Field of the invention:
The present invention provides novel processes for the preparation of l,3-Thiazol-5-ylmethyl[(2R,5R)-5-{[(2S)-2-[(m^
amino]-4-(morpholin-4-yl)butanoyl]amino}-lJ6-diphenylhexan-2-yl]carbamate having the following structural formula-1
Formula-1 The present invention also provides novel intermediates which are useful in the preparation of the compound of formula-1. 10
Background of the invention:
Cytochrome P450 monooxygenase inhibitors such as l,3-Thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)-lJ3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl) butanoyl]amino}-l,6-diphenylhexan-2-yl]carbamate having the structural formula-1 and
15 also known as Cobicistat. The compound of formula-1 of the present invention is used in the treatment of human immunodeficiency virus (HIV). This is approved in US under the brand name of TYBOST®. The drug was approved in US also in combining with Elvitegravir, Emtricitabine; Tenofovir disoproxil fiimarate with the brand name is STRIBILD®.
Various synthetic routes are available for the synthesis of the compound of formula-1.
20 US8148374 patent first disclosed the compound of formula-1 and process for its preparation. The compound of formula-1 is a straight chain having three peptide bonds. US'374 disclose some possibilities to preparation of the compound of formula-1.

The disclosed process involves the usage of strong basic agents leading to lower yields and less purity due to the formation of byproducts.
The present inventors have developed a novel processes for the preparation of the compound of formula-1 it has many advantages; like using simple and mild bases such as alkali metal salts avoiding pyrophoric bases making it conducive for large scale production at an industrial level; Lesser reaction times; Avoiding column chromatography technique for the purification. It also avoids the formation by-products and unwanted isomers especially in the final product, improving the yield and quality. Formation of N-oxide impurity is inhibiting by the usage of antioxidant in the reaction.
Brief description of the invention:
The first aspect of the present invention is to provide a novel process for the preparation of the compound of formula-1.
The second aspect of the present invention is to provide an improved process for the preparation of the compound of formula-13.
The third aspect of the present invention is to provide a novel intermediate compound of the general formula-8 or its salts.
The fourth aspect of the present invention is to provide a process for the preparation of compound of the general formula-8 or its salts. Brief Description of the Drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form-M of the compound of formula-8ai.
Figure 2: Illustrates the DSC of crystalline form-M of the compound of formula-8ai.
Detailed description of the invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane, cycloheptane, pet ether, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, di-tert-butyl ether, dimethoxy methane, 1,2-dimethoxyethane, diglyme, 1,4-dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl

acetate, isopropyl acetate, n-butyl acetate, iso-butyl acetate, tert-butyl acetate, diethyl carbonate and the like; "polar-aprotic solvents" such as dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), hexamethylphosphoramide (HMPA) and the like; "nitrile solvents" such as acetonitrile,
5 propionitrile, butyronitrile, isobutyronitrile and like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol, 2-pentanol, ethylene glycol, diethylene glycol, propylene glycol, 2-ethyl
) hexanol, benzyl alcohol and the like; "polar solvents" such as water; acetic acid or mixtures thereof.
The term "stable amorphous cobicistat" refers to solid dispersion of cobicistat with silicondioxide.
The term "suitable base" used in the present invention refers to inorganic bases selected
5 from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide,
) potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide, lithium bis(trimethysilyl)amide (LiHMDS) and the like; "alkyl metals" such as n-butyl lithium and like; "metal hydrides" such as lithium hydride, sodium hydride, potassium hydride and the like;
5 "alkali metal phosphates" such as disodium hydrogen phosphate, dipotassiumhydrogen phosphate; and "organic bases" selected from but not limited to methyl amine, ethyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), n-methyl pyridine (NMP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene
) (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole; or mixtures thereof.

The term "acid" used in the present invention refers to inorganic acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc; organic acids such as acetic acid, maleic acid, malic acid, tartaric acid, oxalic acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid; chiral acids such as S-(+) mandelic acid, R-(-)
5 mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (lR)-(-)-camphor sulfonic acid, (IS)- (+)-camphor sulfonic acid, (1R)-(+)-bromocamphor-10-sulfonic acid, (lS)-(-)- bromocamphor-10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L- tartaricacid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (+)-dipara-tolyl-D-tataric acid, (-)-dipara-tolyl-L-
D tataricacid, L(-)- pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid, L-lysine, D-lysine etc., and like.
The term "salts" used in the present invention refers to acid addition salts selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; organic acids such as acetic acid, maleic acid, malic acid, oxalic acid,
5 trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid; chiral acids such as S-(+) mandelic acid, R-(-) mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (lR)-(-)-camphor sulfonic acid, (IS)- (+)-camphor sulfonic acid (lR)-(+)-bromocamphor-10-sulfonic acid, (lS)-(-)- bromocamphor-10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L- tartaricacid monohydrate, (+)-
3 Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (+)-dipara-tolyl-D-tataric acid, (-)-dipara-tolyl-L-tataricacid, L(-)- pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid, L-lysine, D-lysine etc., and like.
The term "oxidizing agent" used in the present invention includes, for example, peracids such as m-chloroperbenzoic acid, peracetic acid, and the like; and an inorganic oxidizing agent
5 such as manganese dioxide, sodium periodate, hydrogen peroxide, dinitrogen tetroxide, hydroperoxide, iodobenzene acetate, t-butyl hypochlorite, sulfuryl chloride, potassium peroxymonosulfate, sodium hypochlorite in presence of TEMPO, DABCO, Dess-martin reagent, oxaloyl chloride in DMSO etc.
The term "halogenating agent" used in the present invention refers to brominating agent
3 such as N-bromosuccinamide (NBS), bromine, carbon tetrabromide, phosphorous bromide,

phosphorous tribromide, phosphorous pentabromide or sodium bromide in combination with trimethylsilyl chloride; the term chlorinating agent is selected from thionyl chloride, oxalyl chloride, sulfuryl chloride, phosphorous oxychloride, carbon tetra chloride, phosphorous trichloride, phosphorous pentachloride, N-chlorosuccinamide (NCS) and like; and iodinating agent such as trimethyl iodide, hydrogen iodide or sodium iodide optionally in combination with triphenyl phosphine, trimethylsilyl chloride.
The term "condensing agent or coupling agent" used in the present invention is selected
form NjN^dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC),
carbonyldiimidazole (CDI), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(EDC.HC1), HATU, alkyl or aryl chloroformates such as ethyl chloroformate,
benzylchloroformate, DPPA, thionyl chloride, pivalyl chloride, oxalyl chloride, phosphorous
oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl),
benzotriazol-1 -yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), methane
sulfonyl chloride and the like; optionally in combination with l-hydroxy-7-azatriazole (HOAt),
1-hydroxybenzotriazole (HOBt), l-hydroxy-lH-l,2,3-triazole-4-carboxylate (HOCt), TBTU, N-
hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS), 4-
dimethylaminopyridine (DMAP).
The term "amine protecting group (or) N-protecting group" used in the present invention is selected from but not limited to tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxy carbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4-dimethoxy benzyl (DMPM), tosyl (Ts), trifluoroacetyl (TFA) group and the like.
The suitable amine protecting agent is selected such that it is capable of protecting the nitrogen atom with any of the above mentioned amine protecting groups.
Suitable amine protecting agent is selected from but not limited to di-tert.butyl dicarbonate (DIBOC), benzyl chloroformate, fluorenylmethyloxy carbonyl chloride (FMOC chloride), acetyl chloride, acetic anhydride, benzoyl halides, benzyl halides, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid, trifluoroacetyl chloride and the like.

