Rimegepant ndiye mankhwala okhawo padziko lonse lapansi omwe amagwiritsa ntchito ukadaulo wa mapiritsi osungunuka pakamwa omwe ali ndi patent ndipo ndiye mankhwala oyamba padziko lonse lapansi omwe angagwiritsidwe ntchito pochiza komanso kupewa matenda a mutu waching'alang'ala.
Pa 27 February, 2020, bungwe la US Food and Drug Administration (FDA) linavomereza kugulitsidwa kwa mapiritsi a remdesivir panicol sulfate pansi pa dzina loti Nurtec® ODT.
Mpaka pano, njira zazikulu zopangira mankhwala zomwe zimagwiritsidwa ntchito popanga mankhwala a remepiride ndi njira ziwiri zomwe zafotokozedwa ndi wopanga woyamba, Bristol-Myers Squibb, pogwiritsa ntchito (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-[[triisopropylsyl]oxy]-5H-cycloheptatrienepyridin-5-one (chophatikiza 1) ngati chinthu choyambira.
Njira 1: Remegapan imakonzedwa kudzera mu njira zisanu ndi chimodzi zomwe zimaphatikizapo, pakati pa zinthu zina: kuchepetsa gulu la ketone ndi sodium borohydride, chlorination ya gulu la hydroxyl ndi triphenylphosphine ndi N-chlorosuccinimide, kusintha atomu ya chlorine ndi sodium azide, kuchotsa siliconization ndi tetrabutylammonium fluoride, kuphatikiza, ndi kuchepetsa gulu la azide ndi trimethylphosphine. Njirayi ikuwonetsedwa pansipa (Chithunzi 3):
Njira Yachiwiri: Pogwiritsa ntchito compound 1 ngati chinthu choyambira, remepam imapangidwa m'magawo atatu (njira imodzi ya tetraisopropoxytitanium, alumina, ndi palladium pa kaboni kuti ipange key intermediate 2a, deprotection kuti ipange key intermediate 2b, ndi coupling). Njirayi ikuwonetsedwa pansipa (Chithunzi 4):
Monga momwe tingawonere kuchokera mu kapangidwe kake, molekyulu ya mankhwala yogwira ntchito ya Remegapan ili ndi malo atatu a chiral. Kupanga chiral amine pamalo 5 a cycloheptane kumabweretsa vuto lalikulu pakukulitsa kupanga kwa mankhwala yogwira ntchito. Kafukufuku wowonjezereka adzayang'ana kwambiri pakukonza njira zopangira mankhwala ofunikira a 2a/2b.
Patent CN114957247A ikufotokoza njira yokonzekera ma key intermediates 2a/2b: pogwiritsa ntchito compound 3a ngati chinthu choyambira, stereoselective ring-opening reaction imachitika ndi Lewis reagent kuti ipange compound 3b, yomwe kenako imadutsa mu Suzuki reaction, silanization protection, substitution, and deprotection kuti ipereke key intermediate 2b pafupifupi 54% ya zokolola zonse. Njirayi ikuwonetsedwa pansipa (Chithunzi 5):
Patent CN116768938A ikufotokoza njira yokonzekera key intermediate 2a: pogwiritsa ntchito carbonyl compound (4a) ngati chinthu choyambira, intermediate 1 imakonzedwa mwa kuchepetsa, kuteteza TIPS, ndi kuchitapo kanthu ndi 2,3-difluorobromobenzene. Intermediate 1 imadutsa mu asymmetric reduction-amination reaction pansi pa ntchito ya FeⅡ/EDTA complexing catalyst kenako imadutsa mu ammonolysis ndi 20% aqueous ammonia kuti ipereke key intermediate 2a (Chithunzi 6a).
Mu mabuku ena (Zhejiang Chemical Industry, 2022, 53(8). 13-18.), njira yokonzekera key intermediate 2b yafotokozedwa: pogwiritsa ntchito compound 2 ngati zinthu zopangira, key intermediate 2b imapezeka kudzera mu AlⅢ/EDTA catalysis. Njirayi ndi iyi (Chithunzi 6b):
Ma Patent CN116640811A/CN116083385A amafotokoza njira yokonzekera ma key intermediates 2a/2b: pogwiritsa ntchito compound 1/2 ngati chinthu choyambira, ma key chiral intermediates 2a/2b amapangidwa mwachindunji kudzera mu transaminase reaction ya sitepe imodzi. Njirayi sikuti imangokhala ndi gawo lalifupi lopangidwa komanso imawongolera kwambiri kusankha kwa chiral ndi phindu la ma key intermediates 2a/2b. Kuphatikiza apo, njira yokonzekera imadziwika ndi zochitika zofatsa komanso ntchito zotetezeka pambuyo pokonza, zomwe zimakwaniritsa zofunikira pakupanga mafakitale (Chithunzi 7).
