CN115536609B - 一种氢同位素标记沃替西汀的合成方法 - Google Patents
一种氢同位素标记沃替西汀的合成方法 Download PDFInfo
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- CN115536609B CN115536609B CN202210964978.4A CN202210964978A CN115536609B CN 115536609 B CN115536609 B CN 115536609B CN 202210964978 A CN202210964978 A CN 202210964978A CN 115536609 B CN115536609 B CN 115536609B
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- Prior art keywords
- vortioxetine
- potassium
- lithium
- alkali metal
- deuterated
- Prior art date
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- YQNWZWMKLDQSAC-UHFFFAOYSA-N vortioxetine Chemical compound CC1=CC(C)=CC=C1SC1=CC=CC=C1N1CCNCC1 YQNWZWMKLDQSAC-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 229960002263 vortioxetine Drugs 0.000 title claims abstract description 52
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 title claims abstract description 18
- 239000001257 hydrogen Substances 0.000 title claims abstract description 18
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- -1 alkali metal salt Chemical class 0.000 claims abstract description 48
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 239000003054 catalyst Substances 0.000 claims abstract description 28
- 239000007789 gas Substances 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 23
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 21
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 15
- 229910052805 deuterium Inorganic materials 0.000 claims abstract description 15
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 claims abstract description 8
- 229910052722 tritium Inorganic materials 0.000 claims abstract description 8
- 238000011049 filling Methods 0.000 claims abstract description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims abstract description 5
- 239000000376 reactant Substances 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 7
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 229910052792 caesium Inorganic materials 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 4
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 claims description 4
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 4
