Rimegepant ni wo muti rukumbi ku isi urwanya CGRP receptor antagonist ukoresha ikoranabuhanga rya patented ryo gushwanyaguza ibinini mu kanwa, kandi ni wo muti wa mbere ku isi ushobora gukoreshwa mu kuvura no gukumira ibitero by’umutwe bikomeye.
Ku ya 27 Gashyantare 2020, Ikigo gishinzwe Ibiribwa n'Imiti muri Amerika (FDA) cyemeje kwamamaza ibinini bya remdesivir panicol sulfate ku izina rya Nurtec® ODT.
Kugeza ubu, inzira z'ingenzi zikoreshwa mu buhanga mu gukwirakwiza umuti wa remepiride ni inzira ebyiri zagaragajwe n'uwakoze umuti wa mbere, Bristol-Myers Squibb, hakoreshejwe (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-[[triisopropylsyl]oxy]-5H-cycloheptatrienepyridin-5-one (icyiciro cya 1) nk'ibikoresho byo gutangira.
Inzira ya 1: Remegapan itegurwa binyuze mu buryo bw'intambwe esheshatu burimo, harimo: kugabanya itsinda rya ketone hamwe na sodium borohydride, klorination y'itsinda rya hydroxyl hamwe na triphenylphosphine na N-chlorosuccinimide, gusimbuza atome ya chlorine na sodium azide, gukuraho siliconization hamwe na tetrabutylammonium fluoride, guhuza, no kugabanya itsinda rya azide hamwe na trimethylphosphine. Inzira igaragara hano hepfo (Ishusho ya 3):
Inzira ya 2: Hakoreshejwe imvange ya 1 nk'ibikoresho byo gutangira, remepam ikorwa mu ntambwe eshatu (uburyo bumwe bwo gukora tetraisopropoxytitanium, alumina, na palladium kuri karuboni kugira ngo hakorwe urufunguzo hagati ya 2a, gusenya uburinzi kugira ngo hakorwe urufunguzo hagati ya 2b, no guhuza). Inzira igaragara hano hepfo (Ishusho ya 4):
Nkuko bigaragara mu miterere y'imiti, igice cy’imiti gikora cya Remegapan gifite ibice bitatu bya chiral. Gukora amine ya chiral ku mwanya wa 5 wa cycloheptane bitera imbogamizi ikomeye mu kongera umusaruro w’igice cy’imiti gikora. Ubushakashatsi burambuye buzibanda ku kunoza inzira yo gukora imisemburo y’imiti y’ingenzi ya 2a/2b.
Patenti CN114957247A isobanura uburyo bwo gutegura intermediates z'urufunguzo 2a/2b: hakoreshejwe compound 3a nk'ibikoresho byo gutangira, reaction ya stereoselective ring-opening ibaho hamwe na reagent ya Lewis kugira ngo ikore compound 3b, hanyuma inyura muri Suzuki reaction, silanization protection, substitution, and deprotection kugira ngo ihe intermediate y'urufunguzo 2b mu musaruro rusange wa hafi 54%. Ubu buryo bugaragara hano hepfo (Ishusho ya 5):
Patenti CN116768938A isobanura uburyo bwo gutegura urufunguzo hagati ya 2a: hakoreshejwe imvange ya karuboni (4a) nk'ibikoresho byo gutangira, urufunguzo hagati ya 1 rutegurwa hakoreshejwe uburyo bwo kugabanya, kurinda TIPS, no gusubiza hamwe na 2,3-difluorobromobenzene. Urufunguzo hagati ya 1 runyura mu buryo butari bumwe bwo kugabanya-guhindura ibintu munsi y'igikorwa cya katalyst ya FeⅡ/EDTA hanyuma runyura mu buryo bwa ammonolysis hamwe na ammonia y'amazi ya 20% kugira ngo rutange urufunguzo hagati ya 2a (Ishusho ya 6a).
Mu yindi nyandiko (Zhejiang Chemical Industry, 2022, 53 (8). 13-18.), uburyo bwo gutegura urufunguzo hagati ya 2b burasobanurwa: hakoreshejwe imvange ya 2 nk'ibikoresho fatizo, urufunguzo hagati ya 2b ruboneka binyuze muri AlⅢ/EDTA catalysis. Uburyo ni ubu bukurikira (Ishusho ya 6b):
Patenti CN116640811A/CN116083385A isobanura uburyo bwo gutegura intermediates z'ingenzi 2a/2b: hakoreshejwe compound 1/2 nk'ibikoresho byo gutangira, intermediates z'ingenzi 2a/2b zikorwa mu buryo butaziguye binyuze mu buryo bwa transaminase reaction y'intambwe imwe. Ubu buryo ntibugira intambwe ngufi gusa ahubwo bunatuma cyane uburyo chiral itoranywa n'umusaruro w'intermediates z'ingenzi 2a/2b. Byongeye kandi, uburyo bwo gutegura burangwa n'uburyo bworoshye bwo gukora response hamwe n'ibikorwa by'umutekano nyuma yo gutunganya, byujuje ibisabwa mu nganda (Ishusho ya 7).
