Ko te Rimegepant anake te rongoā kaiārai i te kaiwhakawhiwhi CGRP o te ao e whakamahi ana i te hangarau papa pakaru ā-waha kua patenttia, ā, koia te rongoā tuatahi o te ao ka taea te whakamahi hei rongoā me te ārai i ngā whakaekenga migraine whakapeka.
I te 27 o Pēpuere, 2020, i whakaaetia e te US Food and Drug Administration (FDA) te hokohoko o ngā papa remdesivir panicol sulfate i raro i te ingoa waitohu Nurtec® ODT.
Tae noa ki tēnei wā, ko ngā huarahi matua hanga ki te matū rongoā hohe remepiride ko ngā huarahi e rua i whakaaturia e te kaihanga taketake, a Bristol-Myers Squibb, mā te whakamahi i te (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-[[triisopropylsilyl]oxy]-5H-te cycloheptatrienepyridin-5-one (pūhui 1) hei rauemi tīmatanga.
Ara 1: Ka whakaritea a Remegapan mā te tauhohenga e ono ngā taahiraa, tae atu ki: te whakaiti i te rōpū ketone ki te konutai borohydride, te whakakōroiroi i te rōpū hydroxyl ki te triphenylphosphine me te N-chlorosuccinimide, te whakakapinga o te ngota chlorine ki te konutai azide, te whakakorenga i te siliconization ki te tetrabutylammonium fluoride, te hononga, me te whakaiti i te rōpū azide ki te trimethylphosphine. Kei raro nei te ara (Pikitia 3):
Ara 2: Mā te whakamahi i te matū 1 hei rauemi tīmatanga, ka hangaia te remepam i roto i ngā taahiraa e toru (te tauhohenga kotahi-taahiraa o te tetraisopropoxytitanium, te alumina, me te palladium ki te waro hei whakaputa i te takawaenga matua 2a, te tango tiaki hei whakaputa i te takawaenga matua 2b, me te hononga). Kei raro nei te ara (Pikitia 4):
E kitea ana i te tātai hanganga, e toru ngā pokapū chiral o te matū rongoā hohe a Remegapan. He wero nui te hanga i tētahi amine chiral i te tūranga-5 o te cycloheptane hei whakanui ake i te hanga o te matū rongoā hohe. Ka arotahi atu ngā rangahau ki te whakapai ake i te tukanga hanga mō ngā takawaenga matua 2a/2b.
E whakaahua ana te Patene CN114957247A i tētahi tikanga mō te whakarite i ngā takawaenga matua 2a/2b: mā te whakamahi i te matū 3a hei rauemi tīmatanga, ka puta he tauhohenga whakatuwhera mowhiti whiriwhiri-ā-roto me te matū Lewis hei hanga i te matū 3b, kātahi ka pāngia e te tauhohenga Suzuki, te tiakitanga silanization, te whakakapinga, me te tango tiaki hei whakatutuki i te hua katoa o te takawaenga matua 2b tata ki te 54%. Kei raro nei te tikanga (Pikitia 5):
E whakaahua ana te Patene CN116768938A i tētahi tikanga mō te whakarite i te takawaenga matua 2a: mā te whakamahi i te matū carbonyl (4a) hei rauemi tīmatanga, ka whakaritea te takawaenga 1 mā te whakaiti, te tiaki TIPS, me te tauhohenga ki te 2,3-difluorobromobenzene. Ka pāngia te takawaenga 1 e tētahi tauhohenga whakaiti-amination kore taurite i raro i te mahi a tētahi whakakorikori matatini FeⅡ/EDTA, kātahi ka pāngia e te ammonolysis me te 20% ammonia wai hei whakaputa i te takawaenga matua 2a (Pikitia 6a).
I roto i tētahi atu tuhinga (Zhejiang Chemical Industry, 2022, 53(8). 13-18.), kua whakaahuatia tētahi tikanga mō te whakarite i te takawaenga matua 2b: mā te whakamahi i te matū 2 hei rauemi mata, ka whiwhihia te takawaenga matua 2b mā te whakakorikori AlⅢ/EDTA. Ko te tikanga e whai ake nei (Pikitia 6b):
E whakaahua ana ngā Patene CN116640811A/CN116083385A i tētahi tikanga mō te whakarite i ngā takawaenga matua 2a/2b: mā te whakamahi i te matū 1/2 hei rauemi tīmatanga, ka hangaia tika ngā takawaenga chiral matua 2a/2b mā te tauhohenga transaminase kotahi-taahiraa. Ehara i te mea he poto noa te taahiraa hangahanga o tēnei tukanga engari he nui hoki te whakapai ake i te whiriwhiri chiral me te hua o ngā takawaenga matua 2a/2b. Hei tāpiri, ko te tikanga whakarite e tohuhia ana e ngā āhuatanga tauhohenga ngawari me ngā mahi tukatuka haumaru, e tutuki ana i ngā whakaritenga whakaputa ahumahi (Pikitia 7).