The term "deprotecting agent" used in the present invention is selected based on the protecting group employed. The deprotecting agent is selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates, ammonia, ammonium cerium(IV) nitrate (CAN); and organic bases such as methylamine, ethylamine, diethylamine, triethylamine, piperidine; hydrogenating agents such as Pd/C, Pd(OH)2/C (Pearlman's catalyst), palladium acetate, platinum oxide, platinum black, sodium borohydride, Na-liquid ammonia, Raney-Ni, tri(Ci-C6)alkylsilanes, tri(Ci-C6)alkylsilyl halides and the like.
The term "reducing agent" used in the present invention refers to palladium catalyst, such as selected from: palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate, palladium on silica, and palladium hydroxide on carbon (Pearlman's catalyst), Pt/C, Pt02, Fe, Fe in acidic media like acetic acid, NH4C1; Sn-HCl, Stannous chloride (SnCfe), Zn in acidic media like acetic acid, NH4CI, Zinc dust, Ni, Raney Ni, Lithium aluminium hydride, sodium borohydride, potassium borohydride, lithium borohydride, sodium aluminium hydride. Optionally, the product is contacted with a strong inorganic or organic acid prior to conducting the hydrogenation. The acid is selected from hydrochloric, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, oxalic acid, tartaric acid, citric acid, malic acid, benzoic acid, 4-nitrobenzoic acid, methanesulfonic acid, trifluoromethane sulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid and 4-toluenesulfonic acid.
The term "antioxidant" used in the present invention is used to inhibit the formation of N-
oxide impurity and is selected from thiols, ascorbic acid; preferably L-ascorbic acid.
The first aspect of the present invention provides a novel process for the preparation of 1 >Thiazol-5-ylmethyl[(2R^
carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-l,6-diphenylhexan-2-yl]carbamate compound of formula-1 comprising of:
a) Reacting L-methionine with bromoacetic acid in presence of a suitable acid in a suitable

solvent to provide (S)-3-aminodihydrofuran-2(3H)-one compound of formula-3 or its salts,
b) condensing the compound of formula-3 or its salts with the l-(2-isopropylthiazol-4-yl)-N-methylmethanamine compound of formula-2 or its salts in presence of a suitable condensing agent in a suitable solvent to provide (S)-l-((2-isopropylthiazol-4-yl)methyl)-l-methyl-3-(2-oxotetrahydrofiiran-3-yl)urea compound of formula-4,
c) treating the compound of formula-4 with a suitable halogenating agent in an alcohol solvent and optionally in a mixture of other solvent followed by reacting the obtained compound with morpholine to provide a corresponding ester compound of general formula-5,
d) optionally converting the compound of general formula-5 into its acid addition salts of compound of general formula-6,
e) reacting the compound of general formula-S or formula-6 with a suitable base in a suitable solvent to provide compound of general formula-7,
which on in-situ condensing with the compound of general formula-8 or its salts
in presence of a suitable condensing agent in a suitable solvent to provide the compound
of general formula-9
which on in-situ treating with a suitable deprotecting agent in a suitable solvent to
provide compound of formula-10,
f) optionally converting the compound of formula-10 into its acid addition salts to provide the compound of general formula-11,
g) optionally treating the compound of general formula-11 with a suitable base in a suitable solvent to provide compound of formula-10,
h) reacting the compound of formula-10 with the compound of general formula-13 in
presence of a base in a suitable solvent and optionally in presence of a suitable
antioxidant to provide the compound of formula-1, i) optionally purifying the compound of formula-1 from a suitable solvent to provide pure
compound of formula-1.
The preferred embodiment of the present invention provides a novel process for the preparation of l,3-Thiazol-5-ylmethyl[(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)-l,3-

thiazol-4-yl]methyl} carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-l,6-diphenylhexan-2-yl]carbamate compound of formula-1 comprising of:
a) Reacting L-methionine with bromoacetic acid in presence of acetic acid in the mixture of isopropanol and water to provide (S)-3-aminodihydrofuran-2(3H)-one compound of formula-3, further it is treating with isopropanolic-HCl in isopropanol to provide (S)-3-aminodihydrofuran-2(3H)-one hydrochloride compound of formula-3a,
b) condensing the compound of formula-3 a with the 1 -(2-isopropylthiazol-4-yl)-N-methylmethanamine dihydrochloride compound of formula-2a in presence of CDI and triethyl amine in dichloromethane to provide (S)-l-((2-isopropylthiazol-4-yl)methyl)-l-methyl-3-(2-oxotetrahydrofuran-3-yl)urea compound of formula-4,
c) treating the compound of formula-4 with sodium bromide and trimethyl silylchloride in methanol and followed by reacting the obtained compound with morpholine to provide a the compound of formula-5a,
d) treating the compound of formula-5a in-situ with oxalic acid to provide the compound of formula-6a,
e) basifying the compound of formula-6a using aqueous sodium bicarbonate solution and treating the obtained compound with aqueous potassium carbonate solution in dichloromethane to provide compound of formula-7a,
f) condensing the compound of formula-7a in-situ with the compound of formula-8ai in presence of EDC.HC1, HOBT and diisopropyl ethylamine to provide the compound of formula-9a,
g) treating the compound of formula-9a in-situ with hydrochloric acid in dichloromethane followed by treating with aqueous potassium carbonate solution to provide the compound of formula-10,
h) reacting the compound of formula-10 with the 4-nitrophenyl thiazol-5-ylmethyl carbonate compound of formula-13a in presence of diisopropyl ethyl amine in isopropanol to provide the compound of formula-1.
The above aspect of the present invention is schematically represented as follows: Scheme-1

Further the compound of formula-1 obtained above is converted to a solid dispersion of cobicistat with silicondioxide, comprising of:

a) Dissolving the cobicistat compound of formula-1 in a suitable solvent,
b) adding silicon dioxide to the reaction mixture of step-a)
c) distilling the solvent from the reaction mixture,
d) adding a second solvent to the obtained compound in step-c),
e) isolating the solid dispersion of cobicistat with silicondioxide.
Wherein in step-a) a suitable solvent is selected from chloro solvents, preferably
dichloromethane;
In step-d) the suitable second solvent is selected from hydrocarbon solvents; preferably
hexane, heptane;
In step-e) isolating refers to the solvent removing by known techniques such as filtering,
decanting or distilling.
Intermediate compounds of the present invention can be converted into their acid addition salts.
The second aspect of the present invention provides an improved process for the
preparation of the compound of general formula-13 comprising of; reacting the thiazol-5-yl-
methanol compound of formula-12 with a suitable alkyl or aryl haloformate in presence of a
suitable base in a suitable solvent to provide the compound of general formula-12.
Wherein the alkyl or aryl haloformate are selected from methyl chloroformate, ethyl chloroformate, phenyl chloroformate, benzyl chloroformate; suitable base and suitable solvent are same as defined above.
The third aspect of the present invention provides a novel intermediate compound of the general formula-8 or their salts,
wherein Pi, P2 are individually selected from H or amine protecting group with the proviso that Pi and P2 both are not SH'.
Preferred embodiment of the present invention provides a crystalline tert-butyl (2R, 5R)-5-amino-l,6~diphenylhexan-2-yl-carbamate hydrochloride compound of formula-8ai, herein after designated as crystalline form-M and which is characterized by:

