FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for Preparation of Ritonavir
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 - 400 601, India
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention relates to a novel process for preparing an antiretroviral drug commonly known as ritonavir.
BACKGROUND OF THE INVENTION
Ritonavir, also known as "Norvir" is a protease inhibitor. It is used to treat HIV infection and AIDS. Ritonavir is also indicated in combination with other antiretroviral agents such as Lopinavir known as "Kaletra" for the treatment of HIV-infection.
The chemical name of Ritonavir is l,3-thiazol-5-ylmethyl N-[(2S)3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2-{[methyl({[2-(propan-2-yl)-l,3-thiazol-4-yl]methyl})carbamoyl]amino}butanamido]-l,6-diphenylhexan-2-yl]carbamate which is represented by formula I,

Ritonavir was disclosed for the first time in W09414436.This patent
describes a process for the preparation of ritonavir by coupling N-((N-methyl-
N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine of formula II
with (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-l,6-
diphenyl- 3-hydroxyhexane of formula III in presence of an 1-
hydroxybenzotriazole hydrate and a diimide such as N-ethyl-N'-
dimethylaminopropyl carbodiimide, N,N'-Dicyclohexylcarbodiimide etc to
give (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)
amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1.6-diphenyl -3-hydroxyhexane, i.e Ritonavir of formula I as shown in below

reaction scheme -1. Such process is not suitable for industrial scale production of Ritonavir because the diimides are toxic and sensitizers. They have many other handling and workup problems such as the use of HOBt which is found to be explosive and toxic. The HOBt is required in equimolar ratio and the reaction is lengthy. Also the use of DCC forms DCU as bi-product whose complete removal is very difficult. Moreover, HOBt and DCC are expensive reagents.

W09414436also describes an alternative process for the preparation of ritonavir as shown in below reaction scheme - 2. This process involves the conversion of compound of formula II into a mixed anhydride of formula IV(wherem R* is lower alky/) by reaction with an alkyl chloroformate such as isobutylchloroformate or by reaction with an alkanoyl chloride such as pivaloylchloride. The mixed anhydride of formula IV is then reacted (without isolation) with compound of formula III. Because of the high reactivity of the

mixed anhydride intermediate, this process often leads to unacceptable amounts of undesired side products.
Scheme - 2

US patent 5,567,823 describes a process for the preparation of ritonavir which is shown in below reaction scheme - 3. This process involves three steps which are carried out insitu. The first step involves the conversion of compound of formula II into a mixed anhydride of formula IV (wherein R* is lower alkyl) by reaction with an alkyl chloroformate such as isobutylchloroformate or by reaction with an alkanoyl chloride such as pivaloylchloride. In the second step, the mixed anhydride of formula IV is converted to an intermediate activated ester derivative of formula V (R** is

selected from the group consisting of succinimid-1-yl, benzotriazol-1-yl, phthalimid-1-yl, 5-norbornene-2,3-dicarboximidyl, quinolin-8-yl, 1,2,3-benzotrazin-4(3H)-on-3-yl, piperidin-1-yl, pentachlorophenyl, 2,4,5-trichlorophenyl, 2-nitrophenyl, 4-nitropheny], pentafluorophenyl and the like). In the third step, the activated ester of formula V is reacted with compound of formula III to give the final product ritonavir. The drawback of this process is that it involves an additional step of conversion of a mixed anhydride to an ester. This may not be desired at the industrial scale production.

Thus there is a continuing need to develop a coupling process for the preparation of ritonavir which gives good yield and have short reaction time, which obviates the use of 1-hydroxybenzotriazole (HOBt) & DCC and eliminate the additional step i.e. conversion of a mixed anhydride to an ester before reacting with compound III.

The present inventors have developed a cost effective process for preparation of ritonavir which overcomes most of the above drawback.
Summary of the Invention
The principal aspect of the present invention is to provide a process for the preparation ofl,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2- {[methyl({ [2-(propan-2-y])-1,3-thiazol-4-yl]memyI})carbamoyl]amino}butanamido]-l,6-diphenylhexan-2-yl]carbamateof formula I, which comprises:
a) couplingN-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine of formula II with 2-ChIoro-4,6- dimethoxy-l,3,5-triazine (CDMT), in presence of base and an organic solvent to form an intermediate ester compound of formula VI; and
b) reacting insitu the ester compound obtained in step a) with (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyI)amino)-l,6-diphenyl- 3-hydroxyhexane of formula III to give l,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2-{[methyI({[2-(propan-2-yl)-l,3-thiazol-4-yl]methyl}) carbamoyl]amino}butanamido]-l,6-diphenylhexan-2-yl]carbamate of formula I.
The process of the present invention may be illustrated by the below reaction scheme -4:


