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WO 2012/145932 Al 1 November 2012 (01.11.2012) P O P C T

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WO 2012/145932 Al 1 November 2012 (01.11.2012) 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 2012/145932 Al 1 November 2012 (01.11.2012) P O P C T (51) International Patent Classification: (CN). CAI, Zhenwei [US/US]; 36 Hills Drive, Belle C07C 279/16 (2006.01) C07C 279/02 (2006.01) Mead, NJ 08502 (US). AN, Rongcang [CN/CN]; No. 35- C07C 277/08 (2006.01) 1, XunYeYiLu, TieXi District, ShenYang, Liaoning 110000 (CN). WANG, Weihua [CN/CN]; No. 37, North (21) International Application Number: ZhongGong Street, TieXi District, ShenYang, liaoning PCT/CN201 1/073575 110000 (CN). DONG, Xuejun [CN/CN]; No. 69, Chong- (22) International Filing Date: ShanZhongLu, HuangGu District, ShenYang, liaoning 29 April 201 1 (29.04.201 1) 110000 (CN). (25) Filing Language: English (74) Agent: CHINA PAT INTELLECTUAL PROPERTY OFFICE; 2nd Floor, Zhongguancun Intellectual Property (26) Publication Language: English Building Block B, No.21 Haidian South Road, Haidian (71) Applicants (for all designated States except US): PHAR- Beijing 100080 (CN). MARESOURCES (SHANGHAI) CO., LTD. [CN/CN]; (81) Designated States (unless otherwise indicated, for every 2nd Floor, Building IB, No. 528 Rui Qing Road, Pu Dong, kind of national protection available): AE, AG, AL, AM, Shanghai 201201 (CN). KAIYUAN HENGTAI AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, PHARMA CO., LTD. [CN/CN]; No. 3 Beihuan Road, In CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, dustrial Zone of Kaiyuan, Tieling, Liaoning 112300 (CN). DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (72) Inventors; and HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (75) Inventors/Applicants (for US only): CHEN, Ping KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, [US/US]; 47 Balsam Court, Hillsborough, NJ 08844 (US). MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, LI, Yinqiang [CN/CN]; No. 6, Rm. 902, 782 lane, ZhouD- OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, ong Road, NanHui District, Shanghai 2013 18 (CN). SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, PENG, Shaoping [CN/CN]; No. 45, Rm. 302, 825 Lane, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. ChenHui Road, PuDong New District, Shanghai 200120 (84) Designated States (unless otherwise indicated, for every (CN). JIANG, Shengli [CN/CN]; No. 116, 2727 Lane, kind of regional protection available): ARIPO (BW, GH, HuNan Road, PuDong New District, Shanghai 200120 GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, [Continued on nextpage] (54) Title: A NOVEL PROCESS FOR THE PREPARATION OF PERAMIVIR AND INTERMEDIATES THEREOF (57) Abstract: The present invention relates to a novel process for preparing peramivir NH formula (I) or a pharmaceutically acceptable salt thereof, and to intermediates used therein. w o 2012/145932 Ai Iinn iiiiiii 1mil i mil il i 1ill i mil i inn i i mill i i i ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Published: TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, — with international search report (Art. 21(3)) EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). A NOVEL PROCESS FOR THE PREPARATION OF PERAMIVIR AND INTERMEDIATES THEREOF Field of the Invention [0001] The present invention relates to a novel process for the preparation of peramivir or a pharmaceutically acceptable salt thereof, and to novel intermediates thereof. In particular, this invention relates to a more efficient process for the preparation of peramivir or a pharmaceutically acceptable salt thereof, comprising highly diastereoselective reactions by utilizing less reaction steps to obtain peramivir. Background of the Invention [0002] Peramivir has the chemical name of (1 , ,3 ,4R)-3-[(l S)-l-acetamido-2-ethyl-butyl] -4-(diaminomethylideneamino)- 2-hydroxy-cyclopentane-l-carboxylicacid, and has the following structure: (I) [0003] Peramivir is currently being developed as an antiviral drug, and in particular, for treatment of influenza. Acting as a neuraminidase inhibitor, peramivir can efficiently inhibit the replication of all type of influenza viruses. Peramivir can be administered via injection, and is known to be well-tolerated and cause only mild adverse effect. [0004] Several processes relating to the preparation of peramivir are disclosed in CN1227466, CN12823 16, and WO01/00577A1. [0005] As shown in Scheme 1, C 1227466 discloses a process comprising ring-opening of chiral 2-azabicyclo [2.2. 