FIELD OF INVENTION

The invention relates to a novel process for the preparation of (4S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1 -benzoxazin-2-one (Effavirenz) of Formula I, which is useful as human immunodeficiency (HIV) reverse transcriptase inhibitors.

BACKGROUND OF INVENTION

Reverse transcription is a common feature of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral sequences by reverse transcription of the viral RNA genome. Reverse transcriptase, therefore, is a clinically relevant target for the chemotherapy of retroviral infections because the inhibition of virally encoded reverse transcriptase would interrupt viral replication. The synthesis of Efavirenz and structurally similar reverse transcriptase inhibitors are disclosed in US 5,519,021 and the corresponding WO 95/20389 which is depicted in the following scheme.

This general method teaches,

(1) metallation of the pivalamide of parachloroaniline with n-butyl lithium followed by nucleophillic substitution with an ester to form a ketone,

(2) synthesis of a tertiary carbinol by grignard addition to the ketone and

(3) cyclization of unprotected amine with the carbinol by addition of large excess of condensing agent to form a benzoxazinone.

The process requires further purification of the optical isomers through use of an optically active resolving agent such as (-) camphanic acid.

The above scheme has many disadvantages like long reaction times, use of anhydrous conditions and use of solvents like THF which is pyrophoric in nature.

Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence that has been described by Thompson, et al., Tetrahedron Letters 1995, 36, 8937-8940, as well WO 96/37457 which is shown below.

The p-methoxy benzyl aniline starting material is synthesized by benzylating the aniline nitrogen with p-methoxybenzyl chloride.

Additionally, the overall process generates a large volume of heavy metal waste in the waste stream due to ceric ammonium nitrate oxidation in the debenzylation step.

The other disadvantage in this process is the use of phosgene in cyclization process, which is a toxic and highly hazardous gas, which requires special handling.

WO 98/34928 discloses the preparation of Efavirenz compound of formula I comprising cyclization of an amino alcohol using alkyl or aryl chloroformates and base. The process is depicted in the following scheme.

The main disadvantage of the above process is the use of aryl chloroformates which upon heating, decomposes into phosgene and if it comes in contact with water it produces toxic, corrosive fumes.

The present invention discloses an efficient method for the cyclization of an amino alcohol with an urea giving rise to effavirenz.

OBJECTIVE OF THE INVENTION

An object of the present invention is to provide a process for the preparation of (4S)-6-chloro-4-(cyclopropylethynyl)-l,4-dihydro-4-(trifluoromethyl)-2H-3,l-benzoxazin-2-one.

SUMMARY OF THE INVENTION

The instant invention discloses a novel and efficient method for the preparation of (4S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1 -benzoxazin-2-one (Efavirenz) of the Formula I which comprises,
cyclization of an amino alcohol or a salt thereof of Formula II with a compound of Formula III to give compound of Formula I and its pharmaceutically acceptable salts.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes a novel cyclization process for the preparation of efavirenz compound of Formula I from compound of formula II.

We have surprisingly found that compound of formula I can be prepared in good yield and high purity by cyclisation of compound of formula II with urea.

This cyclisation of compound of formula II is effected in a suitable reaction media which includes aromatic hydro carbons, aqueous alcohols, ketones and ethers etc.

Preferably, the above cyclisation is conducted in polar solvents like acetonitrile and aromatic hydrocarbons like toluene, xylene etc. More preferably toluene.

Optionally, the above cyclisation is conducted in presence of an acid. The suitable acids may include mineral acids for example hydrochloric acid, sulphuric acids etc. organic acids like, para-toluenesulphonic acid, acetic acid and trifluoro acetic acid etc.

The cyclisation is conveniently effected at elevated temperatures, most conveniently at reflux temperature of the reaction mixture. The reaction may be conveniently carried out under an inert gas atmosphere like nitrogen.

After completion of the reaction as monitored by TLC, the reaction mixture was cooled to room temperature and then water was added. The obtained aqueous layer was extracted with toluene twice and the combined organic layer was concentrated under reduced pressure. The obtained residue was cooled to room temperature and triturated with methanol. After repeated tirturations the obtained solid was finally re crystallized from toluene and heptane mixtures to get (4S)-6-chloro-4-(cyclopropylethynyl)-l,4-dihydro-4-(trifluoromethyl)-2H-3,1 -benzoxazin-2-one (Efavirenz).

The efavirenz obtained by the above process is characterized by spectroscopic methods.
The compound of formula-II is prepared by the known methods in the literature.

Where it is desired to isolate compound of formula I as a physiologically acceptable salt, this may be formed by conventional methods for example by treatment with an appropriate acid in a suitable solvent.

The main advantage of this invention is the cyclisation of an amino alcohol with urea which is a cheap source and non-hazardous in nature.
While the foregoing written description of the invention enables one of ordinary skill to make and use what is considered presently to be the best mode thereof, those of ordinary skill will understand and appreciate the existence of variations, combinations and equivalents of the specific embodiment, method and examples herein. The invention should therefore not be limited by the above described embodiment, method and examples, but by all embodiments and methods within the scope and spirit of the invention.

EXAMPLE

A solution of (S)-5-chloro-a-(cyclopropylethynyl)-2-amino-a-(trifluoroethyl)benzene methanol(10 gm, 0.034 mole) and urea (2.48 gm, 0.0414 mole in toluene are refluxed in the presence of para-tolunesulphonic acid (PTSA) (0.31 gm, 0.0006 mole) for 20 hrs. After completion of the reaction as monitored by Thin Layer Chromatorgraphy (TLC), the reaction mixture was cooled to room temperature and then 30 ml of water was added. The obtained aqueous layer was extracted with toluene. The combined toluene layers were concentrated under reduced pressure. The obtained residue was cooled to room temperature and 30 ml of methanol was added and stirred. Methanol was distilled of to remove the toluene traces. Again methanol was added to the residue and cooled to 10-15 °C. To this residue water was added at 10-15 °C and stirred for 3 hrs. The obtained white solid was re crystallized in toluene and heptane mixture to get 9.2gms of (4S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1 -benzoxazin-2-one (Efavirenz).

Yield : 85 %, MR : 136-139°C, SOR -92.8°

CLAIMS:

1) A process for the preparation of compound of formula I

Which comprises reacting a compound of formula II

with a compound of formula III

2) The process according to claim 1, where the cyclisation of compound of formula II is carried out an organic solvent.

3) The process according to claim 2, where an organic solvent is aromatic hydrocarbons or aliphatic hydrocarbons.

4) The process according to claim 2, wherein an organic solvent is aromatic hydrocarbon like toluene, xylene and more preferably toluene.

5) The process according to claim 1, wherein the cyclisation is carried out optionally in the presence of an acid selected from hydrochloric acid, Sulphuric acid, trifluoro acetic acid and p-toluene sulphonic acid.

6) The process according to claim 5, where in the acid is para toluene sulphonic acid.