Rimegepant bụ naanị ọgwụ CGRP nke na-egbochi ndị na-anabata ihe nke na-eji teknụzụ mbadamba ndị na-emebi ihe nke nwere ikike n'ọnụ, ọ bụkwa ọgwụ mbụ n'ụwa nke enwere ike iji maka ọgwụgwọ na mgbochi nke mwakpo isi ọwụwa.
Na Febụwarị 27, 2020, US Food and Drug Administration (FDA) kwadoro ire ahịa mbadamba remdesivir panicol sulfate n'okpuru aha njirimara Nurtec® ODT.
Ruo taa, ụzọ ndị bụ isi e si emepụta ọgwụ na-aga remepiride bụ ụzọ abụọ nke onye nrụpụta mbụ ahụ, Bristol-Myers Squibb, kpughere, site na iji (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-[[triisopropylsilyl]oxy]-5H-cycloheptatrienepyridin-5-one (nchịkọta 1) dị ka ihe mmalite.
Ụzọ nke 1: A na-akwadebe Remegapan site na mmeghachi omume nzọụkwụ isii nke gụnyere, tinyere ihe ndị ọzọ: mbelata nke otu ketone na sodium borohydride, itinye chlorine nke otu hydroxyl na triphenylphosphine na N-chlorosuccinimide, nnọchi nke atọm chlorine na sodium azide, desiliconization na tetrabutylammonium fluoride, njikọ, na mbelata nke otu azide na trimethylphosphine. Ụzọ ahụ dị n'okpuru (Foto nke 3):
Ụzọ nke Abụọ: Site na iji ihe mejupụtara 1 dị ka ihe mmalite, a na-emepụta remepam n'usoro atọ (mmeghachi omume otu nzọụkwụ nke tetraisopropoxytitanium, alumina, na palladium na carbon iji mepụta isi etiti 2a, deprotection iji mepụta isi etiti 2b, na njikọ). E gosiri ụzọ ahụ n'okpuru (Foto 4):
Dịka a pụrụ ịhụ site na usoro nhazi, ihe mejupụtara ọgwụ Remegapan nwere ebe atọ chiral. Ịmepụta chiral amine na ọnọdụ ise nke cycloheptane na-eweta nnukwu ihe ịma aka maka ịbawanye mmepụta nke ihe mejupụtara ọgwụ na-arụ ọrụ. Nnyocha ọzọ ga-elekwasị anya na imeziwanye usoro mmepụta maka isi ihe dị n'etiti 2a/2b.
Patent CN114957247A na-akọwa ụzọ e si akwadebe ihe ndị dị mkpa 2a/2b: site na iji ihe mejupụtara 3a dị ka ihe mmalite, mmeghachi omume mmeghe mgbanaka stereoselective na-eme na ihe Lewis reagent iji mepụta ihe mejupụtara 3b, nke na-eme mmeghachi omume Suzuki, nchebe silanization, nnọchi, na deprotection iji nye isi etiti 2b ihe dị ka 54% mmepụta zuru oke. E gosiri usoro a n'okpuru (Foto 5):
Patent CN116768938A na-akọwa ụzọ e si akwadebe isi etiti 2a: site na iji carbonyl compound (4a) dị ka ihe mmalite, a na-akwadebe etiti 1 site na mbelata, nchebe TIPS, na mmeghachi omume na 2,3-difluorobromobenzene. Intermediate 1 na-enweta mmeghachi omume mbelata-amination asymmetric n'okpuru ọrụ nke FeⅡ/EDTA complexing catalyst wee banye ammonolysis na 20% ammonia mmiri iji mepụta isi etiti 2a (Foto 6a).
N'akwụkwọ ọzọ (Zhejiang Chemical Industry, 2022, 53(8). 13-18.), a kọwara ụzọ e si akwadebe isi etiti 2b: site na iji compound 2 dị ka ihe eji arụ ọrụ, a na-enweta isi etiti 2b site na AlⅢ/EDTA catalysis. Usoro a dị ka ndị a (Fig. 6b):
Akwụkwọ ikike CN116640811A/CN116083385A na-akọwa ụzọ e si akwadebe ihe ndị dị mkpa 2a/2b: site na iji ihe mejupụtara 1/2 dị ka ihe mmalite, a na-emepụta ihe ndị dị mkpa 2a/2b ozugbo site na mmeghachi omume transaminase otu nzọụkwụ. Usoro a abụghị naanị na ọ nwere obere usoro sịntetik kamakwa ọ na-eme ka nhọrọ chiral na mmepụta nke ihe ndị dị mkpa 2a/2b ka mma nke ukwuu. Ọzọkwa, a na-eji usoro nkwadebe ahụ mara ọnọdụ mmeghachi omume dị nro na ọrụ nchekwa mgbe nhazi gasịrị, nke na-emezu ihe achọrọ maka mmepụta ụlọ ọrụ (Foto 7).