Chiral alcohol compound 4b ndi chiyambi cha key chiral amine intermediates 2a/2b. Pakadali pano, njira zopangira zomwe zimapezeka pagulu zimagawidwa m'magulu awiri: mankhwala ndi chemoenzymatic.
Mu mabuku (Organic Letters, 2012, 14(18): 4938–4941), kampani yomwe idachita kafukufuku woyambirira idafotokoza njira yopangira 4b kudzera mu kuchepetsa kosagwirizana: pogwiritsa ntchito dimethyl 2,3-pyridinedicarboxylate (5a) ngati chinthu choyambira, 4a yapakati idapezeka kudzera mu Dieckmann cyclization ndi decarboxylation reaction, kenako chiral alcohol compound idapangidwa kudzera mu kuchepetsa kosagwirizana pogwiritsa ntchito chitsulo chothandizira Rh-(R-Binapine)(COD)BF₄ ndi kusintha kwa 100% ndi ee≥99.9% (Chithunzi 8).
Poyamba, kampani yofufuza idatchula mu patent CN102066358B kuti diketone compound (4a) idachepetsedwa kufika pa 4b ndi njira ya enzymatic, koma sinaulule zambiri zenizeni zokhudza zomwe zimachitika; pambuyo pake, zidanenedwa m'mabuku (Organic Letters, 2012, 14(18):4938-4941) kuti diketone compound idachepetsedwa kufika pa 4b pansi pa catalysis ya ketone reductase ES-KRED-119 yokhala ndi zokolola za 81% ndi mtengo wa ee wa 99.2% (Chithunzi 9).
Ketone reductase ES-KRED-119 yomwe imagwiritsidwa ntchito mu njira ya enzyme yomwe ili pamwambapa idagulidwa ku Shangke Biopharmaceutical (Shanghai) Co., Ltd. Shangke Biopharmaceutical idasintha enzyme mu patent CN202410502187.9, ndipo kuchuluka kwa substrate kumatha kufika 100 g/L.
Kuchepetsa kwa enzyme asymmetric kumakwaniritsa bwino zofunikira zamakampani popanga mankhwala a chiral alcohol (4b). Kafukufuku wotsatira wayang'ana kwambiri pakukonza ma catalyst kapena kufufuza ndikuwongolera ma ketone reductases, zomwe sizikambidwa mwatsatanetsatane pano.
[2] LEAHY DAVID K., FANG Y., CHAN COLLIN ndi ena. Njira yopangira CGRP receptor antagonist cycloheptapyridine: USA 8669368B2 [P]. 11.03.2014.
[3] Ruan Shiwen, Yang Gongchao, Zhang Wei, ndi ena. Njira zopangira rimegepant ndi zinthu zake zapakati: China, 114957247A[P]. 2022-08-30.
[4] He Lingyun, Chen Binhui, Yu Yang. Njira yokonzekera chothandizira chachitsulo ndi mankhwala apakati a rimexam: China, 116768938A[P]. 2023-09-19.
[5] Lin Weikang. Kafukufuku woyambirira pa ukadaulo wa kapangidwe ka chiral moiety ya CGRP receptor antagonist Remegapan kudzera mu njira yosakanikirana ya catalytic amination [J]. Zhejiang Chemical Industry, 2022, 53(8):13-18.
[6] Iye Lingyun, Chen Binhui, Yu Yang. Njira yokonzekera rimexam yapakatikati: China, 116640811A[P]. 2023-08-25.
[8] Ma Yulei, Jiao Xuecheng, Wang Zujian, ndi ena. Kupanga bwino kwambiri kwa ma key polymer intermediates pogwiritsa ntchito modified transaminase [J]. Organic Process Research and Development, 2022, 26(7):1971–1977.
[9] David K. Leahy, Yu Fan, Lopa V. Desai, ndi ena. Kupanga bwino komanso kosinthika kwa enantioselective kwa otsutsana ndi CGRP [J]. Organic Letters, 2012, 14(18): 4938–4941.
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