Its powder X-Ray diffractogram having peaks at 6.14, 9.91, 16.20, 18.16, 18.52, 19.73, 22.15, 23.92± 0.2 degrees of two theta and PXRD pattern is same as depicted in figure-1;
Its DSC thermogram showing an endotherm at 218.38°C as illustrated in figure-2.
The fourth aspect of the present invention provides a process for the preparation of the 5 compound of the general formula-8 or their salts, comprising of; treating the compound of formula-15 or its free base compound of formula-14
r ui mum-1 J
wherein the acid is selected from inorganic acids, organic acids or chiral acids; with suitable amino-protecting agents optionally in presence of a suitable base in a suitable solvent to provide the compound of general formula-8 or their salts, optionally purifying the compound of formula-8 or their salts.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of tert-butyl (2R, 5R)-5-amino-l,6-diphenylhexan-2-yl-carbamate hydrochloride, comprising of:
a) Treating the (2R, 5R)-l,6-diphenylhexane-2,5-diamine dihydrochloride with DIBOC in presence of triethyl amine in methanol to provide the tert-butyl (2R, 5R)-5-amino-l,6-diphenylhexan-2-yl-carbamate;
b) treating the obtained compound with ethyl acetate-HCl in ethyl acetate to provide the compound of formula-8aj;
c) purifying the obtained compound in the mixture of ethyl acetate and water to provide the compound of formula-8ai.
The compound of formula-8 or their salts obtained from the present invention are useful in the preparation of the compound of formula-1. HPLC Method of Analysis: a) Cobicistat and its related substances were analyzed by HPLC with the following
chromatographic conditions: Apparatus: A liquid chromatograph is equipped with variable wavelength UV Detector. Column:
12

Zobrax bonus RP, 250 x 4.6 mm, 5 \xm (or) Equivalent; Wavelength: 235 nm; Column temperature: 30°C; Injection volume: 20 |iL; Diluent: Methanol & Water; Needle wash: Diluent; Elution: Gradient; Buffer: Transfer accurately 1.0 mL of perchloric acid into a 1000 mL of milli-Q-water, mix well and adjust pH=2.8 with diluted NaOH solution. Mobile phase-A: Buffer; Mobile phase-B: Acetonitrile:Methanol:Buffer [75:5:20 v/v/v]
b) Tert-butyl (2R, 5R)-5-amino-1,6-diphenylhexan-2-yl-carbamate hydrochloride and its
related substances were analyzed by HPLC with the following chromatographic conditions:
Apparatus: A liquid chromatograph is equipped with variable wavelength UV Detector. Column: Zobrax bonus RP, 250 x 4.6 mm, 5 |im (or) Equivalent; Wavelength: 215 nm; Column temperature: 40°C; Injection volume: 10 \iL; Diluent: Acetonitrile & Water; Needle wash: Diluent; Elution: Gradient; Buffer: First filter lOOOmL of milli-Q-water then add l.OmL of perchloric acid and mix well. Mobile phase-A: Buffer; Mobile phase-B: Acetonitrile:Methanol:Buffer [75:20:5 v/v/v]
c) (S)-N-((2R,5R)-5-amino-l,6-diphenylhexan-2-yl)-2-(3-((2-isopropylthiazol-4-yl)methyl)-3-
methylureido)-4-morpholinobutanamide and its related substances were analyzed by HPLC
with the following chromatographic conditions:
Apparatus: A liquid chromatograph is equipped with variable wavelength UV Detector. Column:
Unison UK C18 UP, 100 x 2 mm, 3 |im (or) Equivalent; Wavelength: 215 nm; Column
temperature: 40°C; Injection volume: 2 |aL; Diluent: 0.1% HC104 in milli-Q-water:Methanol
(1:1 v/v); Needle wash: Methanol; Elution: Gradient; Buffer: Weigh and transfer accurately 1.0
gm of 1-octane sulphonic acid sodium sit anhydrous in to a lOOOmL of milli-Q-water, mix well
and filter. Then add lmL of perchloric acid and mix well.
Mobile phase-A: Buffer; Mobile phase-B: Acetonitrile:Buffer:Methanol [75:20:5 v/v/v]
Chiral HPLC Method of Analysis:
a) Cobicistat analyzed by Chiral Purity by HPLC with the following chromatographic
conditions: Apparatus: A liquid chromatograph is equipped with variable wavelength UV Detector. Column: Chiral Pack IA-3, 250 x 4.6 mm, 3 jam (or) Equivalent; Wavelength: 235 nm; Column temperature: 35°C; Injection volume: 20 jaL; Diluent: Mobile phase; Needle wash: Diluent; Elution: Isocratic; Mobile phase: n-hexane:MTBE:Ethanol:Dichloromethane:l-

propanol:Trifluoro acetic acid:Ethanolamine [65:15:10:5:5:0.1:0.2 v/v/v/v/v/v/v]
b) Tert-butyl (2R, 5R)-5-amino-1,6-diphenylhexan-2-yl-carbamate hydrochloride by chiral
purity with the following conditions: Apparatus: A liquid chromatograph is equipped with variable wavelength UV Detector. Column: Chiral Pack IC-3, 250 x 4.6 mm (or) Equivalent; Wavelength: 215 nm; Column temperature: 30°C; Injection volume: 15 \xL\ Diluent: Solution-A:Solution-B (75:25 v/v); Needle wash: Methanol; Elution: Isocratic;
Solution-A: n-hexane; Solution-B: Isopropanol:l-Propanol:Isopropylamine (600:400:2 v/v/v). Mobile phase: Solution-A:Splution-B (90:10 v/v)-Premix
The following impurities are observed during the preparation of Cobicistat as per the present invention:
The process for the preparation of the compound of formula-14 or formula-15 of the present invention is schematically represented as follows:

wnerein n, rz are inaiviauauy seieccea irom n or amine protecting group wim me proviso main ana rz oomare noi n
Examples:
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.
Example-1: Preparation of (S)-3-aminodihydrofuran-2(3H)-one hydrobromide compound of formula-3a:
A solution of L-methionine (50 gm) and water (75 ml) was added to a mixture of 2-bromoacetic acid (49.8 gm), isopropanol (95.4 ml) and acetic acid (71.5 ml) at 25-30°C. The reaction mixture was heated to 90-95°C and stirred for 18 hrs at the same temperature. Distilled off the solvent completely under reduced pressure and co-distilled with isopropanol. Isopropanol (63.7 ml) and IPA.HC1 (111 ml) were added to the obtained compound at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 5 hours at the same temperature. Cooled the reaction mixture to 20-25 °C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed twice with isopropanol and dried to get the title compound. Yield: 38.5 gm.
i r

