Indian Patents. 269133:" IMPROVED PROCESS FOR PREPARATION OF EFAVIRENZ "

Title of Invention	" IMPROVED PROCESS FOR PREPARATION OF EFAVIRENZ "
Abstract	A simple, cost-effective process for preparation of efavirenz of formula (1) comprising reacting a solution of 5-chloro-a-(cyclopropylethynyl)-2-amino-a-trifluoromethyl) benzene methanol of formula (1I) in an organic solvent with triphosgene in the presence of an inorganic base at a temperature range -5°C to 25°C, adding water and isolating compound of formula (1).

Full Text	FORM 2 THE PATENTS ACT 1970 (Act 39 of 1970) & THE PATENTS RULE, 2003 PROVISIONAL SPECIFICATION (SECTION 10 and Rule 13) "NOVEL PROCESS" Emcure Pharmaceuticals Limited., an Indian company, registered under the Indian Company's Act 1957 and having its registered office at THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION FIELD OF THE INVENTION The invention relates to a simple, cost-effective novel process for the preparation of a reverse transcriptase inhibitor. BACKGROUND OF THE INVENTION Acquired Immunodeficiency Syndrome (AIDS) is a fatal disease of the immune system transmitted through blood especially by sexual contact or contaminated needles and is presumed to be caused by the HIV virus, which is an RNA genetically unique retrovirus, having a gene not found to date in other retroviruses. One of the many drugs found to be active against HIV virus is efavirenz of formula (I), chemically known as (-)-6-chloro-4-cyclopropyl-etliynyl-4-trifluoromethyl-l,4-dmydro-2H-3.1-benzoxazin-2-one. Efavirenz maiketed as Sustiva is clinically active specifically against human immunodeficiency virus type 1 (HIV-1) and is a non-nucleoside, reverse transcriptase inhibitor. The activity of Efavirenz is mediated predominantly by non-competitive inhibition of HIV-1 RT without affecting HIV-2 RT and human cellular DNA polymerases alpha, beta, gamma and delta. Efavirenz was fust disclosed in US 5,519,021 (assigned to Merck). The patent discloses a method in which efavirenz (I) is obtained by reaction of 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-l,l,l-trifluoro-3-butyn-2-ol of formula (II) with a large excess of carbonyl diimidazole of formula (III) for obtaining the oxazinone ring. 2 (II) (I) The reaction solvent utilized is dry tetrahydrofuran, which has a tendency to develop peroxides during storage, In order to obtain dry telrahydrofuran flee of peroxides, purification and drying agents are required, and such process of purification and drying adds on to the cost. As reported in the well accepted literature, Textbook of Practical Organic. Chemistry - Vogel; 5th Edition, page 406-407 discloses use of solid potassium hydroxide followed by refluxing over calcium hydride or lithium aluminium hydride for drying teuahydrofuran. Also, the related note draws attention towards the hazards of drying with respect to peroxides during purification. The volume of tetrahydrofuran utilized is also about 16 times of starting material, which is also quite high for commercial use. The reaction is carried out at 55ºc and takes about 24 hours for completion. Further, the work up of the reaction involving distillation of tetrahydrofiiran is quite risky and dangerous due to the peroxides. The residue is redissolved in edhyl acetate and partitioned with water followed by re-extraction with ethyl acetate. The process also has an elaborate work up method requiring aqueous washings with dilute acid, alkaline solution and brine followed by separation of organic layer, drying over a drying agent and subsequent distillations, which consumes lot of time and utility. Moreover during such washings, tliere is a danger of fomiation of emulsion. This lowers the yield as in the case of US 5,519,021 to about 85%, thereby making the process unsuitable for commercial purpose. Therefore, US 5,519,021 suffers from various shortcomings such as: 1) Risk of using tetxahydrofuran, which is known to have an explosive nature due to its tendency to develop peroxides on storage, 2) Stringent condition such as an anhydrous atmosphere is required, as dry tetrahydrofuran is enroloyed as solvent for the reaction, 3 3) Large volume of tetrahydrofuran is required, 4) Long reaction time reduces the efficiency of the reaction and also increases the reactor occupancy, 5) Repeated washings with aqueous solvent such as dilute acid, alkaline solution and brine increases the load on the effluent treatment plant, 6) Tendency to form emulsion during alkaline work up reduces the yield. LIS 5,633,405 (assigned to Merck) discloses another process for obtaining an efavirenz derivative-of formula (VI) by reaction of the amino alcohol of formula (IV) with phosgene utilizing a mixture of toluene and telrahydrofuran as solvent and triethyl amine as a base. The use of tetrahydrofuran creates an additional step of purification for peroxide removal. Product isolation involves quenching with cold water, followed by extraction with yet another solvent like ethyl acetate. Based on the example, emulsion formed has to be broken with saturated brine solution. Emulsions generally take long tune for breaking, which affects me time cycle, reactor occupancy etc. Further washings of the organic layer are carried out with citric acid solution followed by brine solution. The organic layer thus obtained is dried over sodium sulphate and concentrated to give brown oil, which is then reciystalhzed from a 5:1 mixture of hexane: ethyl acetate to give the compound of formula (VI) in 85% yield. There is an additional step of deprotection of the nitrogen atom in the oxazinone ring of the compound of formula (VI) with a reagent like ceric ammonium nitrate to give efavirenz, which was isolated by column chromatography. 