WO2018229798A1

WO2018229798A1 - Process for the preparation of bictegravir and intermediate thereof

Info

Publication number: WO2018229798A1
Application number: PCT/IN2018/050390
Authority: WO
Inventors: Manjinder Singh Phull; Dharmaraj Ramachandra Rao; Dilip Ramdas Birari
Original assignee: Cipla Limited
Priority date: 2017-06-13
Filing date: 2018-06-13
Publication date: 2018-12-20
Also published as: ZA201803942B

Abstract

The present invention provides processes and intermediates for the synthesis of bictegravir and its pharmaceutical salt.

Description

PROCESS FOR THE PREPARATION OF BICTEGRAVIR AND INTERMEDIATE THEREOF

Technical field of the Invention:

The present invention relates to novel intermediates and processes for preparation of novel intermediates as well as use of these intermediates in the synthesis of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13, 13a- octahydro-2,5-methanopyrido [l ',2' :4,5]pyrazino [2, l-b][l,3]oxazepine-10- catboxamide or its pharmaceutically acceptable salts and novel process for synthesis of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)- 2,3,4,5,7,9,13, 13a-octahydro-2,5-methanopyrido [l ',2' :4,5]pyrazino [2, 1- b][l,3]oxazepine-10-catboxamide or its pharmaceutically acceptable salts.

Background of the Invention:

(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13, 13a- octahydro-2,5-methanopyrido[ ,2' :4,5]pyrazino[2, l-b][l,3]oxazepine-10- catboxamide sodium salt is also known as Bictegravir sodium (I).

Bictegravir or its pharmaceutically acceptable salts is an HIV integrase inhibitor which is used to inhibit the activity of HIV integrase and used to reduce HIV replication and thus to treat HIV infections.

Bictegravir sodium is approved drug by USFDA, in combination with Emtricitabine and Tenofovir alafenamide for treatment of HIV. Bictegravir belongs to class of polycyclic carbamoylpyridone compounds and is disclosed in WO2014100323. This patent application also discloses process for preparation of Bictegravir.

WO2015195656 describes various processes for preparation of intermediates used in the synthesis of Bictegravir and further processes for synthesis of Bictegravir or its pharmaceutically acceptable salts.

Summary of the Invention:

It is an object of the present invention to provide novel intermediates for the synthesis of Bictegravir or its pharmaceutically acceptable salts.

It is another object of the present invention to provide processes for the preparation of intermediates used in the synthesis of Bictegravir or its pharmaceutically acceptable salts.

It is yet another object of this invention to provide simple and novel processes for the preparation of Bictegravir or its pharmaceutically acceptable salts using novel key intermediates.

It is further object of this invention to provide a pharmaceutical composition comprising Bictegravir or its pharmaceutically acceptable salts prepared by the processes of the present invention and pharmaceutically acceptable carrier, diluent or excipients.

It is another object of this invention to use pharmaceutical composition defined hereinabove for the treatment of HIV infections.

Detailed Description of the Invention:

The present invention relates to novel intermediate compound (1) useful in the synthesis of Bictegravir or its pharmaceutically acceptable salts.

(1)

In another aspect, the novel intermediate (1) of the present invention is obtained by process comprising steps of :

(a) hydrolysing compound (2) with a suitable acid or mixture of acids in a suitable solvent to get compound (3);

(b) reacting the compound (3) with compound (4) or salt thereof using a suitable base to get compound (5) and

(c) demethylating the compound (5) in presence of Lewis acid and a suitable solvent to get compound (1).

The synthesis is depicted below in scheme - 1.

Scheme - 1 Bracket indicates that the process of the present invention is carried without isolation of compound (3). In the context of the present invention, the term "without isolation" means that the product being referred to as not being isolated as a solid, for example it is not isolated from the reaction mass and dried to form a solid. Thus, "without isolation" may mean that the product remains in solution and is then used directly in the next synthetic step, or it may mean that solvent is substantially removed from a solution of the product such that the product is present as a residue, but not as a solid.