Detail Description of the Invention
Accordingly in an embodiment of the invention, coupling reaction in step a) is carried out in presence of an organic base selected from pyridine, methyl amine, triethylamine, imidazole, benzimidazole, histidine, N-methyl morpholine and the like, preferably N-methyl morpholine. The coupling reaction in step a) is carried out in presence of an inert organic solvent selected from ethyl acetate, toluene, benzene, xylene, DMF, THF and the like, preferably ethyl acetate at a temperature in the range of -20 to 30° C, preferably 25-30° C.
In another embodiment of the invention, an intermediate ester compound of formula VI obtained in step a) by coupling N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine of formula II with 2-

Chloro-4,6- dimethoxy-l,3,5-triazine (CDMT) Is not isolated and reacted
insitu further with (2S,3S,5S)-5-amino-2-(N-((5-
thiazolyl)methoxycarbonyl)amino)-l,6-diphenyl- 3-hydroxyhexane of formula III in the same above set of inert organic solvents preferably ethyl acetate at the temperature range of 0 to 30° C preferably at 25-30° C to obtain ritonavir of formula I. The obtained ritonavir is further crystallized by ethyl acetate/n-heptane.
The present invention is illustrated by the following examples, which are not to limit the scope of the invention.
Example:
a) Preparation of l,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2-{[methyl({[2-(propan-2-yl)-l,3-thiazol-4-yl]methyl}) carbamoyl]amino}butanamido]-l,6-diphenylhexan-2-yl]carbamate :
N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine (38 g) and ethyl acetate (1000 ml) were charged into the flask under stirring at 25-30°C. 2-Chloro-4,6-' dimethoxy-l,3,5-triazine (CDMT) (23 g) and N-methyl morpholine (13 g) are added into the flask, stirred for 1 hour at 25-30 °C.(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-l,6-diphenyl-3-hydroxyhexane (50 g) was added to the above reaction mixture, stirred for 6 hours at 25-30 °C. After completion of reaction, DM water was added to the above reaction mass, stirred for 30 minutes. Two layers were separated, ethyl acetate layer containing product was washed with 10% citric acid solution, and washing was repeated once again. Ethyl acetate layer was again washed with 10% sodium carbonate solution; washing was repeated for two times. The collected ethyl acetate layer was washed with DM water and concentrated to residue below 45 C under reduced pressure. To the residue a mixture of ethyl acetate (500 ml) and n-heptane (250 ml) was added, above reaction mass was heated to 65-70 °C, filtered. The filtrate was heated to 65-70 °C, allowed to cool slowly. Further cooled to 0-5 °C and maintained for 1 hour. Solid was filtered, washed with a mixture ethyl acetate and n-heptane and dried.
Yield: 80g.

We claim:
1. A process for the preparation of l,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2-{[methyl({[2-(propan-2-yl)-l,3-thiazol-4-yl]methyl} )carbamoyI]amino} butanamido]-1,6-diphenylhexan-2-yl]carbamate of formula I, which comprises:

I a) couplingN-((N-methyl-N-((2-isopropyl-4-
thiazolyl)methyl)amino)carbonyl)-L-valine of formula II with 2-Chloro-4,6- dimethoxy-l,3,5-triazine (CDMT), in presence of base and an organic solvent to form an intermediate ester compound of formula VI; and

b) reacting insitu the ester compound obtained in step a) with (2S,3S,5S)-
5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-l,6-diphenyl- 3-
hydroxyhexane of formula III to obtain l,3-thiazoI-5-ylmethyl N-
[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2-{[methyl({[2-(propan-2-
yl)-l,3-thiazol-4-yl]methyl}) carbamoyl]amino}butanamido]-l,6-
diphenylhexan-2-yl]carbamate of formula I.


2. A process according to claim 1,where in the base is an organic base selected from pyridine, methyl amine, imidazole, benzimidazole, histidine, N-methyl morpholine etc. preferably N-methyl morpholine.
3. A process according to claim I, wherein the base is N-methyl morpholine.
4. A process according to claim 1, wherein organic solvent is selected from ethyl acetate, toluene, benzene, xylene, DMF, THF etc. preferably ethyl acetate.
5. A process according to claim 1, wherein organic solvent is ethyl acetate.
6. A process according to claim 1, wherein the intermediate ester compound of formula VI obtained in step a) is not isolated.
7. A process according to claim 1, wherein the ritonavir of formula 1 is crystalised by ethylacetae and n-heptane.