4 The process has the following disadvantages: 1) Reaction is carried out with a binary solvent mixture of toluene and tetrahydrofuran. Further, a third solvent like ethyl acetate is required for extraction to give the crude product. Also, a fourth solvent like hexane in combination with ethyl acetate is employed for purification of the product of formula (VI). Utilization of four different solvents leads to manifold increase in cost, raises the inventory of solvents and further also increases the load on the effluent due to the use of a water-miscible solvent like tetrahydrofuran. 2) The specification itself acknowledges that emulsification is an inherent part of the process. Isolation of any product from an emulsion is quite tedious and cumbersome on an industrial scale, leading to loss in yield. 3) The product obtained after such a laborious work-up requires to be purified by recrystallization. 4) Utilization of cerie ammonium nitrate in the final deprotection step to give efavirenz (I) generates an enormous load on effluent treatment as it is quite difficult to remove the heavy metal on a commercial scale. In short, the whole process is quite long, thereby reducing the overall efficiency of the process. This process has also been disclosed in Journal of Organic Chemistry 1998, 63, 8536-8543 and Tetrahedron Letters 1995, 56, 8937-8940. US 5,932,726 (assigned to DuPont) discloses a process for the preparation of efavirenz of formula (I) by reaction of the efavirenz intermediate (II) with phosgene in a solvent such as heptane, toluene and tetrahydrofuran or mixtures thereof. The preferred solvent is a mixture of heptane and tetrahydrofuran. During the reaction a third solvent like methanol is added. After the reaction heptane is added and the mixture partially concentrated. A mixture of heptane and tetrahydiofiiran is added and the resulting mixture washed with aqueous sodium bicarbonate solution followed by water. The mixture was wanned to 50°C and diluted with heptane to obtain the product. 5 The drawbacks of the process are: 1) Process requires three solvents, namely heptane, telrahydrofuran and methanol, Out of these 3 solvents, telrahydrofuran (65°C) and methanol (65°C), have identical boiling points, therefore recovery of these solvents in a pure form is quite difficult. Both these solvents are water-soluble; hence recovery of these solvents based on their water solubility also is not possible, 2) Tlie total volume of the solvents required for the reaction and before isolation is about 12 times the batch size. Isolation of the product requires an additional 9.0 times volume of a mixture of heptane and letrahydrofuran. Therefore, the total volume required is about 21 times the batch size, which is quite high for reactions to be carried out on a large scale, leading to considerable cost escalation. 3) work-up involves distillation of tetrahydrofuran, which is very dangerous due to its explosive nature associated with peroxide formation during storage, 4) work up involves washing with dilute alkali solution wherein there is a tendency for emulsification, which is quiet, tedious to remove on a commercial scale. Eniulsification reduces die yield and demulsification consumes lot of time and energy on a large scale, Therefore, the process disclosed in US 5,932,726 is quite costly due to the large amount of solvents, and is also lengthy, laborious and cumbersome for industrial scale. Synthesis 2000, 4, 479-495 and Journal of Organic Chemistry 199S, 63(23) S536-S543 also discloses a similar process for the preparation of the henzoxazmoue ring for the preparation of efavirenz of formula (I). 6 US 6,147,210 (assigned to DuPont Pharmaceuticals) discloses a process in which the desired benzoxazinone ring was obtained comprising reaction of compound of fomiula (VII) in toluene / hexane mixture utilizing n-butyl lithium as base. The reaction was refluxed for 4 hours for completion of reaction. The product was isolated by quenching with a mixture of 5% acetic acid and t-butyl methyl ether. The organic layer was separated, washed twice with sodium chloride solution and concentrated to get a residue from which the product was isolated by addition of heptane. This process has the following drawbacks: 1) The reaction requires about 5.5 times of a solvent mixture of toluene and acetonitrile followed by 5 times volume the batch size each of 5% acetic acid solution and methyl t-butyl ether. Also an additional 5 times of a third solvent like heptane is added during isolation of the product. Thus, the total volume of solvent required is about 20 times the batch size, reduces the batch size, increases the time cycle for each batch run and reduces the efficiency of the process. 