Example-2:Preparation of (S)-3-aminodihydrofuran-2(3H)-one hydrobromide[formula-3a]
A solution of L-methionine (100 gm) and water (150 ml) was added to a mixture of 2-bromoacetic acid (100 gm), isopropanol (200 ml) and acetic acid (150 ml) at 25-30°C. The reaction mixture was heated to 95-100°C and stirred for 5 hrs at the same temperature. Distilled off the solvent completely under reduced pressure and co-distilled with isopropanol. Isopropanol (450 ml) and IPA.HC1 (200 ml) were added to the obtained compound at 25-30°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound. Yield: 80 gm; M.R.: 222-225°C; SOR: [a]20D=(-)l 9.767° (C=l in H20, UV 589nm)
Example-3: Preparation of (S)-l-((2-isopropylthiazol-4-yl)methyl)-l-methyl-3-(2-oxotetra hydrofuran-3-yl)urea compound of formula-4:
Carbonyldiimidazole (46.7 gm) and diisopropyl ethyl amine (106 gm) were added to a mixture of (S)-3-aminodihydrofuran-2-(3H)-one hydrobromide (50 gm) and dichloromethane (1000 ml) at 25-30°C under nitrogen atmosphere. The reaction mixture was cooled to 15-20°C and stirred for 10 hours at 15-20°C. l-(2-isopropyl thiazol-4-yl)-N-methylmethanamine dihydrochloride (66.8 gm) was added to the reaction mixture at 15-20°C and stirred for 12 hours at the same temperature. The temperature of the reaction mixture was raised to 25-30°C. Water was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Organic layer was washed with 20% citric acid solution followed by washed with aq. sodium bicarbonate solution. Distilled off the solvent from the organic layer under reduced pressure to get the title compound. Yield: 71 gm. Example-4: Preparation of (S)-l-((2-isopropylthiazol-4-yl)methyl)-l-methyl-3-(2-oxotetra hydrofuran-3-yl)urea compound of formula-4:
A mixture of (S)-3-aminodihydrofuran-2-(3H)-one hydrobromide (100 gm) and dichloromethane (550 ml) was cooled to 0-5°C under nitrogen atmosphere. Carbonyldiimidazole (100 gm) followed by triethylamine (49 gm) was slowly added to the reaction mixture at 0-5°C and stirred it for 3 hrs the same temperature. 1 -(2-isopropyl thiazol-4-yl)-N-methylmethanamine dihydrochloride (108.7 gm) followed by triethylamine (100 gm) was slowly added to the reaction mixture at 0-5°C. The temperature of the reaction mixture was raised to 25-30°C and stirred for 6 hrs at the same temperature. Water was added to the reaction mixture at 25-30°C and stirred for

15 minutes at the same temperature. Both the organic and aqueous layers were separated. Organic layer was washed with 20% acetic acid solution followed by washed with aqueous sodium bicarbonate solution and further washed with water. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 150 gm; HPLC ■ Purity: 95.04%; Chiral purity: 99.46%, R- isomer: 0.54%.
Example-5: Preparation of (S)-methyl-2-(3-((2-isopropylthiazol-4-yl)methyl)-3-methyl ureido)-4-morpholinobutanoate oxalate compound of formula-6a:
Methanol (48 ml) was added to a mixture of (S)-l-((2-isopropylthiazol-4-yl)methyl)-l-methyl-3-(2-oxotetrahydrofuran-3-yl)urea (40 gm) and dichloromethane (200 ml) at 25-30°C. Sodium iodide (70.29 gm) was added to the reaction mixture at 25-30°C and cooled it to 0-5°C. Trimethyl silyl chloride (67 gm) was slowly added to the reaction mixture at 0-5°C. Temperature of the reaction mixture was raised to 20-25°C and stirred for 6 hrs at 20-25°C. Cooled the reaction mixture to 0-5°C. Morpholine (117.5 ml) was slowly added to the reaction mixture at 0-5°C and temperature of the reaction mixture was raised to 20-25°C. Stirred the reaction mixture for 12 hrs at 20-25°C. Filtered the reaction mixture and washed with dichloromethane. Distilled off the solvent from the filtrate completely under reduced pressure and co-distilled with ethyl acetate. Ethyl acetate (200 ml) was added to the obtained compound and stirred at 25-30°C for 20 minutes. A solution of Oxalic acid (25.4 gm) dissolved in acetone (200 ml) was added to the reaction mixture at 25-30°C and stirred for 3 hrs at the same temperature. The obtained solid was filtered, washed with the mixture of ethyl acetate and acetone and dried to get the title compound. Yield: 67.71 gm.
Example-6: Preparation of (S)-methyl-2-(3-((2-isopropylthiazol-4-yl)methyl)-3-methyl ureido)-4-morpholinobutanoate oxalate [formula-6a(R=CH3,Acid=Oxalic acid)]: Sodium bromide (173 gm) was added to a mixture of (S)-l-((2-isopropylthiazol-4-yl)methyl)-l-methyl-3-(2-oxotetrahydrofuran-3-yl)urea (100 gm), methanol (120 ml) and dichloromethane (1000 ml) at 25-30°C under nitrogen atmosphere. Trimethyl silyl chloride (182.6 gm) was slowly added to the reaction mixture at 25-30°C and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 0-5°C. Morpholine (293 ml) was slowly added to the reaction mixture at 0-5°C and temperature of the reaction mixture was raised to 25-30°C. Stirred the reaction mixture for 12 hrs at 25-30°C. Filtered the reaction mixture and washed with

dichloromethane. Water was added to the filtrate and stirred for 20 minutes. Both the organic and aqueous layers were separated. Organic layer was washed with water followed by washed with aqueous sodium bicarbonate solution. Distilled off the solvent from the organic layer completely under reduced pressure and co-distilled with isopropanol. Isopropanol (400 ml) was added to the obtained compound and stirred for 20 minutes at 25-30°C. A solution of Oxalic acid (42.4 gm) dissolved in isopropanol (600 ml) was added to the reaction mixture at 25-30°C and stirred for 3 hrs at the same temperature. The obtained solid was filtered, washed with isopropanol and dried to get the title compound. Yield: 80.5 gm; M.R.: 130-135°C; HPLC Purity: 98.40%; Chiral purity: 99.27%, R- isomer: 0.73%.
Example-7:Preparation of 6-methoxy-6-oxohexanoicacid compoundofformula-23a(R=CH3) Conc.HCl (8.6 ml) was added to a mixture of adipic acid compound of formula-22 (100 gm) and methanol (27.7 ml) at 25-30°C. The reaction mixture was heated to 80-85°C and stirred for 8 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Toluene (100 ml) was added to the reaction mixture and stirred for 45 minutes at 25-30°C. Filtered the reaction mixture and washed with toluene. Water was added to the filtrate. Basifying the reaction mixture with aqueous sodium carbonate solution. Both the organic and aqueous layers were separated and aqueous layer was washed with toluene. Dichloromethane was added to the aqueous layer. Acidifying the reaction mixture using Conc.HCl. Both the organic and aqueous layers were separated. Aqueous layer was extracted with dichloromethane and distilled off the solvent from the organic layer completely under reduced pressure to get the title compound; Yield: 109.6 gm. Example-8: Preparation of (S)-methyl-6-oxo-6-(2-oxo-4-phenyloxazolidin-3-yl)hexanoate compound of formula-24a (R=CH3, R2 =Ph)
(S)-4-phenyloxazolidin-2-one compound of formula-17a (33.86 gm) and DMAP (2.77 gm) was added to a mixture of 6-methoxy-6-oxohexanoic acid (35 gm) and dichloromethane (175 ml) at 25-30°C. DCC (54.13 gm) was slowly added to the reaction mixture at 25-30°C and stirred the reaction mixture for 5 hrs at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 60 minutes at the same temperature. The obtained unwanted solid was filtered. Washed the filtrate with 5% dilute HC1 solution, followed by with water. Further washed the organic layer with 5% aqueous sodium carbonate solution followed by with water. Distilled off the solvent from the organic layer completely under reduced pressure. Pet ether was added to the

