DESC:Field of Invention
The present invention relates to a new process for preparing (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one, known as efavirenz, a highly potent non-nucleoside reverse transcriptase inhibitor (NNRTI). The present invention also relates to novel intermediates for the synthesis of efavirenz and processes for preparing the same.

Background of the Invention
The present invention is directed to a new process for the synthesis of benzoxazinone compounds, particularly efavirenz, a non-nucleoside reverse transcriptase inhibitor useful for the treatment of Human Immunodeficiency Virus (HIV).
Non-nucleoside reverse-transcriptase inhibitors are antiretroviral drugs used in the treatment of HIV infection. They act by inhibiting reverse transcriptase, an enzyme that controls the replication of the genetic material of HIV. Many compounds are effective in the treatment of HIV which is the retrovirus that causes progressive destruction of the human immune system. Effective treatment through inhibition of HIV reverse transcriptase is known for non-nucleoside based inhibitors. Benzoxazinones have been found to be useful non-nucleoside based inhibitors of HIV reverse transcriptase.
Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) approved by FDA on Sep 17, 1998, sold under the trade name, SUSTIVA® in the form of oral capsules. As per the label approved by FDA, it is used as such and in combination with other antiretroviral agents for the treatment of HIV infection. The activity of Efavirenz is mediated predominantly by non-competitive inhibition of HIV-1 reverse transcriptase (RT) without affecting HIV-2 RT and human cellular DNA polymerases alpha, beta, gamma and delta.
Efavirenz is chemically described as (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its empirical formula is C14H9ClF3NO2 and has a structural formula:

The following discussion of prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Efavirenz is first disclosed in US patent no. 5,519,021 which mentions process for the preparation of Efavirenz which involves cyclisation of racemic mixture of 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol using 1,1’-carbonyl diimidazole as carbonyl delivering agent to give racemic efavirenz. Further, resolution of the racemic efavirenz is carried out using (-) camphanic acid chloride to yield optically pure efavirenz.
U.S patent no. 5,633,405 discloses another process for obtaining efavirenz which involves reaction of an amino alcohol (I) with phosgene in a mixture of toluene and tetrahydrofuran as solvent and triethyl amine as a base to give a protected compound (II), which on deprotection gives efavirenz, said process may be shown as follows:

US patent no. 5,922,864 discloses a process comprising cyclizing an amino alcohol intermediate using alkyl or aryl chloroformates such as 4-nitrophenyl chloroformate, methyl chloroformate and ethyl chloroformate.
U.S patent no. 5,932,726 discloses a process for the preparation of efavirenz of formula I which involves reaction of the efavirenz intermediate of formula II with phosgene in a solvent such as heptane, toluene and tetrahydrofuran or mixtures thereof. The process is shown as follows:

US patent no. 5,952,528 discloses an efficient process for preparation of chiral amino alcohol by addition of n-butyl lithium and cyclopropylacetylene to a ketone in presence of a chiral organozinc complex comprising of chiral additive and dialkyl zinc. Alternatively, the chiral amino alcohol is prepared by adding chloromagnesium complex of cyclopropylacetylene to the ketone in presence of the chiral organozinc complex.

U.S patent no. 6,015,926 discloses a process for the preparation of efavirenz, which involves reaction of amino alcohol with phosgene in methyl tert-butyl ether or toluene as solvent and aqueous potassium bicarbonate solution.

U.S patent no. 6,114,569 discloses a process in which the benzoxazinone ring is formed by reaction of the carbamate derivative of an efavirenz intermediate in the presence of an aqueous solution of a base in a solvent selected from the group consisting of MTBE, toluene, tetrahydrofuran, acetonitrile, dimethylacetamide, N-methylpyrrolidinone or mixtures thereof.


However, this process involves the use of multiple solvents. The requirement of multiple solvents increases the inventory and hence the process cost considerably.
U.S patent no. 6,147,210 discloses a process in which the desired benzoxazinone ring was obtained by reaction of an intermediate (IV) in toluene / hexane mixture utilizing n-butyl lithium as base.

This reaction requires utilization of high volume of solvents which reduces the batch size, increases the time cycle for each batch run and reduces the efficiency of the process. Also the use of multiple solvents increases the inventory and the overall cost of the process. Further, n-butyl lithium, methyl tert-butyl ether, finds limited use due to environmental and health concern as they easily pollute ground water. All these shortcomings dissuade the use of the above disclosed process for the preparation of efavirenz on an industrial scale.
U.S patent no. 8,604,189 discloses a process for the preparation of efavirenz which comprise reaction of an amino alcohol intermediate (II) with triphosgene in an organic solvent and an inorganic base, neutralizing the reaction mixture, adding water and isolating the product. The product thus isolated does not require any further purification for preparing the desired form of efavirenz.

