DESC:FIELD OF INVENTION
The present invention relates to process for preparation of Lenacapavir Sodium which is economically and industrially viable process.

BACKGROUND OF THE INVENTION
Lenacapavir Sodium is chemically known as Sodium (4-chloro-7-(2-((S)-1-(2((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4] cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl) ethyl)-6(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl) (methylsulfonyl)amide, which has been approved as a tablet having dosage strength 300 mg as well as Injection having dosage strength 463.5 mg/1.5 mL (309 mg/mL) in single-dose vials under the trade name SUNLENCA®. SUNLENCA is a human immunodeficiency virus type 1 (HIV-1) capsid inhibitor, in combination with other antiretroviral(s), is indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. Lenacapavir Sodium is structurally represented as follows:

Lenacapavir as well as its pharmaceutically acceptable salts were disclosed in
US 9,951,043 B2 (US ‘043) and US 10,071,985 B2 (US ‘985) of Gilead Sciences. Further, discloses the pharmaceutically acceptable salts includes an appropriate base, such as an alkali metal (such as Li+, Na+, and K+), an alkaline earth metal (for example, magnesium), ammonium and NX4+ (wherein X is C1-C4 alkyl); organic carboxylic acids such as acetic acid, benzoic acid, camphorsulfonic acid, citric acid, glucoheptonic acid, gluconic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, mandelic acid, and etc. Further, discloses the synthesis of Lenacapavir Free base of Formula I(a), which is as shown below:

US 10,696,657 B2 (US ‘657) of Gilead Sciences Inc, discloses the process for the preparation of Lenacapavir, salts & co-crystals.

The prior-art process involves 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate as amide coupling reagent along with Hunig's base (N,N-diisopropylethylamine). However, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate is environmentally hazardous and a costly reagent and hence not suitable for industrial preparations and is economically not viable process.

Further, the prior-art process involves the chromatographic purifications and is also not applicable for bulk production.

The present inventors have repeated the prior-art process using 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate in amide coupling reaction and this reaction leads to lower yield as well as lower purity and yields Lenacapavir having N,N-Dimesyl impurity, which is structurally as shown below:

Further, the prior-art process leads the formation of N,N-Dimesyl impurity upto 6.0% in the preparation of Lenacapavir, wherein process involves 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate and hence this process is not economically viable process and industrially not applicable process.

In view of the above, there is a need for an industrially applicable and cost-effective process for the preparation of Lenacapavir and its pharmaceutically acceptable salt thereof, which is free of N,N-Dimesyl impurity.

The present inventors have developed a process for the preparation of Lenacapavir using Propylphosphonic anhydride as amide coupling reagent, which is nontoxic, nonallergenic / nonsensitizing reagent, easier to handle, an exceptional reagent for amide formation and its reaction selectivity property leads lesser possibility of epimerization and accordingly final API having higher yields as well as higher purity. Hence, the present invention process is industrially applicable and economically viable process.

OBJECTIVES

An objective of the present invention is to provide a process for the preparation of Lenacapavir or its pharmaceutically acceptable salts, which involves propylphosphonic anhydride as amide coupling reagent, which is economically suitable and industrially viable process.

Another objective of the present invention is to provide a process for the preparation of Lenacapavir or its pharmaceutically acceptable salts, having higher yield, purity and is free of N,N-Dimesyl impurity.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of Lenacapavir of Formula I(a) or its pharmaceutically acceptable salts thereof,

comprising:
(a) condensing the amine compound of Formula (II)

with the acid compound of Formula (III)

in presence of an amide coupling reagent along with Hunig's base in a suitable solvent to yield compound of Formula (IV): and

(b) converting the compound of Formula IV to Lenacapavir free base of Formula I(a) or its pharmaceutically acceptable salt.
wherein, amide coupling reagent is propylphosphonic anhydride and Hunig’s base is N,N-Diisopropylethylamine or triethylamine.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of Lenacapavir or its pharmaceutically acceptable salt thereof, comprising: (a) condensing the amine compound of Formula (II) with the acid compound of Formula (III) in presence of an amide coupling reagent, propylphosphonic anhydride along with Hunig's base selected from the group comprising of N,N-Diisopropylethylamine or triethylamine; in a suitable solvent selected from the group comprising of alcohols, ketones, halogenated solvents, ethers, esters, hydrocarbons, nitriles, polar aprotic solvents or mixture of solvents thereof to yield compound of Formula (IV); (b) converting the obtained compound of Formula (IV) to Lenacapavir Free base of Formula I(a) or its pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides conversion of compound of Formula (IV) to Lenacapavir Free base of Formula I(a) or its pharmaceutically acceptable salt thereof comprising: treating the compound of Formula (IV) with sodium source selected from the group comprising of sodium hydroxide, sodium alkoxides, sodium 2-ethylhexanoate in presence of a suitable solvent selected from the group comprising of alcohols, ketones, halogenated solvents, ethers, esters, hydrocarbons, nitriles, polar aprotic solvents or mixture of solvents thereof to yield Lenacapavir Free base of Formula I(a) or its sodium salt.

