CN114835580A - Method for introducing gamma-deuteration into carbonyl compound - Google Patents
Method for introducing gamma-deuteration into carbonyl compound Download PDFInfo
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- CN114835580A CN114835580A CN202210540934.9A CN202210540934A CN114835580A CN 114835580 A CN114835580 A CN 114835580A CN 202210540934 A CN202210540934 A CN 202210540934A CN 114835580 A CN114835580 A CN 114835580A
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- 238000000034 method Methods 0.000 title claims abstract description 53
- 150000001728 carbonyl compounds Chemical class 0.000 title claims abstract description 14
- 229910052805 deuterium Inorganic materials 0.000 claims abstract description 56
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000012046 mixed solvent Substances 0.000 claims abstract description 28
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 20
- -1 olefin compound Chemical class 0.000 claims abstract description 14
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000000758 substrate Substances 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 239000003999 initiator Substances 0.000 claims abstract description 8
- 239000011259 mixed solution Substances 0.000 claims abstract description 8
- 150000003254 radicals Chemical class 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 81
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- 125000001931 aliphatic group Chemical group 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- HDMHBHNRWDNNCD-UHFFFAOYSA-N 1-[(2-hydroxyethoxy)methyl]-6-(phenylsulfanyl)thymine Chemical compound OCCOCN1C(=O)NC(=O)C(C)=C1SC1=CC=CC=C1 HDMHBHNRWDNNCD-UHFFFAOYSA-N 0.000 claims description 2
- XMNIXWIUMCBBBL-UHFFFAOYSA-N 2-(2-phenylpropan-2-ylperoxy)propan-2-ylbenzene Chemical compound C=1C=CC=CC=1C(C)(C)OOC(C)(C)C1=CC=CC=C1 XMNIXWIUMCBBBL-UHFFFAOYSA-N 0.000 claims description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims 1
- 238000005286 illumination Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 41
- 125000000524 functional group Chemical group 0.000 abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 63
- 239000007810 chemical reaction solvent Substances 0.000 description 27
- 239000012969 di-tertiary-butyl peroxide Substances 0.000 description 26
- 239000007788 liquid Substances 0.000 description 26
- 238000000746 purification Methods 0.000 description 26
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 22
- XTCXSNIRIUQZLY-UHFFFAOYSA-N benzyl 2-sulfanylacetate Chemical compound SCC(=O)OCC1=CC=CC=C1 XTCXSNIRIUQZLY-UHFFFAOYSA-N 0.000 description 21
- 238000004949 mass spectrometry Methods 0.000 description 17
- 230000000052 comparative effect Effects 0.000 description 12
- 238000006467 substitution reaction Methods 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- CORMBJOFDGICKF-UHFFFAOYSA-N 1,3,5-trimethoxy 2-vinyl benzene Natural products COC1=CC(OC)=C(C=C)C(OC)=C1 CORMBJOFDGICKF-UHFFFAOYSA-N 0.000 description 2
- UAJRSHJHFRVGMG-UHFFFAOYSA-N 1-ethenyl-4-methoxybenzene Chemical compound COC1=CC=C(C=C)C=C1 UAJRSHJHFRVGMG-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- PDELBHCVXBSVPJ-UHFFFAOYSA-N 2-ethenyl-1,3,5-trimethylbenzene Chemical compound CC1=CC(C)=C(C=C)C(C)=C1 PDELBHCVXBSVPJ-UHFFFAOYSA-N 0.000 description 2
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000003172 aldehyde group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000005620 boronic acid group Chemical group 0.000 description 2