However, use of triphosgene is not advisable due to environmental hazards and health concerns.
U.S patent no. 8,710,218 describes a process wherein an optically pure (-)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol is reacted with carbonyl delivering agent selected from carbonyldiimidazole, diphenylcarbonate and triphosgene in tetrahydrofuran to give an optically pure (-)-6-chloro-4-cyclopropyl ethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (efavirenz).

PCT patent publication no WO2015/118515 describes process for the preparation of efavirenz, comprising reacting a compound (2) with 2,2,2-
trifluoroethanol or ethyl trifluoro acetic acid followed by the reaction with cyclopropyl acetylene in the presence of a Grignard reagent to give efavirenz.

International patent application no WO2015/129630 describes the preparation of (S)-2-(5-chloro-2-nitrophenyl)-4-cyclopropyl-1,1,1-trifluoro-but-3-yn-2-ol (2) as a key intermediate for efavirenz, wherein the process comprises reacting a compound of formula 1 with a trifluoromethyl trimethylsilane in the presence of a cinchona alkaloid phase transfer catalyst.

Based on the foregoing, it is evident that the prior art has the following drawbacks: a) costly, laborious processes which are cumbersome and not feasible for industrial scale production; b) use of multiple solvents and in high volumes increases the inventory and overall cost of the process, reducing the batch size, increases the time cycle for each run, thereby reducing the efficiency of the process and also increases the reactor occupancy; c) use of reagents such as triphosgene, diphosgene, methyl-tertiary butyl ether are not preferred on commercial scale due to environmental hazards and health concerns; d) cyclisation methods disclosed in the prior art have problems associated with the formation of by-products and require an additional purification step to prepare the desired form of the product; e) products obtained have an enantioselectivity of less than 50 % and with low purity.
In the view of the shortcomings of the prior art, there remains a need to develop an alternate route for preparing the benzoxazinone compounds with high enantioselectivity, and purity using less expensive and environment friendly reagents or solvents, which are feasible on a commercial scale.
The present inventors have surprisingly found an alternative new process for the synthesis of (-) 6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-1, 4-dihydro-2H-3, 1-benzoxazin-2-one (efavirenz) and novel intermediates thereof, overcoming the disadvantages of the prior art.
Object of invention
An object of the present invention is to provide a new process for preparing non-nucleoside reverse transcriptase inhibitor, efavirenz, represented by a compound of formula VI.

VI
Also, an object of the invention is to provide new compounds useful as intermediates for the synthesis of efavirenz, and preparation process thereof.
It is an object of the present invention to provide a new reaction route for preparing an optically pure compound, (-) 6-chloro-4-cyclopropylethynyl-4-trifluoro methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one preferably a reaction route which avoids the drawbacks of the prior art.
An object of the present invention is to provide a new process utilizing a specific catalyst derived from alkaloids in the production of an NNRTI, particularly (-) 6-chloro4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3, 1-benzoxazin-2-one, thereby providing a green alternative approach for the synthesis.
The main objective of the present invention is to provide a cost-effective and commercially feasible process for the preparation of efavirenz, avoiding the use of multiple solvents in large volumes.
It is also an object of the invention to provide a new process for preparing efavirenz, having pharmaceutically acceptable purity and with quantitative yields. Another objective of the present invention is to provide a process for the preparation of Efavirenz which employs less expensive, easily available and environment friendly A further object of the invention is to provide a new process for the preparation of efavirenz, useful for the preparation of medicaments for the treatment of diseases and conditions influenced by the inhibition of reverse transcriptase.
Summary of Invention
The present invention provides a new cost-effective, highly enantioselective process for the preparation of efavirenz, represented by a compound of formula VI.

VI
In one embodiment, the present invention provides a new process for the preparation of efavirenz, which comprises the steps of:
a) Acylating 4-chloroaniline, represented by a compound of formula I, with a chloroformate compound of formula Ia,

wherein R denotes a C1-6 alkyl or an aryl group, to obtain a compound of formula II. In preferred embodiments, the alkyl group is methyl, ethyl, isobutyl, npentyl, benzyl and an aryl group is preferably phenyl and pentachlorophenyl.

b) Reacting a compound of formula II with a compound of formula IIb in the presence of a lewis acid and a suitable solvent to form a compound of formula III, where R is defined as herein before. In preferred embodiments, a lewis acid is selected from aluminium chloride, iron (III) chloride, tin (IV) chloride and borontrifluoride etherate.