Ko te matū waipiro chiral 4b he matū mua mō ngā takawaenga amine chiral matua 2a/2b. I tēnei wā, e rua ngā momo huarahi hanga e wātea ana i te marea: te matū me te chemoenzymatic.
I roto i ngā tuhinga (Organic Letters, 2012, 14(18): 4938–4941), i whakaahuahia e te kamupene nāna i whakahaere te rangahau taketake tētahi huarahi hei hanga i te 4b mā te whakaiti koretake: mā te whakamahi i te dimethyl 2,3-pyridinedicarboxylate (5a) hei rauemi tīmatanga, i whiwhihia te 4a takawaenga mā te tauhohenga Dieckmann cyclization me te decarboxylation, kātahi ka hangaia te matū waipiro chiral mā te whakaiti koretake mā te whakamahi i tētahi whakakorikori whakarewa Rh-(R-Binapine)(COD)BF₄ me te huringa o te 100% me te ee≥99.9% (Pikitia 8).
I te tīmatanga, i whakahuatia e te kamupene rangahau i roto i te patent CN102066358B i whakaitihia te matū diketone (4a) ki te 4b mā te tikanga whākōkī, engari kāore i whakaaturia ngā mōhiohio motuhake mō te tauhohenga; i muri mai, i pūrongohia i roto i ngā tuhinga (Organic Letters, 2012, 14(18):4938-4941) i whakaitihia te matū diketone ki te 4b i raro i te whakaterenga o te ketone reductase ES-KRED-119 me te hua tauhohenga o te 81% me te uara ee o te 99.2% (Pikitia 9).
I hokona mai te ketone reductase ES-KRED-119 i whakamahia i roto i te tikanga whākōkī i runga ake nei i Shangke Biopharmaceutical (Shanghai) Co., Ltd. Nā Shangke Biopharmaceutical i whakarerekē te whākōkī i roto i te patent CN202410502187.9, ā, ka taea e te kukū o te matūriki te eke ki te 100 g/L.
He pai ake te whakaiti taurite kore whākōkī ki ngā whakaritenga ahumahi mō te hanga i ngā pūhui waipiro chiral (4b). Kua arotahi ngā rangahau i muri mai ki te whakapai ake i ngā whakakorikori, ki te tirotiro rānei me te arotau i ngā ketone reductases, kāore e matapakihia whānuitia i konei.
[2] LEAHY DAVID K., FANG Y., CHAN COLLIN me ētahi atu. Tikanga mō te whakaputa i te cycloheptapyridine, he kaitukino i te kaiwhakawhiwhi CGRP: USA 8669368B2 [P]. 11.03.2014.
[3] Ruan Shiwen, Yang Gongchao, Zhang Wei, et al. Ngā tikanga hanga mō te rimegepant me ōna takawaenga: Haina, 114957247A[P]. 2022-08-30.
[4] He Lingyun, Chen Binhui, Yu Yang. Tikanga mō te whakarite i te whakakorikori rino me te hua takawaenga o te rimexam: Haina, 116768938A[P]. 2023-09-19.
[5] Lin Weikang. He rangahau tuatahi mō te hangarau hanga o te wāhanga chiral fluorinated o te kaiwhakawhiwhi CGRP antagonist Remegapan mā te tikanga amination catalytic asymmetric [J]. Zhejiang Chemical Industry, 2022, 53(8):13-18.
[6] He Lingyun, Chen Binhui, Yu Yang. Tikanga mo te whakarite rimexam takawaenga: Haina, 116640811A[P]. 2023-08-25.
[8] Ma Yulei, Jiao Xuecheng, Wang Zujian, me ētahi atu. Te hanga tino whai hua o ngā takawaenga matua o te polymer mā te whakamahi i te transaminase kua whakarerekētia [J]. Rangahau me te Whakawhanaketanga Tukanga Organic, 2022, 26(7):1971–1977.
[9] David K. Leahy, Yu Fan, Lopa V. Desai, et al. Te hanganga enantioselective whai hua me te tauine o ngā kaitukino CGRP [J]. Organic Letters, 2012, 14(18): 4938–4941.
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