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 claims description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- CPRMKOQKXYSDML-UHFFFAOYSA-M rubidium hydroxide Chemical compound [OH-].[Rb+] CPRMKOQKXYSDML-UHFFFAOYSA-M 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- HLZIGZQAUDKTBR-UHFFFAOYSA-N [Cs]CC1=CC=CC=C1 Chemical compound [Cs]CC1=CC=CC=C1 HLZIGZQAUDKTBR-UHFFFAOYSA-N 0.000 claims description 3
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 3
- WWUXUITYSVCHKK-UHFFFAOYSA-N methanidylbenzene;rubidium(1+) Chemical compound [Rb+].[CH2-]C1=CC=CC=C1 WWUXUITYSVCHKK-UHFFFAOYSA-N 0.000 claims description 3
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 3
- KBGJIKKXNIQHQH-UHFFFAOYSA-N potassium;methanidylbenzene Chemical compound [K+].[CH2-]C1=CC=CC=C1 KBGJIKKXNIQHQH-UHFFFAOYSA-N 0.000 claims description 3
- 229910052701 rubidium Inorganic materials 0.000 claims description 3
- 229910000106 rubidium hydride Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- BLHLJVCOVBYQQS-UHFFFAOYSA-N ethyllithium Chemical compound [Li]CC BLHLJVCOVBYQQS-UHFFFAOYSA-N 0.000 claims description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 2
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 claims description 2
- YNXURHRFIMQACJ-UHFFFAOYSA-N lithium;methanidylbenzene Chemical compound [Li+].[CH2-]C1=CC=CC=C1 YNXURHRFIMQACJ-UHFFFAOYSA-N 0.000 claims description 2
- HAUKUGBTJXWQMF-UHFFFAOYSA-N lithium;propan-2-olate Chemical compound [Li+].CC(C)[O-] HAUKUGBTJXWQMF-UHFFFAOYSA-N 0.000 claims description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 2
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 claims description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- YHOBGCSGTGDMLF-UHFFFAOYSA-N sodium;di(propan-2-yl)azanide Chemical compound [Na+].CC(C)[N-]C(C)C YHOBGCSGTGDMLF-UHFFFAOYSA-N 0.000 claims description 2
- OWMHBKYAOYHOQK-UHFFFAOYSA-N sodium;methanidylbenzene Chemical compound [Na+].[CH2-]C1=CC=CC=C1 OWMHBKYAOYHOQK-UHFFFAOYSA-N 0.000 claims description 2
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 4
- 239000004210 ether based solvent Substances 0.000 claims 2
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000005311 nuclear magnetism Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- VNGRUFUIHGGOOM-UHFFFAOYSA-N vortioxetine hydrobromide Chemical compound Br.CC1=CC(C)=CC=C1SC1=CC=CC=C1N1CCNCC1 VNGRUFUIHGGOOM-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 238000006664 bond formation reaction Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000004431 