Rimegepant ndiyo yega mushonga weCGRP receptor antagonist pasi rose inoshandisa tekinoroji yemapiritsi inonyungudika nemuromo uye ndiyo mushonga wekutanga pasi rose unogona kushandiswa pakurapa nekudzivirira kurwiswa kwemigraine kwakanyanya.
Musi wa27 Kukadzi 2020, US Food and Drug Administration (FDA) yakabvumidza kutengeswa kwemapiritsi e remdesivir panicol sulfate pasi pezita rekuti Nurtec® ODT.
Kusvika pari zvino, nzira huru dzekugadzira remepiride dzinoshandiswa mukugadzira mishonga inoshanda inzira mbiri dzakaburitswa nemugadziri wekutanga, Bristol-Myers Squibb, achishandisa (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-[[triisopropylsyl]oxy]-5H-cycloheptatrienepyridin-5-one (compound 1) sechinhu chekutanga.
Nzira 1: Remegapan inogadzirwa kuburikidza nekuita kwematanho matanhatu kunosanganisira, pakati pezvimwe zvinhu: kuderedza boka reketone ne sodium borohydride, chlorination yeboka rehydroxyl ne triphenylphosphine ne N-chlorosuccinimide, kutsiviwa kweatomu yechlorine ne sodium azide, desiliconization ne tetrabutylammonium fluoride, coupling, uye kuderedza boka reazide ne trimethylphosphine. Nzira yacho inoratidzwa pazasi (Mufananidzo 3):
Nzira 2: Uchishandisa compound 1 sechinhu chekutanga, remapam inogadzirwa mumatanho matatu (imwe-nhanho yekuita kwe tetraisopropoxytitanium, alumina, uye palladium pakabhoni kuti igadzire key intermediate 2a, deprotection kuti igadzire key intermediate 2b, uye coupling). Nzira yacho inoratidzwa pazasi (Mufananidzo 4):
Sezvinogona kuonekwa kubva muchimiro chemushonga, chinhu chinoshanda cheRemegapan molecule chine nzvimbo nhatu dzechiral. Kugadzira chiral amine panzvimbo ye5 yecycloheptane kunopa dambudziko guru rekuwedzera kugadzirwa kwechinhu chinoshanda chemishonga. Tsvagiridzo yakawedzerwa ichatarisa pakuvandudza maitiro ekugadzira zvinhu zvepakati pe2a/2b.
Patent CN114957247A inotsanangura nzira yekugadzira key intermediates 2a/2b: uchishandisa compound 3a sechinhu chekutanga, stereoselective ring-opening reaction inoitika neLewis reagent kuti igadzire compound 3b, iyo inobva yaita Suzuki reaction, silanization protection, substitution, uye deprotection kuti key intermediate 2b iwane goho rinenge 54%. Nzira iyi inoratidzwa pazasi (Mufananidzo 5):
Patent CN116768938A inotsanangura nzira yekugadzira key intermediate 2a: uchishandisa carbonyl compound (4a) sechinhu chekutanga, intermediate 1 inogadzirwa nekuderedza, kudzivirira TIPS, uye kuita ne 2,3-difluorobromobenzene. Intermediate 1 inopinda mu asymmetric reduction-amination reaction pasi pechiito cheFeⅡ/EDTA complexing catalyst uye yobva yapinda mu ammonolysis ne 20% aqueous ammonia kuti ibudise key intermediate 2a (Mufananidzo 6a).
Mune rimwe bhuku (Zhejiang Chemical Industry, 2022, 53(8). 13-18.), nzira yekugadzira key intermediate 2b inotsanangurwa: uchishandisa compound 2 sezvinhu zvisina kugadzirwa, key intermediate 2b inowanikwa kuburikidza neAlⅢ/EDTA catalysis. Nzira yacho ndeiyi inotevera (Mufananidzo 6b):
Mapatent CN116640811A/CN116083385A anotsanangura nzira yekugadzira key intermediates 2a/2b: uchishandisa compound 1/2 sechinhu chekutanga, key chiral intermediates 2a/2b inogadzirwa zvakananga kuburikidza ne one-step transaminase reaction. Maitiro aya haana kungoita nhanho pfupi yekugadzira chete asiwo anovandudza zvakanyanya chiral selectivity uye goho re key intermediates 2a/2b. Uyezve, nzira yekugadzirira inoratidzwa nemamiriro ekuita zvinyoro uye mashandiro akachengeteka mushure mekugadzirisa, ayo anosangana nezvinodiwa zvekugadzira mumaindasitiri (Mufananidzo 7).
Chiral alcohol compound 4b ndiyo inotungamira kune key chiral amine intermediates 2a/2b. Parizvino, nzira dzekugadzira dzinowanikwa pachena dzinowira muzvikamu zviviri: zvemakemikari uye zvemakemikari.
