Rimegepant ke mohanyetsi feela lefatšeng oa CGRP receptor o sebelisang theknoloji ea matlapa a qhalanang ka molomo a nang le patente 'me ke moriana oa pele lefatšeng o ka sebelisoang bakeng sa kalafo le thibelo ea litlhaselo tse matla tsa migraine.
Ka la 27 Hlakola 2020, Tsamaiso ea Lijo le Lithethefatsi ea US (FDA) e amohetse papatso ea matlapa a remdesivir panicol sulfate tlasa lebitso la lebitso la Nurtec® ODT.
Ho fihlela joale, litsela tse ka sehloohong tsa maiketsetso ho ea ho motsoako o sebetsang oa meriana oa remepiride ke litsela tse peli tse senotsoeng ke moetsi oa pele, Bristol-Myers Squibb, a sebelisa (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-[[triisopropylsyl]oxy]-5H-cycloheptatrienepyridin-5-one (motsoako oa 1) e le thepa ea ho qala.
Tsela ea 1: Remegapan e lokisoa ka karabelo ea mehato e tšeletseng e kenyeletsang, har'a lintho tse ling: phokotso ea sehlopha sa ketone ka sodium borohydride, chlorination ea sehlopha sa hydroxyl ka triphenylphosphine le N-chlorosuccinimide, ho nkeloa sebaka ha athomo ea chlorine ka sodium azide, ho tlosoa ha siliconization ka tetrabutylammonium fluoride, ho kopanya le phokotso ea sehlopha sa azide ka trimethylphosphine. Tsela e bontšitsoe ka tlase (Setšoantšo sa 3):
Tsela ea 2: Ho sebelisoa motsoako oa 1 e le thepa ea ho qala, remapam e etsoa ka mehato e meraro (karabelo ea mohato o le mong ea tetraisopropoxytitanium, alumina, le palladium holim'a khabone ho hlahisa senotlolo sa 2a, ho senyeha ha tšireletso ho hlahisa senotlolo sa 2b, le ho kopana). Tsela e bontšitsoe ka tlase (Setšoantšo sa 4):
Jwalo ka ha ho ka bonwa ho tswa foromong ya sebopeho, motsoako o sebetsang wa meriana wa Remegapan molek'hule o na le ditsi tse tharo tsa chiral. Ho theha amine ya chiral boemong ba 5 ba cycloheptane ho hlahisa phephetso e kgolo bakeng sa ho eketsa tlhahiso ya motsoako o sebetsang wa meriana. Diphuputso tse ding di tla shebana le ho ntlafatsa tshebetso ya ho kopanya bakeng sa di-intermediate tsa bohlokwa tsa 2a/2b.
Patent CN114957247A e hlalosa mokhoa oa ho lokisa li-intermediate tsa senotlolo 2a/2b: ho sebelisoa motsoako oa 3a e le thepa ea ho qala, karabelo ea ho bula lesale e khethang stereoselective e etsahala ka reagent ea Lewis ho theha motsoako oa 3b, ebe e feta karabelong ea Suzuki, tšireletso ea silanization, phetolo, le ho senyeha ho fana ka senotlolo sa bohareng ba 2b ka chai e ka bang 54%. Mokhoa ona o bontšitsoe ka tlase (Setšoantšo sa 5):
Patent CN116768938A e hlalosa mokhoa oa ho lokisa senotlolo sa 2a: ho sebelisoa motsoako oa carbonyl (4a) e le thepa ea ho qala, sesebelisoa sa 1 se lokisoa ka ho fokotsa, tšireletso ea TIPS, le karabelo ka 2,3-difluorobromobenzene. Sesebelisoa sa 1 se mahareng se feta karabelong ea ho fokotsa-ho fokotsa e sa lekanang tlas'a ketso ea catalyst ea FeⅡ/EDTA complexing ebe se feta ammonolysis ka 20% ammonia ea metsi ho hlahisa senotlolo sa 2a se mahareng (Setšoantšo sa 6a).
Lingoliloeng tse ling (Zhejiang Chemical Industry, 2022, 53(8). 13-18.), mokhoa oa ho lokisa senotlolo sa 2b o hlalositsoe: ho sebelisoa motsoako oa 2 e le thepa e tala, senotlolo sa 2b se fumanoa ka AlⅢ/EDTA catalysis. Mokhoa ona o tjena (Setšoantšo sa 6b):
Litokelo tsa molao CN116640811A/CN116083385A li hlalosa mokhoa oa ho lokisa li-intermediate tsa bohlokoa 2a/2b: ho sebelisoa motsoako oa 1/2 e le thepa ea ho qala, li-intermediate tsa bohlokoa tsa chiral 2a/2b li hlahisoa ka kotloloho ka karabelo ea transaminase ea mohato o le mong. Ts'ebetso ena ha e na mohato o mokhutšoanyane oa maiketsetso feela empa hape e ntlafatsa haholo khetho ea chiral le tlhahiso ea li-intermediate tsa bohlokoa 2a/2b. Ho feta moo, mokhoa oa ho lokisa o khetholloa ka maemo a bobebe a karabelo le ts'ebetso e sireletsehileng ea kamora ts'ebetso, e fihlelang litlhoko tsa tlhahiso ea indasteri (Setšoantšo sa 7).