Suitable solvent for steps (a), (b) and (c) may be selected from but not limited to acids (such as but not limited to acetic acid, formic acid), esters (such as but not limited to ethyl acetate, isopropyl acetate), ethers (such as but not limited to tetrahydrofuran, 2-methyl tetrahydrofuran, t-butyl methyl ether), alcohols (such as but not limited to methanol, ethanol, isopropanol, t-butanol), ketones (such as but not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone), alkylitriles (such as but not limited to acetonitrile, propionitril), hydrocarbons including halogenated hydrocarbons (such as but not limited to toluene, xylene, dichloromethane), alkylcarbonate (such as but not limited to dimethyl carbonate, diethyl carbonate), aprotic polar solvents (such as but not limited to sulfolane, dimethyl sulfoxide, N-methyl pyrrolidone) or mixture thereof.

The base used in step (b) may be inorganic or organic.

Inorganic base may be selected from but not limited to sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tert. butoxide, potassium acetate, sodium acetate, cesium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide, ammonium hydroxide, sodium methoxide, potassium methoxide, and the like. Organic base may be selected from but not limited to pyridine, dimethyl amine, triethyl amine, Ν,Ν-diisopropylethyl amine, l,8-Diazabicyclo[5.4.0]undec-7-ene, N-methyl morpholine, Ν,Ν-dimethyl piperazine, N-methyl piperidine.

In a more specific aspect, the preferred base is potassium carbonate. The molar equivalents of potassium carbonate and compound (4) is usually taken in the range of 1 to 1.5 equivalents of each w.r.t. compound (2), preferably 1.2 equivalent of each w.r.t. compound (2).

This particular ratio is very important to carry out the reaction smoothly otherwise sticky reaction mass and more of impurity formation was observed with even if the ratio is slightly altered.

The acid used in step (a) and step (b) may be inorganic or organic.

Inorganic acid may be selected from but not limited to hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid.

Organic acid may be selected from but not limited to acetic acid, oxalic acid, succinic acid, citric acid, trifluoroacetic acid, methane sulfonic acid (MSA), formic acid, p-toluene sulfonic acid or combinations thereof.

In a preferred aspect, the acid is acetic acid taken in combination with methane sulfonic acid. In more preferred aspect, the volume of acetic acid and MSA is taken in the range of 0.9 to 1.3 and 0.02 to 0.08 respectively w.r.t compound (2), preferably the volume used is 1 & 0.05 respectively w.r.t compound (2).

The volume of acetic acid is the key to control the formation of impurities as higher volumes leads to more impurities which affects the yield of the desired compounds (5) and (1). Lewis acid used in step (c) may be selected from group but not limited to aluminium chloride, aluminium bromide, boron trichloride, boron trifluoride, iron bromide, iron chloride, lithium bromide, magnesium bromide, tin chloride.

Step (a) may be carried out at the reflux temperature of the solvent.

Step (b) may be carried out at the temperature in the range of 0°C to 40°C, preferably at 20°C to 30°C.

Step (c) may be carried out at the temperature in the range of 20°C to reflux temperature of the solvent.

Another aspect of the invention provides process for preparation of Bictegravir using intermediate (1) which process comprises step of reacting intermediate (1) with compound (6) to get Bictegravir.

Th nthesis is depicted below in scheme - II.

This reaction is carried out in a suitable solvent in presence of a peptide coupling reagent and optionally in presence of a suitable base.

Suitable solvent may be selected from but not limited to acids (such as but not limited to acetic acid, formic acid), esters (such as but not limited to ethyl acetate, isopropyl acetate), ethers (such as but not limited to tetrahydrofuran, 2-methyl tetrahydrofuran), alcohols (such as but not limited to methanol, ethanol, isopropanol, t-butanol), ketones (such as but not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone), alkylitriles (such as but not limited to acetonitrile, propionitril), hydrocarbons including halogenated hydrocarbons (such as but not limited to toluene, xylene, dichloromethane), alkylcarbonate (such as but not limited to dimethyl carbonate, diethyl carbonate), aprotic polar solvents (such as but not limited to sulfolane, dimethyl sulfoxide, N-methyl pyrrolidone).

Peptide coupling reagent may be selected from but not limited to (1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate also known as HATU, 0-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium tetrafluorob orate (TBTU), dicyclohexylcarbodiimide (DCC), 0-benzotriazole-N,N',N'-tetramethyl uronium hexafluoro phosphate (HBTU), benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphate, l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC HQ), Benzotriazol-1- yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), Benzotriazol- 1 -yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyBOP), Bromo-tripyrrolidino-phosphonium hexafluorophosphate (PyBrOP),

Diisopropylcarbodiimide (DIC), 4-(N,N-Dimethylamino)pyridine (DAMP).