2) Utilization of four solvents such as toluene, hexane, methyl tert-butyl ether and heptane increases the inventory of solvents. Further, the use of methyl tert-butyl ether as a solvent finds limited use due to environmental and health concerns as it easily pollutes ground water http://en.wikipedia.org/wiki/Metthvl tert-butyl ether, 3) Successive washings with sodium chloride solution during isolation of compound of fomiula (I) suggests that diere is a distinct possibility of emulsion formation during work up. All these shortcomings dissuade the use of the above disclosed process for preparation of efavirenz on an industrial scale. Synthetic Communications 27(24), 4373-4384 (1997) also reports a similar process. 7 US 6,015,926 (assigned to Merck & Co) discloses a process for the preparation of efavirenz by reaction of amino alcohol of formula (II) with phosgene utilizing methyl tert-bulyl ether or toluene as solvent and aqueous potassium bicarbonate solution. After the reaction, the organic layer is separated and after brine washing is concentrated. Efavirenz of formula (I) is isolated after the addition of ethanol or isopropanol to the residue. The crude efavirenz thus obtained is reciystallized by dissolving in isopropanol and adding water. Use of methyl tert-butyl ether is generally not preferred on a commercial scale due to environmental hazards and health concerns. Further, the reaction and isolation of efavirenz (I) requires solvents such as i) toluene or methyl tert-butyl ether during reaction, ii) ethanol or isopropanol dining isolation and iii) mixture of isopropanol and water during recrystallization of efavirenz (I). The requirement of multiple solvents increases the inventoiy and mcrease the process cost considerably. US 6,114,569 (assigned to Merck) discloses a process in winch the benzoxazinone ring is formed by reaction of the carbamate derivative of an efavirenz intermediate of formula (VIII) in the presence of an aqueous solution of a base utilizing a solvent from the group selected frorn methyl t-butyl ether, toluene, tetrahydrofuran, aeetonitrile, dimethyl acetamide, N-methylpyrrolidinone or mixtures thereof. 8 The reaction utilizes a liigh amoimt of solvent like teuahydrofuran, upto 14 times the batch size for the reaction. After the reaction the mixture is quenched with a very dilute aqueous solution of a base (21 times), followed by addition of a second solvent like methyl tert-butyl edier (14 times). After the base treatment, the organic layer was concentrated and the residue diluted with ethanol or isopropanol for isolation of the impure product of fomiula (I), wliich is then recrystallized from a high dilution (about 110 times) of an aqueous solution of isopropanol or ethanol. This process although not utilizing phosgene for the preparation of the benzoxazinone ring has the following disadvantages: i) requires a solvent dilution of upto 14 times of the batch size during the reaction. Quenching is done with an additional 21 times batch size of an aqueous solution of an inorganic base. A second solvent such as methyl tert-butyl edier is added in up to 14 times dilution. This raises the total volume to about 50 times, wliich is exorbitantly high for commercial scale. Such high volumes drastically reduces the batch size, ii) Distillation of such high volume of solvent during isolation increases the time cycle for each batch run, consumes enormous amount of time, energy such that tile efficiency of the process gets phenomenally reduced, iii) The compound of formula (I) thus isolated with enormously liigh dilution of solvent requires an additional recrystallization thus introducing an additional step of purification and also raises the cost tremendously. 9 Based on the foregoing, it is evident that prior art has the following drawbacks: 1) Requires anhydrous reaction condition. Further, utilization of solvents like tetrahydrofuran, which are prone to develop peroxides on storage, requires solvent purification for removing the peroxides. 2) Requires high dilution of solvents, which reduce the batch size, increases the distillation time, eventually increasing the time cycle for each run, thereby reducing the efficiency of the process. 3) Utilization of multiple solvents for obtaining compound of formula (I) increases the solvent inventory reduces the possibility of obtaining a pure solvent for reuse when boiling points are close. Use of multiple solvents also increases the process cost considerably. 4) Emulsion formation during work up significantly reduces the yield or requires enormous time for de-emulsification. 5) Efavirenz of formula (I) isolated after the cyclization require an additional step of purification for obtaining the desired form of Efavirenz. 