I-Rimegepant ingukuphela komphikisi we-CGRP receptor emhlabeni osebenzisa ubuchwepheshe bethebhulethi obuqabula ngomlomo obunelungelo lobunikazi futhi ingumuthi wokuqala emhlabeni ongasetshenziswa kokubili ekwelapheni nasekuvimbeleni ukuhlaselwa yikhanda elibuhlungu.
Ngomhlaka-27 kuNhlolanja 2020, i-US Food and Drug Administration (FDA) yavuma ukudayiswa kwamaphilisi e-remdesivir panicol sulfate ngaphansi kwegama lomkhiqizo i-Nurtec® ODT.
Kuze kube manje, izindlela eziyinhloko zokwenziwa zesithako semithi esisebenzayo i-repiride yizindlela ezimbili ezidalulwe ngumkhiqizi wokuqala, iBristol-Myers Squibb, esebenzisa i-(6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-[[triisopropylsyl]oxy]-5H-i-cycloheptatrienepyridin-5-one (inhlanganisela 1) njengento yokuqala.
Umzila 1: I-Remegapan ilungiswa ngesenzo sezinyathelo eziyisithupha esihilela, phakathi kwezinye izinto: ukunciphisa iqembu le-ketone nge-sodium borohydride, ukuncishiswa kweqembu le-hydroxyl nge-triphenylphosphine kanye ne-N-chlorosuccinimide, ukufaka esikhundleni i-athomu ye-chlorine nge-sodium azide, ukususa i-siliconization nge-tetrabutylammonium fluoride, ukuhlanganisa, kanye nokunciphisa iqembu le-azide nge-trimethylphosphine. Indlela iboniswe ngezansi (Isithombe 3):
Umzila 2: Kusetshenziswa i-compound 1 njengento yokuqala, i-remepam yenziwa ngezinyathelo ezintathu (ukusabela kwesinyathelo esisodwa kwe-tetraisopropoxytitanium, i-alumina, ne-palladium ku-carbon ukukhiqiza i-key intermediate 2a, ukuwohloka kokuvikela ukukhiqiza i-key intermediate 2b, kanye nokuxhumanisa). Umzila uboniswe ngezansi (Isithombe 4):
Njengoba kungabonakala kufomula yesakhiwo, isithako semithi esisebenzayo i-Remegapan molecule sinezikhungo ezintathu ze-chiral. Ukudala i-chiral amine endaweni engu-5 ye-cycloheptane kuletha inselele enkulu yokwandisa ukukhiqizwa kwesithako semithi esisebenzayo. Ucwaningo olwengeziwe luzogxila ekuthuthukiseni inqubo yokwenziwa kwezidakamizwa ezibalulekile ze-2a/2b.
I-Patent CN114957247A ichaza indlela yokulungiselela ama-key intermediates 2a/2b: kusetshenziswa i-compound 3a njengento yokuqala, kwenzeka ukusabela kwe-stereoselective ring-opening nge-reagent ye-Lewis ukwakha i-compound 3b, bese kuba nokusabela kwe-Suzuki, ukuvikelwa kwe-silanization, ukufakwa esikhundleni, kanye nokususwa kokuvikelwa ukuze kunikezwe i-key intermediate 2b cishe ku-54% yesivuno iyonke. Indlela iboniswe ngezansi (Isithombe 5):
I-Patent CN116768938A ichaza indlela yokulungiselela i-key intermediate 2a: kusetshenziswa i-carbonyl compound (4a) njengento yokuqala, i-intermediate 1 ilungiswa ngokunciphisa, ukuvikelwa kwe-TIPS, kanye nokusabela nge-2,3-difluorobromobenzene. I-Intermediate 1 idlula ku-asymmetric reduction-amination reaction ngaphansi kwesenzo se-FeⅡ/EDTA complexing catalyst bese idlula ku-ammonolysis ene-20% ammonia yamanzi ukuze ikhiphe i-key intermediate 2a (Isithombe 6a).
Kwesinye isikole (iZhejiang Chemical Industry, 2022, 53(8). 13-18.), indlela yokulungiselela i-key intermediate 2b ichazwe: kusetshenziswa i-compound 2 njengento eluhlaza, i-key intermediate 2b itholakala nge-AlⅢ/EDTA catalysis. Indlela yile elandelayo (Isithombe 6b):
Amalungelo obunikazi CN116640811A/CN116083385A achaza indlela yokulungiselela ama-key intermediates 2a/2b: kusetshenziswa i-compound 1/2 njengento yokuqala, ama-key chiral intermediates 2a/2b akhiqizwa ngqo nge-transaminase reaction yesinyathelo esisodwa. Le nqubo ayinayo nje kuphela isinyathelo esifushane sokwenziwa kodwa futhi ithuthukisa kakhulu ukukhetha kwe-chiral kanye nesivuno sama-key intermediates 2a/2b. Ngaphezu kwalokho, indlela yokulungiselela ibonakala ngezimo zokusabela ezithambile kanye nemisebenzi ephephile yangemva kokucubungula, ehlangabezana nezidingo zokukhiqiza zezimboni (Isithombe 7).