Motsoako oa joala oa chiral 4b ke selelekela sa li-intermediate tsa chiral amine tsa bohlokoa tsa 2a/2b. Hona joale, litsela tsa maiketsetso tse fumanehang phatlalatsa li oela likarolong tse peli: lik'hemik'hale le chemoenzyme.
Lingoliloeng (Organic Letters, 2012, 14(18): 4938–4941), khamphani e entseng phuputso ea pele e hlalositse tsela ea ho kopanya 4b ka phokotso e sa lekanang: ho sebelisoa dimethyl 2,3-pyridinedicarboxylate (5a) e le thepa ea ho qala, 4a e mahareng e fumanoe ka karabelo ea Dieckmann cyclization le decarboxylation, ebe motsoako oa chiral alcohol o entsoe ka phokotso e sa lekanang ho sebelisoa catalyst ea tšepe Rh-(R-Binapine)(COD)BF₄ ka phetoho ea 100% le ee≥99.9% (Setšoantšo sa 8).
Qalong, khamphani ea lipatlisiso e boletse ho patent CN102066358B hore motsoako oa diketone (4a) o fokolitsoe ho 4b ka mokhoa oa enzymatic, empa ha oa ka oa senola tlhahisoleseling e tobileng mabapi le karabelo; hamorao, ho tlalehiloe libukeng (Organic Letters, 2012, 14(18):4938-4941) hore motsoako oa diketone o fokolitsoe ho 4b tlas'a catalysis ea ketone reductase ES-KRED-119 ka chai ea karabelo ea 81% le boleng ba ee ba 99.2% (Setšoantšo sa 9).
Ketone reductase ES-KRED-119 e sebelisitsoeng mokhoeng oa enzymatic o kaholimo e rekiloe ho Shangke Biopharmaceutical (Shanghai) Co., Ltd. Shangke Biopharmaceutical e fetotse enzyme ho patent CN202410502187.9, 'me mahloriso a substrate a ka fihla ho 100 g/L.
Phokotso e sa lekanang ea enzyme e lumellana hantle le litlhoko tsa indasteri bakeng sa ho kopanya metsoako ea joala ea chiral (4b). Lithuto tse latelang li shebane le ho ntlafatsa li-catalyst kapa ho hlahloba le ho ntlafatsa li-reductase tsa ketone, tse ke keng tsa tšohloa ka botlalo mona.
[2] LEAHY DAVID K., FANG Y., CHAN COLLIN jj. Mokhoa oa ho hlahisa cycloheptapyridine, mohanyetsi oa receptor oa CGRP: USA 8669368B2 [P]. 11.03.2014.
[3] Ruan Shiwen, Yang Gongchao, Zhang Wei, jj. Mekhoa ea maiketsetso bakeng sa rimegepant le metsoako ea eona e bohareng: China, 114957247A[P]. 2022-08-30.
[4] He Lingyun, Chen Binhui, Yu Yang. Mokhoa oa ho lokisa sesebelisoa sa tšepe se bakang khase le sehlahisoa se mahareng sa rimexam: China, 116768938A[P]. 2023-09-19.
[5] Lin Weikang. Thuto ea pele mabapi le theknoloji ea ho kopanya karolo ea chiral e nang le fluorinated ea Remegapan ea mohanyetsi oa receptor oa CGRP ka mokhoa oa asymmetric catalytic amination [J]. Zhejiang Chemical Industry, 2022, 53(8):13-18.
[6] He Lingyun, Chen Binhui, Yu Yang. Mokhoa oa ho lokisa rimexam mahareng: China, 116640811A[P]. 2023-08-25.
[8] Ma Yulei, Jiao Xuecheng, Wang Zujian, jj. Tlhahiso e sebetsang hantle haholo ea li-intermediate tsa polymer tsa bohlokoa ho sebelisoa transaminase e fetotsoeng [J]. Patlisiso le Nts'etsopele ea Ts'ebetso ea Organic, 2022, 26(7):1971–1977.
[9] David K. Leahy, Yu Fan, Lopa V. Desai, jj. Motswako o sebetsang hantle le o ka atolosoang wa dihlopha tse hanyetsanang le CGRP [J]. Organic Letters, 2012, 14(18): 4938–4941.
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