Preferably, the coupling agent may be used with an additive such as 1- hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 2- hydroxypyridine-N-oxide (HOPO), l-hydroxy-7-azabenzotriazole (HO At), N- hydroxy-5-norbornene-2,3-dicarboximide (HO B).

Alternatively, this step may be carried out in presence of suitable amide forming reagents such as carbonyl diimidazole (CDI); alkyl haloformate such as methyl chloroformate, ethyl chloroformate; chlorodimethoxy triazine (CDMT).

Optional base is selected from inorganic base and organic base.

A suitable inorganic base according to the present invention is selected from the group consisting of alkali metal hydroxides, alkali metal carbonates and alkali metal alkoxides. The organic base is selected form the group consisting of pyridine, diethyl amine, triethyl amine, diisopropyl ethyl amine, N-methyl morpholine, N,N- dimethyl piperazine and N-methyl piperidine.

Particularly suitable base for use in the above process according to the present invention is diisopropyl ethyl amine to accelerate the reaction.

The further aspect of the invention provides novel intermediates (7) and (8) useful in the synthesis of Bictegravir or its pharmaceutically acceptable salts.

The process for preparation of these intermediates comprises following steps :

(a) reacting the intermediate (1) with tertiary-butyldimethylsilyl chloride (TBDMSC1) to get intermediate (7);

(b) reacting the intermediate (7) with compound (6) to get intermediate (8); and

(c) deprotecting the intermediate (8) to get Bictegravir.

The synthesis is depicted below in scheme - III.

Scheme - III

The above step (a) is carried out in presence of a suitable organic base.

Organic base is selected from pyridine, dimethyl amine, triethyl amine, N,N- diisopropyl ethyl amine, l,8-Diazabicyclo[5.4.0]undec-7-ene, N-methyl morpholine, Ν,Ν-dimethyl piperazine, N-methyl piperidine.

The step (b) is carried out in a suitable solvent in presence of common peptide coupling reagent in presence of a suitable base.

Suitable solvent may be the same as described for scheme-I .

Peptide coupling reagents and base are the same as described above for scheme - II.

Alternatively, this step may be carried out in presence of suitable amide forming reagents such as CDI; alkyl haloformate such as methyl chloroformate, ethyl chloroformate; chlorodimethoxy triazine (CDMT). The further aspect of the invention provides another novel intermediate of formula (9) useful in the synthesis of Bicte ravir or its pharmaceutically acceptable salts.

(9)

Synthesis of Intermediate of formula (9) comprises following steps :

a) demethylating compound of formula (10) to get intermediate of formula (9); and b) reacting the intermediate of formula (9) with compound of formula (4) to give Bictegravir.

Th nthesis is depicted below in scheme

Bictegravir

Scheme -IV

Compound of formula (10) is known and can be made by the processes known in the art. Step (a) of demethylation reaction is carried out in suitable solvent and in presence of Lewis acid.

Suitable solvent and Lewis acid are the same as described above for scheme - 1.

In step (b), first the compound of formula (9) is hydrolysed in presence of suitable acid and a solvent to get geminal diols of compound of formula (11) which is then converted to Bictegravir by reaction with compound of formula (4) in presence of a suitable solvent and a base.

Suitable solvent and base are the same as described above for scheme - 1.

Usually the geminal diol of compound of formula (11) is formed in situ.

The further aspect of the invention provides novel intermediates (12) and (13) useful in the synthesis of Bictegravir or its pharmaceutically acceptable salts.

This process which comprises following steps :

(a) demethylating compound of formula (10) to get intermediate of formula (9);

(b) reacting the intermediate (9) with tertiary-butyldimethylsilyl chloride (TBDMSC1) to get intermediate (12);

(c) reacting the intermediate (12) with compound (4) to get intermediate (13); and

(d) hydrolysing the intermediate (13) to get Bictegravir.

Compound (9) is prepared by hydrolysing compound of formula (10).

The synthesis is depicted below in scheme - V.

Bictegravir Scheme -V

Step (a) of demethylation reaction is carried out in suitable solvent and in presence of Lewis acid.

Suitable solvent and Lewis acid are the same as described above for scheme - 1.