obtained compound at 25-30°C and stirred for 2 hrs at 25-30°C. The obtained solid was filtered, washed with pet ether and dried to get the title compound. Yield: 66.7 gm. ExampIe-9: Preparation of (S)-6-oxo-6-(2-oxo-4-phenyloxazoUdin-3-yl)hexanoic acid compound of formula-29a (R2 =Ph)
A mixture of (S)-methyl-6-oxo-6-(2-oxo-4-phenyIoxazolidin-3-yl)hexanoate (15 gm) and acetonitrile (75 ml) was cooled to 0-5°C. Conc.HCl (45 ml) was slowly added to the reaction mixture, raised the temperature to 25-30°C and stirred for 24 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture. Cooled the reaction mixture to 25-30°C, added water and ethyl acetate. Basifying the reaction mixture using 20% aqueous sodium carbonate solution. Both the organic and aqueous layers were separated and aqueous layer was washed with ethyl acetate. Ethyl acetate was added to the aqueous layer and acidifying the reaction mixture using Conc.HCl and separated the layers. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 14.3 gm Example-10: Preparation of l,6-bis((S)-2-oxo-4-phenyloxazolidin-3-yl)hexane-l,6-dione compound of formula-30a (R2 =Ph)
(S)-4-phenyloxazolidin-2-one (5.32 gm) and DMAP (0.44 gm) were added to a mixture of (S)-6-oxo-6-(2-oxo-4-phenyloxazolidin-3-yl)hexanoic acid (10 gm) and dichloromethane (50 ml) at 25-30°C. DCC (9.2 gm) was slowly added to the reaction mixture at 25-30°C and stirred the reaction mixture for 5 hrs at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 60 minutes at the same temperature. The obtained unwanted solid was filtered. Washed the filtrate with 5% dilute HC1 solution, followed by with water. Further washed the organic layer with 5% aqueous sodium carbonate solution followed by with water. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 14.9 gm.
Example-11: Preparation of (2R, 5R)-2,5-dibenzyl-l,6-bis((S)-2-oxo-4-phenyloxazolidin-3-yl)hexane-l,6-dione compound of formula-19a (R2 =Ph)
A mixture of l,6-bis((S)-2-oxo-4-phenyloxazolidin-3-yl)hexane-l,6-dione (5 gm) and tetrahydrofuran (25ml) was cooled to -75°C to -70°C and NaHMDS (4.2 gm) was slowly added to the above reaction mixture. Stirred the reaction mixture for 30 minutes at the same temperature. Benzyl bromide (3.92 gm) in tetrahydrofuran (5 ml) was slowly added to the

reaction mixture at -75°C to -70°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 4 hrs at the same temperature. Cooled the reaction mixture to 0-5 °C and quenched with aqueous ammonium chloride solution. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium chloride solution and distilled off the solvent under reduced pressure to get the title compound. Yield: 7.09 gm. Example-12: Preparation of (2R,5R)-2,5-dibenzylhexanedioicacid compound of formula-20 A mixture of (2R, 5R)-2,5-dibenzyl-l,6-bis((S)-2-oxo-4-phenyloxazolidin-3-yl)hexane-l56-dione (10 gm) and tetrahydrofuran (70 ml) was stirred at 0-5°C for 15 minutes. Hydrogen peroxide in water (2.48 gm) was added to the reaction mixture at 0-5°C. Lithium hydroxide monohydrate (1.36 gm) was slowly added to the reaction mixture at 0-5°C and stirred for 2 hrs at the same temperature. Quenched the reaction mixture with aqueous sodium sulfite solution. Raised the temperature of the reaction mixture to 25-30°C. The reaction mixture was washed with dichloromethane. Acidifying the reaction mixture with dilute HC1 at 25-30°C. Ethyl acetate was added to the reaction mixture and stirred for 10 minutes. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Distilled off the solvent completely under reduced pressure to get the title compound. Yield: 5.29 gm Example-13: Preparation of (2R, 5R)-l,6-diphenylhexane-2,5-diamine mandelate compound of formula-15a (Acid=Mandelic acid)
A mixture of (2R, 5R)-2,5-dibenzylhexanedioic acid (5gm), acetone (45 ml) and water (5 ml) was cooled to 0-5°C. Triethylamine (6.75 gm) and ethyl chloroformate (7.64 gm) was slowly added to the reaction mixture at 0-5°C. Stirred the reaction mixture for 1 1/2 hours at the same temperature. A solution of Sodium azide (4.9 gm) dissolved in water were slowly added to the reaction mixture at 0-5°C and stirred the reaction mixture for 3 hours at the same temperature. Toluene and water was added to the reaction mixture. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Heated the organic layer to 100-105°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Cone. HC1 (21 ml) mixed with water (14 ml) was added to the reaction mixture. Heated the reaction mixture to 85-90°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was washed with toluene. Basifying the

reaction mixture with aqueous sodium hydroxide solution. Ethyl acetate was added to the reaction mixture. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution and distilled off the solvent completely from organic layer under reduced pressure. The residue obtained was dissolved in ethyl acetate. L(+) Madelic acid (2.32 gm) dissolved in ethyl acetate was slowly added to the reaction mixture at 20-25°C and stirred for 6 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 3.0 gm.
Example-14: Preparation of Tert-butyl (2R, 5R)-5-amino-l,6-diphenylhexan-2-yl-carbamate compound of formula-8a (Pi=H, P2=BOC)
A mixture of (2R, 5R)-l,6-diphenylhexane-2,5-diamine-24iydroxy-2-phenylacetate (10 gm), dichloromethane (100 ml) and water (50 ml) was cooled to 5-10°C. Basifying the reaction mixture with aqueous potassium carbonate solution. The reaction mixture was stirred for 30 minutes at 5-10°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. The organic layer was washed with water and dried over sodium sulphate. Triethylamine (4.97 ml) and DiBOC (2.59 gm) were added to the organic layer at 25-30°C and stirred for 4 hrs at the same temperature. Water was added to the reaction mixture and stirred for 30 minutes at 25-30°C. Both the organic and aqueous layers were separated and the organic layer was washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure to get the title compound. Yield: 10.79 gm. Example-15: Preparation of Tert-butyl (2R, 5R)-5-amino-l,6-diphenylhexan-2-yl-carbamate hydrochloride compound of formula-8ai
Triethyl amine (29.64 gm) was slowly added to a mixture of (2R, 5R)-1,6-diphenylhexane-2,5-diamine dihydrochloride (100 gm), methanol (600 ml) at 25-30°C and stirred for 10 minutes. A solution of DiBOC (57.35 gm) in methanol (50 ml) was added to the above reaction mixture at 25-30°C and stirred for 3 hrs. Dichloromethane followed by water was added to the reaction mixture and stirred for 15 minutes at 25-30°C. Both the organic and aqueous layers were separated and the organic layer was washed water. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with ethyl acetate. Ethyl acetate (600 ml) was added to the obtained compound and cooled to 5-10°C. Ethyl acetate-