deuterium atom Chemical group 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical class IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 208000024714 major depressive disease Diseases 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000007040 multi-step synthesis reaction Methods 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229960004030 vortioxetine hydrobromide Drugs 0.000 description 2
- NLWBEORDOPDUPM-UHFFFAOYSA-N 1,2,3,4-cyclopentanetetracarboxylic dianhydride Chemical compound O=C1OC(=O)C2C1C1C(=O)OC(=O)C1C2 NLWBEORDOPDUPM-UHFFFAOYSA-N 0.000 description 1
- VHFAOWAVVYWLCS-UHFFFAOYSA-N 2-bromo-3-phenylbenzenethiol Chemical compound BrC1=C(C=CC=C1C1=CC=CC=C1)S VHFAOWAVVYWLCS-UHFFFAOYSA-N 0.000 description 1
- YUQUNWNSQDULTI-UHFFFAOYSA-N 2-bromobenzenethiol Chemical compound SC1=CC=CC=C1Br YUQUNWNSQDULTI-UHFFFAOYSA-N 0.000 description 1
- YMDZDFSUDFLGMX-UHFFFAOYSA-N 2-chloro-n-(2-chloroethyl)ethanamine;hydron;chloride Chemical compound [Cl-].ClCC[NH2+]CCCl YMDZDFSUDFLGMX-UHFFFAOYSA-N 0.000 description 1
- CUGPDVWIMLFIQR-UHFFFAOYSA-N 2-methylpropan-2-olate;rubidium(1+) Chemical compound [Rb+].CC(C)(C)[O-] CUGPDVWIMLFIQR-UHFFFAOYSA-N 0.000 description 1
- GHTUADBHTFHMNI-UHFFFAOYSA-N 4-bromo-1-iodo-2-methylbenzene Chemical compound CC1=CC(Br)=CC=C1I GHTUADBHTFHMNI-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 208000025967 Dissociative Identity disease Diseases 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000949477 Toona ciliata Species 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 125000005264 aryl amine group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- HOVYSSCJTQTKMV-UHFFFAOYSA-N cesium azanide Chemical compound [NH2-].[Cs+] HOVYSSCJTQTKMV-UHFFFAOYSA-N 0.000 description 1
- NVBVGMKBMCZMFG-UHFFFAOYSA-N cesium;2-methylpropan-2-olate Chemical compound [Cs+].CC(C)(C)[O-] NVBVGMKBMCZMFG-UHFFFAOYSA-N 0.000 description 1
- RHCKAZZDNDQWHY-UHFFFAOYSA-N cesium;bis(trimethylsilyl)azanide Chemical compound [Cs+].C[Si](C)(C)[N-][Si](C)(C)C RHCKAZZDNDQWHY-UHFFFAOYSA-N 0.000 description 1
- XDPCFUNJJWMBFH-UHFFFAOYSA-N cesium;ethanolate Chemical compound [Cs+].CC[O-] XDPCFUNJJWMBFH-UHFFFAOYSA-N 0.000 description 1
