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WO 2015/084763 A2 11 June 2015 (11.06.2015) P O P C T

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WO 2015/084763 A2 11 June 2015 (11.06.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/084763 A2 11 June 2015 (11.06.2015) P O P C T (51) International Patent Classification: (74) Common Representative: MERCK SHARP & DOHME C07D 401/06 (2006.01) CORP.; 126 East Lincoln Avenue, Rahway, New Jersey 07065-0907 (US). (21) International Application Number: PCT/US20 14/068008 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 2 December 2014 (02.12.2014) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (25) Filing Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (26) Publication Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (30) Priority Data: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 61/91 1,686 4 December 2013 (04. 12.2013) PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/017,542 26 June 2014 (26.06.2014) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant: MERCK SHARP & DOHME CORP. [US/US]; 126 East Lincoln Avenue, Rahway, New Jersey (84) Designated States (unless otherwise indicated, for every 07065-0907 (US). kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (72) Inventors; and TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicants (for US only): CAO, Yang [CN/US]; 126 East TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Lincoln Avenue, Rahway, New Jersey 07065-0907 (US). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, GAUTHIER, Donald, R., Jr. [US/US]; 126 East Lincoln LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Avenue, Rahway, New Jersey 07065-0907 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, HUMPHREY, Guy, R. [US/US]; 126 East Lincoln Aven GW, KM, ML, MR, NE, SN, TD, TG). ue, Rahway, New Jersey 07065-0907 (US). ITOH, Tetsuji [JP/US]; 126 East Lincoln Avenue, Rahway, New Jersey Declarations under Rule 4.17 : 07065-0907 (US). JOURNET, Michel [FR/US]; 15 Aza — as to applicant's entitlement to applyfor and be granted a lea Lane, Somerset, New Jersey 08873 (US). QIAN, Gang patent (Rule 4.1 7(H)) [US/US]; 969 Ridge Road, South Brunswick, New Jersey — as to the applicant's entitlement to claim the priority of the 08852 (US). SHERRY, Benjamin, D. [US/US]; 126 East earlier application (Rule 4.1 7(in)) Lincoln Avenue, Rahway, New Jersey 07065-0907 (US). TSCHAEN, David, M. [US/US]; 126 East Lincoln Aven Published: ue, Rahway, New Jersey 07065-0907 (US). — without international search report and to be republished upon receipt of that report (Rule 48.2(g)) (54) Title: PROCESS FOR MAKING REVERSE TRANSCRIPTASE INHIBITORS -5°C -25 ° C Ethyl Ester (1.0 equiv.), Enone (1.5 equiv.), toluene (0.6 ) < Vol. KOi-Am (1.5 equiv.), Triethylamine Trifluoroacetic 1.0 0.54 : 0.34 : 0.25 toluene (1.7 ) (4.0 equiv.) Anhydride ( .0 equiv.) 00 © FIG. 1 (57) Abstract: The present invention is directed to a novel process for synthesizing 3-(substituted phenoxy)-l-[(5-oxo-4,5-dihydro- o lH-l,2,4-triazol-3-yl)methyl])-pyridin-2(lH)-one derivatives. The compounds synthesized by the processes of the invention are HIV reverse transcriptase inhibitors useful for inhibiting reverse transcriptase and HIV replication, and the treatment of human immun - odeficiency virus infection in humans. TITLE OF THE INVENTION PROCESS FOR MAKING REVERSE TRANSCRIPTASE INHIBITORS BACKGROUND OF THE INVENTION The retrovirus designated human immunodeficiency virus (HIV), particularly the strains known as HIV type-1 (HIV-1) and type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease known as acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which makes them highly susceptible to debilitating and ultimately fatal opportunistic infections. Replication of HIV by a host cell requires integration of the viral genome into the host cell's DNA. Since HIV is a retrovirus, the HIV replication cycle requires transcription of the viral RNA genome into DNA via an enzyme known as reverse transcriptase (RT). Reverse transcriptase has three known enzymatic functions: The enzyme acts as an RNA-dependent DNA polymerase, as a ribonuclease, and as a DNA-dependent DNA polymerase. In its role as an RNA-dependent DNA polymerase, RT transcribes a single- stranded DNA copy of the viral RNA. As a ribonuclease, RT destroys the original viral RNA and frees the DNA just produced from the original RNA. And as a DNA-dependent DNA polymerase, RT makes a second, complementary DNA strand using the first DNA strand as a template. The two strands form double-stranded DNA, which is integrated into the host cell's genome by the integrase enzyme. It is known that compounds that inhibit enzymatic functions of HIV RT will inhibit HIV replication in infected cells. These compounds are useful in the prophylaxis or treatment of HIV infection in humans. Among the compounds approved for use in treating HIV infection