6) Utilization of a reagent like ceric ammonium nitrate for deprotection of the nitrogen atom in the oxazinone ring drastically increases the load on the effluent treatment due to heavy metal contamination. OBJECT OF THE INVENTION An object of the invention is to provide a simple, efficient and cost-effective process for the preparation of efavirenz of formula (I) without the utilization of multiple organic solvents. Another object of the invention is to provide efavirenz of formula (I) having phamraeeutically acceptable purity and with quantitative yield without an additional step of purification. Yet another object of the invention is to provide efavirenz of formula (I) by reducing the solvent volume, processing time for each batch cycle and utilizing a simple work up procedure for isolation of efavirenz of formula (I). 10 SUMMARY OF THE INVENTION One aspect of the invention relates to a process for preparing efavirenz of fonnnla (I) comprising reaction of a compound of formula (II) with triphosgene in an organic solvent, in the presence of a base, adding water and isolating compound of formula (I). Another aspect of the invention relates to a process for preparing efavirenz of formula (I) comprising reaction of a compound of formula (II) with triphosgene in acetonitrile, in the presence of an aqueous solution of an inorgamic base, adding water and isolating compound of formula (I). DETAILED DESCRIPTION OF THE INVENTION Tlie present inventors after noting the deficiency of prior art process have developed a simple cost-effective process, which has the following features: 1) Use of a single organic solvent for eyelization of the compound of formula (II) to give a compound of formula (I), 2) Absence of anhydrous or other stringent conditions like low temperature for completion of reaction and isolation of product, 3) Utilization of optimal amount of solvent during the reaction, 4) Does not require a reagent like ceric ammonium nitrate for obtaining efavirenz of formula (I), thereby reducing the load considerably on the effluent, 5) Obviate the necessity for having an additional step of purification after isolation of compound of formula (I) from the reaction, 6) Absence of any extraction step or possibility of emulsion formation during isolation, 7) Obtaining the desired form of Efavirenz (I) directly from the reaction in one-pot. The present hivention relates to a novel process for the preparation of efavirenz of formula (I) by a process comprising reaction of 5-chloro- α-(eyclopropyl ethynyl)-2-amino-a-(vrifluoromethyl)benzenemethanol of formula (II) with triphosgene in an organic solvent and in the presence of a base. After completion of the reaction, the reaction was 11 quenched with a base. Water was then added to the reaction mixture and the product separating out was filtered and dried. The product of formula (I) was obtained in quantitative yield with purity conforming to pharmacopeial specification. The product thus isolated did not require any further puiification for preparing the desired form of efavirenz (I). (II) (I) In an embodiment, 5-chloro-a-(cyclopropylemynyl)-2-amino- α-(trifluoromethyl)benzene methanol of formula (II) was added to an organic solvent. The organic solvent is a water-miscible solvent selected from the group comprising of nitriles, ketones etc. The solvent added was between 1.0 volume and 3.0 volumes per gram of compound of formula (II). Triphosgene of foiinula (V) dissolved in the same organic solvent was added to the mixture of compound of formula (II). Triphosgene as compared to phosgene gas is a crystalline solid and is very easy to handle on an industrial scale. After completion of reaction, (he nrixture was neiilralized with an aqueous solution of an inorganic base. Water was then added to the reaction mixture. The compound of formula (I) separating out was filtered washed with water and dried. 12 Efavirenz of formula (I) was isolated in quantitative yield and was found to conform to pharmacopeial specification. Efavirenz of formula (I) thus isolated did not require any further reerystallizations or purification for obtaining the desired fonn of Efavirenz of formula (I). Efavirenz of formula (I) had X-ray diffraction (20) values and Differential Scanning Calorimetry data conforming to Form I of Efavirenz of fomiula (I). The following examples are meant to be illusliative of the present invention. Tliese examples exemplify the invention and are not be construed as limiting the scope of the invention. 13 Example (S)-5-Chloro- α-(cyclopropylethynyl)-2-annno- α -(trifluoromethyl) benzene methanol (lOOgms; 0.345 moles) was added to acetonitrile (100ml) in a 1000 ml flask, under continuous purging of nitrogen. Sodium bicarbonate (42.30 gms) dissolved in water (200 ml) was added to the flask at 25 to 30°C and the mixture cooled to -10°C. Triphosgene was dissolved in acetomtiile (50 gms; 0.168 moles in 200 ml of acetonitrile) and added to the reaction mixture between -10 and -5°C. The reaction mixture was stirred for 1 hour at -10 to -5°C and further stilted at 20-25°C till completion of reaction as monitored by HPLC. The reaction mixture was neutralized with sodium caibonate solution (30 gms in 100 ml DM water). Water (150ml) was then gradually added to the reaction mixture at room temperature. The mixture was cooled to 10°C to 15°C, and filtered. The wet cake was washed with DM water (400 ml) and dried under vacuum. Yield: 106 gms. % Yield: 97.25. Purity: 99.72%. Dated Twenty nine (29th ) this day of May, 2008. Umesh Zope Registered Patent Agent For, Emcure Pharmaceuticals Ltd. 14