The step (b) is carried out in a suitable solvent in presence a suitable base.

Suitable solvent and base are the same as described above for scheme - II.

The step (c) is carried out in presence of a suitable solvent, base and an acid.

The solvent, base and acid used for step (c) are the same as described above for scheme - 1. Another aspect of the invention provides novel process for preparation of Bictegravir which comprises following steps:

(a) reacting compound (6) with compound (14) to get compound (15);

(b) treating the compound (15) with Dimethyl formamide dimethyl acetal (DMF- DMA) to get compound (16);

(c) reacting the compound (16) with compound (17) to get compound (18);

(d) cyclising the compound (18) with dimethyl oxalate to get compound (19);

(e) hydrolysing the compound (19) in situ to get compound (20);

(f) treating the compound (20) with compound of formula (4) to get compound (21); and

(g) treating the compound (21) with alkali metal hydroxide to get Bictegravir. The synthesis is depicted below in scheme - VI.

The step (a) is carried out in presence of a suitable solvent at an elevated temperature.

Suitable solvent is as described above for scheme - 1. Elevated temperature is the higher temperature in the range of 100 to 150°C. The step (b) is carried out by Knovenagel condensation with dimethyl formamide- dimethyl acetal (DMF-DMA) to get compound (16).

In step (c), dimethyl amino group of compound (16) is displaced with compound (17) to get compound (18).

Cyclisation in step (d) is carried out with dimethyl oxalate in a suitable solvent to get compound (19).

Suitable solvent is as described above for scheme - 1.

In step (e), first the compound (19) is hydrolysed in suitable acid and a solvent to get geminal diol of compound (20).

Step (f) involves conversion of the compound (20) to compound (21) by reaction with compound (4) in presence of a suitable solvent and a base.

Suitable solvent and base are the same as described above for scheme - 1.

Step (g) comprises reacting compound (21) with suitable alkali metal hydroxide to get Bictegravir.

Suitable alkali metal hydroxide are selected from but not limited to sodium hydroxide, lithium hydroxide, potassium hydroxide.

For all the above reactions, the intermediate steps may be carried out in situ without isolating the intermediates or the intermediates may be isolated prior to proceed with the next step.

For the reaction schemes from III to VI some of the steps may be carried out at lower temperature as low as below 0°C in the range of 0 to -50°C. Also some steps may be carried out room temperature in the range of 25°C to 30°C or may be at reflux temperature of the solvent used.

Bictegravir obtained by the process of the present invention is further converted to its pharmaceutically acceptable salt in a conventional manner known in the art. The pharmaceutically acceptable salt may be calcium, sodium, potassium, magnesium.

The preferred salt is sodium salt wherein Bictegravir is treated with sodium hydroxide in a suitable solvent to give sodium salt of Bictegravir. Suitable solvent is as described above for scheme - 1.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Examples

Example 1 :

Preparation of Bictegravir Sodium:

100 g of compound (2) was charged along with acetonitrile 800 ml followed by acetic acid 100 ml and methane sulphonic acid 5 ml. The contents were heated at 70-80°C and maintained for 6-8 hours. The reaction mass was cooled to room temperature and 52 g of compound (4) was added to it followed by addition of potassium carbonate 52.5 g. The reaction mass was stirred for 16-18 hours and 1000 ml of water was added to the reaction mass and then extracted with dichloromethane 1000 ml. The reaction mass was re-extracted two more times with dichloromethane. The combined organic layer was washed with water 500 ml and concentrated to get residue. 300 ml of methanol was charged to the residue and stirred for 30 minutes and then filtered. The residue was washed with methanol 50 ml and then dried and then recrystallized from dichloromethane / methyl tert-butyl ether to get pure compound (5).

Yield - 70 g

HPLC Purity: > 99.5 %

65 g of compound (5) was charged along with tetrahydrofuran 1300 ml into a reaction flask followed by addition of 195 ml of tert-butyl alcohol and the contents were cooled to 10-15^°C. 141 g of lithium bromide was added to the reaction mass and stirred for 18-20 hours. Water 650 ml was added to reaction mass and stirred for 30 minutes. (1 : 1) aq. HC1 65 ml was added and stirred for 30 minutes. The crystallized solid was filtered and washed with water 650 ml and then dried under vacuum for 15-20 hours. The so obtained compound (1) then recrystallized from N- methyl-2-pyrrolidone /water to get pure compound (1).

