I-Rimegepant yeyona kuphela i-CGRP receptor antagonist ehlabathini esebenzisa ubuchwepheshe beepilisi ezidityanisiweyo ngomlomo kwaye liyeza lokuqala emhlabeni elinokusetyenziselwa unyango kunye nokuthintela ukuhlaselwa kwe-migraine ngokukhawuleza.
Ngomhla wama-27 kuFebruwari 2020, i-US Food and Drug Administration (FDA) yavuma ukuthengiswa kweepilisi ze-remdesivir panicol sulfate phantsi kwegama lebrendi iNurtec® ODT.
Ukuza kuthi ga ngoku, iindlela eziphambili zokwenziwa kwesithako esisebenzayo seyeza i-repiride ziindlela ezimbini ezityhilwe ngumvelisi 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 (i-compound 1) njengesixhobo sokuqala.
Indlela 1: I-Remegapan ilungiswa nge-reaction enamanyathelo amathandathu equka, phakathi kwezinye izinto: ukunciphisa iqela le-ketone nge-sodium borohydride, i-chlorination yeqela le-hydroxyl nge-triphenylphosphine kunye ne-N-chlorosuccinimide, ukutshintsha i-atom ye-chlorine nge-sodium azide, ukususa i-siliconization nge-tetrabutylammonium fluoride, ukudibanisa, kunye nokunciphisa iqela le-azide nge-trimethylphosphine. Indlela iboniswe ngezantsi (Umzobo 3):
Indlela yesi-2: Ukusebenzisa i-compound 1 njengesixhobo sokuqala, i-remepam yenziwa ngamanyathelo amathathu (i-reaction yenyathelo elinye ye-tetraisopropoxytitanium, i-alumina, kunye ne-palladium kwi-carbon ukuvelisa i-key intermediate 2a, i-deprotection ukuvelisa i-key intermediate 2b, kunye ne-coupling). Indlela iboniswe ngezantsi (Umfanekiso 4):
Njengoko kunokubonwa kwifomyula yolwakhiwo, isithako esisebenzayo samayeza iRemegapan molecule sinamaziko amathathu e-chiral. Ukudala i-chiral amine kwindawo yesi-5 ye-cycloheptane kubeka umngeni omkhulu wokwandisa imveliso yesithako esisebenzayo samayeza. Uphando olongezelelweyo luza kugxila ekuphuculeni inkqubo yokwenziwa kwezinto eziphambili eziphakathi kwe-2a/2b.
Ilungelo lomenzi CN114957247A lichaza indlela yokulungiselela ii-key intermediates 2a/2b: kusetyenziswa i-compound 3a njengesixhobo sokuqala, kwenzeka i-stereoselective ring-opening reaction kunye ne-Lewis reagent ukwenza i-compound 3b, ethi emva koko idlule kwi-Suzuki reaction, i-silanization protection, i-substitution, kunye ne-deprotection ukuze inike i-key intermediate 2b kwi-54% yesivuno iyonke. Le ndlela iboniswe ngezantsi (Umfanekiso 5):
Ilungelo lomenzi CN116768938A lichaza indlela yokulungiselela i-key intermediate 2a: kusetyenziswa i-carbonyl compound (4a) njengesixhobo sokuqala, i-intermediate 1 ilungiswa ngokunciphisa, ukukhuselwa kwe-TIPS, kunye nokusabela nge-2,3-difluorobromobenzene. I-Intermediate 1 idlula kwi-asymmetric reduction-amination reaction phantsi kwesenzo se-FeⅡ/EDTA complexing catalyst ize emva koko idlule kwi-ammonolysis ene-20% ye-ammonia yamanzi ukuze ivelise i-key intermediate 2a (Umfanekiso 6a).
Kwenye incwadi (iZhejiang Chemical Industry, 2022, 53(8). 13-18.), indlela yokulungiselela i-key intermediate 2b ichazwe: kusetyenziswa i-compound 2 njengezinto eziluhlaza, i-key intermediate 2b ifunyanwa nge-AlⅢ/EDTA catalysis. Le ndlela ilandelayo (Umzobo 6b):
Iipatenti ze-CN116640811A/CN116083385A zichaza indlela yokulungiselela ii-key intermediates 2a/2b: kusetyenziswa i-compound 1/2 njengesixhobo sokuqala, ii-key chiral intermediates 2a/2b ziveliswa ngokuthe ngqo nge-transaminase reaction yenyathelo elinye. Le nkqubo ayinayo nje kuphela inyathelo elifutshane lokwenziwa kodwa ikwaphucula kakhulu ukukhetha kwe-chiral kunye nemveliso yee-key intermediates 2a/2b. Ngaphezu koko, indlela yokulungiselela ibonakaliswa ziimeko zokusabela ezithambileyo kunye nemisebenzi ekhuselekileyo emva kokucubungula, ehlangabezana neemfuno zemveliso yemizi-mveliso (Umzobo 7).