and AIDS are the RT inhibitors 3'-azido- 3'-deoxythymidine (AZT), 2',3'- dideoxyinosine (ddl), 2',3'- dideoxycytidine (ddC), d4T, 3TC, nevirapine, delavirdine, efavirenz, abacavir, emtricitabine, and tenofovir. The RT inhibitor 3-chloro-5-({l-[(4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol- 3-yl)methyl]-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl}oxy)benzonitrile, related compounds and methods for making the same are illustrated in WO 201 1/120133 Al, published on October 6, 201 1, and US 201 1/0245296 Al, published on October 6, 201 1, both of which are hereby incorporated by reference in their entirety. The present invention is directed to a novel process for synthesizing 3-(substituted phenoxy)-l-[(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)methyl])-pyridin-2(l H )-one derivatives. The compounds synthesized by the processes of the invention are HIV reverse transcriptase inhibitors useful for inhibiting reverse transcriptase and HIV replication, and the treatment of human immunodeficiency virus infection in humans. SUMMARY OF THE INVENTION The present invention is directed to a novel process for synthesizing 3- (substituted phenoxy)-l-[(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)methyl])-pyridin-2(l H )-one derivatives. The compounds synthesized by the processes of the invention are HIV reverse transcriptase inhibitors useful for inhibiting reverse transcriptase and HIV replication, and the treatment of human immunodeficiency virus infection in humans. BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 shows a schematic of the flow reactor for the aldol condensation step used in the process for synthesizing 3-(substituted phenoxy)-l-[(5-oxo-4,5-dihydro-lH-l,2,4- triazol-3-yl)methyl])-pyridin-2(l H )-one. DETAILED DESCRIPTION OF THE INVENTION The invention encompasses a method for synthesizing a compound of Formula I I 2 wherein R is C alkyl, K and K are independently CH3 , CF3 , CHF , CH CF3 , OCH3 , CI, Br, F, CN or SCH3 , and R2 is CF3, CI or Br, comprising Step 1 - conducting an aldol addition of an ester of Formula B B with a compound of Formula C o R OC^alkyl c in the presence of a first base in a hydrocarbon or ethereal organic solvent at a first reduced temperature, wherein the first base is a metal alkoxide or metal amide base, to form Intermediate D, and optionally isolating Intermediate D D; Step 2 - reacting Intermediate D with an organic acid anhydride or sulfonyl chloride in the presence of a second base, wherein the second base is a tertiary amine base, at a second reduced temperature in a hydrocarbon or ethereal organic solvent, which solvent can be the same or different as that in Step 1, to form Intermediate E, and optionally isolating Intermediate E Step 3 - cyclizing Intermediate E in the presence of a nitrogen source having formula H3+n wherein Xn = a non-coordinating counteranion and n = 0 (zero) or 1, at a first elevated temperature in a mixture of alcohol and organic solvent to make a compound of Formula F F; and Step 4 - coupling the compound of Formula F with a compound of Formula A N-NH A wherein χ is a leaving group, in the presence of a third base selected from an inorganic base or a tertiary amine base in a polar aprotic or protic solvent to yield the compound of Formula I. Alternatively, after performing Steps 1 and 2 as described above, Steps 3 and 4 described above can be replaced with Step 3A a s follows: Step 3A - cyclizing Intermediate E in the presence of a compound of Formula A A wherein χ is H , at an elevated temperature in a mixture of alcohol and organic solvent to make a compound of Formula I. The following scheme is an example of Step 3A. The invention also encompasses a method for synthesizing a compound of Formula F 2 wherein K and K are independently CH3 , CF3 , CHF , CH CF3 , OCH3, CI, Br, F, CN or SCH3 , and R2 is CF3, CI or Br, comprising Step 1 - conducting an aldol addition of an ester of Formula B -4alkyl B with a compound of Formula C in the presence of a first base in a hydrocarbon or ethereal organic solvent at a first reduced temperature, wherein the first base is a metal alkoxide or metal amide base, to form Intermediate D, and optionally isolating Intermediate D Step 2 - reacting Intermediate D with an organic acid anhydride or sulfonyl chloride in the presence of a second base, wherein the second base is a tertiary amine base, at a second reduced temperature in a hydrocarbon or ethereal organic solvent, which solvent can be the same or different as that in Step 1, to form Intermediate E, and optionally isolating Intermediate E E ; Step 3 - cyclizing Intermediate E in the presence of a nitrogen source having formula Η3+η η , wherein Xn = a non-coordinating counteranion and n = 0 or 1, at a first elevated temperature in a mixture of alcohol and organic solvent to make the compound of Formula F.
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