Chiral alcohol compound 4b bụ ihe na-ebute ụzọ na isi chiral amine intermediates 2a/2b. Ugbu a, ụzọ sịntetik dị n'ihu ọha na-adaba n'ụdị abụọ: kemịkalụ na chemoenzymatic.
N'akwụkwọ ndị e dere (Organic Letters, 2012, 14(18): 4938–4941), ụlọ ọrụ ahụ mere nnyocha mbụ ahụ kọwara ụzọ isi mepụta 4b site na mbelata asymmetric: site na iji dimethyl 2,3-pyridinedicarboxylate (5a) dị ka ihe mmalite, enwetara 4a etiti site na mmeghachi omume cyclization Dieckmann na decarboxylation, wee mepụta ngwakọta mmanya chiral site na mbelata asymmetric site na iji ihe na-eme ka ihe na-akpali akpali nke ígwè Rh-(R-Binapine)(COD)BF₄ nwee mgbanwe nke 100% na ee≥99.9% (Foto 8).
Ná mmalite, ụlọ ọrụ nyocha ahụ kwuru na patent CN102066358B na e belatara ngwakọta diketone (4a) na 4b site na usoro enzymatic, mana ekpugheghị ozi kpọmkwem gbasara mmeghachi omume ahụ; e mechara, akọpụtara ya na akwụkwọ (Organic Letters, 2012, 14(18):4938-4941) na e belatara ngwakọta diketone na 4b n'okpuru catalysis nke ketone reductase ES-KRED-119 yana mmepụta mmeghachi omume nke 81% na uru ee nke 99.2% (Foto 9).
A zụtara ketone reductase ES-KRED-119 ejiri mee ihe n'ụzọ enzymatic dị n'elu site na Shangke Biopharmaceutical (Shanghai) Co., Ltd. Shangke Biopharmaceutical gbanwere enzyme dị na patent CN202410502187.9, ntinye substrate ahụ nwekwara ike iru 100 g/L.
Mbelata asymmetric nke enzyme dabara nke ọma maka ihe ụlọ ọrụ mmepụta ihe maka mmepụta nke chiral alcohol compounds (4b). Ọmụmụ ihe ndị sochirinụ lekwasịrị anya n'ịkwalite ihe mkpali ma ọ bụ nyocha na imeziwanye ketone reductases, nke a gaghị atụle nke ọma ebe a.
[2] LEAHY DAVID K., FANG Y., CHAN COLLIN na ndị ọzọ. Ụzọ e si emepụta cycloheptapyridine, CGRP, onye na-emegide ihe nnabata: USA 8669368B2 [P]. 11.03.2014.
[3] Ruan Shiwen, Yang Gongchao, Zhang Wei, na ndị ọzọ. Usoro e ji emepụta ihe maka rimegepant na ihe ndị dị n'etiti ya: China, 114957247A[P]. 2022-08-30.
[4] He Lingyun, Chen Binhui, Yu Yang. Ụzọ e si akwadebe ihe na-akpali ígwè na ihe dị n'etiti rimexam: China, 116768938A[P]. 2023-09-19.
[5] Lin Weikang. Ọmụmụ ihe mbụ gbasara teknụzụ mmepụta nke ihe ndị na-eme ka ihe na-eme ka ihe na-eme ka ihe na-eme ka ihe na-eme ka ihe na-eme ka ihe na-eme ka ihe na-eme ka ihe na-eme ka ihe na-eme ka ihe na-eme ka ihe na-adịghị mma nke CGRP receptor antagonist Remegapan dị nro site na usoro asymmetric catalytic amination [J]. Zhejiang Chemical Industry, 2022, 53(8):13-18.
[6] He Lingyun, Chen Binhui, Yu Yang. Usoro maka ịkwadebe rimexam etiti: China, 116640811A[P]. 2023-08-25.
[8] Ma Yulei, Jiao Xuecheng, Wang Zujian, na ndị ọzọ. Nhazi nke isi ihe polymer dị irè nke ukwuu site na iji transaminase agbanwere agbanwe [J]. Nnyocha na Mmepe Usoro Organic, 2022, 26(7):1971–1977.
[9] David K. Leahy, Yu Fan, Lopa V. Desai, na ndị ọzọ. Nhazi enantioselective dị irè ma dịkwa oke mma nke ndị na-emegide CGRP [J]. Akwụkwọ edemede Organic, 2012, 14(18): 4938–4941.
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