FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
An Improved Process for Preparation of Maraviroc
APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD.
2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India
Indian Company incorporated under the Companies Act 1956
The following specification particularly describes the invention and the manner in which it is performed.

FIELD OF INVENTION
The present invention relates to an improved process for the preparation of Maraviroc of Formula I by reductive animation using ammonium salt.

Formula I
The present invention also relates to an improved process for the preparation of polymorphic Form B of Maraviroc.
BACKGROUND OF INVENTION
4,4-difluoro-N-{(lS)-3-[3-(3-isopropyl- 5-methyl-4H-l,2,4-triazol-4-yl)-8-
azabicyclo[3.2.1]oct-8-yl]-l-phenylpropyl}cyclohexanecarboxamide of Formula I, commonly known as Maraviroc,


Formula I
is an antiretroviral drug in the CCR5 receptor antagonist class used in the treatment of HIV infection.
Maraviroc and various processes for preparation of Maraviroc were disclosed in US6667314. One of the process as described in US6667314 is depicted as follows in scheme I.


Scheme I discloses the preparation of Maraviroc wherein sodium triacetoxyborohydride is used as reagent for reductive animation. Further it is reported in said patent that this reaction takes place in presence or absence of acid catalyst like acetic acid.
Use of sodium triacetoxyborohydride as a reducing agent is a major disadvantage of the above process as sodium triacetoxyborohydride is highly moisture sensitive and is sparingly soluble in common organic solvent. Hence, while carrying out the process in large scale using sodium triacetoxyborohydride special care is needed. Also, sodium triacetoxyborohydride is expensive thereby making process for preparation of Maraviroc expensive.
Inventors of the present invention have developed an improved process for preparation of Maraviroc which overcomes the above discussed disadvantage. The process of the present invention comprises reductive amination by using ammonium salt as a reducing agent that provides a simpler, industrially scaleable and economic process for preparation of Maraviroc.
OBJECT OF INVENTION
It is an object of invention to ameliorate at least one of disadvantage of the prior art and/or to provide a useful alternative process for preparation of Maraviroc.
Another object of the present invention is to provide an improved process for the preparation of Maraviroc by reductive amination using ammonium salt such as ammonium formate or ammonium acetate.
Another object of the present invention is to provide Maraviroc with HPLC purity of greater than or equal to 99%.

Another object of the present invention is to provide an improved process for the preparation of polymorphic Form B of Maraviroc.
Yet another object of the present invention is to provide simple, cost effective and industrially viable process for preparation of Maraviroc.
SUMMARY OF INVENTION
According to an aspect of the present invention, there is provided an improved process for preparation of Maraviroc of Formula I by reductive animation

Formula I
comprising,
reacting an amine of Formula II

with a difluoroaldehyde of Formula III


Formula III
in presence of ammonium salt and an organic solvent.
According to another aspect of the present invention, there is provided an improved process for preparation of polymorphic Form B of Maraviroc of Formula I comprising steps of,
a) reacting an amine of Formula II with a difluoroaldehyde of Formula III in presence of ammonium salt and an organic solvent
b) refluxing the reaction mixture of step a) for 1 to 4 hours
c) acidifying the reaction mixture to pH 1 to 2 at 20-3 5°C
d) separating aqueous acidic layer and organic layer
e) basifying aqueous acidic layer obtained in step d) to pH 12 to 13 at 5-25°C

f) extracting the basified aqueous layer of step e) with the organic solvent
g) concentrating organic solvent and isolating the desired product.
DETAILED DESCRIPTION OF INVENTION
The present invention relates to the improved, simple and economic process for the preparation of Maraviroc of Formula I by reductive amination using ammonium salt.

The process of the present invention for preparation of Maraviroc of formula I is depicted in the scheme II as below,


Scheme II
In an aspect of the present invention, there is provided an improved process for preparation of Maraviroc of Formula I by reductive amination using ammonium salt

Formula I
comprising,
reacting an amine of Formula II


Formula II
with a difluoroaldehyde of Formula III

Formula III
in presence of ammonium salt and an organic solvent.
In another aspect of the present invention, there is provided an improved process for preparation of polymorphic Form B of Maraviroc of Formula I comprising steps of,
a) reacting an amine of Formula II with a difluoroaldehyde of Formula III in presence of ammonium salt and an organic solvent
b) refluxing the reaction mixture of step a) for 1 to 4 hours
c) acidifying the reaction mixture to pH 1 to 2 at 20-3 5°C
d) separating aqueous acidic layer and organic layer
e) basifying aqueous acidic layer obtained in step d) to pH 12 to 13 at 5-25°C
f) extracting the basified aqueous layer of step e) with the organic solvent