- MKUWVMRNQOOSAT-UHFFFAOYSA-N but-3-en-2-ol Chemical compound CC(O)C=C MKUWVMRNQOOSAT-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical group OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 239000001082 (3R)-3-sulfanylpentan-2-one Substances 0.000 description 1
- MKJIEFSOBYUXJB-VFJJUKLQSA-N (3r,11br)-3-(2-methylpropyl)-9,10-bis(trideuteriomethoxy)-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizin-2-one Chemical compound C1CN2C[C@@H](CC(C)C)C(=O)C[C@@H]2C2=C1C=C(OC([2H])([2H])[2H])C(OC([2H])([2H])[2H])=C2 MKJIEFSOBYUXJB-VFJJUKLQSA-N 0.000 description 1
- QWMJEUJXWVZSAG-UHFFFAOYSA-N (4-ethenylphenyl)boronic acid Chemical compound OB(O)C1=CC=C(C=C)C=C1 QWMJEUJXWVZSAG-UHFFFAOYSA-N 0.000 description 1
- SKYXLDSRLNRAPS-UHFFFAOYSA-N 1,2,4-trifluoro-5-methoxybenzene Chemical compound COC1=CC(F)=C(F)C=C1F SKYXLDSRLNRAPS-UHFFFAOYSA-N 0.000 description 1
- BOVQCIDBZXNFEJ-UHFFFAOYSA-N 1-chloro-3-ethenylbenzene Chemical compound ClC1=CC=CC(C=C)=C1 BOVQCIDBZXNFEJ-UHFFFAOYSA-N 0.000 description 1
- CEWDRCQPGANDRS-UHFFFAOYSA-N 1-ethenyl-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(C=C)C=C1 CEWDRCQPGANDRS-UHFFFAOYSA-N 0.000 description 1
- SZECUQRKLXRGSJ-UHFFFAOYSA-N 3-Mercapto-2-pentanone Chemical compound CCC(S)C(C)=O SZECUQRKLXRGSJ-UHFFFAOYSA-N 0.000 description 1
- ABAPGTZHOYRXAH-UHFFFAOYSA-N CC(C(C1=CC=C(C)C=C1)=O)S Chemical compound CC(C(C1=CC=C(C)C=C1)=O)S ABAPGTZHOYRXAH-UHFFFAOYSA-N 0.000 description 1
- LXXNWCFBZHKFPT-UHFFFAOYSA-N Ethyl 2-mercaptopropionate Chemical compound CCOC(=O)C(C)S LXXNWCFBZHKFPT-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- NSJNRJYQQPRCLF-UHFFFAOYSA-N N-methyl-2-sulfanylacetamide Chemical compound CNC(=O)CS NSJNRJYQQPRCLF-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- PBGVMIDTGGTBFS-UHFFFAOYSA-N but-3-enylbenzene Chemical compound C=CCCC1=CC=CC=C1 PBGVMIDTGGTBFS-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 125000004431 deuterium atom Chemical class 0.000 description 1
- 229950005031 deutetrabenazine Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 description 1
- 229960002373 loxoprofen Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229930015698 phenylpropene Natural products 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- HJWLCRVIBGQPNF-UHFFFAOYSA-N prop-2-enylbenzene Chemical compound C=CCC1=CC=CC=C1 HJWLCRVIBGQPNF-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 239000010891 toxic waste Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- KOZCZZVUFDCZGG-UHFFFAOYSA-N vinyl benzoate Chemical compound C=COC(=O)C1=CC=CC=C1 KOZCZZVUFDCZGG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种在羰基化合物中引入γ‑氘代的方法，所述方法为：将烯烃化合物和α‑羰基硫醇化合物溶于有机溶剂和氘水的混合溶剂中，得到混合溶液；在混合溶液中加入加入膦试剂和自由基引发剂，在光照条件下反应，即可将底物转化为相应的γ‑氘代羰基化合物。本发明引入氘代的方法具有氘代效率较高、选择性好、官能团耐受性好、高产率、反应条件温和、无需金属参与反应、底物范围广的特点，特别适合在碳链的特定位置选择性引入氘代。The present invention provides a method for introducing γ-deuterium into carbonyl compounds. The method comprises the following steps: dissolving an olefin compound and an α-carbonyl thiol compound in a mixed solvent of an organic solvent and deuterium water to obtain a mixed solution; Adding a phosphine reagent and a free radical initiator to the mixed solution, and reacting under light conditions, the substrate can be converted into a corresponding γ-deuterated carbonyl compound. The method for introducing deuterium in the present invention has the characteristics of high deuteration efficiency, good selectivity, good functional group tolerance, high yield, mild reaction conditions, no need for metal to participate in the reaction, and a wide range of substrates, and is especially suitable for specific carbon chains. Position-selective introduction of deuterium.