Further the compound of formula IIb is prepared by reacting a compound of formula IIa with inorganic acid chloride in dichloromethane. In preferred embodiments, the inorganic acid chloride is selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride and oxalyl chloride.

c) Contacting a compound of formula III with an organosilicon compound in the presence of a cinchona alkaloid based catalyst and a quaternary ammonium salt to give compound of formula IV, where R is defined as herein before.

In preferred embodiments, the organosilicon compound is trifluoromethyl trimethylsilane and the quaternary ammonium salt is tetramethyl ammonium fluoride (TMAF). The reaction may be carried out in one or more organic solvents or a mixtures thereof;
d) Treating a compound of formula IV with tetra butyl ammonium fluoride (TBAF) in suitable solvent at room temperature, wherein the hydroxy protecting group is cleaved to yield a compound of formula V, where R is defined as herein before.

e) Reacting a compound of formula V with suitable base, where it undergoes cyclisation to yield a compound of formula VI (efavirenz). Suitable bases are sodium methoxide, sodium ethoxide in methanol and ethanol respectively.

In a second embodiment, the present invention provides a novel compound of formula III, useful as an intermediate for the synthesis of efavirenz,

where R is methyl, ethyl, isobutyl, npentyl, benzyl and an aryl group is preferably phenyl and pentachlorophenyl..
In a third embodiment, the present invention provides a novel compound of formula IV, useful as an intermediate for the synthesis of efavirenz,

where R is methyl, ethyl, isobutyl, npentyl, benzyl and an aryl group is preferably phenyl and pentachlorophenyl.
In a fourth embodiment, the present invention provides a novel compound of formula V, useful as an intermediate for the synthesis of efavirenz,

where R is pentachlorophenyl.
In a fifth embodiment, the present invention provides a green synthetic approach, wherein the novel process for preparing efavirenz comprises using a cinchona derived quaternary ammonium salt for asymmetric phase transfer catalysis. Preferably, the cinchona derived alkaloid is a quinine based quaternary ammonium salt represented by a compound of formula A:

(A)
In the present context, the present invention provides a metal free catalytic process for the synthesis of efavirenz in 99% enantiomeric excess, which may be achieved by an enantioselective quinine based alkaloid chiral catalyst.
In a sixth embodiment, the present invention provides a new, economic, enantioselective process for the preparation of efavirenz, novel intermediates thereof and their use in the preparation of medicaments useful for the treatments of diseases and conditions for which it is indicated.
Detailed description of the invention
The present invention relates to a new process for the preparation of compound (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2one, represented by a compound of formula VI,

VI
Also described are the novel intermediates useful for the synthesis of efavirenz and the process for preparing the same.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
The term ‘'NNRTI’’ as used herein refers to non-nucleoside reverse transcriptase inhibitors, that are antiviral drugs used for the treatment of human immuno deficiency virus (HIV). NNRTIs inhibit reverse transcriptase, an enzyme that controls the replication of the genetic material of HIV. In the preferred embodiments of the invention, the NNRTI is efavirenz.
The term “efavirenz” as used herein encompasses both racemic and chiral forms of efavirenz.
As used herein, the term “protecting group” refers to a compound that is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or
“deprotection” occurs after the completion of the reaction or reactions in which it would interfere.
The term “alkyl” as used herein refers to a radical or a part of a radical as a straight or branched carbon chain, and is preferably a C1-6 alkyl.
The term “aryl” as used herein refers to a phenyl unsubstituted or optionally substituted.
As used herein, the term “enantiomeric excess” (ee) refers to the measurement of purity of chiral substances. It reflects the degree to which a sample contains one enantiomer in greater amounts than the other. By way of example, a racemic mixture has an ee of 0%, while a single completely pure enantiomer has an ee of 100%.
In an embodiment, the present invention provides a new process for the preparation of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1benzoxazin-2-one i.e., efavirenz, wherein the process comprises subjecting a compound of formula V to cyclization, as shown below.

