FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for the preparation of Cobicistat intermediate
SeQuent Scientific Limited
A Company Incorporated Under The Companies Act, 1956
Having Registered Office at
116 Vardhman Industrial Complex, L.B.S Marg,
Thane (W), Mumbai - 400601, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:

Field of Invention
The present invention relates to a novel process for the preparation of key intermediate of cobicistat, a drug under experimental investigation for use in the treatment of infection with the human immunodeficiency virus (HIV).
Background of the Invention
Cobicistat is a drug under experimental investigation for use in the treatment of infection with the human immunodeficiency virus (HIV). It has the ability to inhibit liver enzymes that metabolize other medications used to treat HIV, notably elvitegravir, an HIV integrase inhibitor currently under investigation itself. By combining cobicistat with elvitegravir, higher concentrations of elvitegravir are achieved in the body with lower dosing, theoretically enhancing elvitegravir's viral suppression while diminishing its adverse side-effects. If approved by the U.S. Food and Drug Administration, cobicistat will be part of the four-drug, fixed-dose combination HIV treatment known as the "Quad Pill". The Quad Pill is currently in Phase III clinical trials, and is owned by Giiead Sciences. The chemical name of cobicistat is thiazol-5-ylmethyl N-[l-benzyl-4-[[2-[[(2-isopropylthiazol-4-yl)methyl-methyl-carbamoyl]amino]-4-morpholino-butanoyl]amino]-5-phenyl-pentyl]carbamate represented by formula I,


The compound (2S, 3S, 5S)-5-amino-2-(N-((5-thiazolyl)-
methoxycarbonyl)amino)-l,6-diphenylhexane hydrochloride of formula II is a key intermediate in the preparation of cobicistat of formula I.

There are few process reported for the preparation of this compound. US patent application number US 20100256366 describes a process for the preparation of (2S, 3S, 5S)-5-amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-l,6-diphenylhexane hydrochloride starting from L-phenylalaninol . L-phenylalaninol was treated with diisopropylethylamine and N,N-dimethylsulfamoyl chloride to form a protected amino alcohol. Thus obtained protected amino alcohol was treated with sodium hydride in presence of a solvent to form (S)-2-benzyl-N,N-dimethylaziridine-l-sulfonamide. The (S)-2-benzyl-N,N-dimethylaziridine-l-sulfonamide was treated with n-butyllithium in hexane and 2,2,6,6-tetramethylpiperidine to obtain protected diamine. The protected diamine was heated with 1,3-diaminopropane to obtain de-protected unsaturated diamine. The unsaturated diamine was reduced with palladium on carbon to obtain a diamine. The obtained diamine was treated with hydrochloric acid in dioxane to obtain diamine-dihydrochloride. Diamine-dihydrochloride was treated with 4-nitrophenyI-l,3-thiazol-5-ylmethyl carbonate and diisopropylethylamine to form (2S, 3S, 5S)-5-amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-l,6-diphenylhexane hydrochloride. This process can be illustrated by the below reaction scheme - 1.


The major drawback in the above stated prior art is the use of hazardous protecting reagent like N,N-dimethylsulfamyoyl chloride, a hazardous base like sodium hydride for formation of aziridine ring and handling of hazardous n-butyllithium at low temperature for aziridine ring opening. This process also involves costly palladium on carbon for reduction of unsaturated diamine. Moreover, the prior art process involves eight steps and forms large quantity of organic and inorganic waste products, which makes it undesirable for industrial scale manufacturing. Thus there is a need to develop a process which reduces the number of steps drastically, minimizes waste significantly and makes the reaction easy to handle on industrial scale.