Description
技术领域technical field
本发明涉及分子标记技术领域，具体地，涉及一种在羰基化合物中引入γ-氘代的方法。The present invention relates to the technical field of molecular labeling, in particular, to a method for introducing γ-deuterium into carbonyl compounds.
背景技术Background technique
氘代作为一种重要的标记手段，在药物代谢，新反应机制研究、核磁、质谱等研究中有着重要应用。在药物分子的适当位置引入氘代，能够极大地改变药物的代谢以及药代动力学性质。2017年，FDA批准了第一个氘代药物，deutetrabenazine，极大地促进了氘代药物的研究和氘代方法的发展。As an important labeling method, deuterium has important applications in drug metabolism, new reaction mechanism research, nuclear magnetic resonance, mass spectrometry and other research. The introduction of deuterium at the appropriate position of the drug molecule can greatly alter the metabolism and pharmacokinetic properties of the drug. In 2017, the FDA approved the first deuterated drug, deutetrabenazine, which greatly facilitated the research on deuterated drugs and the development of deuterated methods.
传统的氘取代化合物合成常使用氢同位素交换策略，通过单个步骤在化合物中引入氘同位素而不需要重新合成，在原子及步骤的经济性方面具有优势，发展比较充分的H/D交换过程通常由酸/碱或过渡金属催化。然而，酸/碱催化的氢同位素交换过程虽然可以选择性地氘取代分子中酸性或碱性C–H键，但通常要求较高的反应温度，很可能破坏或影响反应底物中的其他敏感官能团；过渡金属催化存在的主要不足则在于氘取代的区域选择性不佳及不同底物的氘取代率不稳定，限制了其在有机合成化学中的广泛应用，并且，在碳链的特定位置选择性地引入氘代，仍然很有挑战性和实用性。有鉴于此，本领域亟需一种能够在碳链的特定位置高效选择地引入氘代的方法。The traditional synthesis of deuterium-substituted compounds often uses a hydrogen isotope exchange strategy. Deuterium isotopes are introduced into the compound through a single step without re-synthesis. It has advantages in terms of atom and step economy. A fully developed H/D exchange process is usually composed of Acid/base or transition metal catalysis. However, although the acid/base catalyzed hydrogen isotope exchange process can selectively deuterium replace the acidic or basic C–H bonds in the molecule, it usually requires a higher reaction temperature and is likely to destroy or affect other sensitive substances in the reaction substrate. functional group; the main disadvantage of transition metal catalysis is the poor regioselectivity of deuterium substitution and the unstable deuterium substitution rate of different substrates, which limit its wide application in organic synthetic chemistry, and, in specific positions in the carbon chain The selective introduction of deuterium remains challenging and practical. In view of this, there is an urgent need in the art for a method that can efficiently and selectively introduce deuterium at a specific position of the carbon chain.
