Rimegepant yog tib lub tshuaj CGRP receptor antagonist hauv ntiaj teb uas siv cov thev naus laus zis patented orally disintegrating tablet thiab yog thawj cov tshuaj hauv ntiaj teb uas siv tau rau kev kho thiab tiv thaiv kev mob taub hau loj heev.
Thaum Lub Ob Hlis 27, 2020, Lub Chaw Saib Xyuas Khoom Noj thiab Tshuaj (FDA) ntawm Tebchaws Meskas tau pom zoo rau kev lag luam ntawm cov tshuaj remdesivir panicol sulfate hauv qab lub npe lag luam Nurtec® ODT.
Txog niaj hnub no, cov kev tsim tshuaj tseem ceeb rau cov khoom xyaw tshuaj remepiride yog ob txoj kev uas tau tshaj tawm los ntawm tus neeg tsim khoom qub, Bristol-Myers Squibb, siv (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-[[triisopropylsilyl]oxy]-5H-cycloheptatrienepyridin-5-one (compound 1) ua cov khoom pib.
Txoj Kev 1: Remegapan tau npaj los ntawm kev ua tshuaj rau kauj ruam uas muaj, ntawm lwm yam: kev txo cov ketone pawg nrog sodium borohydride, chlorination ntawm cov hydroxyl pawg nrog triphenylphosphine thiab N-chlorosuccinimide, kev hloov pauv ntawm cov chlorine atom nrog sodium azide, desiliconization nrog tetrabutylammonium fluoride, kev sib txuas, thiab kev txo cov azide pawg nrog trimethylphosphine. Txoj kev tau qhia hauv qab no (Daim Duab 3):
Txoj Kev 2: Siv cov tshuaj 1 ua cov khoom pib, remepam raug tsim ua peb kauj ruam (ib kauj ruam ntawm kev sib xyaw ntawm tetraisopropoxytitanium, alumina, thiab palladium ntawm cov pa roj carbon los tsim cov khoom siv nruab nrab tseem ceeb 2a, kev tiv thaiv los tsim cov khoom siv nruab nrab tseem ceeb 2b, thiab kev sib txuas). Txoj kev tau qhia hauv qab no (Daim Duab 4):
Raws li pom los ntawm cov qauv mis, cov khoom xyaw tshuaj Remegapan molecule muaj peb lub chaw chiral. Kev tsim cov chiral amine ntawm 5-txoj haujlwm ntawm cycloheptane ua rau muaj kev cov nyom loj rau kev nthuav dav ntawm cov khoom xyaw tshuaj. Kev tshawb fawb ntxiv yuav tsom mus rau kev txhim kho cov txheej txheem tsim cov khoom siv intermediates tseem ceeb 2a / 2b.
Daim Ntawv Pov Thawj CN114957247A piav qhia txog ib txoj kev npaj cov tshuaj intermediates tseem ceeb 2a/2b: siv cov tshuaj 3a ua cov khoom pib, qhov kev sib xyaw ua ke ntawm lub nplhaib qhib stereoselective tshwm sim nrog Lewis reagent los tsim cov tshuaj 3b, uas tom qab ntawd dhau los ntawm kev sib xyaw ua ke Suzuki, kev tiv thaiv silanization, kev hloov pauv, thiab kev tshem tawm kom tau txais cov tshuaj intermediate tseem ceeb 2b hauv kwv yees li 54% tag nrho cov txiaj ntsig. Txoj kev no tau qhia hauv qab no (Daim Duab 5):
Daim Ntawv Pov Thawj CN116768938A piav qhia txog ib txoj kev rau kev npaj cov tshuaj nruab nrab tseem ceeb 2a: siv cov tshuaj carbonyl (4a) ua cov khoom pib, cov tshuaj nruab nrab 1 yog npaj los ntawm kev txo qis, kev tiv thaiv TIPS, thiab kev sib xyaw nrog 2,3-difluorobromobenzene. Cov tshuaj nruab nrab 1 dhau los ntawm kev sib xyaw ua ke tsis sib xws hauv qab kev ua ntawm FeⅡ/EDTA complexing catalyst thiab tom qab ntawd dhau los ntawm ammonolysis nrog 20% aqueous ammonia kom tau txais cov tshuaj nruab nrab tseem ceeb 2a (Daim Duab 6a).