Full Text

FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
PROVISIONAL SPECIFICATION
(SECTION 10 and Rule 13)
"NOVEL PROCESS"

Emcure Pharmaceuticals Limited.,
an Indian company, registered under the Indian Company's Act 1957
and having its registered office at
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION

FIELD OF THE INVENTION
The invention relates to a simple, cost-effective novel process for the preparation of a reverse transcriptase inhibitor.
BACKGROUND OF THE INVENTION
Acquired Immunodeficiency Syndrome (AIDS) is a fatal disease of the immune system transmitted through blood especially by sexual contact or contaminated needles and is presumed to be caused by the HIV virus, which is an RNA genetically unique retrovirus, having a gene not found to date in other retroviruses.
One of the many drugs found to be active against HIV virus is efavirenz of formula (I), chemically known as (-)-6-chloro-4-cyclopropyl-etliynyl-4-trifluoromethyl-l,4-dmydro-2H-3.1-benzoxazin-2-one. Efavirenz maiketed as Sustiva is clinically active specifically against human immunodeficiency virus type 1 (HIV-1) and is a non-nucleoside, reverse transcriptase inhibitor. The activity of Efavirenz is mediated predominantly by non-competitive inhibition of HIV-1 RT without affecting HIV-2 RT and human cellular DNA polymerases alpha, beta, gamma and delta.

Efavirenz was fust disclosed in US 5,519,021 (assigned to Merck). The patent discloses a method in which efavirenz (I) is obtained by reaction of 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-l,l,l-trifluoro-3-butyn-2-ol of formula (II) with a large excess of carbonyl diimidazole of formula (III) for obtaining the oxazinone ring.
2

(II) (I)
The reaction solvent utilized is dry tetrahydrofuran, which has a tendency to develop peroxides during storage, In order to obtain dry telrahydrofuran flee of peroxides, purification and drying agents are required, and such process of purification and drying adds on to the cost. As reported in the well accepted literature, Textbook of Practical Organic. Chemistry - Vogel; 5th Edition, page 406-407 discloses use of solid potassium hydroxide followed by refluxing over calcium hydride or lithium aluminium hydride for drying teuahydrofuran. Also, the related note draws attention towards the hazards of drying with respect to peroxides during purification. The volume of tetrahydrofuran utilized is also about 16 times of starting material, which is also quite high for commercial use.
The reaction is carried out at 55ºc and takes about 24 hours for completion. Further, the work up of the reaction involving distillation of tetrahydrofiiran is quite risky and dangerous due to the peroxides. The residue is redissolved in edhyl acetate and partitioned with water followed by re-extraction with ethyl acetate. The process also has an elaborate work up method requiring aqueous washings with dilute acid, alkaline solution and brine followed by separation of organic layer, drying over a drying agent and subsequent distillations, which consumes lot of time and utility. Moreover during such washings, tliere is a danger of fomiation of emulsion. This lowers the yield as in the case of US 5,519,021 to about 85%, thereby making the process unsuitable for commercial purpose.
Therefore, US 5,519,021 suffers from various shortcomings such as:
1) Risk of using tetxahydrofuran, which is known to have an explosive nature due to its tendency to develop peroxides on storage,
2) Stringent condition such as an anhydrous atmosphere is required, as dry tetrahydrofuran is enroloyed as solvent for the reaction,
3

3) Large volume of tetrahydrofuran is required,
4) Long reaction time reduces the efficiency of the reaction and also increases the reactor occupancy,
5) Repeated washings with aqueous solvent such as dilute acid, alkaline solution and brine increases the load on the effluent treatment plant,
6) Tendency to form emulsion during alkaline work up reduces the yield.
LIS 5,633,405 (assigned to Merck) discloses another process for obtaining an efavirenz derivative-of formula (VI) by reaction of the amino alcohol of formula (IV) with phosgene utilizing a mixture of toluene and telrahydrofuran as solvent and triethyl amine as a base. The use of tetrahydrofuran creates an additional step of purification for peroxide removal.
Product isolation involves quenching with cold water, followed by extraction with yet another solvent like ethyl acetate. Based on the example, emulsion formed has to be broken with saturated brine solution. Emulsions generally take long tune for breaking, which affects me time cycle, reactor occupancy etc. Further washings of the organic layer are carried out with citric acid solution followed by brine solution. The organic layer thus obtained is dried over sodium sulphate and concentrated to give brown oil, which is then reciystalhzed from a 5:1 mixture of hexane: ethyl acetate to give the compound of formula (VI) in 85% yield.

