US 12,486,286 B2
Process and polymorphic forms of bictegravir and its pharmaceutically acceptable salts or co-crystals thereof
Ram Thaimattam, Hyderabad (IN); Sureshbabu Radhakrishnan, Hyderabad (IN); Pavan Kumar Seethamraju, Hyderabad, IN (US); Satheesh Beeravalli, Hyderabad (IN); Uma Maheswara Rao Pampana, Hyderabad (IN); Anil Kumar Reddy Shamakura, Hyderabad (IN); Ravindra Babu Bollu, Hyderabad (IN); and Uma Maheswer Rao Vasireddi, Hyderabad (IN)
Assigned to LAURUS LABS LIMITED, Hyderabad (IN)
Appl. No. 17/629,985
Filed by LAURUS LABS LIMITED, Hyderabad (IN)
PCT Filed Jun. 18, 2020, PCT No. PCT/IB2020/055690
§ 371(c)(1), (2) Date Jan. 25, 2022,
PCT Pub. No. WO2020/255004, PCT Pub. Date Dec. 24, 2020.
Claims priority of application No. 2019 41024196 (IN), filed on Jun. 18, 2019; application No. 2019 41044872 (IN), filed on Nov. 5, 2019; and application No. 2020 41025395 (IN), filed on Jun. 17, 2020.
Prior Publication US 2022/0306650 A1, Sep. 29, 2022
Int. Cl. C07D 498/18 (2006.01)
CPC C07D 498/18 (2013.01) [C07B 2200/13 (2013.01)] 27 Claims
 
1. A process for the preparation of bictegravir of Formula I:

OG Complex Work Unit Chemistry
comprising:
a) reacting a compound of Formula II with a compound of Formula III in the presence of at least one suitable activation agent and at least one suitable base in at least one suitable solvent to obtain a compound of Formula IV:

OG Complex Work Unit Chemistry
and
b) demethylating the compound of Formula IV in the presence of at least one suitable deprotecting agent to obtain the bictegravir of Formula I;
wherein the at least one suitable activation agent in step a) is selected from the group consisting of 2-chloro-4,6-dimethoxy-1,3,5-triazine, carbonyldiimidazole, 1-ethyl-3-(3-dimethyl amino propyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate, O-(1H-6-Chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluoro phosphate, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, propyl phosphonic anhydride, dicyclohexylcarbodiimide, 3-hydroxytriazolo[4,5-b]pyridine, thionyl chloride, oxalyl chloride, phosphorus oxychloride, pivaloyl chloride, acetic anhydride, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, methanesulfonyl chloride and p-toluenesulfonyl chloride, and any combination thereof,
wherein the at least one suitable base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium amide, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylamine, diisopropyl ethylamine, N-methyl piperidine, N-ethylpiperidine, and any combination thereof,
wherein the at least one suitable solvent is selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, ethylacetate, isopropyl acetate, butyl acetate, acetonitrile, propionitrile, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, methylene chloride, ethylene chloride, chloroform, toluene, xylene, dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, and any combination thereof, and
wherein the at least one suitable deprotecting agent is selected from the group consisting of magnesium chloride, magnesium bromide, magnesium iodide, magnesium hydroxide, lithium chloride, lithium bromide, lithium iodide, lithium hydroxide, lithium trisiamyl borohydride, lithium triethyl borohydride, tri-sec-butyl borohydride, boron tribromide, aluminium chloride-triethylamine complex, aluminium chloride-N,N-dimethyl aniline complex, and any combination thereof.