Yield - 58 g

HPLC Purity: > 99.0 %

50 g of compound (1) was charged along with 500 ml of dimethyl carbonate followed by 52 g of N, N'-Carbonyl Diimidazole. The reaction mass was heated at 40-50^°C and maintained for 5 hours and then cooled to room temperature. 39.4 g of compound (6) was added to the reaction mass and stirred for 1 hour. 500 ml of water added to the reaction mass and extracted with 500 ml ethyl acetate. Then back extracted with ethyl acetate 500 ml one more time and washed combined organic layer with 50 ml IN HC1. The organic layer was washed with saturated sodium bicarbonate solution 250 ml followed by water 500 ml. The layer was partially concentrated, filtered and then the filtrate was distilled out completely. 150 ml of methanol was added to the residue and heated to 45-50^°C and maintained for 1 hour. Then cooled to 0-10°C, filtered and washed with chilled methanol 50 ml and finally recrystallized from methanol to obtain Bictegravir.

Yield - 65 g

HPLC Purity: > 99.5 % The recrystallized Bictegravir was dissolved in 500 ml methanol at 60-65°C in a separate reaction flask. In another reaction flask 4.5 g sodium hydroxide was dissolved in 500 ml water at room temperature. Hot methanol solution was added into aq. sodium hydroxide solution slowly within 2-3 hours at room temperature and the crystallized solid suspension was stirred for 1 hour. The product was filtered, washed with 250 ml of water and then dried at 50-55^°C under reduced pressure for 15-20 hours to obtain Bictegravir Sodium.

Yield : 65g

Example 2

Preparation of Bictegravir Sodium:

100 g of compound (2) was charged along with Dimethyl carbonate 1500 ml followed by acetic acid 100 ml and methane sulphonic acid 5 ml. The contents were heated at 70-80°C and maintained for 6-8 hours. The reaction mass was cooled to room temperature and 52 g of compound (4) was added followed by 52.5 g of potassium carbonate and the reaction mass was stirred for 16-18 hours. 1000 ml of water was added to the reaction mass and extracted with 1000 ml dichloromethane. Again re-extracted two more times with dichloromethane. The combined organic layer was washed with water 500 ml and concentrated to get residue. 300 ml methanol was charged to the residue and stirred for 30 minutes and then filtered. Further the residue was washed with methanol 50 ml and dried and then recrystallized the material from dichloromethane / methyl tert-butyl ether to get compound (1).

Yield: 60.0 g

HPLC Purity: > 99.0 +%

65 g of compound (5) was charged along with 650 ml of acetonitrile into a reaction flask . The contents were cooled to 10-15°C and 141 g of lithium bromide was added to it. The reaction mass stirred for 18-20 hours and 650 ml of water was added to it at 10-15°C and stirred for 30 minutes. (1 : 1) aq. HC1 65 ml was added and stirred for 30 minutes. The crystallized solid was filtered, washed with water 650 ml and dried under vacuum for 15-20 hours and then recrystallized from N- methyl-2-pyrrolidone /water to get pure compound (1).

Yield: 50.0 g

HPLC Purity: > 99.0 %

50 g of compound (1) was charged along with acetonitrile 500 ml followed by 85 ml of Hunig base (Ν,Ν-Diisopropylethylamine) and stirred for 1 hours at room temperature. HATU was added to the reaction mass and stirred for 1 hour and then 39.4 g of compound (6) was added followed by stirring for 4 hours. 500 ml of water was added to the reaction mass followed by addition of 100 ml IN HCl. The reaction mass was extracted with 500 ml ethyl acetate and then back extracted with ethyl acetate 500 ml one more time and washed the combined organic layer with 250 ml of saturated sodium bicarbonate solution followed by water 500 ml. The organic layer was partially concentrated and filtered. The filtrate was distilled out completely, 150 ml methanol was added to the residue and then heated to 45-50°C and maintained for 1 hour. The residues was then cooled to 0-10°C, filtered and washed with chilled methanol 50 ml and finally recrystallized from methanol to obtain Bictegravir.