There is an additional step of deprotection of the nitrogen atom in the oxazinone ring of the compound of formula (VI) with a reagent like ceric ammonium nitrate to give efavirenz, which was isolated by column chromatography.
4

The process has the following disadvantages:
1) Reaction is carried out with a binary solvent mixture of toluene and tetrahydrofuran. Further, a third solvent like ethyl acetate is required for extraction to give the crude product. Also, a fourth solvent like hexane in combination with ethyl acetate is employed for purification of the product of formula (VI). Utilization of four different solvents leads to manifold increase in cost, raises the inventory of solvents and further also increases the load on the effluent due to the use of a water-miscible solvent like tetrahydrofuran.
2) The specification itself acknowledges that emulsification is an inherent part of the process. Isolation of any product from an emulsion is quite tedious and cumbersome on an industrial scale, leading to loss in yield.
3) The product obtained after such a laborious work-up requires to be purified by recrystallization.
4) Utilization of cerie ammonium nitrate in the final deprotection step to give efavirenz (I) generates an enormous load on effluent treatment as it is quite difficult to remove the heavy metal on a commercial scale. In short, the whole process is quite long, thereby reducing the overall efficiency of the process.
This process has also been disclosed in Journal of Organic Chemistry 1998, 63, 8536-8543 and Tetrahedron Letters 1995, 56, 8937-8940.
US 5,932,726 (assigned to DuPont) discloses a process for the preparation of efavirenz of formula (I) by reaction of the efavirenz intermediate (II) with phosgene in a solvent such as heptane, toluene and tetrahydrofuran or mixtures thereof. The preferred solvent is a mixture of heptane and tetrahydrofuran. During the reaction a third solvent like methanol is added. After the reaction heptane is added and the mixture partially concentrated. A mixture of heptane and tetrahydiofiiran is added and the resulting mixture washed with aqueous sodium bicarbonate solution followed by water. The mixture was wanned to 50°C and diluted with heptane to obtain the product.
5

The drawbacks of the process are:
1) Process requires three solvents, namely heptane, telrahydrofuran and methanol, Out of these 3 solvents, telrahydrofuran (65°C) and methanol (65°C), have identical boiling points, therefore recovery of these solvents in a pure form is quite difficult. Both these solvents are water-soluble; hence recovery of these solvents based on their water solubility also is not possible,
2) Tlie total volume of the solvents required for the reaction and before isolation is about 12 times the batch size. Isolation of the product requires an additional 9.0 times volume of a mixture of heptane and letrahydrofuran. Therefore, the total volume required is about 21 times the batch size, which is quite high for reactions to be carried out on a large scale, leading to considerable cost escalation.
3) work-up involves distillation of tetrahydrofuran, which is very dangerous due to its explosive nature associated with peroxide formation during storage,
4) work up involves washing with dilute alkali solution wherein there is a tendency for emulsification, which is quiet, tedious to remove on a commercial scale. Eniulsification reduces die yield and demulsification consumes lot of time and energy on a large scale,
Therefore, the process disclosed in US 5,932,726 is quite costly due to the large amount of solvents, and is also lengthy, laborious and cumbersome for industrial scale.
Synthesis 2000, 4, 479-495 and Journal of Organic Chemistry 199S, 63(23) S536-S543 also discloses a similar process for the preparation of the henzoxazmoue ring for the preparation of efavirenz of formula (I).
6

US 6,147,210 (assigned to DuPont Pharmaceuticals) discloses a process in which the desired benzoxazinone ring was obtained comprising reaction of compound of fomiula (VII) in toluene / hexane mixture utilizing n-butyl lithium as base. The reaction was refluxed for 4 hours for completion of reaction. The product was isolated by quenching with a mixture of 5% acetic acid and t-butyl methyl ether. The organic layer was separated, washed twice with sodium chloride solution and concentrated to get a residue from which the product was isolated by addition of heptane.

This process has the following drawbacks:
1) The reaction requires about 5.5 times of a solvent mixture of toluene and acetonitrile followed by 5 times volume the batch size each of 5% acetic acid solution and methyl t-butyl ether. Also an additional 5 times of a third solvent like heptane is added during isolation of the product. Thus, the total volume of solvent required is about 20 times the batch size, reduces the batch size, increases the time cycle for each batch run and reduces the efficiency of the process.
2) Utilization of four solvents such as toluene, hexane, methyl tert-butyl ether and heptane increases the inventory of solvents. Further, the use of methyl tert-butyl ether as a solvent finds limited use due to environmental and health concerns as it easily pollutes ground water http://en.wikipedia.org/wiki/Metthvl tert-butyl ether,
3) Successive washings with sodium chloride solution during isolation of compound of fomiula (I) suggests that diere is a distinct possibility of emulsion formation during work up. All these shortcomings dissuade the use of the above disclosed process for preparation of efavirenz on an industrial scale.
Synthetic Communications 27(24), 4373-4384 (1997) also reports a similar process.
7

US 6,015,926 (assigned to Merck & Co) discloses a process for the preparation of efavirenz by reaction of amino alcohol of formula (II) with phosgene utilizing methyl tert-bulyl ether or toluene as solvent and aqueous potassium bicarbonate solution. After the reaction, the organic layer is separated and after brine washing is concentrated. Efavirenz of formula (I) is isolated after the addition of ethanol or isopropanol to the residue. The crude efavirenz thus obtained is reciystallized by dissolving in isopropanol and adding water.