HC1 (100 ml) was slowly added to the reaction mixture at 5-10°C and stirred it for 3 hrs. Filtered the precipitated solid and washed with ethyl acetate. The obtained compound was slurried in the mixture of water and ethyl acetate. Filtered solid and washed with ethyl acetate and dried to get the title compound. Yield: 60.5 gm; M.R..: 217-219°C, HPLC Purity: 99.65%; Chiral purity: 99.98%, S,S- isomer: 0.02%; PXRD pattern of the obtained compound is illustrated in figure-1 and its DSC in figure-2.
Example-16: Preparation of (S)-N-((2R,5R)-5-amino-l,6-diphenylhexan-2-yl)-2-(3-((2-isopropylthiazol-4-yl)methyl)-3-methylureido)-4-morpholinobutanamide hydrochloride
Water (50 ml) was added to a mixture of (S)-methyl-2-(3-((2-isopropylthiazol-4-yl)methyl)-3-methylureido)-4-morpholinobutanoate oxalate (13,25 gm) and dichloromethane (100 ml) at 25-30°C. Cooled the reaction mixture to 10-15°C. Basifying the reaction mixture with aqueous sodium bicarbonate solution. The reaction mixture was stirred for 30 minutes at 10-15°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulphate and distilled off the solvent completely under reduced pressure. Ethanol (50 ml) was added the above obtained compound at 25-30°C and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 5-10°C. A solution of potassium hydroxide (2.57 gm) dissolved in water was slowly added to the reaction mixture at 5-10°C and stirred for 3 hrs at the same temperature. Distilled off the solvent completely under reduced pressure and co-distilled with dichloromethane. Dichloromethane was added to the obtained compound and stirred for 15 minutes at 25-30°C. Tert-butyl (2R, 5R)-5-amino-l,6-diphenylhexan-2-yl-carbamate (10 gm) in dichloromethane, HOBT (4.4 gm), EDC.HC1 (7.7 gm) and diisopropylethylamine (7 ml) were added to the reaction mixture at 25-30°C and stirred for 18 hrs at the same temperature. Water was added to the reaction mixture and stirred for 30 minutes at 25-30°C. Both the organic and aqueous layers were separated and the organic layer was washed with water and aqueous citric acid solution. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate was added to the obtained compound and cooled to 5-10°C. Conc.HCl was slowly added to the reaction mixture at 5-10°C. Raised the temperature of the reation mixture to 25-30°C and stirred for 3 hrs at the same temperature. Water was added to the reaction mixture and stirred for 20 minutes at 25-30°C. Both the organic

and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with aqueous sodium carbonate solution followed by with aqueous sodium chloride solution and cooled the organic layer to 5-10°C. Acidifying the reaction mixture with ethyl acetate.HCl solution and stirred for 4 hrs at 5-10°C- Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 18.21 gm. Example-17: Preparation of (S)-N-((2R,5R)-5-amino-l,6-diphenylhexan-2-yl)-2-(3-((2-isopropylthiazol-4-yl)methyl)-3-methylureido)-4-morpholinobutanamide
Water (250 ml) was added to a mixture of (S)-methyl-2-(3-((2-isopropylthiazol-4-yl)methyl)-3-methylureido)-4-morpholinobutanoate oxalate (90.5 gm) and dichloromethane (500 ml) at 25-30°C. Cooled the reaction mixture to 10-15°C. Basifying the reaction mixture with aqueous sodium bicarbonate solution. The reaction mixture was stirred for 30 minutes at 10-15°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with water and distilled off the solvent completely under reduced pressure. Dichloromethane (150 ml) was added the above obtained compound at 25-30°C and cooled the reaction mixture to 5-10°C. A solution of potassium hydroxide (15.8 gm) dissolved in 18 ml of water was slowly added to the reaction mixture at 5-10°C and stirred for 5 hrs at the same temperature. Dichloromethane (500 ml) was added to the reaction mixture at 5-10°C and cooled to 0-5°C. Tert-butyl (2R, 5R)-5-amino-l,6-diphenylhexan-2-yl-carbamate hydrochloride (50 gm) and diisopropylethylamine (36.5 ml) were added to the reaction mixture at 0-5°C and stirred for 60 minutes at the same temperature. HOBT (23.35 gm) was added to the above reaction mixture at 0-5°C and stirred for 60 minutes at the same temperature. A solution of EDC.HC1 (40.2 gm) in 500 ml of dichloromethane was slowly added to the above reaction mixture at 0-5 °C. Raised the temperature of the reaction mixture to 5-10°C and stirred for 12 hrs at the same temperature. Water was added to the reaction mixture and stirred for 30 minutes at 5-10°C. Both the organic and aqueous layers were separated and the organic layer was washed with aqueous potassium carbonate solution and followed by water. Cooled the organic layer to 0-5°C and hydrochloric acid (300 ml) was slowly added to the reaction mixture at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 6 hrs at the same temperature. Separated both the organic and aqueous layers and extracted the product using water from the organic layer. Combined the aqueous

