid (Formula 22).
Acetic acid (600 gm) and methane sulfonic acid (6 gm) was added to l-(2,2-dimethoxy-ethyl)-3-methoxy-4-oxo-l,4-dihydro-pyridine-2,5- dicarboxylicacid dimethyl ester boron complex at 50°C temperature. The reaction mixture was heated to 65°C, stirred for 24 hours, cooled to less than 55°C and distilled off solvent completely under vacuum. Acetonitrile (1000 mL) and acetic acid (18 gm) was charged at a 50° C temperature and raised the temperature to 65°C. (3R)-3-amino butan-l-ol (32.4 gm) in acetonitrile (200 mL) was slowly added and the reaction mass was maintained at the same temperature for 18 hours. The mixture was concentrated and cooled to 40°C. Methanol (2x200 mL) was added, the mixture was concentrated and cooled to 25 °C. Methylene chloride (1500 mL) and IN HC1 solution was added and the compound was extracted with methylene chloride. Methanol was added and the resultant mixture was concentrated. Methanol (400 mL) was added and stirred the reaction mass for 4 hours. The product was collected by filtration and dried under vacuum (35 gm).
Example 7: Preparation of (3S,llaR)-N-[(2,4-difluorophenyl)methyl]-3- methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7, ll,lla-hexahydro[l,3]oxazolo[3,2- a]pyrido[l,2-d]pyrazine-8-carboxamide (Formula 23).
(3S,1 laR)-3-methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,l 1, 1 la- hexahydro[l,3]oxazolo [3,2-a]pyrido[l,2-d]pyrazine-8-carboxylic acid (100 gm) and carbonyldimidazole (78.89 gm) were suspended in acetonitrile (1000 mL). The mixture was heated to a temperature of 75°C and stirred for 1 hour. The resulting solution was cooled to a temperature of 20°C and treated with 2,4- difluorobenzyl amine solution (55.2 gm was dissolved in 200 mL of acetonitrile). The reaction mixture was maintained for 2 hours, concentrated and the compound was extracted with ethyl acetate (1000 mL). Isopropyl alcohol (500 mL) was added at a temperature of 40°C, stirred the reaction mass for 30 minutes at a temperature of 50°C and the cooled the reaction mass to 25°C. The reaction mixture was maintained for 8 hours at the same temperature. The product was collected by filtration and dried under vacuum (85 gm).
Example 8: Preparation of Sodium salt of (3S,llaR)-N-[(2,4- difluorophenyl)methyl]-3-methyl-6-hydroxy-5,7-dioxo-2,3,5,7,ll9lla- hexahydro [l,3]oxazolo[3,2-a]pyrido[l,2-d]pyrazine-8-carboxamide (Formula
I).
(3S,l laR)-N-[(2,4-difluorophenyl)methyl]-3-methyl-6-(methyloxy)-5,7-dioxo- 2,3,5, 7, 11,11 a-hexahydro[ 1 ,3 ]oxazolo[3 ,2-a]pyrido[ 1 ,2-d]pyrazine-8- carboxamide (100 gm) was dissolved in acetonitrile (1000 mL) and magnesium bromide hexahydrate (161 gm) was added. The mixture was heated to 80°C for 2 hours, quenched with HC1 and then extracted with methylene dichloride. Methanol (1452 mL) and n-butanol (4840 mL) was added at a temperature of 27°C and then the temperature of the reaction mass was raised to 77°C. Stirred the reaction mass for 1 hour at the same temperature to get a clear solution. The reaction mass was cooled to a temperature of 37°C and then methanolic sodium hydroxide was slowly added. Cooled the reaction mass to 25°C and stirred for 20 hours. The product was filtered, washed with n-butanol and dried under vacuum (90 gm).
Although the invention has been described in terms of particular embodiments in an application, one of ordinary skill in the art, in light of the teachings herein, can generate additional embodiments and modifications without departing from the spirit of, or exceeding the scope of, the claimed invention. Accordingly, it is understood that the descriptions herein are proffered only to facilitate comprehension of the invention and should not be construed to limit the scope thereof.