Wherein in a compound of formula V, R denotes alkyl preferably methyl, ethyl, isobutyl, npentyl, benzyl and an aryl group is preferably phenyl and pentachlorophenyl; the process comprises reacting a compound of formula V with catalytic amount of a base.
According to present invention, cyclisation of the compound of formula V, is carried out in a suitable solvent to form compound of formula VI, preferable solvents being selected from methanol, ethanol in the presence of a base. The base is selected from sodium methoxide and sodium ethoxide.
In another embodiment, the present invention provides a new process for preparing a compound of formula V, where R is defined as herein before, said process comprises reacting a compound of formula IV with tetra butyl ammonium fluoride to cleave the hydroxy protecting group in the presence of suitable solvent at room temperature to form the compound of the formula V.

In the present context, preferable solvents are selected from tetrahydrofuran, acetone, ethyl acetate, dimethylformamide, acetonitrile, more preferably tetrahydrofuran, and acetone.
In another embodiment, the present invention provides a new process for preparing a compound of formula IV, where R is defined as hereinbefore, characterised in that a compound of formula III is reacted with an organosilicon compound in the presence of an alkaloid based asymmetric phase transfer catalyst and a suitable solvent to form a compound of formula IV. The reaction may be carried out in one or more solvents or mixtures thereof. Preferred solvents include toluene and dichloromethane (MDC).

Organosilicon compounds have emerged as highly competitive alternatives to transition metal catalysts due to the drawbacks of the inherent transition metal catalyzed organic transformations. The lack of toxicity, high chemical stability, and low molecular weight of organosilanes make them ideal for use. Of the widely available organosilane compounds, trifluoromethyl organosilanes are most commonly used in cross-coupling reactions and addition reactions. In preferred embodiments of the invention the organosilicon compound may be selected from trimethylsilyltrifluoromethane (TMSCF3) and triethylsilyltrifluoromethane (TESCF3). In most preferred embodiments, the organosilane compound is TMSCF3, commonly known as Ruppert-Prakash reagent.
Further, the novel process of the present invention comprises utilizing a catalytic amount of cinchona alkaloid derived quaternary ammonium salt for asymmetric catalysis.
Cinchona alkaloids are a group of natural products isolated from the bark of cinchona tree. The use of cinchona alkaloids as chiral resolving agents dates back to seventeenth century. The most interesting application of cinchona alkaloids in chemistry resides in their ability to promote enantioselective transformations in both homogeneous and heterogeneous catalyses. Of the widely known cinchona alkaloids, readily available and inexpensive alkaloids such as quinine, quinidine, cinchonine, and cinchonidine are among the most privileged chirality inducers in the area of asymmetric catalysis. In preferred embodiments of the invention, a quinine derived quaternary ammonium salt is used.

(A)
In another embodiment, the present invention provides a process for preparing a compound of formula III, where R is defined as herein before, said process comprising acylation of the compound of formula II in a suitable solvent in the presence of a lewis acid selected from aluminium chloride, iron (III) chloride, tin (IV) chloride and borontrifluoride etherate, more preferably aluminium chloride.

The solvent employed in the reaction may be selected from dichloromethane, chloroform. The preferable solvent is dichloromethane. The compound of formula IIb may be obtained by reacting a compound of formula IIa with an inorganic acid chloride, preferably with thionyl chloride in dichloromethane.

In another embodiment, the present invention provides a process for preparing a compound of formula II, said process comprises reacting 4-chloroaniline, represented by a compound of formula I,

with a compound of formula Ia,

Where R is alkyl group preferably methyl, ethyl, isobutyl, npentyl, benzyl and an aryl group is preferably phenyl and pentachlorophenyl. The reaction may be carried out using a suitable base in dichloromethane. In preferred embodiments, the suitable bases are selected from triethyl amine, tributylamine, and diisopropyl ethyl amine, more preferably triethyl amine is used.
In another embodiment, the present invention provides an improved process for preparing enantiomerically pure (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl -1,4-dihydro-2H-3,1-benzoxazin-2-one, wherein the process involves more than 80% enantiomeric excess of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro -2H-3,1-benzoxazin-2-one further enrichment to more than 99% by recrystallization using solvents such as dichloromethane, chloroform, toluene, heptane or mixtures thereof.
In another embodiment, the present invention provides a new process for the preparation of efavirenz i.e. (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4dihydro-2H-3,1-benzoxazin-2-one, and novel intermediates thereof and their use in the preparation of medicaments useful for the treatment of diseases or conditions influenced by inhibition of HIV reverse transcriptase.
The following scheme particularly describe the embodiments of the invention without limiting the scope thereof.