layers and washed the aqueous layer with dichloromethane. Dichloromethane was added to the aqueous layer and cooled to 0-5°C. Basified the reaction mixture using aqueous potassium carbonate solution and stirred for 30 minutes at the same temperature. Both the organic and aqueous layers were separated and aqueous layer was extracted with dichloromethane. Combined the organic layers at 25-30°C and washed with water followed by with aqueous citric acid solution and then washed with water. Distilled off the solvent completely from the organic layer under reduced pressure and get the title compound. Yield: 95 gm; HPLC Purity: 96.74%. Example-18: Preparation of 4-nitrophenyl thiazol-5-ylmethyl carbonate compound of formula-13a [R=4-nitrophenyl]
100 gm of thiazol-5-yl methanol was dissolved in 850 ml of dichloromethane at 25-30°C. Triethylamine (151.3 ml) and bis(4-nitrophenyl)carbonate (264.2 gm) was added to the reaction mixture and stirred the reaction mixture for 3 hrs at 25-30°C. Water was added to the reaction mixture and stirred for 20 minutes. Separated both the aqueous and organic layers. 30% aqueous sodium carbonate solution was added to the organic layer and stirred the reaction mixture. Filtered the obtained byproduct and washed with dichloromethane. Separated both the aqueous and organic layers from the filtrate. The organic layer was washed with water followed by aqueous sodium chloride solution. Distilled off the solvent from the organic layer and co-distilled with isopropanol. Isopropanol (200 ml) was added to the obtained compound and stirred the reaction mixture for 2 hrs at 25-30°C. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 135.5 gm; M.R: 80-83°C; Purity by HPLC: 99.53%. Example-19: Preparation of Cobicistat compound of formula-1
Water (2.5 ml) was added to a mixture of (S)-N-((2R,5R)-5-amino-l,6-diphenylhexan-2-yl)-2-(3-((2«isopropylthiazol-4-yl)methyl)-3-methylureido)-4-morpholinobutanamide hydrochloride (0.25 gm) and dichloromethane (2.5 ml). Cooled the reaction mixture to 5-10°C. Basifying the reaction mixture with aqueous sodium carbonate solution and stirred for 20 minutes at 5-10°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. The organic layer was washed with water. 4-nitrophenyl thiazol-5-ylmethyl carbonate (0.08 gm) and diisopropylethylamine (0.097 ml) were added to the organic layer at 25-30°C and stirred for 15 hrs at the same temperature. Water was added to the reaction mixture and stirred for 20 minutes at 25-30°C. Both the organic and aqueous layers were separated. Organic

layer was washed with aqueous sodium carbonate solution and followed by with 5% aqueous citric acid solution. Cooled the organic layer to 5-10°C. Acidifying the reaction mixture with 20% aqueous citric acid solution. Separated both the organic and aqueous layers. Basifying the reaction mixture with aqueous sodium carbonate solution. Dichloromethane was added to it and separated both the organic and aqueous layers. The aqueous layer was extracted with dichloromethane and combined the organic layers. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 0.29 gm. Example-20: Preparation of cobicistat of the compound of formula-l (S)-N-((2R55R)-5-ammo-1 ^
methylureido)-4-morpholinobutanamide (2 gm) was dissolved in isopropanol (10 ml). Diisopropyl ethylamine (0.54 gm), L-ascorbic acid (0.055 gm) and 4-nitrophenyl thiazol-5-ylmethyl carbonate (0.79 gm) were slowly added to the above reaction mixture at 25-30°C and stirred it for 18 hrs at the same temperature. Water was added to the reaction mixture and stirred for 10 minutes at 25-30°C. Acidified the reaction mixture with dilute hydrochloric acid solution and dichloromethane was added to it. Separated both the organic and aqueous layers. Aqueous citric acid solution was added to the organic layer and stirred for 10 minutes. Separated both the organic and aqueous layers. The compound was extracted from organic layer using aqueous citric acid solution. Combined the aqueous layers, dichloromethane was added to the aqueous layer and neutralized the reaction mixture with saturated sodium carbonate solution at 10-15°C. Separated both the organic and aqueous layers. Aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with aqueous sodium carbonate solution. Silicondioxide (3 gm) was added to the organic layer at 20-25°C and stirred the reaction mixture for 30 minutes at the same temperature. Filtered the reaction mixture and washed with dichloromethane. The filtrate was acidified saturated citric acid solution and separated both the organic and aqueous layers. Aqueous layer was washed with dichloromethane at 10-15°C. Dichloromethane was added to aqueous layer at 10-15°C and neutralized the reaction mixture using aqueous sodium carbonate solution and stirred for 20 minutes at the same temperature. Separated both the organic and aqueous layers and the aqueous layer was extracted with dichloromethane. Combined the organic layers, washed with water and distilled off the solvent from the organic layer completely to get the title compound. Yield: 1.2 gm

Example-21: Preparation of solid dispersion of Cobicistat with silicondioxide
(S)-N-((2R,5R)-5-amino-l,6-dipte^
methylureido)-4-morpholinobutanamide (50 gm) was dissolved in isopropanol (200 ml) and cooled to 10-15°C. Diisopropyl ethylamine (10.2 gm), L-ascorbic acid (1.38 gm) and 4-nitrophenyl thiazol-5-ylmethyl carbonate (17.6 gm) were added to the above reaction mixture at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred it for 18 hrs at the same temperature. Water was added to the reaction mixture and stirred for 10 minutes at 25-30°C. Acidified the reaction mixture with dilute hydrochloric acid solution and dichloromethane was added to it. Separated both the organic and aqueous layers. Aqueous citric acid solution was added to the organic layer and stirred for 10 minutes. Separated both the organic and aqueous layers. The compound was extracted from organic layer using aqueous citric acid solution. Combined the aqueous layers, dichloromethane was added to the aqueous layer and neutralized the reaction mixture with saturated sodium carbonate solution at 10-15°C. Separated both the organic and aqueous layers. Organic layer was washed with 5% aqueous citric acid solution and followed by with 5% aqueous sodium carbonate solution. Cooled the organic layer to 10-15°C, silicondioxide (100 gm) was added to the organic layer at 10-15°C and stirred the reaction mixture for 60 minutes at the same temperature. Filtered the reaction mixture and washed with dichloromethane. The filtrate was washed with 5% aqueous citric acid solution. Acidified the organic layer with saturated citric acid solution and separated both the organic and aqueous layers. Aqueous layer was washed with dichloromethane at 10-15°C. Dichloromethane was added to aqueous layer at 10-15°C and neutralized the reaction mixture using aqueous sodium carbonate solution and stirred for 20 minutes at the same temperature. Separated both the organic and aqueous layers and the organic layer was cooled to 10-15°C. Filtered the organic layer through hyflow bed and washed with dichloromethane. Silicon dioxide (25 gm) was added to the filtrate at 5-10°C and distilled off the solvent completely form the reaction mixture under reduced pressure. Co-distilled with n-hexane, 500 ml of n-hexane was added to the obtained compound at 25-30°C and stirred the reaction mixture for 45 minutes. Filtered the obtained solid, washed with n-hexane and dried to get the title compound. Yield: 43 gm. HPLC purity: 99.75%, Chiral Purity: 99.25%, RRR Isomer impurity: 0.75%; Particle size distribution: D10: 19.143 |im, D50: 43.301 ^m, D90: 84.854 jjm.

