Rimegepant ita ce kawai maganin hana karɓar CGRP a duniya wanda ke amfani da fasahar kwamfutar hannu mai lalacewa ta baki kuma ita ce magani na farko a duniya da za a iya amfani da shi don magancewa da kuma rigakafin hare-haren migraine mai tsanani.
A ranar 27 ga Fabrairu, 2020, Hukumar Abinci da Magunguna ta Amurka (FDA) ta amince da tallata allunan remdesivir panicol sulfate a ƙarƙashin sunan Nurtec® ODT.
Zuwa yanzu, manyan hanyoyin roba zuwa ga sinadarin magunguna masu aiki remepiride hanyoyi ne guda biyu da kamfanin Bristol-Myers Squibb na asali ya bayyana, ta amfani da (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-[[triisopropylsilyl]oxy]-5H-cycloheptatrienepyridin-5-one (mahaɗi 1) a matsayin kayan farawa.
Hanya ta 1: An shirya Remegapan ta hanyar wani mataki na mataki shida wanda ya haɗa da: rage ƙungiyar ketone tare da sodium borohydride, chlorination na ƙungiyar hydroxyl tare da triphenylphosphine da N-chlorosuccinimide, maye gurbin ƙwayar chlorine da sodium azide, desiliconization tare da tetrabutylammonium fluoride, haɗawa, da rage ƙungiyar azide tare da trimethylphosphine. Hanyar an nuna ta a ƙasa (Hoto na 3):
Hanya ta 2: Ta amfani da mahaɗin 1 a matsayin kayan farawa, an haɗa remepam a matakai uku (mataki ɗaya na tetraisopropoxytitanium, alumina, da palladium akan carbon don samar da matsakaicin matsakaici na 2a, rashin kariya don samar da matsakaicin matsakaici na 2b, da haɗin gwiwa). An nuna hanyar a ƙasa (Hoto na 4):
Kamar yadda za a iya gani daga tsarin tsari, sinadarin magunguna masu aiki na Remegapan yana da cibiyoyin chiral guda uku. Samar da chiral amine a matsayi na 5 na cycloheptane yana haifar da babban ƙalubale wajen haɓaka samar da sinadarin magunguna masu aiki. Ƙarin bincike zai mayar da hankali kan inganta tsarin haɗa magunguna masu mahimmanci 2a/2b.
Patent CN114957247A ya bayyana wata hanya ta shirya maɓallan tsakiya 2a/2b: ta amfani da mahaɗin 3a a matsayin kayan farawa, amsawar buɗe zobe mai zaɓin stereosective yana faruwa tare da Lewis reagent don samar da mahaɗin 3b, wanda daga nan zai shiga amsawar Suzuki, kariyar silanization, maye gurbinsa, da kuma cire kariya don samar da matsakaicin matsakaicin 2b a cikin kusan kashi 54% na yawan amfanin ƙasa. An nuna hanyar a ƙasa (Hoto na 5):
Patent CN116768938A ya bayyana wata hanya ta shirya maɓallin tsakiya na 2a: ta amfani da mahaɗin carbonyl (4a) a matsayin kayan farawa, ana shirya matsakaici na 1 ta hanyar ragewa, kariyar TIPS, da kuma amsawa tare da 2,3-difluorobromobenzene. Matsakaicin 1 yana fuskantar amsawar rage-amination mara daidaituwa a ƙarƙashin aikin mai haɗakar FeⅡ/EDTA sannan ya sha ammonolysis tare da ammonia mai ruwa 20% don samar da maɓallin tsakiya na 2a (Hoto na 6a).
A wani wallafe-wallafen (Zhejiang Chemical Industry, 2022, 53(8). 13-18.), an bayyana wata hanya ta shirya maɓallin tsakiya na 2b: ta amfani da mahaɗin 2 a matsayin kayan aiki, maɓallin tsakiya na 2b ana samun shi ta hanyar AlⅢ/EDTA catalysis. Hanyar ita ce kamar haka (Hoto na 6b):
Lambobin mallaka CN116640811A/CN116083385A sun bayyana wata hanya ta shirya manyan hanyoyin sadarwa 2a/2b: ta amfani da mahaɗi 1/2 a matsayin kayan farawa, manyan hanyoyin sadarwa 2a/2b ana samar da su kai tsaye ta hanyar amsawar transaminase mataki ɗaya. Wannan tsari ba wai kawai yana da ɗan gajeren mataki na roba ba, har ma yana inganta zaɓin chiral da yawan amfanin manyan hanyoyin sadarwa 2a/2b sosai. Bugu da ƙari, hanyar shiri tana da alaƙa da yanayin amsawa mai sauƙi da ayyukan bayan sarrafawa masu aminci, waɗanda suka cika buƙatun samar da masana'antu (Hoto na 7).