- QIWWQTLNHRQHFW-UHFFFAOYSA-N cesium;propan-2-olate Chemical compound [Cs+].CC(C)[O-] QIWWQTLNHRQHFW-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- JBOAOTRFANJYGJ-UHFFFAOYSA-N ethanolate;rubidium(1+) Chemical compound [Rb+].CC[O-] JBOAOTRFANJYGJ-UHFFFAOYSA-N 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- BNHFWQQYLUPDOG-UHFFFAOYSA-N lithium;1,2,2,3-tetramethylpiperidine Chemical compound [Li].CC1CCCN(C)C1(C)C BNHFWQQYLUPDOG-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- BWWYHSLPXSWCEC-UHFFFAOYSA-N methanolate;rubidium(1+) Chemical compound [Rb+].[O-]C BWWYHSLPXSWCEC-UHFFFAOYSA-N 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000010651 palladium-catalyzed cross coupling reaction Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- GGAWRDMPIWWBAE-UHFFFAOYSA-N propan-2-olate;rubidium(1+) Chemical compound [Rb+].CC(C)[O-] GGAWRDMPIWWBAE-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
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Abstract
本发明公开了一种氢同位素标记沃替西汀的新型合成方法,属于有机合成技术领域。包括如下步骤:惰性气氛下,以碱金属盐为催化剂,沃替西汀为反应物,向反应容器中充入氘气或加入氘代二甲基亚砜或充入氚气,在预定温度下密闭反应预定时间,即得氢同位素标记沃替西汀,包括氘代沃替西汀和氚代沃替西汀。该方法催化剂廉价易得,反应条件温和,选择性好,产率高,标记效率高,工艺简单,操作简便,可一步制备氘代产物和氚代产物;为氘代沃替西汀和氚代沃替西汀的制备开辟了新的低成本且绿色高效的途径,具有较高的应用价值。
Description
技术领域
本发明属于化学合成领域,涉及一种氢同位素标记沃替西汀的合成方法。
背景技术
抑郁症是一种常见的心理疾病,以连续且长期的心情低落为主要的临床特征,对患者的工作能力、睡眠、学习、饮食及享受当下的快乐产生困扰,更严重者会出现幻听、被害妄想症、多重人格等精神分裂症状,是现代人心理疾病最重要的类型。沃替西汀氢溴酸盐是一种双芳基硫烷基胺类抗抑郁药,用于抑郁症及焦虑症的治疗。沃替西汀主要通过增加中枢神经系统的五羟色胺(5-HT)浓度发挥抗抑郁作用,对于治疗重型抑郁症有较好的有效性、安全性和耐受性。
通常情况下,为了达到治疗效果会增加沃替西汀的用药量,从而不可避免使人体产生较多的副作用。由于C-D键比于C-H键具有更好的稳定性,氘代药物在体内的代谢相对缓慢、半衰期延长,在临床应用方面带来降低药量、降低药物副作用等益处。临床试验数据表明,氘代沃替西汀氢溴酸盐比沃替西汀氢溴酸盐对重度抑郁症治疗更有疗效,达到相同治疗效果的药量减少。因此,实现氘代沃替西汀的合成对于新药的研发具有重要意义。在生命科学的研究中,氚代化合物是必不可少的研究工具,是药物代谢动力学等研究的关键工具。
在专利CN104059030A所述的方法中,使用含有不同个数氘原子取代的氘代间二甲苯、邻溴苯硫酚和Boc保护哌嗪为起始原料,通过卤化、钯催化碳硫键形成、钯催化碳氮键形成和脱保护四步反应制备得到含有不同个数氘原子取代的氘代沃替西汀。甲基氘代的间二甲苯通过1,3-二卤苯和氘代碘甲烷的反应制备获得,价格昂贵(250mg 538美元,A2B ChemLLC),且通常需要订制,供货时间在两周以上。除此之外,该方法需要两步钯催化的交叉偶联反应,钯催化剂和膦配体价格昂贵,不利于大规模生产,并且容易在产物分子中残留过渡金属,需要额外的除去过程。在CN107513048A所述的方法中,使用2-碘-5-溴甲苯和邻溴苯硫酚通过碘化亚铜催化偶联反应构建碳硫键,再通过和二(2-氯乙基)胺盐酸盐在碱性条件下构建哌嗪环,从而构建沃替西汀骨架;然后通过胺基保护、锂卤交换、与碘甲烷取代反应、脱保护过程制备4-位甲基氘代的沃替西汀。该方法在合成后期引入氘甲基,一定程度上提高了整个过程的氘代反应效率,然而反应仍需要通过催化偶联反应、胺基保护和脱保护过程。两种氘代沃替西汀的合成需要通过多步合成的方法,费时、费力、成本高、废物排放多,不利于大规模生产。氢同位素交换法是制备氘代化合物和氚代化合物最直接有效的方法。随着碳氢键活化反应的发展,过渡金属催化的氢同位素交换反应被广泛应用于氘代和氚代化合物的合成,但通常需要价格昂贵的过渡金属催化剂或者具有复杂结构的配体。目前,通过氢同位素交换反应,直接实现氘代或者氚代沃替西汀的合成反应未见报道。
发明内容
为了克服现有的氘代沃替西汀和氚代沃替西汀的制备过程复杂,原料昂贵等不足的问题,本发明的目的是旨在提供一种温和、高效、简单的氘代沃替西汀和氚代沃替西汀的新型合成方法。