g) concentrating organic solvent and isolating the desired product.
According to an embodiment of the present invention, the molar ratio of difluoroaldehyde of Formula III with respect to amine of Formula II is in range of 0.5 to 1.5.
According to another embodiment of the present invention, the ammonium salt used as a reducing agent is selected from ammonium formate or ammonium acetate, preferably ammonium formate.
The molar ratio of ammonium salt with respect to amine of Formula II is in range of 1 to 3.
According to another embodiment of the present invention, the organic solvent used is selected from water immiscible halogenated and non-halogenated solvents wherein the halogenated solvent like dichloromethane, 1,2-dichloroethane, carbon tetrachloride, chloroform and the non-halogenated solvent like cyclohexane, diethyl ether, ethyl acetate, methyl isobutyl ketone, heptane, hexane, methyl-tert-butyl ether, pentane, toluene, xylene, tetrahydrofuran is used, preferably organic solvent used is ethyl acetate.
According to yet another embodiment of the present invention the product obtained is polymorphic Form B of Maraviroc.
The Maraviroc obtained has HPLC purity of greater than or equal to 99%.

The details of the invention provided in the following example are given by the way of illustration only and should not be construed to limit the scope of the present invention.
EXAMPLES Example 1
To 3 gm of amine of Formula II was added 120 ml of ethyl acetate and 1.77 gm of ammonium formate and then the reaction mixture was heated to reflux temperature. To this mixture was added in 2 hours a solution of 4.15 gm of difluoroaldehyde of Formula III in 90 ml of ethyl acetate and the reaction mixture was maintained at 78°C for 2 to 3 hours. After completion of the reaction, the reaction mixture was cooled to 25 to 30°C and was acidified (pH 1-2) using 10% HC1 solution. The organic layer and aqueous acidic layer were separated and the organic layer was extracted with 50 ml of 10% HC1 solution. The aqueous acidic layers were combined and washed with 100 ml (2 X 50 ml) of ethyl acetate. The aqueous acidic layer was further cooled to 10-15°C and basified (pH 12-13) using 10% sodium hydroxide by maintaining temperature of about 15 to 20°C. The basified aqueous layer was extracted with 300 ml (3 X 100 ml) of ethyl acetate. The ethyl acetate layer thus obtained was washed with brine solution and was then concentrated under vacuum at 45 to 50°C. To the concentrated mass was added 25 ml of ethyl acetate and then the mixture was heated to 40°C at this temperature solid precipitated out. The mixture was then cooled to 25-30°C and was stirred for 30 minutes. The solid product obtained was filtered and washed with ethyl acetate followed by drying the solid at 60°C for 12 hours to obtain Maraviroc. Yield: 3.2 gm (49%) HPLC Purity: 99.9%

We claim
1. An improved process for preparation of Maraviroc of Formula I by reductive animation

Formula I
comprising
reacting an amine of Formula II

Formula II
with a difluoroaldehyde of Formula III


Formula III
in presence of ammonium salt and an organic solvent
2. An improved process for preparation of polymorphic Form B of Maraviroc of Formula I

Formula I
comprising steps of
a) reacting an amine of Formula II


Formula II
with a difluoroaldehyde of Formula III

Formula III
in presence of ammonium salt and an organic solvent
b) refluxing the reaction mixture of step a) for 1 to 4 hours
c) acidifying the reaction mixture to pH 1 to 2 at 20-3 5 °C
d) separating aqueous acidic layer and organic layer
e) basifying aqueous acidic layer obtained in step d) to pH 12 to 13 at 5-25°C
f) extracting the basified aqueous layer of step e) with the organic solvent
g) concentrating organic solvent and isolating the desired product
3. The process as claimed in claim 1 or 2, wherein the ammonium salt used as a reducing agent is selected from ammonium formate or ammonium acetate, preferably ammonium formate

4. The process as claimed in claim 3, wherein the molar ratio of ammonium salt with respect to amine of Formula II is in range of 1 to 3
5. The process as claimed in claim 1 or 2, wherein the organic solvent used is selected from water immiscible halogenated and non-halogenated solvents wherein the halogenated solvent like dichloromethane, 1,2-dichloroethane, carbon tetrachloride, chloroform and the non-halogenated solvent like cyclohexane, diethyl ether, ethyl acetate, methyl isobutyl ketone, heptane, hexane, methyl-tert-butyl ether, pentane, toluene, xylene, tetrahydrofuran is used, preferably organic solvent used is ethyl acetate
6. The process as claimed in claim 1 or 2, wherein the molar ratio of difluoroaldehyde of Formula III with respect to amine of Formula II is in range of 0.5 to 1.5.