Hauv lwm cov ntaub ntawv (Zhejiang Chemical Industry, 2022, 53(8). 13-18.), ib txoj kev rau kev npaj cov tshuaj intermediate 2b tau piav qhia: siv cov tshuaj 2 ua cov khoom siv raw, cov tshuaj intermediate 2b tau txais los ntawm AlⅢ/EDTA catalysis. Txoj kev yog raws li nram no (Daim duab 6b):
Cov ntawv pov thawj CN116640811A/CN116083385A piav qhia txog ib txoj kev rau kev npaj cov tshuaj intermediates tseem ceeb 2a/2b: siv cov tshuaj compound 1/2 ua cov khoom pib, cov tshuaj chiral intermediates tseem ceeb 2a/2b raug tsim ncaj qha los ntawm kev ua ib kauj ruam transaminase. Cov txheej txheem no tsis yog tsuas yog muaj ib kauj ruam luv luv xwb tab sis kuj tseem txhim kho qhov kev xaiv chiral thiab cov txiaj ntsig ntawm cov tshuaj intermediates tseem ceeb 2a/2b. Ntxiv mus, txoj kev npaj no yog tus cwj pwm los ntawm cov xwm txheej tsis tshua muaj kev cuam tshuam thiab kev ua haujlwm tom qab ua tiav zoo, uas ua tau raws li cov kev cai tsim khoom lag luam (Daim duab 7).
Chiral alcohol compound 4b yog ib qho ua ntej rau cov tshuaj chiral amine intermediates 2a/2b. Tam sim no, cov kev tsim khoom siv rau pej xeem poob rau hauv ob pawg: tshuaj lom neeg thiab chemoenzymatic.
Hauv cov ntaub ntawv (Organic Letters, 2012, 14(18): 4938–4941), lub tuam txhab uas tau ua qhov kev tshawb fawb thawj zaug tau piav qhia txog txoj hauv kev los tsim 4b los ntawm kev txo qis asymmetric: siv dimethyl 2,3-pyridinedicarboxylate (5a) ua cov khoom pib, nruab nrab 4a tau txais los ntawm Dieckmann cyclization thiab decarboxylation reaction, thiab tom qab ntawd cov cawv chiral tau tsim los ntawm kev txo qis asymmetric siv cov hlau catalyst Rh-(R-Binapine)(COD)BF₄ nrog kev hloov pauv ntawm 100% thiab ee≥99.9% (Daim duab 8).
Thaum xub thawj, lub tuam txhab tshawb fawb tau hais hauv daim ntawv pov thawj patent CN102066358B tias cov tshuaj diketone (4a) tau txo qis mus rau 4b los ntawm txoj kev enzymatic, tab sis tsis tau qhia cov ntaub ntawv tshwj xeeb txog qhov tshuaj tiv thaiv; tom qab ntawd, nws tau tshaj tawm hauv cov ntaub ntawv (Organic Letters, 2012, 14 (18): 4938-4941) tias cov tshuaj diketone tau txo qis mus rau 4b nyob rau hauv qhov catalysis ntawm ketone reductase ES-KRED-119 nrog cov tshuaj tiv thaiv ntawm 81% thiab tus nqi ee ntawm 99.2% (Daim Duab 9).
Cov ketone reductase ES-KRED-119 siv rau hauv txoj kev enzymatic saum toj no tau yuav los ntawm Shangke Biopharmaceutical (Shanghai) Co., Ltd. Shangke Biopharmaceutical hloov kho cov enzyme hauv patent CN202410502187.9, thiab qhov concentration ntawm substrate tuaj yeem ncav cuag 100 g / L.