Yield: 65.0 g

HPLC Purity: > 99.5 %

65 g of Bictegravir was dissolved in 500 ml ethanol at 60-65°C in a separate reaction flask. In another reaction flask 4.5 g of sodium hydroxide was dissolved in 500 ml water at room temperature. Hot methanol solution was added into aq. NaOH solution slowly within 2-3 hours at room temperature and the crystallized solid suspension was stirred for 1 hour at room temperature. The product was filtered and washed with 250 ml of water and dried at 50-55°C under reduced pressure for 15-20 hours to obtain Bictegravir sodium.

Yield : 65 g

Claims

We Claim,

1. A process for the preparation of compound (1)

comprising:

(a) hydrolysing compound (2)

(2)

with a suitable acid or mixture of acids in a suitable solvent to get compound (3);

(3)

(b) reacting the compound (3) with compound (4) or salt thereof

using a suitable base to get compound (5)

and;

2. The process according to claim 1, wherein the acid used in the step (a) is an inorganic acid or organic acid.

3. The process according to claim 2, wherein the acid is acetic acid and methane sulfonic acid.

4. The process according to claim 1, wherein the base used in step (b) is an inorganic base or organic base.

5. The process according to claim 4, wherein the base is potassium carbonate.

6. The process according to claim 1, wherein the Lewis acid used in step (c) is selected from group but not limited to aluminium chloride, aluminium bromide, boron trichloride, boron trifluoride, iron bromide, iron chloride, lithium bromide, magnesium bromide and tin chloride.

7. The process according to claim 6, wherein the Lewis acid is lithium bromide.

8. The process according to any one of the preceding claims, wherein solvent for steps (a), (b) and (c) may be selected from the group consisting of acids, esters, ethers, alcohols, ketones, alkylitriles, hydrocarbons including halogenated hydrocarbons, alkylcarbonate and aprotic polar solvents.

9. The process according to any one of the preceding claims 1, 2 and 3, wherein the hydrolysis reaction in step (a) is carried out at a reflux temperature of the solvent used.

10. The process according to any one of claims 1, 4 and 5, wherein the condensation reaction in step (b) is carried out at a temperature ranging from 0°C to 40°C.

11. The process according to any one of claims 1, 6 and 7, wherein the demethylation reaction in step (c) is carried out at a temperature ranging from 20°C to reflux temperature of the solvent used.

12. The process according to any one of claims 1 to 11, wherein compound (3) is not isolated.

13. A compound of formula 1)

(1)

A process for prep ration of Bictegravir or salt thereof,

Bictegravir

comprising reacting compound (1) with compound (6)

in the presence of a peptide coupling reagent or amide forming reagents.

15. The process according to claim 14, wherein the peptide coupling reagent is selected from but not limited to (l -[Bis(dimethy3amino)methy3ene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), O- (benzotriazol- 1 -yl)-N,N,N' ,Ν' -tetramethyluronium tetrafluorob orate (TBTU), dicyclohexylcarbodiimide (DCC), 0-benzotriazole-N,N',N'-tetram ethyl uronium hexafluoro phosphate (HBTU), benzotriazol- 1- yloxytripyrrolidinophosphonium hexafluorophosphate, l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC HQ), Benzotriazol- 1 -yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), Benzotriazol-l-yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyBOP), Bromo-tripyrrolidino-phosphonium hexafluorophosphate (PyBrOP), Diisopropylcarbodiimide (DIC), 4-(N,N-Dimethylamino)pyridine (DAMP).

16. The process according to claim 14, wherein the amide forming reagent is selected from carbonyl diimidazole (CDI); alkyl haloformate such as methyl chloroformate, ethyl chloroformate; and chlorodimethoxy triazine (CDMT).

17. The process according to any one of claims 14, 15 and 16, wherein the reaction is carried out in the presence of a suitable solvent.

18. The process according to claim 17, wherein the solvent is selected from the group consisting of acids, esters, ethers, alcohols, ketones, alkyl nitriles, hydrocarbons including halogenated hydrocarbons, alkylcarbonate and aprotic polar solvents.

19. The process according to claim 18, wherein the solvent is selected from dimethyl carbonate and acetonitrile.

20. The process according to claims 14 to 19, wherein bictegravir is converted to bictegravir sodium.

21. Use of compound (1) in the preparation of Bictegravir or salt thereof.

22. A pharmaceutical composition comprising Bictegravir or its pharmaceutically acceptable salts prepared according to the process of claims 14 to 20 and pharmaceutically acceptable carrier, diluent or excipients.