In preferred embodiments, the present invention provides the novel compounds represented as follows:

Further the new process for preparing efavirenz and novel intermediates thereof, according to the present invention are illustrated in the following examples. The following specific and non-limiting examples are to be construed as merely illustrative, and do not limit the present disclosure in any way whatsoever.

Examples
Example-1: Preparation of alkyl/aryl 4-chlorophenylcarbamates (II):
In a clean and dry 4 neck 1ltr RBF equipped with mechanical stirrer, charge 0.783 moles of 4-chloro aniline (I) and 5 vol of dichloromethane (MDC). Add 1.17 moles of triethylamine. Cool the reaction mass (RM) to 5-10 ºC and add alkyl or aryl chloroformate dropwise below 10 ºC for 1hr. Stir for 1 hr at 5-10 ºC. After completion of reaction charge 5 vol of water and stir for 30 min. Separate the aqueous and organic layers. Extract the aqueous layer twice with 2.5 vol of MDC. Combine the total organic layers and wash with water followed by brine solution. Concentrate the total organic layer to obtain the title product (85%).
Example-2: Preparation of alkyl/aryl 4-chloro-2-(3-cyclopropylpropioloyl)phenyl carbamates (III):
Take a clean and dry RBF equipped with mechanical stirrer, reflux condenser, additional funnel and nitrogen inlet outlet, charge 0.5657 moles of 3-cyclopropyl propionic acid and 5 vol of MDC. Cool the RM to 0-5 ºC. Add 0.59 moles of thionyl chloride slowly below 5 ºC. After completion of addition, stir for 20 min. Reflux the RM for 1 hr. After completion of reaction, distill out MDC to obtain oily compound. Charge another fresh 5 vol of MDC to the RM. Charge 0.53 moles of alkyl/aryl 4chlorophenylcarbamate (II). Cool the RM to 5-10 oC and add 0.57 moles of aluminium chloride in three portions. Stir the RM for 6h at room temperature (RT). Pour the RM into crushed ice containing concentrated hydrochloric acid. The organic layer is separated from aqueous layer and the aqueous layer extracted three times with MDC. The combined organic layers are washed twice with 10% sodium bicarbonate solution and once with brine solution. The organic layer is dried over anhydrous sodium sulfate and the solvent is distilled off completely under vacuum to obtain the title product (70%).
Example-3: Preparation of optically pure alkyl/aryl (4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-((trimethylsilyl)oxy)but-3-yn-2-yl)phenyl)carbamates (IV):
To a solution of 0.35 moles of alkyl/aryl (4-chloro-2-(3-cyclopropylpropioloyl)phenyl) carbamate(III) in 5 vol of toluene/MDC (1:1) add 0.175 moles of tetramethylammonium fluoride and 0.035 moles of the chiral catalyst, (1R,2S,4S,5R)-2-((R)-butoxy(6methoxyquinolin-4-yl)methyl)-1-((3,3'',5,5''-tetrakis(trifluoromethyl)-[1,1':3',1''terphenyl]-5'-yl)methyl)-5-vinylquinuclidin-1-ium bromide. The RM is cooled to -70oC under nitrogen atmosphere. To the RM, add 0.7 moles of trifluoromethyltrimethylsilane drop-wise over a period of 1h. After stirring the reaction mixture at the same temperature for 10 h, it is quenched with saturated aqueous ammonium chloride. Extract the aqueous layer with MDC, followed by washing the combined organic layers with brine, and dried over anhydrous sodium sulfate. Distill off the solvent completely under vacuum to obtain the title product. (88% yield) which may show optical purity of 82% ee.
Example-4: Preparation of alkyl/aryl 4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2hydroxybut-3-yn-2-yl) phenylcarbamate (V):
Take a clean and dry 4 neck 2ltr RBF equipped with mechanical stirrer, nitrogen inlet, charge alkyl/aryl (S)-(4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-((trimethylsilyl)oxy) but-3-yn-2-yl)phenyl)carbamate (IV) (0.24 mol) and 1 ltr of THF then stir for 20 min. Cool the RM to 0-5 ºC and slowly add 0.2856 mol of tetrabutylammonium fluoride below 5-10 ºC. Stir the RM at same temperature for 1h. After completion of reaction charge 500 ml of water below 30 ºC and 5 vol of ethyl acetate. Separate the organic layer and aqueous layer. Extract the aqueous layer 2 times with 2.5 vol of ethylacetate. Combine organic layers and wash with water followed by brine solution. The organic layer is dried over anhydrous sodium sulfate and distill off completely under vacuum to obtain the title product (81%).
Example-5: Preparation of (S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)1H-benzo[d] [1,3] oxazin-2(4H)-one (efavirenz, VI).
To a solution of sodium methoxide (0.225 mol) in 3 vol of methanol, add a solution of alkyl/aryl 4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl carbamate (V) in 4 vol of methanol at RT. The RM reflux for 3h and distill off the solvent completely under vacuum to obtain a residue. Add 5 vol of methyl tertiary butyl ether(MTBE) to the residue and stir at RT for 1h. Filter the reaction mass over a celite bed and distill off the solvent completely under vacuum to obtain the crude compound (94%) The crude product was recrystallized using chloroform and toluene (1:1) to obtain the title product (69%) with a purity of 99.7% by HPLC and in >99% ee.
Without being limited by theory, the processes according to the present invention may be advantageously used to prepare the complex compounds like Efavirenz and intermediates thereof. It is envisaged that by providing the alternative routes of synthesis of compounds or related compounds or intermediates of the present invention, the shelf life or stability of the product is enhanced and the impurity content of the product is decreased or rather controlled during the preparation of intermediates, thereby contributing to the overall efficacy of the product.
From the foregoing it will be understood that the embodiments of the present invention described above are well suited to provide the advantages set forth, and since many possible embodiments may be made of the various features of this invention, all without departing from the scope of the invention, it is to be understood that all matter hereinbefore set forth or shown in the description and synthetic schemes is to be interpreted as illustrative and that in certain instances some of the features may be used without a corresponding use of other features, all without departing from the scope of the invention.
,CLAIMS:We Claim,
1. A process for preparing 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one i.e., Efavirenz represented by a compound of formula VI, comprising subjecting a compound of formula V to cyclization in the presence of a base and solvent,