I-Chiral alcohol compound 4b sisandulela se-key chiral amine intermediates 2a/2b. Okwangoku, iindlela zokwenziwa ezifumaneka esidlangalaleni zahlulwe zibe ziindidi ezimbini: iikhemikhali kunye nee-chemoenzymatic.
Kwincwadi (Organic Letters, 2012, 14(18): 4938–4941), inkampani eyayiqhuba uphando lokuqala ichaze indlela yokwenza i-4b ngokunciphisa okulinganayo: kusetyenziswa i-dimethyl 2,3-pyridinedicarboxylate (5a) njengesixhobo sokuqala, i-intermediate 4a ifunyenwe nge-Dieckmann cyclization kunye ne-decarboxylation reaction, kwaye emva koko i-chiral alcohol compound yenziwe ngokunciphisa okulinganayo kusetyenziswa i-metal catalyst Rh-(R-Binapine)(COD)BF₄ ngokuguqulwa kwe-100% kunye ne-ee≥99.9% (Umzobo 8).
Ekuqaleni, inkampani yophando ikhankanye kwi-patent CN102066358B ukuba i-diketone compound (4a) yehliswe yaba yi-4b ngendlela ye-enzymatic, kodwa ayizange ityhile ulwazi oluthile malunga nokusabela; kamva, kwaxelwa kwiincwadi (Organic Letters, 2012, 14(18):4938-4941) ukuba i-diketone compound yehliswe yaba yi-4b phantsi kwe-catalysis ye-ketone reductase ES-KRED-119 ene-reaction yield ye-81% kunye nexabiso le-ee le-99.2% (Umfanekiso 9).
I-ketone reductase ES-KRED-119 esetyenziswe kule ndlela ye-enzymatic ingentla ithengwe kwiShangke Biopharmaceutical (Shanghai) Co., Ltd. IShangke Biopharmaceutical iguqule i-enzyme kwi-patent CN202410502187.9, kwaye uxinzelelo lwe-substrate lunokufikelela kwi-100 g/L.
Ukunciphisa i-enzyme asymmetric kulungele ngcono iimfuno zoshishino zokwenziwa kwee-chiral alcohol compounds (4b). Izifundo ezilandelayo zigxile ekuphuculeni ii-catalysts okanye ekuhloleni nasekuphuculeni i-ketone reductases, nto leyo engazukuxoxwa ngayo ngokweenkcukacha apha.
[2] LEAHY DAVID K., FANG Y., CHAN COLLIN et al. Indlela yokuvelisa i-CGRP receptor antagonist cycloheptapyridine: USA 8669368B2 [P]. 11.03.2014.
[3] Ruan Shiwen, Yang Gongchao, Zhang Wei, et al. Iindlela zokwenziwa kwe-rimegepant kunye nezinto ezingaphakathi kwayo: China, 114957247A[P]. 2022-08-30.
[4] UHe Lingyun, uChen Binhui, uYu Yang. Indlela yokulungiselela i-iron catalyst kunye nemveliso ephakathi ye-rimexam: China, 116768938A[P]. 2023-09-19.
[5] Lin Weikang. Uphononongo lokuqala malunga netekhnoloji yokwenziwa kwe-fluorinated chiral moiety ye-CGRP receptor antagonist Remegapan ngendlela ye-asymmetric catalytic amination [J]. Zhejiang Chemical Industry, 2022, 53(8):13-18.
[6] Yena Lingyun, Chen Binhui, Yu Yang. Indlela yokulungiselela i-rimexam ephakathi: China, 116640811A[P]. 2023-08-25.
[8] Ma Yulei, Jiao Xuecheng, Wang Zujian, et al. Ukwenziwa okusebenzayo kakhulu kwe-key polymer intermediates kusetyenziswa i-modified transaminase [J]. Uphando lweNkqubo ye-Organic kunye noPhuhliso, 2022, 26(7):1971–1977.
[9] UDavid K. Leahy, uYu Fan, uLopa V. Desai, et al. Ukwenziwa kwe-enantioselective esebenza kakuhle nenokukhuliswa kwee-CGRP antagonists [J]. Iileta ze-Organic, 2012, 14(18): 4938–4941.
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