We claim:
1. A novel process for the preparation of l53-Thiazol-5-ylmethyl[(2R,5R)-5-{[(2S)-2-
[(methyl{[2-(propan-2-yl)-l,3-thiazol-4-yl]methyl} carbamoyl)amino]-4-(morpholin-4-
yl)butanoyl]amino}-l,6-diphenylhexan-2-yl]carbamate compound of formula-1 comprising of:
a) Treating the (S)-l-((2-isopropylthiazol-4-yl)methyl)-l-methyl-3-(2-oxotetrahydro furan-3-yl)urea compound of formula-4with a suitable halogenating agent in a suitable alcohol solvent and optionally in a mixture of other solvent followed by reacting the obtained compound with morpholine to provide a corresponding ester compound of general formula-5,
b) optionally converting the compound of general formula-5 into its acid addition salts of compound of general formula-6,
c) reacting the compound of general formula-5 or formula-6 with a suitable base in a suitable solvent to provide compound of general formula-7,
d) compound of general formula-7 in-situ condensing with the compound of general formula-8 or its salts in presence of a suitable condensing agent in a suitable solvent to provide the compound of general formula-9
e) compound of general formula-9 in-situ treating with a suitable deprotecting agent in a suitable solvent to provide compound of formula-10,
f) optionally converting the compound of formula-10 into its acid addition salts to provide the compound of general formula-11,
g) optionally treating the compound of general formula-11 with a suitable base in a suitable solvent to provide compound of formula-10,
h) reacting the compound of formula-10 with the compound of general formula-13 in

presence of a base in a suitable solvent and optionally in presence of a suitable
antioxidant to provide the compound of formula-1, i) optionally purifying the compound of formula-1 from a suitable solvent to provide pure
compound of formula-1. 5 2. The process according to claim 1, wherein in step-a) a suitable halogenating agent is preferably sodium bromide in combination with trimethylsilyl chloride; a suitable solvent is selected from the mixture of alcohol and dichloromethane;
in step-c) a suitable base is inorganic bases, preferably alkali metal carbonates, alkali metal
bicarbonates, alkali hydroxides;
) in step-d) a suitable condensing agent is selected form DCC, CDI, DIC, EDC.HC1, and the
like; optionally in combination with HOAt, HOBt, HOCt, TBTU, DMAP further in presence of a base;
in step-e) a suitable deprotecting agent is selected from a strong acid; preferably inorganic acid; most preferably hydrochloric acid;
> in step-h) a suitable base selected from inorganic base, organic base; preferably organic base;
most preferably diisopropyl ethylamine; a suitable antioxidant is selected from thiols, ascorbic
acid; preferably L-ascorbic acid.
3. A novel process for the preparation of l,3-Thiazol-5-ylmethyl[(2R,5R)-5-{[(2S)-2-
[(methyl {[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl} carbamoyl)amino]-4-(morpholin-4-
) yl)butanoyl]amino}-l,6-diphenylhexan-2-yl]carbamate compound of formula-1 comprising
of:
a) Reacting the compound of formula-10 with the compound of general formula-13 in presence of a base in a suitable solvent and optionally in presence of antioxidant to provide the compound of formula-1,
> b) optionally purifying the compound of formula-1 from a suitable solvent to provide pure
compound of formula-1.
4. A process for the preparation of the compound of the general formula-8 or their salts,

wherein Pi, P2 are individually selected from H or amine protecting group with the proviso that Piand P2 both are not 6H'
comprising of; treating the compound of formula-15 or its free base compound of formula-14 with a suitable amino-protecting agents optionally in presence of a suitable base in a suitable solvent to provide the compound of general formula-8 or their salts, optionally purifying the compound of formula-8 or their salts.
5. A process according to claim 4, the suitable amino protecting agent is selected form but not limited to di-tert.butyl dicarbonate (DIBOC), benzyl chloroformate, fluorenylmethyloxy carbonyl chloride (FMOC chloride), acetyl chloride, acetic anhydride, benzoyl halides, benzyl halides, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid, trifluoroacetyl chloride and the like; preferably DIBOC; a suitable base is selected from inorganic base, organic base; preferably organic base; most preferably triethyl amine.
5. A process for the preparation of tert-butyl (2R, 5R)-5-amino-l,6-diphenylhexan-2-yl-carbamate hydrochloride,
comprising of:
a) Treating the (2R, 5R)- l,6-diphenylhexan-2,5-diamine dihydrochloride

with DIBOC in presence of a suitable base in a suitable solvent to provide the tert-butyl
(2R, 5R)-5-amino-l,6-diphenylhexan-2-yl-carbamate; b) treating the obtained compound with suitable hydrochloric acid source in a suitable
solvent; to provide the compound of formula-8ai; optionally purifying the obtained
compound from a suitable solvent or a mixture of solvents. Wherein in step-a) the suitable base is selected from inorganic base, organic base; preferably organic base; most preferably triethyl amine;
in step-b) the suitable hydrochloric acid source is selected from methanolic-HCl, ethyl acetate HO, isopropanolic-HO, butanolic-HCl, HC1 gas, anhydrous HO, aqueous HO and like; preferably ethyl acetate HC1;
7. A process for the preparation of crystalline tert-butyl (2R, 5R)-5-amino-l,6-diphenylhexan-2-
yl-carbamate hydrochloride the compound of , comprising of:
a) Treating the (2R, 5R)-5-amino-l,6-diphenylhexan-2-yl-carbamate dihydrochloride with DIBOC in presence of triethylamine in methanol to provide the tert-butyl (2R, 5R)-5-amino-1,6-diphenylhexan-2-yl-carbamate;
b) treating the obtained compound with ethyl acetate HC1 in ethyl acetate;
c) purifying the obtained compound in the mixture of ethyl acetate and water compound of formula-8ai.

8. Crystalline tert-butyl (2R, 5R)-5-amino-l,6-diphenylhexan-2-yl-carbamate hydrochloride compound of formula-8ai.
9. A novel process for the preparation of cobicistat compound of formula-1 comprising of:
a) Treating the (S)-l-((2-isopropylthiazol-4-yl)methyl)-l-methyl-3-(2-oxotetrahydrofuran-3-yl)urea compound of formula-4,

with sodium bromide and trimethyl silylchloride in a mixture of methanol and dichloromethane; followed by reacting the obtained compound with morpholine to provide the compound of formula-5a,
Formula-5a b) treating the compound of formula-5a in-situ with oxalic acid to provide the compound of formula-6a,
Formula-6a c) basifying the compound of formula-6a using aqueous sodium bicarbonate solution and treating the obtained compound with aqueous potassium hydroxide solution in dichloromethane to provide compound of formula-7a,
Formula-7a d) the compound of formula-7a in-situ condensing with the compound of formula-8ai

Formula-8ai in presence of EDC.HC1, HOBT and diisopropylethyl amine to provide the compound of formula-9a,
Fromula-9a e) treating the compound of formula-9a which on in-situ with hydrochloric acid in dichloromethane followed by treating with aqueous potassium carbonate solution to provide the compound of formula-10,
Formula-10 f) reacting the compound of formula-10 with the compound of formula-13a
Formula-13a in presence of diisopropyl ethyl amine in isopropanol and in presence of L-ascorbic acid to provide the compound of formula-1.
10. An improved process for the preparation solid dispersion of cobicistat with silicondioxide comprising of:

a) Dissolving cobicistat compound of formula-1 in a suitable solvent,
b) adding silicon dioxide to the reaction mixture obtained in step-a),
c) distilling off the solvent from the reaction mixture,
d) adding a second solvent to obtained compound in step-c),
e) isolating solid dispersion of cobicistat with silicondioxide;
Wherein in step-a) suitable solvent is selected from chloro solvents, hydrocarbon solvents or mixtures thereof; in step-d) a suitable solvent is selected from hydrocarbon solvent; in step-e) isolating refers to the solvent removing by known techniques such as filtering, decanting or distilling.
11. Stable amorphous Cobicistat obtained according to the any of preceding claims having purity >99%; preferably >99.5%; most preferably >99.7%.
12. Stable amorphous Cobicistat obtained according to the any of preceding claims having chiral purity >99%.