Sinadarin barasa na Chiral 4b wani abu ne da ke ƙara wa sinadarin chiral amine mai mahimmanci girma 2a/2b. A halin yanzu, hanyoyin roba da ake da su a bainar jama'a sun kasu kashi biyu: sinadarai da kuma sinadaran chemoenzymatic.
A cikin wallafe-wallafen (Organic Letters, 2012, 14(18): 4938–4941), kamfanin da ya gudanar da binciken farko ya bayyana hanyar haɗa 4b ta hanyar rage asymmetric: ta amfani da dimethyl 2,3-pyridinedicarboxylate (5a) a matsayin kayan farawa, an sami matsakaicin 4a ta hanyar Dieckmann cyclization da decarboxylation reaction, sannan aka haɗa sinadarin chiral alcohol ta hanyar rage asymmetric ta amfani da ƙarfe mai kara kuzari Rh-(R-Binapine)(COD)BF₄ tare da juyawar 100% da ee≥99.9% (Hoto na 8).
Da farko, kamfanin binciken ya ambaci a cikin takardar izinin mallaka ta CN102066358B cewa an rage mahaɗin diketone (4a) zuwa 4b ta hanyar hanyar enzymatic, amma bai bayyana takamaiman bayani game da mahaɗin ba; daga baya, an ruwaito a cikin wallafe-wallafen (Organic Letters, 2012, 14(18):4938-4941) cewa mahaɗin diketone an rage shi zuwa 4b a ƙarƙashin catalysis na ketone reductase ES-KRED-119 tare da yawan amsawar da ya kai 81% da ƙimar ee na 99.2% (Hoto na 9).
An sayi ketone reductase ES-KRED-119 da aka yi amfani da shi a cikin hanyar enzymatic da ke sama daga Shangke Biopharmaceutical (Shanghai) Co., Ltd. Shangke Biopharmaceutical ya gyara enzyme a cikin takardar izinin mallaka CN202410502187.9, kuma yawan substrate zai iya kaiwa 100 g/L.
Rage sinadarin enzyme wanda ba shi da alaƙa da juna ya fi dacewa da buƙatun masana'antu don haɗa sinadarai na giya na chiral (4b). Nazarin da suka biyo baya sun mayar da hankali kan inganta abubuwan da ke haifar da sinadarai ko tantancewa da inganta abubuwan rage sinadarin ketone, wanda ba za a tattauna dalla-dalla a nan ba.
[2] LEAHY DAVID K., FANG Y., CHAN COLLIN da sauransu. Hanyar samar da cycloheptapyridine mai hana karɓar CGRP: Amurka 8669368B2 [P]. 11.03.2014.
[3] Ruan Shiwen, Yang Gongchao, Zhang Wei, da sauransu. Hanyoyin roba don rimegepant da tsaka-tsakinsa: China, 114957247A[P]. 2022-08-30.
[4] He Lingyun, Chen Binhui, Yu Yang. Hanyar shirya sinadarin ƙarfe mai kara kuzari da kuma samfurin matsakaici na rimexam: China, 116768938A[P]. 2023-09-19.
[5] Lin Weikang. Nazarin farko kan fasahar haɗakar ƙwayoyin chiral mai fluoride na CGRP receptor antagonist Remegapan ta hanyar hanyar asymmetric catalytic amination [J]. Zhejiang Chemical Industry, 2022, 53(8):13-18.
[6] He Lingyun, Chen Binhui, Yu Yang. Hanyar shirya rimexam matsakaici: China, 116640811A[P]. 2023-08-25.
[8] Ma Yulei, Jiao Xuecheng, Wang Zujian, da sauransu. Haɗakar manyan hanyoyin polymer masu inganci ta amfani da transaminase da aka gyara [J]. Binciken Tsarin Halitta da Ci Gaban Halitta, 2022, 26(7):1971–1977.
[9] David K. Leahy, Yu Fan, Lopa V. Desai, da sauransu. Haɗakar masu adawa da CGRP mai inganci da kuma iya daidaitawa [J]. Haruffan Halitta, 2012, 14(18): 4938–4941.
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