Inzoga ya Chiral 4b ni intandaro y'ibinyabutabire by'ingenzi bya chiral amine 2a/2b. Muri iki gihe, inzira z'ubukorano ziboneka ku mugaragaro ziri mu byiciro bibiri: ubutabire n'ubutabire bwa chimique.
Mu nyandiko (Organic Letters, 2012, 14 (18): 4938–4941), ikigo cyakoze ubushakashatsi bwa mbere cyasobanuye inzira yo gukora 4b binyuze mu kugabanya ibintu bingana: hakoreshejwe dimethyl 2,3-pyridinedicarboxylate (5a) nk'ibikoresho byo gutangira, 4a yo hagati yabonetse binyuze mu gukora cyclization ya Dieckmann no gukora decarboxylation, hanyuma imvange ya chiral alcohol ikorwa binyuze mu kugabanya ibintu bingana hakoreshejwe catalyst y'icyuma Rh-(R-Binapine)(COD)BF₄ hamwe n'impinduka ya 100% na ee≥99.9% (Ishusho ya 8).
Mbere na mbere, ikigo cy’ubushakashatsi cyavuze muri patenti CN102066358B ko imvange ya diketone (4a) yagabanutse igera kuri 4b hakoreshejwe uburyo bwa enzymatic, ariko ntiyerekane amakuru yihariye yerekeye uko ibintu byagenze; nyuma, byatangajwe mu nyandiko (Organic Letters, 2012, 14 (18): 4938-4941) ko imvange ya diketone yagabanutse igera kuri 4b bitewe n’uburyo bwa catalysis ya ketone reductase ES-KRED-119 hamwe n’umusaruro w’ingaruka wa 81% n’agaciro ka ee ka 99.2% (Ishusho ya 9).
Ketone reductase ES-KRED-119 yakoreshejwe muri ubwo buryo bwa enzyme bwavuzwe haruguru yaguzwe muri Shangke Biopharmaceutical (Shanghai) Co., Ltd. Shangke Biopharmaceutical yahinduye enzyme muri patenti CN202410502187.9, kandi igipimo cya substrate gishobora kugera kuri 100 g/L.
Kugabanya enzymes bihuye neza n'ibisabwa mu nganda mu gukora inzoga za chiral (4b). Ubushakashatsi bwakurikiyeho bwibanze ku kunoza catalysts cyangwa gusuzuma no kunoza ketone reductases, ibyo bitazavugwaho birambuye hano.
[2] LEAHY DAVID K., FANG Y., CHAN COLLIN n'abandi. Uburyo bwo gukora cycloheptapyridine, antagonist ya CGRP receptor: USA 8669368B2 [P]. 11.03.2014.
[3] Ruan Shiwen, Yang Gongchao, Zhang Wei, n'abandi. Uburyo bwo gukora kuri rimegepant n'ibindi biyigize: Ubushinwa, 114957247A[P]. 2022-08-30.
[4] He Lingyun, Chen Binhui, Yu Yang. Uburyo bwo gutegura katalyst y'icyuma n'umusaruro w'intera wa rimexam: Ubushinwa, 116768938A[P]. 2023-09-19.
[5] Lin Weikang. Inyigo y'ibanze ku ikoranabuhanga ryo guhuza fluorinated chiral moiety ya CGRP receptor antagonist Remegapan binyuze mu buryo butagira ingano bwa catalytic amination [J]. Zhejiang Chemical Industry, 2022, 53 (8):13-18.
[6] We Lingyun, Chen Binhui, Yu Yang. Uburyo bwo gutegura rimexam hagati: Ubushinwa, 116640811A [P]. 2023-08-25.
[8] Ma Yulei, Jiao Xuecheng, Wang Zujian, n'abandi. Gukora neza cyane imvange y'ibinyabutabire bya polymer hakoreshejwe transaminase yahinduwe [J]. Ubushakashatsi n'Iterambere ry'Imikorere y'Ingirabuzimafatizo, 2022, 26 (7): 1971–1977.
[9] David K. Leahy, Yu Fan, Lopa V. Desai, n'abandi. Uburyo bwiza kandi bushobora kwaguka bwo gukora CGRP antagonists [J]. Organic Letters, 2012, 14 (18): 4938–4941.
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