本发明提供了一种氢同位素标记沃替西汀的新型合成方法,包括以下步骤:
以碱金属盐为催化剂,以芳烃、醚或烷烃为溶剂,以沃替西汀为反应物,向反应容器中充入氘气或加入氘代二甲基亚砜或充入氚气,在预定温度下密闭反应预定时间,即得氢同位素标记沃替西汀,所述氢同位素标记沃替西汀包括氘代沃替西汀和氚代沃替西汀。
其中,所述沃替西汀为商业可得1-[2-(2,4-甲基苯硫基)苯基]哌嗪,所述氘代沃替西汀的反应式如下式1所示:
所述氚代沃替西汀的反应式如下式2所示:
本发明中,所述催化剂选自碱金属氢氧化物、碱金属醇盐、碱金属氢化物、碱金属烃基化合物和碱金属氨基化合物等中的任意一种或多种的组合。
其中,所述碱金属氢氧化物选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铷和氢氧化铯等中的至少一种或多种的组合;优选地,为氢氧化钠、氢氧化钾。
其中,所述碱金属醇盐选自甲醇锂、乙醇锂、异丙醇锂、叔丁醇锂、甲醇钠、乙醇钠、异丙醇钠、叔丁醇钠、甲醇钾、乙醇钾、异丙醇钾、叔丁醇钾、烷氧基铷和烷氧基铯等中的至少一种或多种的组合;优选地,为叔丁醇钾。
所述烷氧基铷选自甲醇铷、乙醇铷、异丙醇铷和叔丁醇铷中的至少一种或多种的组合。
所述烷氧基铯选自甲醇铯、乙醇铯、异丙醇铯和叔丁醇铯中的至少一种或多种的组合。
其中,所述碱金属氢化物选自氢化锂、氢化钠、氢化钾、氢化铷和氢化铯等中的至少一种或多种的组合;优选地,为氢化钾、氢化铷和氢化铯。
其中,所述碱金属烃基化合物选自甲基锂、三甲基硅甲基锂、乙基锂、正丁基锂、仲丁基锂、叔丁基锂、苄基锂、苯基锂、苄基钠、苄基钾、苄基铷和苄基铯中的至少一种或多种的组合;优选地,为苄基钾、苄基铷和苄基铯。
其中,所述碱金属氨基化合物选自氨基锂、二甲氨基锂、二乙氨基锂、二异丙基氨基锂、双三甲基硅基氨基锂、四甲基哌啶锂、氨基钠、二异丙基氨基钠、双三甲基硅基氨基钠、氨基钾、二甲氨基钾、二乙氨基钾、二异丙基氨基钾、双三甲基硅基氨基钾、四甲基哌啶钾、二甲氨基铷、二乙氨基铷、二异丙基氨基铷、双三甲基硅基氨基铷、四甲基哌啶铷、二甲氨基铯、二乙氨基铯、二异丙基氨基铯、双三甲基硅基氨基铯和四甲基哌啶铯中的至少一种或多种的组合;优选地,为双三甲基硅基氨基钾、双三甲基硅基氨基铯。
本发明中,所述催化剂的用量为沃替西汀摩尔量的1%-150%;优选地,为30%。
本发明中,所述溶剂为芳烃溶剂、烷烃溶剂或醚类溶剂等中的任意一种及其组合。
其中,芳烃溶剂包括苯、氘代苯、叔丁基苯等。
其中,烷烃溶剂包括正己烷、环己烷、甲基环己烷、环庚烷、辛烷、十氢化萘等。
其中,醚类溶剂包括乙醚、甲基叔丁基醚、甲基环戊基醚、正丁基醚、四氢呋喃、四氢吡喃、二氧六环等。
本发明中,所述氘气的压力为1-50bar;优选地,为4bar。
本发明中,所述氚气的压力为0.1-0.9bar;优选地,为0.3bar。
本发明中,所述反应的温度为60℃-120℃;优选地,为80℃。
本发明中,所述反应的时间为12-96小时;优选地,为48小时。
本发明优选在惰性气氛下进行。
本发明独创性地提出一种在碱金属催化剂、氘气或者氚气气氛下加热反应,以沃替西汀为起始物料,合成所述的氘代沃替西汀和氚代沃替西汀的方法。本发明以碱金属盐为催化剂,成本低,绿色环保;且碱金属试剂具有储量丰富、廉价易得等特点,催化应用潜力巨大。以沃替西汀为起始原料,一步合成氘代沃替西汀和氚代沃替西汀,省去传统的多步合成步骤,工艺简单,适合工业化生产。本发明将碱金属盐作为催化剂,应用于沃替西汀的氢同位素交换反应,为氘代沃替西汀以及氚代沃替西汀的制备开辟了绿色、高效的新途径,具有较高的应用价值。
附图说明
图1是本发明的实施例2中氘代沃替西汀的氢谱图;
图2是本发明的实施例2中氘代沃替西汀的碳谱图;
图3是本发明的实施例3中沃替西汀和氚代沃替西汀混合物氢谱图;
图4是本发明的实施例3中沃替西汀和氚代沃替西汀混合物氚谱图;
图5是本发明的实施例3中沃替西汀的质谱图;
图6是本发明的实施例3中氚代沃替西汀的质谱图。
具体实施方式
以下具体实施例旨在进一步说明本发明内容,而不是限制本发明权利要求的保护范围。
实施例1:沃替西汀氘代反应催化剂的筛选
在惰性气氛下,以碱金属盐为催化剂,沃替西汀为反应物,向反应容器中加入芳烃溶剂、烷烃溶剂或醚类溶剂中的任意一种或多种溶剂,搅拌,充入氘气,在40℃-150℃下密闭反应12h-96h,得到氘代沃替西汀,氘代率如下表1所示。
表1
反应条件:沃替西汀(0.1mmol),催化剂(10-30mol%),溶剂(0.5mL),在30mL反应釜中反应;KHMDS(双三甲基硅基氨基钾),CsHMDS(双三甲基硅基氨基铯),CsF(氟化铯),LiHMDS(双三甲基硅基氨基锂),TMPLi(四甲基哌啶锂),KOtBu(叔丁醇钾),TMSCH2Li(三甲基硅甲基锂),LDA(二异丙基氨基锂)。a反应48小时之后置换新鲜氘气再反应48小时。
由表1数据可知,由本发明实施例1、2、12-15可知,不同的碱金属盐均可作为氘代反应的催化剂,以双三甲基硅基氨基铯为催化剂催化的甲基氘代选择性比较好。
由本发明实施例2、3可知,在反应温度、氘气压强、溶剂、催化剂以及催化剂摩尔量均相同的情况下,可以通过延长反应时间提高氘代率。
由本发明实施例2、5可知,在反应温度、反应时间、溶剂、催化剂以及催化剂摩尔量均相同的情况下,可以通过提高氘气压力提高氘代率。
由本发明实施例3、6可知,在反应温度、反应时间、氘气压强、溶剂、催化剂均相同的情况下,可以通过增加催化剂浓度提高氘代率。