In view of the importance of this compound for the preparation of cobicistat, the present inventors found a novel process after continued research, which fulfils the above stated objectives and provides a two steps industry friendly process to obtain this key intermediate of cobicistat.
Summary of the invention
According to the principal aspect of the present invention there is disclosed a novel process for the preparation of (2S, 3S, 5S)-5-amino-2-(N-((5-thiazolyl> methoxycarbonyl)amino)-l,6-diphenylhexane hydrochloride of formula II which comprises:
a) converting (2S, 3S, 5S)-5-(t-Butyloxycarbonylamino)-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-l,6-diphenyl-3-hydroxyhexane of formula IV using 1,1'-thiocarbonyldiimidazole in presence of solvent to obtain (2S, 3S, 5S)-5-(t-Butyloxycarbonylamino)-2-(N-((5-thiazolyl)-methoxycarbonyI)amino)-l,6-diphenyl-3-0-(thiocarbonylimidazolyl) hexane of formula III; and
b) reducing (2S, 3S, 5S)-5-(t-Butyloxycarbonylamino)-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-l ,6-diphenyl-3-0-(thiocarbonylimidazolyl) hexane of formula III using a reducing agent in presence of a solvent to obtain (2S, 3S, 5S)-5-amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-l,6-diphenylhexane hydrochloride of formula II.
The present invention can be illustrated by the below reaction scheme:


In another aspect of the present invention, (2S, 3S, 5S)-5-(t-Butyloxycarbonylamino)-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-l,6-diphenyl-3-0-(thiocarbonyIimidazolyl) hexane of formula III is novel, which is a valuable precursor for (2S, 3S, 5S)-5-amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-l,6-diphenylhexane hydrochloride of formula II, an important intermediate for cobicistat of formula I.


Detail Description of the Invention
Accordingly in an embodiment of the invention, the conversion of (2S, 3S, 5S)-5-(t-Butyloxycarbonylamino)-2-{N-((5-thiazolyl)-methoxycarbonyI)amino)-l,6-diphenyl-3-hydroxyhexane of formula IV into (2S, 3S, 5S)-5-(t-Butyloxycarbonylamino)-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-l,6-diphenyl-3-0-(thiocarbonylimidazolyl) hexane of formula III is carried out using a reagent l,l'-thiocarbonyldiimidazole in presence of an inert organic solvent selected from toluene, benzene, xylene, dimethylformamide (DMF), tetrahydrofuran (THF) and the like, preferably THF at about the reflux temperature of the solvents selected.
In another embodiment of the invention, the isolation of (2S, 3S, 5S)-5-(t-butyloxycarbonylamino)-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-l,6-diphenyl-3-0-(thiocarbonylimidazolyl) hexane is carried out by an aliphatic and aromatic hydrocarbon solvent preferably n-heptane.
In another embodiment of the invention, the reduction of (2S, 3S, 5S)-5-(t-butyloxycarbonylamino)-2-{N-((5-thiazolyl)-methoxycarbonyl)amino)-l,6-diphenyl-3-0-(thiocarbonylimidazolyl) hexane into (2S, 3S, 5S)-5-amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-l,6-diphenylhexane hydrochloride of formula II is carried out using a reducing agent preferably trialkyltin hydride more preferably tri-n-butyltin hydride and a reagent preferably 2,2'-Azobis(2-methylpropionitrile) in presence of an inert organic solvent selected from ethyl acetate, toluene, benzene, xylene, DMF, THF and the like, preferably toluene at a reflux temperature.
In another embodiment of the invention, the isolation of (2S, 3S, 5S)-5-amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-l,6-diphenylhexane hydrochloride of formula II is done using alcoholic hydrochloric acid preferably isopropanolic hydrochloride (IPA.HC1) at temperature about 25-30°C.
In another embodiment, some of the key advantages of the present invention are as below:
1. The process of the present invention involves only two steps for the preparation of compound of formula II as compared to eight steps in the state-of-art.

2. The process of the present invention obviates the use of hazardous chemicals used in the state-of-art.
3. The process of the present invention minimizes the generation of waste.
4. The process of the present invention obviates the handling of hazardous protecting reagent N,N-dimethtlsulfamoyl chloride, hazardous reagent n-butyllithium at low temperature and costly palladium on carbon.
The present invention can be illustrated by the following examples, which are not to limit the scope of invention.
Example 1: Preparation of (2S, 3S, 5S)-5-amino-2-