Use of methyl tert-butyl ether is generally not preferred on a commercial scale due to environmental hazards and health concerns. Further, the reaction and isolation of efavirenz (I) requires solvents such as
i) toluene or methyl tert-butyl ether during reaction,
ii) ethanol or isopropanol dining isolation and
iii) mixture of isopropanol and water during recrystallization of efavirenz (I).
The requirement of multiple solvents increases the inventoiy and mcrease the process cost considerably.
US 6,114,569 (assigned to Merck) discloses a process in winch the benzoxazinone ring is formed by reaction of the carbamate derivative of an efavirenz intermediate of formula (VIII) in the presence of an aqueous solution of a base utilizing a solvent from the group selected frorn methyl t-butyl ether, toluene, tetrahydrofuran, aeetonitrile, dimethyl acetamide, N-methylpyrrolidinone or mixtures thereof.
8

The reaction utilizes a liigh amoimt of solvent like teuahydrofuran, upto 14 times the batch size for the reaction. After the reaction the mixture is quenched with a very dilute aqueous solution of a base (21 times), followed by addition of a second solvent like methyl tert-butyl edier (14 times). After the base treatment, the organic layer was concentrated and the residue diluted with ethanol or isopropanol for isolation of the impure product of fomiula (I), wliich is then recrystallized from a high dilution (about 110 times) of an aqueous solution of isopropanol or ethanol.
This process although not utilizing phosgene for the preparation of the benzoxazinone ring has the following disadvantages:
i) requires a solvent dilution of upto 14 times of the batch size during the reaction. Quenching is done with an additional 21 times batch size of an aqueous solution of an inorganic base. A second solvent such as methyl tert-butyl edier is added in up to 14 times dilution. This raises the total volume to about 50 times, wliich is exorbitantly high for commercial scale. Such high volumes drastically reduces the batch size, ii) Distillation of such high volume of solvent during isolation increases the time cycle for each batch run, consumes enormous amount of time, energy such that tile efficiency of the process gets phenomenally reduced, iii) The compound of formula (I) thus isolated with enormously liigh dilution of solvent requires an additional recrystallization thus introducing an additional step of purification and also raises the cost tremendously.
9

Based on the foregoing, it is evident that prior art has the following drawbacks:
1) Requires anhydrous reaction condition. Further, utilization of solvents like tetrahydrofuran, which are prone to develop peroxides on storage, requires solvent purification for removing the peroxides.
2) Requires high dilution of solvents, which reduce the batch size, increases the distillation time, eventually increasing the time cycle for each run, thereby reducing the efficiency of the process.
3) Utilization of multiple solvents for obtaining compound of formula (I) increases the solvent inventory reduces the possibility of obtaining a pure solvent for reuse when boiling points are close. Use of multiple solvents also increases the process cost considerably.
4) Emulsion formation during work up significantly reduces the yield or requires enormous time for de-emulsification.
5) Efavirenz of formula (I) isolated after the cyclization require an additional step of purification for obtaining the desired form of Efavirenz.
6) Utilization of a reagent like ceric ammonium nitrate for deprotection of the nitrogen atom in the oxazinone ring drastically increases the load on the effluent treatment due to heavy metal contamination.
OBJECT OF THE INVENTION
An object of the invention is to provide a simple, efficient and cost-effective process for the preparation of efavirenz of formula (I) without the utilization of multiple organic solvents.
Another object of the invention is to provide efavirenz of formula (I) having phamraeeutically acceptable purity and with quantitative yield without an additional step of purification.
Yet another object of the invention is to provide efavirenz of formula (I) by reducing the solvent volume, processing time for each batch cycle and utilizing a simple work up procedure for isolation of efavirenz of formula (I).
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SUMMARY OF THE INVENTION
One aspect of the invention relates to a process for preparing efavirenz of fonnnla (I) comprising reaction of a compound of formula (II) with triphosgene in an organic solvent, in the presence of a base, adding water and isolating compound of formula (I).
Another aspect of the invention relates to a process for preparing efavirenz of formula (I) comprising reaction of a compound of formula (II) with triphosgene in acetonitrile, in the presence of an aqueous solution of an inorgamic base, adding water and isolating compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
Tlie present inventors after noting the deficiency of prior art process have developed a simple cost-effective process, which has the following features:
1) Use of a single organic solvent for eyelization of the compound of formula (II) to give a compound of formula (I),
2) Absence of anhydrous or other stringent conditions like low temperature for completion of reaction and isolation of product,
3) Utilization of optimal amount of solvent during the reaction,
4) Does not require a reagent like ceric ammonium nitrate for obtaining efavirenz of formula (I), thereby reducing the load considerably on the effluent,
5) Obviate the necessity for having an additional step of purification after isolation of compound of formula (I) from the reaction,
6) Absence of any extraction step or possibility of emulsion formation during isolation,
7) Obtaining the desired form of Efavirenz (I) directly from the reaction in one-pot.
The present hivention relates to a novel process for the preparation of efavirenz of formula (I) by a process comprising reaction of 5-chloro- α-(eyclopropyl ethynyl)-2-amino-a-(vrifluoromethyl)benzenemethanol of formula (II) with triphosgene in an organic solvent and in the presence of a base. After completion of the reaction, the reaction was
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quenched with a base. Water was then added to the reaction mixture and the product separating out was filtered and dried. The product of formula (I) was obtained in quantitative yield with purity conforming to pharmacopeial specification. The product thus isolated did not require any further puiification for preparing the desired form of efavirenz (I).