发明内容SUMMARY OF THE INVENTION
针对现有技术中的缺陷，本发明的目的是提供一种在羰基化合物中引入γ-氘代的方法。本发明要解决上述技术问题，关键在于利用化学反应过程中存在的具备单一碳原子中心的活性自由基中间体，使得氘原子能够特异性地与该活性中心结合生成C–D键，进而生成具备单一位点选择性的氘取代化合物，从源头上消除了多位点氘取代化合物生成的可能性。同时，整个过程由无金属介导或催化的常温中性光反应体系驱动，有效地提升了反应底物的官能团耐受性与合成过程的可操作性，同时没有高污染性或毒性的废物产生，合成与后处理的经济成本得到有效控制。在实施结果中，本发明具有引入氘代效率较高、适用底物范围广等优点，特别适合在羰基化合物的γ-碳上引入氘原子取代。本发明的目的是通过以下方案实现的：In view of the defects in the prior art, the purpose of the present invention is to provide a method for introducing γ-deuterium into carbonyl compounds. To solve the above-mentioned technical problems, the key of the present invention is to utilize the active free radical intermediate with a single carbon atom center existing in the chemical reaction process, so that the deuterium atom can specifically combine with the active center to generate a C-D bond, and then generate a C-D bond with a single carbon atom center. The single-site-selective deuterium-substituted compound eliminates the possibility of multi-site deuterium-substituted compounds from the source. At the same time, the whole process is driven by a neutral photoreaction system at room temperature without metal mediation or catalysis, which effectively improves the functional group tolerance of the reaction substrate and the operability of the synthesis process, and no highly polluting or toxic waste is generated. , the economic cost of synthesis and post-processing is effectively controlled. In the implementation results, the present invention has the advantages of high efficiency of introducing deuterium, wide range of applicable substrates and the like, and is particularly suitable for introducing substitution of deuterium atoms on the γ-carbon of carbonyl compounds. The purpose of this invention is to realize through the following scheme:
本发明的第一方面提供一种在羰基化合物中引入γ-氘代的方法，其特征在于，方法如下：A first aspect of the present invention provides a method for introducing γ-deuteration in a carbonyl compound, characterized in that the method is as follows:
步骤一、将烯烃化合物和α-羰基硫醇化合物溶于有机溶剂和氘水的混合溶剂中，得到混合溶液；Step 1, dissolving the olefin compound and the α-carbonyl thiol compound in a mixed solvent of an organic solvent and deuterium water to obtain a mixed solution;
步骤二、在混合溶液中加入加入膦试剂和自由基引发剂，在光照条件下反应，即可将底物转化为相应的γ-氘代羰基化合物。Step 2, adding a phosphine reagent and a free radical initiator to the mixed solution, and reacting under light conditions, the substrate can be converted into a corresponding γ-deuterated carbonyl compound.
优选的，所述步骤一中的烯烃化合物结构式为：
优选的，所述步骤一中的烯烃化合物结构式为：
优选的，所述步骤一中的α-羰基硫醇化合物结构式为：
优选的，所述步骤一中的α-羰基硫醇化合物结构式为：
优选的，所述步骤一中的烯烃化合物与α-羰基硫醇化合物的当量比为1:1～5。Preferably, the equivalent ratio of the olefin compound to the α-carbonylthiol compound in the first step is 1:1-5.
优选的，所述步骤一中的有机溶剂为自二氯甲烷、乙腈、乙酸乙酯、氯仿、丙酮、DMF、氘代甲醇、乙醚、四氢呋喃、甲苯中的一种，所述有机溶剂与氘水的体积比为0.5～5：1。Preferably, the organic solvent in the first step is one selected from dichloromethane, acetonitrile, ethyl acetate, chloroform, acetone, DMF, deuterated methanol, diethyl ether, tetrahydrofuran, and toluene, and the organic solvent and deuterium water The volume ratio is 0.5 to 5:1.
优选有机溶剂为乙酸乙酯，有机溶剂与氘水的体积比优选为2:1。Preferably, the organic solvent is ethyl acetate, and the volume ratio of the organic solvent to deuterium water is preferably 2:1.
优选的，所述步骤二中的膦试剂为Ph2POEt、PPh3、HEPT、PCy3中的一种，所述膦试剂使用当量为相对烯烃化合物的1.0～5.0当量，优选膦试剂为PPh3。Preferably, the phosphine reagent in the second step is one of Ph2POEt, PPh3, HEPT, and PCy3, and the phosphine reagent is used in an equivalent amount of 1.0 to 5.0 equivalents relative to the olefin compound, preferably the phosphine reagent is PPh3.
优选的，所述步骤二中的引发剂为过氧化二叔丁基、过氧化二异丙苯、过氧化二苯甲酰中的一种，所述引发剂使用当量为相对烯烃化合物的2.0～5.0当量，引发剂优选为过氧化二叔丁基。Preferably, the initiator in the second step is one of di-tert-butyl peroxide, dicumyl peroxide, and dibenzoyl peroxide, and the initiator is used in an equivalent weight of 2.0 to 2.0 to olefin compound. 5.0 equivalents, the initiator is preferably di-tert-butyl peroxide.
优选的本发明路线如下所示：The preferred route of the present invention is as follows:
优选的，所述步骤二中的光照条件为将混合溶液置于两个65W家用紧凑型荧光灯(compact fluorescent lamp，CFL)之间，且与灯间距1～10cm，距离较近会造成溶液温度上升影响实验结果。Preferably, the lighting condition in the second step is to place the mixed solution between two 65W household compact fluorescent lamps (CFL), and the distance between the two lamps is 1-10 cm, and the short distance will cause the temperature of the solution to rise. affect the experimental results.
优选的，所述步骤二中的反应时间为6～24h，优选的反应时间为15h。Preferably, the reaction time in the second step is 6-24h, and the preferred reaction time is 15h.
与现有技术相比，本发明具有如下的有益效果：Compared with the prior art, the present invention has the following beneficial effects:
(1)本发明一种在羰基化合物中引入γ-氘取代的方法具有氘代效率较高、产率高的优点，实施产物全部仅于单一位点发生氘取代，无多位点氘取代物质生成，依据优选条件实施获得的产物单一位点氘取代率均超过80％，最高可达96％，其中大部分实施产物可获得良好以上产率，半数实施产物可获得优秀产率，各实施例中最高产率可达98％；(1) a method for introducing γ-deuterium substitution in carbonyl compounds of the present invention has the advantages of higher deuteration efficiency and high yield, and all implementation products only have deuterium substitutions at a single site, and there are no multi-site deuterium substitution substances According to the optimal conditions, the single-site deuterium substitution rate of the products obtained by the implementation of the optimal conditions all exceeds 80%, and the maximum can reach 96%. Most of the implementation products can obtain good and above yields, and half of the implementation products can obtain excellent yields. Each embodiment The highest yield can reach 98%;
(2)本发明一种在羰基化合物中引入γ-氘取代的方法反应条件简单，无需金属介导或者催化，所需原料与生成物质均无明显危险性或毒性，常温下即可进行反应；(2) a method for introducing γ-deuterium substitution into a carbonyl compound of the present invention has simple reaction conditions, does not require metal mediation or catalysis, and the required raw materials and generated substances have no obvious danger or toxicity, and the reaction can be carried out at room temperature;
(3)本发明一种在羰基化合物中引入γ-氘取代的方法官能团耐受性好，底物选择范围广，具备多种官能团取代或分子结构的底物均能顺利反应生成预期产物。(3) The method for introducing γ-deuterium substitution into carbonyl compounds of the present invention has good functional group tolerance and a wide range of substrate selection, and substrates with various functional group substitutions or molecular structures can smoothly react to generate the expected product.
具体实施方式Detailed ways
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变化和改进。这些都属于本发明的保护范围。The present invention will be described in detail below with reference to specific embodiments. The following examples will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be noted that, for those skilled in the art, several changes and improvements can be made without departing from the inventive concept. These all belong to the protection scope of the present invention.
实验的一般操作流程：在50mL的干燥烧瓶中加入4.0当量的PPh3并溶于无水的乙酸乙酯中，然后加入D2O(V:V＝2:1)、烯烃底物(1.0当量)和硫醇底物(3.0当量)并搅拌数分钟。向体系加入DTBP(4.5当量)后，烧瓶被置于双侧各65W的家用紧凑型日光灯下(间隔4cm以保持瓶内体系处于室温下)照射15小时以发生反应。反应结束后，反应液经水洗涤后用乙酸乙酯萃取，合并有机层并经饱和NaCl溶液洗涤、Na2SO4干燥、过滤后浓缩，通过硅胶柱层析色谱纯化以获得目标产物。The general operation procedure of the experiment: 4.0 equiv of PPh 3 was added to a 50 mL dry flask and dissolved in anhydrous ethyl acetate, then D 2 O (V:V=2:1), olefin substrate (1.0 equiv. ) and thiol substrate (3.0 equiv) and stirred for several minutes. After adding DTBP (4.5 equiv.) to the system, the flask was irradiated under 65W domestic compact fluorescent lamps on each side (4 cm apart to keep the system in the flask at room temperature) for 15 hours to react. After the reaction, the reaction solution was washed with water and extracted with ethyl acetate. The organic layers were combined and washed with saturated NaCl solution, dried over Na 2 SO 4 , filtered and concentrated, and purified by silica gel column chromatography to obtain the target product.
实施例1Example 1
按照一般操作流程使用0.5mmol苯乙烯、1.5mmol巯基乙酸苄酯、PPh3(4.0equiv.)、 DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得115mg无色液体，即为产物，产率90％，氘代率85％。核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.43-7.29(m,5H),7.29-7.21(m, 2H),7.21-7.08(m,3H),5.10(s,2H),2.70-2.56(m,1H),2.37(t,J＝7.5 Hz,2H),2.03-1.90(m,2H).13C NMR(101MHz,CDCl3)δ173.3,141.3,136.1, 128.6,128.5,128.4,128.2,126.0,66.2,34.7(t,J＝19.4Hz),33.6,26.4.HRMS (ESI)([M+H]+)Calcd.for C17H17DO2:256.1442；found:256.1444。According to the general operation procedure, 0.5 mmol styrene, 1.5 mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) were used, and the reaction solvent was a mixed solvent of ethyl acetate and deuterium water (6 mL, V:V = 2:1). After the reaction was completed, 115 mg of colorless liquid was obtained after treatment and purification, which was the product with a yield of 90% and a deuteration rate of 85%. NMR and mass spectrometry data: 1 H NMR (400MHz, CDCl 3 ) δ 7.43-7.29(m, 5H), 7.29-7.21(m, 2H), 7.21-7.08(m, 3H), 5.10(s, 2H), 2.70-2.56 (m, 1H), 2.37 (t, J=7.5 Hz, 2H), 2.03-1.90 (m, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 173.3, 141.3, 136.1, 128.6, 128.5, 128.4 , 128.2, 126.0, 66.2, 34.7 (t, J=19.4 Hz), 33.6, 26.4. HRMS (ESI) ([M+H] + ) Calcd. for C 17 H 17 DO 2 : 256.1442; found: 256.1444.
实施例2Example 2
按照一般操作流程使用0.5mmol苯乙烯、1.5mmol巯基乙酸苄酯、PPh3(3.0equiv.)、 DTBP(4.0equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得93mg无色液体，即为产物，产率73％，氘代率86％。核磁数据与实施例1一致。Use 0.5 mmol styrene, 1.5 mmol benzyl thioglycolate, PPh 3 (3.0 equiv.), DTBP (4.0 equiv.) according to the general operation procedure, and the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6 mL, V:V = 2:1). After the reaction, 93 mg of colorless liquid was obtained after treatment and purification, which was the product, the yield was 73%, and the deuteration rate was 86%. The NMR data were consistent with Example 1.
实施例3Example 3
按照一般操作流程使用0.5mmol苯乙烯、1.0mmol巯基乙酸苄酯、PPh3(4.0equiv.)、 DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得79mg无色液体，即为产物，产率62％，氘代率88％。核磁数据与实施例1一致。Use 0.5 mmol styrene, 1.0 mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) according to the general operation procedure, and the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6 mL, V:V = 2:1). After the reaction, 79 mg of colorless liquid was obtained after treatment and purification, which was the product, the yield was 62%, and the deuteration rate was 88%. The NMR data were consistent with Example 1.
实施例4Example 4
按照一般操作流程使用0.5mmol苯乙烯、1.5mmol巯基乙酸苄酯、PPh3(4.0equiv.)、 DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(5mL，V:V＝4:1)。反应结束后，经处理和纯化得117mg无色液体，即为产物，产率92％，氘代率58％。核磁数据与实施例1一致。According to the general operation procedure, 0.5 mmol styrene, 1.5 mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) were used, and the reaction solvent was a mixed solvent of ethyl acetate and deuterium water (5 mL, V:V = 4:1). After the reaction was completed, 117 mg of colorless liquid was obtained after treatment and purification, which was the product with a yield of 92% and a deuteration rate of 58%. The NMR data were consistent with Example 1.
实施例5Example 5
按照一般操作流程使用0.5mmol 2,4,6-三甲基苯乙烯、1.5mmol巯基乙酸苄酯、PPh3 (4.0equiv.)、DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V: V＝2:1)。反应结束后，经处理和纯化得140mg无色液体，即为产物，产率94％，氘代率86％。核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.43-7.26(m,5H),6.81 (s,2H),5.13(s,2H),2.64-2.53(m,1H),2.46(t,J＝7.2Hz,2H),2.25(s, 6H),2.23(s,3H),1.84-1.74(m,2H).13C NMR(101MHz,CDCl3)δ173.3,136.0, 135.3,135.2,135.2,128.9,128.6,128.4,128.3,66.3,34.5,28.5(t,J＝19.3 Hz),24.3,20.8,19.7.HRMS(ESI)([M+H]+)Calcd.for C20H23DO2:298.1912；found: 298.1912。Use 0.5mmol 2,4,6-trimethylstyrene, 1.5mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) according to the general operation procedure, the reaction solvents are ethyl acetate and deuterium water mixed solvent (6 mL, V: V=2:1). After the reaction was completed, 140 mg of colorless liquid was obtained after treatment and purification, which was the product. The yield was 94% and the deuteration rate was 86%. NMR and mass spectrometry data: 1 H NMR (400 MHz, CDCl 3 ) δ 7.43-7.26 (m, 5H), 6.81 (s, 2H), 5.13 (s, 2H), 2.64-2.53 (m, 1H), 2.46 ( t, J=7.2Hz, 2H), 2.25(s, 6H), 2.23(s, 3H), 1.84-1.74(m, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 173.3, 136.0, 135.3, 135.2, 135.2,128.9,128.6,128.4,128.3,66.3,34.5,28.5(t,J=19.3 Hz),24.3,20.8,19.7.HRMS(ESI)([M+H] + )Calcd.for C 20 H 23 DO 2 :298.1912; found: 298.1912.
