The present invention provides processes for the preparation of Form co and Form N of Efavirenz.
(4S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2/-/-3,1-benzoxazin-2-one; commonly known as efavirenz of Formula I is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor. Efavirenz is indicated in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection.
(Formula Removed)
US Patent No. 5,519,021 and its equivalent PCT Patent Applications WO 94/03440, WO 95/20389 describe synthesis of efavirenz. In addition Tetrahedron Letters 36, 937-940 (1995); US Patent No. 5,698,741 and its equivalent PCT Patent Application WO 9637457 also provide various processes for preparation of efavirenz. Further the process for preparation of efavirenz is also reported in US Patent No. 5,663,467 and its equivalent PCT Patent Application WO 9622955.
US Patent No. 6,639,071 and US Patent No. 5,965,729 describe crystalline polymorphic forms of efavirenz designated as Form I, II and III. The specification of the '071 Patent comments that efavirenz previously crystallized from a heptane-tetrahydrofuran (THF) solvent system by the crystallization procedure which require the use of high temperatures (about 90°C) to dissolve the final product produces crystals by nucleation during the cooling process. The crystals which were produced were Form II and are converted to the desired Form I while drying under vacuum at 90°C. This crystallization provides minimal purification and produced material with inconsistent physical properties. The final product slurry is extremely difficult to mix and handle due to its high viscosity and heterogeneous nature.
US Patent No. 6,673,372 provides polymorphic forms of efavirenz designated as Form 2 and Form 5. Our co-pending applications 2167/DEL/2004 and 2169/DEL/2004 provide polymorphic forms of efavirenz designated as Form co and Form N.
The present inventors have developed novel processes for the preparation of efavirenz Form co and Form N.
A first aspect of the present invention provides a process for the preparation of polymorphic Form co of efavirenz which comprises of
a) dissolving efavirenz in a water miscible organic solvent,
b) treating the solution obtained in step a) with a mixture of water, a water miscible organic solvent and an agent for lowering the freezing point of water,
c) treating the solid obtained in step b) with water,
d) isolating Form co of efavirenz from the reaction mass thereof.
Efavirenz prepared by any method known in the art and present in any polymorphic form can be used as starting material. Efavirenz is dissolved in a water miscible alkanol and the solution is added to a mixture of water, a water miscible organic solvent and an agent for lowering the freezing point of water in optional order of succession. The water miscible organic solvent is selected from a group comprising of methanol, ethanol, n-propanol and isopropanol. The agent for lowering the freezing point of water can be an alkali metal salt or an alkaline earth metal salt. The resultant mixture is stirred at a temperature of -10°C or less. After complete precipitation of solids, the solid is filtered and treated with water at a temperature between 0° and 10°C accompanied by stirring. The solid obtained is dried under vacuum to get Form co of efavirenz having characteristic XRPD (Figure 1).
A second aspect of the present invention provides a process for the preparation of polymorphic Form N of efavirenz which comprises of
a) mixing Form co of efavirenz with catalytic quantity of Form N of efavirenz,
b) drying the mixture in step a) under vacuum for sufficient time,
c) isolating Form N of efavirenz from the reaction mass thereof.
The starting compounds such as Form  and Form N of efavirenz can be prepared by the methods provided in 2167/DEL/2004 and 2169/DEL/2004 or in the present invention. Form  of efavirenz is mixed with catalytic quantity of Form N of efavirenz. The mixture is placed in a flask and a vacuum is applied to the mixture for sufficient time to effect the formation of Form N. The vacuum can be applied so as to obtain a pressure of 5 mmHg or less. The process can also be accompanied by the rotation of the flask. The flask can be rotated at a speed of 10 to 100 revolutions per minute. The process is carried out at a temperature of 10°C or less. Further drying is optionally carried out under vacuum at 30° to 45°C. Form N of efavirenz having characteristic XRPD (Figure 2) is isolated from the reaction mass.
Figure 1 depicts XRPD of Form co of efavirenz. Figure 2 depicts XRPD of Form N of efavirenz.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF FORM co OF EFAVIRENZ
A solution of efavirenz (49.17 g) in methanol (300 ml) was prepared and added to a mixture of sodium chloride (150 g), methanol (150 ml) and water (1250 ml) at a temperature of-14°C over a period of 10 minutes. The solution so obtained was stirred at -16° to -20°C for 2 hours, filtered and washed with cold water (1000 ml, 3° to 5°C). The solid obtained was made into slurry with cold water (1250 ml, 3° to 5°C) and stirred for 15 minutes. The solid was filtered and washed again with cold water (50 ml, 3° to 5°C) to obtain the title compound. Yield: 48.5 g
EXAMPLE 2
PREPARATION OF FORM N OF EFAVIRENZ
A mixture of Form co (48 g) and Form N (10.1 g) of efavirenz was loaded in a 2 L rotary evaporator flask and 4 Teflon coated magnetic beads were added. A high vacuum (0 to 2 mmHg) was applied to the rotary evaporator and the evaporator flask was dipped into ice water bath at 0° to 2°C. The rotary evaporator flask was rotated at 20 rpm for 5 minutes and the speed was increased to 60 to 80 rpm. The rotation at 60 to 80 rpm under vacuum was continued for 5 hours at 0° to 2°C. The solid was isolated from the walls of the flask and kept in vacuum oven at 38°C for 15 hours to get the title compound. Yield: 52.5 g

WE CLAIM:
1. A process for the preparation of polymorphic Form co of efavirenz which comprises of
a) dissolving efavirenz in a water miscible organic solvent,
b) treating the solution obtained in step a) with a mixture of water, a water miscible organic solvent and an agent for lowering the freezing point of water,
c) treating the solid obtained in step b) with water,
d) isolating Form co of efavirenz from the reaction mass thereof.

2. A process as claimed in claim 1, wherein the water miscible organic solvent is selected from a group comprising of methanol, ethanol, n-propanol and isopropanol.
3. A process as claimed in claim 1, wherein the agent for lowering the freezing point of water is selected from a group comprising of alkali metal salts or alkaline earth metal salts.
4. A process as claimed in claim 3, wherein the alkali metal salt is sodium chloride.
5. A process as claimed in claim 1, wherein step b) is carried out at a temperature of -10°Corless.
6. A process as claimed in claim 1, wherein step c) is carried out at a temperature between 0° and 10°C.
7. A process for the preparation of polymorphic Form N of efavirenz which comprises of

a) mixing Form co of efavirenz with catalytic quantity of Form N of efavirenz,
b) drying the mixture in step a) under vacuum for sufficient time,
c) isolating Form N of efavirenz from the reaction mass thereof.
8. A process as claimed in claim 7, wherein step b) is carried out at a temperature of
10°Corless.

9. A process as claimed in claim 7, wherein step b) is carried out in a rotary evaporator.
10. A process as claimed in claim 9, wherein the evaporator is rotated at a speed of 10
to 100 revolutions per minute.