(II) (I)
In an embodiment, 5-chloro-a-(cyclopropylemynyl)-2-amino- α-(trifluoromethyl)benzene methanol of formula (II) was added to an organic solvent.
The organic solvent is a water-miscible solvent selected from the group comprising of nitriles, ketones etc.
The solvent added was between 1.0 volume and 3.0 volumes per gram of compound of formula (II).
Triphosgene of foiinula (V) dissolved in the same organic solvent was added to the mixture of compound of formula (II). Triphosgene as compared to phosgene gas is a crystalline solid and is very easy to handle on an industrial scale.
After completion of reaction, (he nrixture was neiilralized with an aqueous solution of an inorganic base.
Water was then added to the reaction mixture. The compound of formula (I) separating out was filtered washed with water and dried.
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Efavirenz of formula (I) was isolated in quantitative yield and was found to conform to pharmacopeial specification.
Efavirenz of formula (I) thus isolated did not require any further reerystallizations or purification for obtaining the desired fonn of Efavirenz of formula (I).
Efavirenz of formula (I) had X-ray diffraction (20) values and Differential Scanning Calorimetry data conforming to Form I of Efavirenz of fomiula (I).
The following examples are meant to be illusliative of the present invention. Tliese examples exemplify the invention and are not be construed as limiting the scope of the invention.
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Example
(S)-5-Chloro- α-(cyclopropylethynyl)-2-annno- α -(trifluoromethyl) benzene methanol (lOOgms; 0.345 moles) was added to acetonitrile (100ml) in a 1000 ml flask, under continuous purging of nitrogen. Sodium bicarbonate (42.30 gms) dissolved in water (200 ml) was added to the flask at 25 to 30°C and the mixture cooled to -10°C. Triphosgene was dissolved in acetomtiile (50 gms; 0.168 moles in 200 ml of acetonitrile) and added to the reaction mixture between -10 and -5°C. The reaction mixture was stirred for 1 hour at -10 to -5°C and further stilted at 20-25°C till completion of reaction as monitored by HPLC. The reaction mixture was neutralized with sodium caibonate solution (30 gms in 100 ml DM water). Water (150ml) was then gradually added to the reaction mixture at room temperature. The mixture was cooled to 10°C to 15°C, and filtered. The wet cake was washed with DM water (400 ml) and dried under vacuum. Yield: 106 gms. % Yield: 97.25. Purity: 99.72%.
Dated Twenty nine (29th ) this day of May, 2008.

Umesh Zope Registered Patent Agent For, Emcure Pharmaceuticals Ltd.
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Documents:

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Patent Number

269133

Indian Patent Application Number

1155/MUM/2008

PG Journal Number

41/2015

Publication Date

09-Oct-2015

Grant Date

01-Oct-2015

Date of Filing

30-May-2008

Name of Patentee

EMCURE PHARMACEUTICALS LIMITED,

Applicant Address

EMCURE HOUSE, T-184, M.I.D.C., BHOSARI, PUNE-411026

Inventors:

#	Inventor's Name	Inventor's Address
1	GURJAR MUKUND KESHAV	EMCURE PHARMACEUTICALS LIMITED, P-1, IT-BT PARK, PHASE-II, MIDC., HINJWADI, PUNE-411057
2	DESHMUKH ABDULRAKHEEB ABDULSUBHAN	EMCURE PHARMACEUTICALS LIMITED, P-1, IT-BT PARK, PHASE-II, MIDC., HINJWADI, PUNE-411057
3	DESHMUKH SANJAY SHANKAR	EMCURE PHARMACEUTICALS LIMITED, P-1, IT-BT PARK, PHASE-II, MIDC., HINJWADI, PUNE-411057
4	MEHTA SATISH RAMANLAL	EMCURE PHARMACEUTICALS LIMITED, P-1, IT-BT PARK, PHASE-II, MIDC., HINJWADI, PUNE-411057

PCT International Classification Number

C07D265/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA