(12) INTERNATIONALAPPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 5 November 2009 (05.11.2009) WO 2009/133538 Al

(51) International Patent Classification: B. Vijayaraghavan, 600 College Road East, Suite 2100, COTD 265/18 (2006.01) Princeton, NJ 08540 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/IB2009/05 1796 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (22) International Filing Date: CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, 1 May 2009 (01 .05.2009) EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (25) Filing Language: English HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (26) Publication Language: English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, (30) Priority Data: NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, 1108/DEL/2008 1 May 2008 (01 .05.2008) IN SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US): RAN- BAXY LABORATORIES LIMITED [IN/IN]; Plot No. (84) Designated States (unless otherwise indicated, for every 90, Sector - 32, Gurgaon, Haryana 122001 (IN). kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (72) Inventors; and ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (75) Inventors/Applicants (for US only): MADHRA, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, Mukesh, Kumar [IN/IN]; H. No. 1036, Sector -06 Urban ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Estate, Karnal, Haryana 132001 (IN). SINGH, Pankaj, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), Kumar [IN/IN]; 23E/16 Dabauli, Kanpur, Uttar Pradesh OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, 208022 (IN). SHARMA, Mukesh [IN/IN]; D-1952 MR, NE, SN, TD, TG). Palam Vihar, Gurgaon, Haryana 122017 (IN). KHAN- Published: DURI, Chandra Has [IN/IN]; D-1952, Palam Vihar, Gurgaon, Haryana 122017 (IN). — with international search report (Art. 21(3)) (74) Common Representative: RANBAXY LABORATO¬ RIES LIMITED; Intellectual Property Department, c/o

(54) Title: PROCESS FOR THE PREPARATION OF EFAVIRENZ

(57) Abstract: The present invention relates to a process for the preparation of Efavirenz (Formula I), wherein triphosgene is used as a cyclizing agent. PROCESS FOR THE PREPARATION OF EFAVIRENZ

Field of the Invention The present invention relates to a process for the preparation of Efavirenz.

Background of the Invention Efavirenz is chemically (S)-6-chloro-4-(cyclopropylethynyl)-l,4-dihydro-4- (trifluoromethyl)-2H-3,l-benzoxazin-2-one of Formula I.

H

FORMULA I Efavirenz is a non-nucleoside, reverse transcriptase inhibitor and it is available in the market for the treatment of HIV-I infection. Efavirenz is prepared by cyclizing (2S)-2-(2-amino-5-chlorophenyl)-4- cyclopropyl-l,l,l-trifluorobut-3-yn-2-ol of Formula II.

FORMULA II

U.S. Patent Nos. 6,040,480 and 6,028,237 describe a method for cyclizing the compound of Formula II by dissolving said compound in a mixture of heptanes and tetrahydrofuran and feeding phosgene to the solution at a temperature below 00C. The method uses 80 mol of phosgene for cyclizing 54.3 mol of the compound of Formula II. U.S. Patent No. 6,015,926 describes a method for cyclizing the compound of Formula II by adding phosgene solution in toluene at 25°C to a mixture of the compound of Formula II, toluene and aqueous potassium bicarbonate. The method uses 1.2 molar equivalents of phosgene for cyclizing 1 mol of the compound of Formula II. U.S. Patent No. 6,015,926 also describes similar method wherein methyl t-butyl ether is used instead of toluene and phosgene is employed in the form of gas. U.S. Patent No. 5,922,864 describes methods for cyclizing the compound of Formula II using chloroformates such as 4-nitrophenyl chloroformate, methyl chloroformate and ethyl chloroformate. These methods use 1.05 to 2 molar equivalents of chloroformates for cyclizing 1 mol of the compound of Formula II. U.S. Patent No. 5,519,021 describes a method for cyclizing a racemic mixture of the compound of Formula II using l,l'-carbonyldiimidazole. The method uses 0.259 mol of l,l'-carbonyldiimidazole for cyclizing 0.0518 mol of a racemic mixture of the compound of Formula II. The cyclization methods described in the prior art for preparing efavirenz employ toxic and hazardous cyclizing agent such as phosgene, which requires extremely careful handling. The present inventors have observed several problems associated with the generation, storage, usage and disposal of phosgene due to its toxicity and gaseous nature. The cyclization reaction using phosgene proceeds slowly and requires a long time for the completion of the reaction as phosgene has to be first absorbed in to the reaction medium. The cyclization methods involving chloroformates or l,l'-carbonyldiimidazole as cyclizing agents have problems associated with the formation of by-products. For example, when 4-nitrophenyl chloroformate is used as a cyclizing agent, the efavirenz is formed along with p-nitrophenol as a major by-product, which is difficult to be removed. On the other hand, l,l'-carbonyldiimidazole is sensitive to moisture and it also results in the formation of imidazole as a major by-product along with efavirenz. Thus, the methods involving chloroformates or l,l'-carbonyldiimidazole as cyclizing agents require additional purification steps to obtain efavirenz with acceptable purity levels. Further, all the cyclization methods described in the prior art use excess quantities of the cyclizing agents, which impacts process economics in large scale operations. In case of chloroformates or l,l'-carbonyldiimidazole, the excessive use of said cyclizing agents also increases the by-product formation. Summary of the Invention The present inventors have developed an advantageous process for the preparation of efavirenz, wherein triphosgene is used as a cyclizing agent. The present inventors have found that the use of triphosgene as a cyclizing agent for cyclizing the compound of Formula II tremendously minimizes the by-product formation and efavirenz can be obtained with high chemical and chiral purity without employing any additional purification steps. Since triphosgene is solid at room temperature, it avoids the handling problems associated with phosgene. The present process can be carried out using less than one molar equivalents of triphosgene. Thus, the present invention provides an efficient, cost effective and industrially applicable process for the preparation of efavirenz. Detailed Description of the Invention A first aspect of the present invention provides a process for the preparation of efavirenz of Formula I

Formula I comprising cyclizing the compound of Formula II

Formula II using triphosgene as a cyclizing agent. The compound of Formula II may be prepared by the methods described in the prior art including those described in U.S. Patent Nos. 6,028,237, 6,040,480 and 6,015,926. The cyclization reaction may be carried out in the presence of a solvent. The solvent may be selected from the group consisting of hydrocarbons, ethers, halogenated hydrocarbons, esters, nitriles, alcohols or mixtures thereof. The solvent may be, for example, hexane, heptane, toluene, methylene chloride, chloroform, methyl t-butyl ether, tetrahydrofuran or mixtures thereof. The reaction may be carried out in the presence of a base. The base may be an organic or inorganic base. The organic base may be an amine, for example, trialkyl amine, N-methylimidazole, quinuclidine, 1-methylpyrrolidine or morpholine. The inorganic base may be a hydroxide, for example, potassium, sodium, calcium, barium or magnesium hydroxide, or a carbonate, for example, sodium carbonate, potassium carbonate, magnesium carbonate, or a bicarbonate, for example, sodium bicarbonate or potassium bicarbonate. Triphosgene may be used in less than about 1 molar equivalent to the molar quantity of the compound of Formula II. For example, about 0.3 to about 0.8 mol of triphosgene may be used for 1 mol of the compound of Formula II. The base and triphosgene may be added together or in optional order of succession to the compound of Formula II in the presence of the solvent. The addition of the base and triphosgene may be carried out at a temperature range of about -5° to about 35°C. Triphosgene may be added as a solid or as a solution in an organic solvent. The cyclization reaction may be facilitated by stirring the reaction mixture at a temperature range of about 00C to about 35°C, for example, about 5° to about 300C. The reaction may be carried out for about 30 minutes to about 4 hours, for example, about 1 hour to about 2 hours. The efavirenz may be isolated from the reaction mixture by layer separation, concentration, distillation, filtration, decantation, precipitation or a combination thereof. The efavirenz may optionally be subjected to further recrystallization. The efavirenz so obtained has a chemical purity of about 99.7% or above, for example, about 99.9% or above, and a chiral purity of about 99.9% or above, for example, about 100%. 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.

EXAMPLES

EXAMPLE 1: PREPARATION OF EFAVIRENZ

Toluene (400 ml) was added to (25r)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl- 1,1,1 - trifluorobut-3-yn-2-ol (100 g) at 20° to 25°C and the reaction mixture was cooled to 100C. Aqueous potassium bicarbonate solution (74.61 g in 300 ml of de-ionized water) was added to the reaction mixture in 10 to 15 minutes. Triphosgene (36.870 g pre-dissolved in 150 ml of toluene) was subsequently added to the reaction mixture in 45 to 75 minutes at 10° to 25°C. The reaction mixture was stirred at 10° to 25°C for 60 minutes and the reaction mixture was quenched with methanol (7 ml) at 10° to 25°C (All the above reaction steps were carried out under nitrogen atmosphere). The layers were separated and the organic layer was washed with de-ionized water followed by dilute hydrochloric acid. The solvent was recovered under reduced pressure and the solid obtained was re- crystallized with methanol: water (3:9) at 25° to 300C. The solid was dried under reduced pressure at 85° to 900C for 15 to 18 hours to obtain the title compound.

Yield: 98.5 g Chemical purity: 99.92% Chiral purity: 100% EXAMPLE 2: PREPARATION OF EFAVIRENZ

Toluene (700 ml) was added to (2S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl- 1,1,1 - trifluorobut-3-yn-2-ol (100 gm) at 20° to 25°C and the reaction mixture was cooled to 100C. Triphosgene (36.870g) was added as a solid to the reaction mixture at 100C in 2 to 3 parts. Aqueous potassium bicarbonate solution (74.61 g in 300 ml of de-ionized water) was subsequently added to the reaction mixture in 45 to 75 minutes at 10° to 25°C. The reaction mixture was stirred at 10° to 25°C for 60 minutes and the reaction mixture was quenched with methanol (7 ml) at 10° to 25°C (All the above reaction steps were carried out under nitrogen atmosphere). The layers were separated and the organic layer was washed with de-ionized water followed by dilute hydrochloric acid. The solvent was recovered under reduced pressure and the solid obtained was re-crystallized with methanol: water (3:9) at 25° to 300C. The solid was dried under reduced pressure at 85° to 900C for 15 to 18 hours to obtain the title compound.

Yield: 95 g

Chemical purity: 99.92%

Chiral purity: 100 %

EXAMPLE 3: PREPARATION OF EFAVIRENZ

Toluene (700 ml) was added to (25r)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl- 1,1,1 - trifluorobut-3-yn-2-ol (100 g) at 20° to 25°C and the reaction mixture was cooled to 00C. Triphosgene (36.870 g) was added as a solid to the reaction mixture at 0° to 5°C in 2 to 3 parts. Aqueous potassium bicarbonate solution (74.61 g in 300 ml of de-ionized water) was subsequently added to the reaction mixture in 45 to 75 minutes at 5° to 100C. The reaction mixture was stirred at 5° to 100C for 60 minutes and the reaction mixture was quenched with methanol (7 ml) at 10° to 25°C (All the above reaction steps were carried out under nitrogen atmosphere). The layers were separated and the organic layer was washed with de-ionized water followed by dilute hydrochloric acid. The solvent was recovered under reduced pressure. The solid obtained was re-crystallized with methanol: water (3:9) at 25° to 300C. The solid was dried under reduced pressure at 85° to 900C for 15 to 18 hours to obtain the title compound.

Yield: 96 g

Chemical purity: 99.83%

Chiral purity: 100 %

EXAMPLE 4: PREPARATION OF EFAVIRENZ

Toluene (700 ml) was added to (2S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl- 1,1,1 - trifluorobut-3-yn-2-ol (100 g) at 20° to 25°C. Triphosgene (36.870 g) was added as a solid to the reaction mixture at 20° to 25°C in 2 to 3 parts. Aqueous potassium bicarbonate solution (74.61 g in 300 ml of de-ionized water) was added to the reaction mixture in 45 to 75 minutes at 25° to 300C. The reaction mixture was stirred at 25° to 300C for 60 minutes and the reaction mixture was quenched with methanol (7 ml) at 10° to 25 0C (All the above reaction steps were carried out under nitrogen atmosphere). The layers were separated and the organic layer was washed with de-ionized water followed by dilute hydrochloric acid. The solvent was recovered under reduced pressure. The solid obtained was re-crystallized with methanol: water (3:9) at 25° to 300C. The solid was dried under reduced pressure at 85° to 900C for 15 to 18 hours to obtain the title compound.

Yield: 96 g

Chemical purity: 99.72%

Chiral purity: 99.90 %

EXAMPLE 5: PREPARATION OF EFAVIRENZ

Dichloromethane (800 ml) was added to (2S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl- l,l,l-trifluorobut-3-yn-2-ol (100 g) at 20° to 25°C and the reaction mixture was cooled to 100C. Aqueous potassium bicarbonate solution (74.61 g in 300 ml of de-ionized water) was added to the reaction mixture in 10 to 15 minutes. Triphosgene (36.870 g pre- dissolved in 150 ml of dichloromethane) was added in 45 to 75 minutes at 10° to 25°C. The reaction mixture was stirred at 10° to 25°C for 60 minutes and the reaction mixture was quenched with methanol (7 ml) at 10° to 25 0C (All the above reaction steps were carried out under nitrogen atmosphere). The layers were separated and the organic layer was washed with de-ionized water followed by dilute hydrochloric acid. The solvent was recovered under reduced pressure. The solid obtained was re-crystallized with methanol: water (3:9) at 25° to 300C. The solid was dried under reduced pressure at 85° to 900C for 15 to 18 hours to obtain the title compound.

Yield: 96.2 g

Chemical purity: 99.89% Chiral purity: 100 %

EXAMPLE 6: PREPARATION OF EFAVIRENZ

Methyl t-butyl ether (900 ml) was added to (2S)-2-(2-amino-5-chlorophenyl)-4- cyclopropyl-l,l,l-trifluorobut-3-yn-2-ol (100 gm) at 20° to 25°C and reaction mixture was cooled to 100C. Aqueous potassium bicarbonate solution (74.61 g in 300 ml of de-ionized water) was added in 10 to 15 minutes. Triphosgene (36.870 g pre-dissolved in 150 ml of Methyl t-butyl ether) was added in 45 to 75 minutes at 10° to 25°C. The reaction mixture was stirred at 10° to 25°C for 60 minutes and the reaction mixture was quenched with methanol (7 ml) at 10° to 25 0C (All the above reaction steps were carried out under nitrogen atmosphere). The layers were separated and the organic layer was washed with de-ionized water followed by dilute hydrochloric acid. The solvent was recovered under reduced pressure. The solid obtained was re-crystallized with methanol: water (3:9) at 25° to 300C. The solid was dried under reduced pressure at 85° to 900C for 15 to 18 hours to obtain the title compound.

Yield: 97.1 g Chemical purity: 99.91% Chiral purity: 100 % We Claim: 1. A process for the preparation of efavirenz of Formula I

Formula I comprising cyclizing a compound of Formula II

Formula II using triphosgene as a cyclizing agent.

2. A process according to claim 1, wherein the cyclization is carried out in the presence of a solvent. 3. A process according to claim 2, wherein the solvent is selected from the group consisting of hydrocarbons, ethers, halogenated hydrocarbons, esters, nitriles, alcohols or mixtures thereof.

4. A process according to claim 1, wherein the cyclization is carried out in the presence of a base.

5. A process according to claim 1, wherein triphosgene is used in less than about 1 molar equivalent to the molar quantity of the compound of Formula II.

6. A process according to claim 1, wherein the cyclization reaction is facilitated by stirring the reaction mixture.

7. A process according to claim 6, wherein the stirring is carried out at a temperature range of about 00C to about 35°C. 8. A process according to claim 6, wherein the stirring is carried out for about 30 minutes to about 4 h. 9. Efavirenz prepared according to the process of claim 1 having a chemical purity of at least 99.7% o and a chiral purity of at least 99.9%. 10. Efavirenz prepared according to the process of claim 1 having a chemical purity of at least 99.9% and a chiral purity of 100%. International application No PCT/IB2009/051796

A. CLASSIFICATION OF SUBJECT MATTER INV. C07D265/18

According to International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) C07D

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted duπng the international search (name of data base and, where practical search terms used) EPO-Internal, WPI Data, BEILSTEIN Data, BIOSIS, EMBASE, CHEM ABS Data

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No

US 6 040 480 A (PIERCE MICHAEL E [US] ET 9,10 AL) 2 1 March 2000 (2000-03-21) cited in the application column 24, lines 54-59 1-8 column 26 lines 44-60 column 29 line 64 - column 30, line 16 column 3 1 lines 12-31 example 7

-/--

Further documents are listed in the continuation of Box C See patent family annex

* Special categories of αted documents "T" later document published after the international filing date π 1 or pno ty date and not in conflict with the application but A' document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention 'E' earlier document but published on or after the international X1 document of particular relevance, the claimed invention filing date cannot be considered novel or cannot be considered to 1L" document which may throw doubts on pnoπty claim(S) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another 1Y1 document of particular relevance, the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the 1O" document referring to an oral disclosure, use exhibition or document is combined with one or more other such docu other means ments such combination being obvious to a person skilled "P" document published prior to the international filing date but in the art later than the priority date claimed '&' document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

10 August 2009 18/08/2009

Name and mailing address of the ISA/ Authorized officer European Patent Office, P B 5818 Patentlaan 2 NL - 2280 HV Rl|swιjk TeI (+31-70) 340-2040, Fax (+31-70) 340-3016 Seymour, Liza

Form PCT/ISA/210 (second sheet) (April 2005) International application No PCT/IB2009/051796

C(Con ϋ nuatlon). DOCUMENTS CONSIDERED TO B E RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

PIERCE MICHAEL E ET AL: "Practical 9,10 Asymmetric Synthesis of Efavirenz (DMP 266), an HIV-I Reverse Transcriptase Inhibitor" JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, EASTON.; US, vol. 63, no. 23, 1 January 1998 (1998-01-01), pages 8536-8543, XP002517531 ISSN: 0022-3263 scheme 8 1-8 pages 8542-8543, syntheses of compound 1

COTARCA L ET AL: "B1s(trichloromethyl ) 1-8 Carbonate in Organic Synthesis" SYNTHESIS, GEORG THIEME VERLAG, STUTTGART, DE, 1 January 1996 (1996-01-01), pages 553-576, XP002090854 ISSN: 0039-7881 sections 2.3, 4.4

HERNANDEZ ET AL: "Synthesis of 1-8 1 ,4-di hydro-benzo[d] [1,3 ]oxazi n-2-ones from phthalides via an aminolysis-Hofmann rearrangement protocol " TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, vol. 48, no. 51, 25 October 2007 (2007-10-25), pages 8972-8975, XP022355451 ISSN: 0040-4039 scheme 1 ; page 8972, left-hand column, paragraphs [0001], [0002]

WO 00/66571 A (AMERICAN HOME PROD [US]; 1-8 LIGAND PHARM INC [US]; ZHANG PUWEN [US]; TERE) 9 November 2000 (2000-11-09) page 23, lines 20-24 page 24, scheme I I page 27, scheme IV examples 9,10,40

ALKHATHLAN H Z : "Synthesis of 1-8 4-alkoxy-4-methyl- and 4-al koxy-4-f 1uoromethyl - 1 ,3-benzo xazi nones" TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol . 59, no. 41, 6 October 2003 (2003-10-06), pages 8163-8170, XP004458569 ISSN: 0040-4020 the whole document

Form PCT/ISA/210 (continuation of second sheet) (April 2005) International application No Information on patent family members PCT/IB2009/051796

Patent document Publication Patent family Publication cited in search report date member(s) date

US 6040480 A 21-03-2000 US 5925789 A 20-07-1999

WO 0066571 A 09-11-2000 UA 72917 C2 15-03-2002

Form PCT/ISA/210 (patent family annex) (April 2005)