In another aspect, the present invention provides conversion of compound of Formula (IV) to Lenacapavir Free base of Formula I(a) or its pharmaceutically acceptable salt thereof comprising: treating the compound of Formula (IV) with Quadrasil and Norit activated carbon (SX Ultra) to remove the palladium, which is used in preparation of Lenacpavir Raw-materials or starting materials. Further, the obtained Lenacapavir Free base is converted to its pharmaceutically acceptable salt. Wherein, QuadraSil is a metal scavenger that is effective at removing palladium (Pd) from solutions. Specifically, QuadraSil MP is a silica-based scavenger from Johnson Matthey that can be used to remove palladium and other metal impurities.

In another embodiment, Lenacapavir free base or its pharmaceutically acceptable salt can be purified by treating with

In another embodiment, obtained Lenacapavir free base can be optionally isolated and optionally purified by conventional methods.

In another embodiment, Lenacapavir free base can be optionally converting to its pharmaceutically acceptable salt.

In another embodiment, obtained pharmaceutically acceptable salt of Lenacapavir can be optionally isolated and optionally purified by conventional methods.

In another embodiment throughout the invention, isolation of Lenacapavir or its pharmaceutically acceptable salt can be performed by conventional methods such as cooling, removal of solvents, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, filtration, centrifugation and the like.

In another embodiment throughout the invention, alcohols are selected from the group comprising of methanol, ethanol, butanol, tert-butanol, isopropanol and the like; ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; the halogenated solvents are selected from the group comprising of dichloromethane, ethylene dichloride, chloroform and the like; ethers are selected from the group comprising of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, isopropyl ether, methyl isobutylether, methyl t-butyl ether, dioxane and the like; esters are selected from the group comprising of ethyl acetate, isopropyl acetate and the like; hydrocarbons are selected from the group comprising of toluene, xylene and the like; nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, acrylonitrile and the like; Polar aprotic solvents are selected from the group comprising of N,N-dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide and the like.

In another embodiment throughout the invention, the mixture of solvents means two or more solvents.

The invention of the present application will be explained in more detail with reference to the following examples, which should not be construed as limiting the scope of the invention in any manner.

Examples

Reference Example 1: Preparation of Lenacapavir Free base

(S)-N-(7-(2-(1-Amino-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide (1757 mg, 2.25 mmol), 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (666 mg, 2.36 mmol), and 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (854 mg, 2.25 mmol) were charged in a round bottom flask and dissolved in N,N-Dimethylformamide (10.0 mL). To the solution was added N,N-Diisopropylethylamine (0.80 mL, 4.49 mmol) at a rapid dropwise rate. After addition was complete, the reaction mixture was stirred at room temperature for 15 minutes to provide the intermediate N-((S)-1-(3-(4-chloro-3-(N-(methylsulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, which was not isolated. To the solution was added 2N aq. sodium hydroxide solution (5.0 mL). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was collected and washed with two portions of 5% lithium chloride solution followed by brine. The organic layer was isolated, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to yield the title compound as an amorphous solid.

Reference Example 2: Preparation of Lenacapavir Sodium

Sodium hydroxide (1 M, 2.9 g, 3.0 equiv.) was added to a reactor containing N-((S)-1-(3-(4-chloro-3-(N-(methylsulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (1.0 g) and 2-Methyltetrahydrofuran (8.4 g) at about 35°C. The mixture was agitated until the reaction was deemed complete. The reaction mixture was adjusted to between about 20 and 40°C. and the bottom layer was removed. The organic layer was washed with water (2.9 g) for about 15 minutes, and the bottom layer was removed. The organic solvent was swapped for ethanol and the solution was concentrated to about 5 volumes and the temperature was adjusted to about 35°C. n-Heptane (3.4 g) was slowly added, and the mixture was aged for about 12 hours. The solids were collected by filtration, and the filter cake was washed with ethanol/n-heptane (1:1). The resultant wet cake was dried under vacuum to afford Lenacapavir Sodium.

Example 1: Preparation of N-((S)-1-(3-(4-chloro-3-(N-(methylsulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide
To the (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridine-3-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)-N-(methylsulfonyl)methanesulfonamide (100 gm), added 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropan[3,4]cyclopenta [1,2-c]pyrazol-1-yl)acetic acid (36 gm), N,N-Dimethylformamide (500 ml) and stirred. The obtained reaction mixture was cooled, added 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (48 gm), added N,N-Diisopropylethylamine (33 gm) and stirred. To the obtained reaction mixture, added water, stirred, filtered the obtained solid, washed with water, and dried the obtained solid to yield N-((S)-1-(3-(4-chloro-3-(N-(methylsulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
N,N-Dimesyl impurity by HPLC: 5.4%

Example 2: Preparation of Preparation of N-((S)-1-(3-(4-chloro-3-(N-(methylsulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide
To the solution of (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridine-3-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)-N-(methylsulfonyl)methanesulfonamide (100 gm) in ethylacetate (500 ml), added 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropan[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (32 gm) and stirred. To the obtained reaction mixture, added propylphosphonic anhydride in ethylacetate (162 ml; propylphosphonic anhydride =50% wt in ethylacetate), N,N-Diisopropylethylamine (33 gm) and stirred. To the obtained reaction mixture, added water (500 ml) stirred, layers were separated and organic layer was co-distilled with 2-Methyltetrahydrofuran to yield N-((S)-1-(3-(4-chloro-3-(N-(methylsulfonyl) methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4] cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
N,N-Dimesyl impurity by HPLC: 0.07%

Example 3: Preparation of Lencapavir Sodium
To the N-((S)-1-(3-(4-chloro-3-(N-(methylsulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, added 2-Methyltetrahydrofuran, sodium hydroxide solution and stirred. The layers were separated and organic layer was treated with activated carbon, filtered the reaction mass and washed with 2-Methyltetrahydrofuran (200 ml), added isopropyl acetate (500 ml), heated and stirred for 15 minutes. The obtained reaction mass was cooled, seeded, stirred and filtered the obtained solid. To the obtained wet solid, added isopropyl acetate, stirred, cooled and filtered the obtained solid. To the obtained solid, added ethanol (200 ml), dried at 60°C to yield Lenacapavir Sodium.
Yield: 55%; Purity by HPLC: 99.4%; N,N-Dimesyl impurity by HPLC: 0.04%.

Example 4: Preparation of Lenacapavir Sodium
To the N-((S)-1-(3-(4-chloro-3-(N-(methylsulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, added 2-Methyltetrahydrofuran, sodium hydroxide solution, and stirred. Layers were separated and aqueous layer extracted with 2-Methyltetrahydrofuran, combined the organic layers and washed with water & sodium chloride solution, co-distilled with ethanol. To the obtained solid, added ethanol, stirred, added n-Heptane and filtered the solid. To the obtained solid, added isopropyl acetate, stirred, filtered, and dried the obtained solid at 55°C to yield Lenacapavir Sodium.
Yield: 50.0%; Purity by HPLC: 99.3%.

Example 5: Preparation of Lencapavir Sodium
To the N-((S)-1-(3-(4-chloro-3-(N-(methylsulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, added 2-Methyltetrahydrofuran, Quadrasil and Norit activated carbon (SX Ultra) and stirred for 3 hours to 4 hours at 25 – 35°C, filtered on hi-flow and washed with 2-methyltetrahydrafuran. To the obtained filtrate, added sodium hydroxide solution and stirred. The layers were separated and organic layer was treated with activated carbon, filtered the reaction mass and washed with 2-Methyltetrahydrofuran (200 ml), added isopropyl acetate (500 ml), heated and stirred for 15 minutes. The obtained reaction mass was cooled, seeded, stirred and filtered the obtained solid. To the obtained wet solid, added isopropyl acetate, stirred, cooled and filtered the obtained solid. To the obtained solid, added ethanol (200 ml), dried at 60°C to yield Lenacapavir Sodium.

Example 6: Preparation of Amorphous Lenacapavir Sodium
To the Lenacapavir sodium, added Methanol, and stirred. To the obtained clear solution, added Quadrasil and Norit activated carbon (SX Ultra) and stirred for 5 hours to 6 hours at 25 – 35°C. Filtered the obtained reaction mass through hi-flow bed and washed with Methanol, and then spray-dried. Dried the obtained solid under vacuum over for 12 hours to 14 hours at 55 – 65°C to yield Amorphous Lenacapavir Sodium.
Yield: 90.0%.

,CLAIMS:1. A process for the preparation of Lenacapavir Sodium of Formula I,

which comprises:
(a) condensing the amine compound of Formula (II)

with the acid compound of Formula (III)

in presence of an amide coupling reagent and Hunig's base in a solvent to obtain compound of Formula (IV); and

(b) converting the compound of Formula IV to Lenacapavir Sodium salt of Formula I.

2. The process as claimed in Claim 1, wherein amide coupling reagent used in step (a) is propylphosphonic anhydride.

3. The process as claimed in Claim 1, wherein Hunig’s base used in step (a) is N,N-Diisopropylethylamine or triethylamine.

4. The process as claimed in Claim 1, wherein solvent used in Step (a) is selected from the group consisting of alcohols, ketones, halogenated solvents, ethers, esters, hydrocarbons, nitriles, polar aprotic solvents or mixture of solvents.