Wherein R represents a C1-6 alkyl group selected from the group consisting of methyl, ethyl, isobutyl, n-pentyl, and benzyl; or an aryl group selected from phenyl and pentachlorophenyl.
2. A process according to claim 1, wherein the base is an alkali metal alkoxide selected from sodium methoxide, sodium ethoxide, and the solvent is an alcoholic solvent.
3. A process for preparing a compound of formula V, comprising the steps:
(a) Reacting a compound of formula III with an organosilane in the presence of an alkaloid based asymmetric phase transfer catalyst and a suitable solvent to form a compound of formula IV;

(b) Reacting the compound of formula IV with tetra butyl ammonium fluoride in a solvent to cleave the silyl ether protecting group to form a compound of formula V;

Wherein R represents a C1-6 alkyl group selected from the group consisting of methyl, ethyl, isobutyl, n-pentyl, and benzyl; or an aryl group selected from phenyl and pentachlorophenyl.
4. A process according to claim 3, wherein in step (a) the organosilane is selected from trimethylsilyltrifluoromethane (TMSCF3) and triethylsilyltrifluoromethane (TESCF3); the alkaloid based asymmetric phase transfer catalyst is quinine derived quaternary ammonium salt represented by a compound of formula A;

(A)
Solvent in step (a) and step (b) is selected from acetone, acetonitrile, ethyl acetate, dimethylformamide, dichloromethane, tetrahydrofuran, and toluene.
5. A process for preparing a compound of formula III, wherein the process comprises the steps:
(a) Acylating 4-chloroaniline (I) with C1-6 alkyl or aryl chloroformate (Ia) in the presence of a base to form a compound of formula II;

(b) Reacting compound II with compound IIb in the presence of a Lewis acid and solvent to form compound of formula III,

Wherein R represents a C1-6 alkyl group selected from the group consisting of methyl, ethyl, isobutyl, n-pentyl, and benzyl; or an aryl group selected from phenyl and pentachlorophenyl.
6. A process according to claim 5, wherein the base in step (a) is selected from triethylamine, tributylamine, and diisopropyl ethyl amine; lewis acid in step (b) is selected from aluminium chloride, iron (III) chloride, tin (IV) chloride and borontrifluoride etherate; solvent in step (a) and (b) is selected from dichloromethane and chloroform.
7. Compound of formula III,

Where R is methyl, ethyl, isobutyl, n-pentyl, benzyl, phenyl and pentachlorophenyl.
8. Compound of formula IV,

Where R is methyl, ethyl, isobutyl, n-pentyl, benzyl, phenyl and pentachlorophenyl.
9. Compound of formula V,

Where R is methyl, ethyl, isobutyl, n-pentyl, benzyl, phenyl and pentachlorophenyl.