Kev txo qis asymmetric enzymatic zoo dua rau cov kev xav tau ntawm kev lag luam rau kev tsim cov chiral cawv sib xyaw (4b). Cov kev tshawb fawb tom qab ntawd tau tsom mus rau kev txhim kho cov catalysts lossis kev tshuaj ntsuam thiab kev ua kom zoo dua ketone reductases, uas yuav tsis tau tham txog ntau yam ntawm no.
[2] LEAHY DAVID K., FANG Y., CHAN COLLIN et al. Txoj kev tsim cov CGRP receptor antagonist cycloheptapyridine: Tebchaws USA 8669368B2 [P]. 11.03.2014.
[3] Ruan Shiwen, Yang Gongchao, Zhang Wei, et al. Cov txheej txheem tsim rau rimegepant thiab nws cov khoom nruab nrab: Tuam Tshoj, 114957247A[P]. 2022-08-30.
[4] He Lingyun, Chen Binhui, Yu Yang. Txoj kev npaj cov hlau catalyst thiab cov khoom nruab nrab ntawm rimexam: Tuam Tshoj, 116768938A[P]. 2023-09-19.
[5] Lin Weikang. Kev tshawb fawb ua ntej ntawm kev siv tshuab ua ke ntawm fluorinated chiral moiety ntawm CGRP receptor antagonist Remegapan los ntawm txoj kev asymmetric catalytic amination [J]. Zhejiang Chemical Industry, 2022, 53(8):13-18.
[6] Li Lin, Chen Binhui, Yu Yang. Txoj kev npaj rimexam nruab nrab: Tuam Tshoj, 116640811A[P]. 2023-08-25 IB.
[8] Ma Yulei, Jiao Xuecheng, Wang Zujian, et al. Kev tsim cov polymer intermediates tseem ceeb siv cov transaminase hloov kho zoo heev [J]. Kev Tshawb Fawb Txog Kev Txhim Kho thiab Kev Txhim Kho, 2022, 26 (7): 1971–1977.
[9] David K. Leahy, Yu Fan, Lopa V. Desai, et al. Kev ua haujlwm zoo thiab scalable enantioselective synthesis ntawm CGRP antagonists [J]. Organic Letters, 2012, 14 (18): 4938–4941.
Lus Ceeb Toom: Tsab xov xwm no yog luam tawm los ntawm Yaozhi.com. Cov duab thiab cov ntawv yog cov tswv cuab ntawm lawv cov kws sau ntawv qub. Daim ntawv luam tawm no tsuas yog rau kev qhia xov xwm xwb thiab tsis qhia txog kev xav ntawm lub platform no. Yog tias koj muaj lus nug txog cov ntsiab lus, txoj cai luam tawm, lossis lwm yam teeb meem, thov tawm lus rau ntawm lub platform no, thiab peb yuav daws nws sai li sai tau.
Luam tawm los ntawm Ministry of Industry and Information Technology. ...
Tus lej daim ntawv tso cai rau kev muab cov kev pabcuam sib txuas lus muaj nqis ntxiv los ntawm Is Taws Nem: YuB2-20120028. Daim ntawv pov thawj ntawm kev tsim nyog rau kev muab cov ntaub ntawv hais txog cov khoom siv kho mob los ntawm Is Taws Nem: (Yu)-Commercial-2021-0017
Yaozhi Lub Vev Xaib: Yaozhi.com | Yaozhi Xov Xwm | Yaozhi Lecture Hall | Yaozhi Media | Yaozhi Data | Tuam txhab tsim nyog | Tiv tauj peb
Luam tawm los ntawm Ministry of Industry and Information Technology. ...
Lub sijhawm tshaj tawm: Lub Ib Hlis-23-2026