Mumabhuku (Organic Letters, 2012, 14(18): 4938–4941), kambani yakaita ongororo yekutanga yakatsanangura nzira yekugadzira 4b kuburikidza nekuderedza kusingaenzaniswi: ichishandisa dimethyl 2,3-pyridinedicarboxylate (5a) sechinhu chekutanga, 4a yepakati yakawanikwa kuburikidza neDieckmann cyclization uye decarboxylation reaction, uye ipapo chiral alcohol compound yakagadzirwa kuburikidza nekuderedza kusingaenzaniswi uchishandisa metal catalyst Rh-(R-Binapine)(COD)BF₄ nekushandurwa kwe100% uye ee≥99.9% (Mufananidzo 8).
Pakutanga, kambani yekutsvagisa yakataura mu patent CN102066358B kuti diketone compound (4a) yakaderedzwa kusvika pa4b nenzira ye enzyme, asi haina kuburitsa ruzivo rwakananga nezve reaction; gare gare, zvakazotaurwa mumabhuku (Organic Letters, 2012, 14(18):4938-4941) kuti diketone compound yakaderedzwa kusvika pa4b pasi pe catalysis ye ketone reductase ES-KRED-119 ine reaction goever ye81% uye ee value ye99.2% (Mufananidzo 9).
Ketone reductase ES-KRED-119 yakashandiswa nenzira ye enzyme iri pamusoro apa yakatengwa kubva kuShangke Biopharmaceutical (Shanghai) Co., Ltd. Shangke Biopharmaceutical yakagadzirisa enzyme iyi mu CN202410502187.9, uye huwandu hwe substrate hunogona kusvika 100 g/L.
Kuderedzwa kweenzyme asymmetric kunokodzera zviri nani zvinodiwa zveindasitiri pakugadzirwa kwemakemikari echiral alcohol (4b). Zvidzidzo zvinotevera zvakatarisa pakuvandudza macatalyst kana kuongorora uye kugadzirisa ketone reductases, izvo zvisingazotaurwi zvakadzama pano.
[2] LEAHY DAVID K., FANG Y., CHAN COLLIN nevamwe. Nzira yekugadzira CGRP receptor antagonist cycloheptapyridine: USA 8669368B2 [P]. 11.03.2014.
[3] Ruan Shiwen, Yang Gongchao, Zhang Wei, nevamwe. Nzira dzekugadzira dze rimugepant nezvinhu zviri pakati payo: China, 114957247A[P]. 2022-08-30.
[4] He Lingyun, Chen Binhui, Yu Yang. Nzira yekugadzira iron catalyst uye chigadzirwa chepakati che rimexam: China, 116768938A[P]. 2023-09-19.
[5] Lin Weikang. Chidzidzo chekutanga pamusoro pehunyanzvi hwekugadzira fluorinated chiral moiety yeCGRP receptor antagonist Remegapan kuburikidza nenzira isina kuenzana ye catalytic amination [J]. Zhejiang Chemical Industry, 2022, 53(8):13-18.
[6] Iye Lingyun, Chen Binhui, Yu Yang. Nzira yekugadzirira rimexam yepakati: China, 116640811A[P]. 2023-08-25.
[8] Ma Yulei, Jiao Xuecheng, Wang Zujian, nevamwe. Kugadzira ma key polymer intermediates zvinobudirira zvikuru uchishandisa modified transaminase [J]. Organic Process Research and Development, 2022, 26(7):1971–1977.
[9] David K. Leahy, Yu Fan, Lopa V. Desai, nevamwe. Kugadzirwa kwe CGRP antagonists kunoshanda uye kunogona kuvandudzwa [J]. Organic Letters, 2012, 14(18): 4938–4941.
Chiziviso: Chinyorwa ichi chakatorwa kubva kuYaozhi.com. Mifananidzo nemagwaro acho zvakachengetwa nevanyori vepakutanga. Chinyorwa ichi ndecheruzivo chete uye hachiratidzi maonero epuratifomu iyi. Kana muine mibvunzo ine chekuita nezviri mukati, kodzero, kana zvimwe zvinhu, ndapota siyai meseji papuratifomu iyi, uye tichazvigadzirisa nekukurumidza.
Kodzero Dzese Dzakachengetedzwa © 2009-2026 YAOZH.COM. Nhamba Yekunyoresa yeBazi reIndasitiri neTekinoroji Yeruzivo: ICP10200070-3
Nhamba yerezinesi yekupa masevhisi ekukurukurirana ane kukosha kuburikidza neInternet: YuB2-20120028. Chitupa chekusimbisa kupa ruzivo nezvemishonga kuburikidza neInternet: (Yu)-Commercial-2021-0017
Yaozhi Websites: Yaozhi.com | Yaozhi News | Yaozhi Lecture Hall | Yaozhi Media | Yaozhi Data | Company Qualifications | Taura nesu
Kodzero Dzese Dzakachengetedzwa © 2009-2026 YAOZH.COM. Nhamba Yekunyoresa yeBazi reIndasitiri neTekinoroji Yeruzivo: ICP10200070-3
Nguva yekutumira: Ndira-23-2026