I-chiral alcohol compound 4b iyisandulela se-chiral amine intermediates 2a/2b. Njengamanje, izindlela zokwenziwa ezitholakala emphakathini ziwela ezigabeni ezimbili: amakhemikhali kanye ne-chemoenzymatic.
Ezincwadini (Organic Letters, 2012, 14(18): 4938–4941), inkampani eyaqhuba ucwaningo lokuqala ichaze indlela yokuhlanganisa i-4b ngokunciphisa okungalingani: kusetshenziswa i-dimethyl 2,3-pyridinedicarboxylate (5a) njengento yokuqala, i-intermediate 4a itholakale nge-Dieckmann cyclization kanye ne-decarboxylation reaction, bese kuba ne-chiral alcohol compound eyenziwe ngokunciphisa okungalingani kusetshenziswa i-metal catalyst Rh-(R-Binapine)(COD)BF₄ ngokuguqulwa okungu-100% kanye ne-ee≥99.9% (Isithombe 8).
Ekuqaleni, inkampani yocwaningo ikhulume ku-patent CN102066358B ukuthi i-diketone compound (4a) yehliswe yaba yi-4b ngendlela ye-enzymatic, kodwa ayizange idalule ulwazi oluthile mayelana nokusabela; kamuva, kwabikwa ezincwadini (Organic Letters, 2012, 14(18):4938-4941) ukuthi i-diketone compound yehliswe yaba yi-4b ngaphansi kwe-catalysis ye-ketone reductase ES-KRED-119 ngenzuzo yokusabela engu-81% kanye nenani le-ee elingu-99.2% (Isithombe 9).
I-ketone reductase ES-KRED-119 esetshenziswe kule ndlela ye-enzymatic engenhla ithengwe kwa-Shangke Biopharmaceutical (Shanghai) Co., Ltd. I-Shangke Biopharmaceutical ishintshe i-enzyme ku-patent CN202410502187.9, futhi ukuhlushwa kwe-substrate kungafinyelela ku-100 g/L.
Ukunciphisa i-enzyme asymmetric kuhambisana kangcono nezidingo zezimboni zokwenziwa kwamakhemikhali e-chiral alcohol (4b). Izifundo ezilandelayo zigxile ekuthuthukiseni ama-catalyst noma ekuhloleni nasekuthuthukiseni ama-ketone reductase, okungeke kuxoxwe ngakho ngokuningiliziwe lapha.
[2] LEAHY DAVID K., FANG Y., CHAN COLLIN nabanye. Indlela yokukhiqiza i-CGRP receptor antagonist cycloheptapyridine: USA 8669368B2 [P]. 11.03.2014.
[3] Ruan Shiwen, Yang Gongchao, Zhang Wei, nabanye. Izindlela zokwenziwa ze-rimegepant kanye nezingxenye zayo eziphakathi: China, 114957247A[P]. 2022-08-30.
[4] He Lingyun, Chen Binhui, Yu Yang. Indlela yokulungiselela i-iron catalyst kanye nomkhiqizo ophakathi we-rimexam: China, 116768938A[P]. 2023-09-19.
[5] Lin Weikang. Ucwaningo lokuqala ngobuchwepheshe bokwenziwa kwe-fluorinated chiral moiety ye-CGRP receptor antagonist Remegapan ngendlela ye-asymmetric catalytic amination [J]. Zhejiang Chemical Industry, 2022, 53(8):13-18.
[6] He Lingyun, Chen Binhui, Yu Yang. Indlela yokulungiselela i-rimexam emaphakathi: China, 116640811A[P]. 2023-08-25.
[8] Ma Yulei, Jiao Xuecheng, Wang Zujian, et al. Ukuhlanganiswa okuphumelelayo kakhulu kwama-key polymer intermediates kusetshenziswa i-transaminase eguquliwe [J]. Ucwaningo Lwezinqubo Zemvelo Nokuthuthukiswa, 2022, 26(7):1971–1977.
[9] UDavid K. Leahy, uYu Fan, uLopa V. Desai, nabanye. Ukuhlanganiswa kwe-enantioselective okusebenza kahle futhi okungalinganiswa kwabaphikisi be-CGRP [J]. Izincwadi Ze-Organic, 2012, 14(18): 4938–4941.
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