Claims

We Claim:
1. A process for the preparation of dolutegravir or a pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting a compound of Formula 18 with boric acid in presence of acetic anhydride to obtain a compound of Formula 19;
Figure imgf000019_0001
b) treating the compound of Formula 19 with an acid and optionally a catalytic amount of protic acid to obtain a compound of Formula 20;
Figure imgf000019_0002
c) reacting the compound of Formula 20 with (R)-3-aminobutane-l-ol, followed by cyclization to obtain a compound of Formula 21;
Figure imgf000019_0003
d) hydrolyzing the compound of Formula 21 with an acid to obtain a compound of Formula 22;
Figure imgf000020_0001
e) reacting the compound of Formula 22 with 2,4-dflurobenzylamine in presence of a coupling agent to obtain a compound of Formula 23; and
Figure imgf000020_0002
converting the compound of Formula 23 to dolutegravir pharmaceutically acceptable salt.
Figure imgf000020_0003
2. The process according to claim 1, wherein the acid used in step b) is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, propionic acid, butanoic acid, pivalic acid, pentanoic acid, hexanoic acid, and mixtures thereof.
3. The process according to claim 1, wherein the protic acid used in step b) is selected from the group consisting of methanesulfonic acid, sulfuric acid, toluene sulfonic acid, hydrochloric acid, and mixtures thereof.
4. The process according to claim 1, wherein the acid used in step b) is acetic acid and the protic acid used in step b) is methane sulfonic acid.
5. The process according to claim 1, wherein the solvent used in step c) is water miscible.
6. The process according to claim 1, wherein the solvent used in step c) is selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate, acetone, Ν,Ν-dimethylformamide, dimethyl sulfoxide, and mixtures thereof.
7. The process according to claim 1, wherein the acid used in step d) is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, propionic acid, butanoic acid, pivalic acid, pentanoic acid, hexanoic acid, and mixtures thereof.
8. The process according to claim 1, wherein the solvent used in step d) is selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate, acetone, Ν,Ν-dimethylformamide, dimethyl sulfoxide, and mixtures thereof.
9. The process according to claim 1, wherein the coupling agent used in step e) is selected from the group consisting of carbonyldiimidazole, Ν,Ν'- dicyclohexylcarbodiimide, Ν,Ν'-diisopropylcarbodiimide, and mixtures thereof.
10. The process according to claim 1, wherein the solvent used in step e) is dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate, acetone, N,N- dimethylformamide, dimethyl sulfoxide, and mixtures thereof.
11. The process according to claim 1, wherein the compound of Formula 23 is reacted with a Lewis acid and then converted to pharmaceutically acceptable salt.
12. The process according to claim 1 1, wherein said pharmaceutically acceptable salt is a sodium salt.
13. A compound selected from the group consisting of:
Figure imgf000022_0001
PCT/IB2014/063758 2013-08-07 2014-08-07 Process for the preparation of dolute-gravir and intermediates thereof WO2015019310A1 (en)

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WO2015118460A1 (en) * 2014-02-07 2015-08-13 Mylan Laboratories Ltd. Crystalline forms of dolutegravir sodium
AU2015215630B2 (en) * 2014-02-07 2018-08-16 Mylan Laboratories Ltd. Crystalline forms of dolutegravir sodium
US10087193B2 (en) 2014-02-07 2018-10-02 Mylan Laboratories Limited Crystalline forms of dolutegravir sodium
WO2015177537A1 (en) * 2014-05-20 2015-11-26 Cipla Limited Process for preparing polycyclic carbamoyl pyridone derivatives and intermediates thereof
CN106565747A (en) * 2016-11-10 2017-04-19 顾世海 Novel method for preparing dolutegravir
WO2019070059A1 (en) 2017-10-06 2019-04-11 塩野義製薬株式会社 Method for stereoselectively producing substituted polycyclic pyridone derivative
KR20200066644A (en) 2017-10-06 2020-06-10 시오노기세야쿠 가부시키가이샤 Method for stereoselective production of substituted polycyclic pyridone derivatives
US11286262B2 (en) 2017-10-06 2022-03-29 Shionogi & Co., Ltd. Stereoselective process for preparing substituted polycyclic pyridone derivatives
WO2019159199A1 (en) * 2018-02-16 2019-08-22 Cipla Limited Continues flow process for the preparation of active pharmaceutical ingredients - polycyclic carbamoyl pyridone derivatives and intermediates thereof
US11634431B2 (en) 2018-07-12 2023-04-25 Laurus Labs Limited Process for purification of protected polycyclic carbamoylpyridone derivatives
CN109293675A (en) * 2018-11-19 2019-02-01 遵义医学院 A kind of improved Du Lutewei preparation process
US11248005B2 (en) 2019-07-08 2022-02-15 Lupin Limited Process for preparation of intermediates used for the synthesis of HIV integrase inhibitor
CN111620891A (en) * 2020-05-27 2020-09-04 上海启讯医药科技有限公司 Totiravi key intermediate solvate polymorph and preparation method and application thereof
WO2022107755A1 (en) 2020-11-17 2022-05-27 塩野義製薬株式会社 Novel acridinium salt and method for producing same

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