1] hept-5-en-3-one, followed by amino-protecting reaction, Diel-Alder conjugate cycloaddition, reduction, acetylation, guanidylation and finally hydrolyzation to yield peramivir. The major drawback of this process is the use of highly expensive starting material 1. In addition, this process is not suitable for scale-up. Scheme 1 [0006] WO2009021404 discloses a method comprising reacting N-Boc-protected chiral 2-azabicyclo [2.2. 1] hept-5-en-3-one and 2-ethylbutylaldehyde as starting material to prepare peramivir as illustrated in Scheme 2. Scheme 2 eram v r [0007] The major disadvantages of this process are long synthetic route, low yield and high production cost. [0008] The present invention relates to a more efficient process for the preparation of peramivir, which comprises shorter synthetic route and higher overall yield. The process is free of chromatographic purification, and suitable for large scale production. Summary of the Invention [0009] In one aspect, the present invention provides a process for preparing peramivir (I), comprising: (a) reacting a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen, with an amidine compound of formula (III), NR3 R2HN R4 wherein R and R3 are each independently a nitrogen-protecting group, and R4 is a leaving group, to provide a compound of formula (IV): wherein Ri, R and R3 are defined as hereinabove; (b) reacting the compound of formula (IV) with a compound of formula (V) N. OH c i (V) to produce a compound of formula (VI), wherein Ri, R and R3 are defined as hereinabove; (c) reducing the compound of formula (VI) using a reducing followed by acetylation to provide a compound of formula (VII), wherein Ri, R and R3 are defined as hereinabove; (d) hydrolyzing the compound of formula (VII), wherein Ri is not H, with a base or an acid to provide a compound of formula (VIII), wherein R and R3 are defined as hereinabove; (e) removing the nitrogen-protecting group (R2 and R3) in the compound of formula (VII), wherein Ri is H, or in the compound of formula (VIII), to provide peramivir (I). [0010] In another aspect, the present invention provides a process for preparing a compound of formula (IV): wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen; R and R3 are each independently a nitrogen-protecting group, the process comprising reacting a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein Ri is defined as hereinabove, with an amidine compound of formula (III), NR3 R2HN R4 wherein R and R3 are defined as hereinabove, and R4 is a leaving group, to provide the compound of formula (IV). [0011] In yet another aspect, the present invention provides a process for preparing a compound of formula (VI): wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen; R and R3 are each independently a nitrogen-protecting group, the process comprising reacting a compound of formula (IV), wherein Ri, R and R3 are defined as hereinabove, with a compound of formula (V to produce the compound of formula (VI). [0012] In a further aspect, the present invention provides a compound of formula (IV), wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen; and R2 and R3 are each independently a nitrogen-protecting group. [0013] In another aspect, the present invention provides a compound of formula (VI), wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen; R and R3 are each independently a nitrogen-protecting group. Brief Description of the Drawings [0014] Figure 1 depicts ^-NMR for compound 13. [0015] Figure 2 depicts ^-NMR for compound 15. [0016] Figure 3 depicts ^-NMR for compound 16. [0017] Figure 4 depicts ^-NMR for compound 17. [0018] Figure 5 depicts ^-NMR for compound peramivir. Detailed Description of the Invention [0019] The present invention relates to a novel process for preparation of peramivir (I), or a pharmaceutically acceptable salt thereof: Peramivir (I) (I)- [0020] The process comprises: (a) reacting a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen, with an amidine compound of formula (III), NR3 R2HN R4 wherein R and R3 are each independently a nitrogen-protecting group, and R4 is a leaving group, to provide a compound of formula (IV) wherein Ri, R and R3 are defined as hereinabove; (b) reacting the compound of formula IV) with a compound of formula (V) to produce a compound of formula (VI), wherein Ri, R and R3 are defined as hereinabove; (c) reducing the compound of formula (VI) using a reducing agent, followed by acetylation to provide a compound of formula (VII), wherein Ri, R and R3 are defined as hereinabove; (d) hydrolyzing the compound of formula (VII), wherein Ri is not H, with a base or an acid to provide a compound of formula (VIII), wherein R and R3 are defined as hereinabove; (e) removing the nitrogen-protecting group (R2 and R3) in the compound of formula (VII), wherein Ri is H, or in the compound of formula (VIII), to provide peramivir (I).
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