由本发明实施例6-11可知,在反应温度、氘气压强、催化剂以及催化剂摩尔量均相同的情况下,沃替西汀可以在不同溶剂条件下进行氘代反应。
由本发明实施例3、4可知,在反应温度、反应时间、氘气压强、溶剂、催化剂以及催化剂摩尔量均相同的情况下,可以通过将反应容器中的气体置换成新的氘气再进行反应提高氘代率。
实施例2:氘代沃替西汀的制备:
惰性气氛下,在30mL高压釜中,依次加入沃替西汀(CAS:508233-74-7,0.1mmol,0.0298g),苯(0.5mL),双三甲基硅基胺基铯(30mol%,0.0088g)。将高压釜密封,充入4bar氘气,在80℃下加热反应48小时。反应液经柱层析分离,得到84%产率的氘代沃替西汀;产物进行核磁1HNMR、13C NMR测试,氘代率为92%,如下式所示:
实施例3:氘代沃替西汀的制备:
惰性气氛下,在25mL的Schlenk反应管中,依次加入沃替西汀(CAS:508233-74-7,0.1mmol,0.0298g),氘代二甲基亚砜(0.5mL),双三甲基硅基胺基铯(30mol%,0.0088g)。将反应管密封,在100℃下加热反应24小时。反应液经柱层析分离,得到88%产率的氘代沃替西汀;产物进行核磁1HNMR、13C NMR测试,氘代率为70%和52%,如下式所示:
实施例4:氘代沃替西汀的制备:
惰性气氛下,在25mL的Schlenk反应管中,依次加入沃替西汀(CAS:508233-74-7,0.1mmol,0.0298g),氘代二甲基亚砜(0.5mL),叔丁醇钾(30mol%,0.0034g)。将反应管密封,在100℃下加热反应24小时。反应液经柱层析分离,得到90%产率的氘代沃替西汀;产物进行核磁1H NMR、13C NMR测试,氘代率为98%,如下式所示:
实施例5:氚代沃替西汀的制备:
在手套箱中,向装配有磁子的1mL氚代反应瓶中,加入CsHMDS(12.0μmol,150mol%)、叔丁基苯(150μL)、沃替西汀(8.0μmol)。氚代反应瓶连接上Swagelok阀门,密封。该反应装置连接至manifold反应器上,反应液通过循环冷冻脱气3次。然后反应液浸泡在液氮(-196℃)中,充入氚气(2.0Ci,0.3atm),随后反应装置密封,加热至90℃搅拌36h。反应结束后,反应体系用EtOH稀释、浓缩3次除去氚代挥发物。粗产物使用Radio-HPLC进行分析,氚代沃替西汀的放射性比活度为99.7Ci/mmol。使用半制备反向HPLC进行分离产物,通过LC-MS和IsoPat2 analysis计算,氚代沃替西汀的氚代率为3.5T/molecule。
本发明的保护内容不局限于以上实施例。在不背离本发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。
Claims (8)
1.一种氢同位素标记沃替西汀的合成方法,其特征在于,包括如下步骤:
以碱金属盐为催化剂,以芳烃、醚或烷烃为溶剂,以沃替西汀为反应物,向反应容器中充入氘气或加入氘代二甲基亚砜或充入氚气,在预定温度下密闭反应预定时间,即得氢同位素标记沃替西汀,其中,所述氢同位素标记沃替西汀包括氘代沃替西汀和氚代沃替西汀;
所述氘代沃替西汀的反应式如下式1所示:
所述氚代沃替西汀的反应式如下式2所示:
所述催化剂选自碱金属氢氧化物、碱金属醇盐、碱金属氢化物、碱金属烃基化合物和碱金属氨基化合物中的任意一种或多种的组合;所述反应的温度为60℃-120℃。
2.根据权利要求1所述的合成方法,其特征在于,所述碱金属氢氧化物选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铷和氢氧化铯中的至少一种;
和/或,所述碱金属醇盐选自甲醇锂、乙醇锂、异丙醇锂、叔丁醇锂、甲醇钠、乙醇钠、异丙醇钠、叔丁醇钠、甲醇钾、乙醇钾、异丙醇钾、叔丁醇钾、烷氧基铷和烷氧基铯中的至少一种;
和/或,所述碱金属氢化物选自氢化锂、氢化钠、氢化钾、氢化铷和氢化铯中的至少一种;
和/或,所述碱金属烃基化合物选自甲基锂、三甲基硅甲基锂、乙基锂、正丁基锂、仲丁基锂、叔丁基锂、苄基锂、苯基锂、苄基钠、苄基钾、苄基铷和苄基铯中的至少一种;
和/或,所述碱金属氨基化合物选自氨基锂、二甲氨基锂、二乙氨基锂、二异丙基氨基锂、双三甲基硅基氨基锂、四甲基哌啶锂、氨基钠、二异丙基氨基钠、双三甲基硅基氨基钠、氨基钾、二甲氨基钾、二乙氨基钾、二异丙基氨基钾、双三甲基硅基氨基钾、四甲基哌啶钾、二甲氨基铷、二乙氨基铷、二异丙基氨基铷、双三甲基硅基氨基铷、四甲基哌啶铷、二甲氨基铯、二乙氨基铯、二异丙基氨基铯、双三甲基硅基氨基铯和四甲基哌啶铯中的至少一种。
3.根据权利要求1所述的合成方法,其特征在于,所述催化剂的用量为沃替西汀摩尔量的1%-150%。
4.根据权利要求1所述的合成方法,其特征在于,所述溶剂为芳烃、烷烃或醚类溶剂中的任意一种及其组合。
5.根据权利要求4所述的合成方法,其特征在于,所述芳烃溶剂包括苯、氘代苯、叔丁基苯;
和/或,所述烷烃溶剂包括正己烷、环己烷、甲基环己烷、环庚烷、辛烷、十氢化萘;
和/或,醚类溶剂包括乙醚、甲基叔丁基醚、甲基环戊基醚、正丁基醚、四氢呋喃、四氢吡喃、二氧六环。
6.根据权利要求1所述的合成方法,其特征在于,所述氘气压力为1-50bar。
7.根据权利要求1所述的合成方法,其特征在于,所述氚气压力为0.1-0.9bar。
8.根据权利要求1所述的合成方法,其特征在于,所述反应的时间为12-96小时。
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