实施例6Example 6
按照一般操作流程使用0.5mmol对甲氧基苯乙烯、1.5mmol巯基乙酸苄酯、PPh3(4.0 equiv.)、DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得117mg无色液体，即为产物，产率82％，氘代率86％。核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.44-7.24(m,5H),7.05(d,J＝8.5 Hz,2H),6.80(d,J＝8.6Hz,2H),5.10(s,2H),3.75(s,3H),2.61-2.51(m, 1H),2.35(t,J＝7.5Hz,2H),1.98-1.85(m,2H).13C NMR(101MHz,CDCl3)δ 173.4,157.9,136.1,133.4,129.4,128.6,128.2,128.2,113.8,66.1,55.2,33.8 (t,J＝19.4Hz),33.5,26.7.HRMS(ESI)([M+H]+)Calcd.forC18H19DO3:286.1548； found:286.1550。According to the general operation procedure, 0.5 mmol p-methoxystyrene, 1.5 mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) were used, and the reaction solvent was a mixed solvent of ethyl acetate and deuterium water (6 mL , V:V=2:1). After the reaction was completed, 117 mg of colorless liquid was obtained after treatment and purification, which was the product. The yield was 82% and the deuteration rate was 86%. NMR and mass spectrometry data: 1 H NMR (400 MHz, CDCl 3 ) δ 7.44-7.24 (m, 5H), 7.05 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.6 Hz, 2H), 5.10 (s, 2H), 3.75 (s, 3H), 2.61-2.51 (m, 1H), 2.35 (t, J=7.5Hz, 2H), 1.98-1.85 (m, 2H). 13 C NMR (101MHz, CDCl) 3 ) δ 173.4, 157.9, 136.1, 133.4, 129.4, 128.6, 128.2, 128.2, 113.8, 66.1, 55.2, 33.8 (t, J=19.4Hz), 33.5, 26.7.HRMS(ESI)([M+H] + ) Calcd.forC 18 H 19 DO 3 :286.1548; found: 286.1550.
实施例7Example 7
按照一般操作流程使用0.5mmol 4-乙烯基苯硼酸、1.5mmol巯基乙酸苄酯、PPh3(4.0 equiv.)、DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得121mg无色液体，即为产物，产率81％，氘代率86％。核磁和质谱数据：1H NMR(400MHz,CD3OD)δ7.66(d,J＝7.6Hz,1H),7.51(d, J＝7.2Hz,1H),7.40-7.22(m,5H),7.20-7.02(m,2H),5.08(s,2H),2.65 -2.52(m,1H),2.33(t,J＝7.3Hz,2H),1.96-1.84(m,2H).13C NMR(101MHz, CD3OD)δ175.0,145.0,137.7,135.1,134.8,129.5,129.3,129.2,128.8,67.2, 35.7(t,J＝19.5Hz),34.4,27.6.HRMS(ESI)([M+Na]+)Calcd.for C17H18DBO4: 322.1331；found:322.1332。According to the general operation procedure, 0.5mmol of 4-vinylbenzeneboronic acid, 1.5mmol of benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) were used, and the reaction solvent was a mixed solvent of ethyl acetate and deuterium water (6 mL , V:V=2:1). After the reaction was completed, 121 mg of colorless liquid was obtained after treatment and purification, which was the product with a yield of 81% and a deuteration rate of 86%. NMR and mass spectrometry data: 1 H NMR (400 MHz, CD 3 OD) δ 7.66 (d, J=7.6 Hz, 1H), 7.51 (d, J=7.2 Hz, 1H), 7.40-7.22 (m, 5H), 7.20-7.02(m, 2H), 5.08(s, 2H), 2.65-2.52(m, 1H), 2.33(t, J=7.3Hz, 2H), 1.96-1.84(m, 2H). 13 C NMR( 101MHz, CD 3 OD)δ175.0,145.0,137.7,135.1,134.8,129.5,129.3,129.2,128.8,67.2,35.7(t,J=19.5Hz),34.4,27.6.HRMS(ESI)([M+Na] + ) Calcd. for C 17 H 18 DBO 4 : 322.1331; found: 322.1332.
实施例8Example 8
按照一般操作流程使用0.5mmol间氯苯乙烯、1.5mmol巯基乙酸苄酯、PPh3(4.0equiv.)、DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得109mg无色液体，即为产物，产率75％，氘代率84％。核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.44-7.28(m,5H),7.24-7.08(m, 3H),7.07-6.97(m,1H),5.12(s,2H),2.66-2.55(m,1H),2.37(t,J＝7.4 Hz,2H),2.01-1.89(m,2H).13C NMR(101MHz,CDCl3)δ173.1,143.4,136.0, 134.2,129.7,128.6,128.3,126.7,126.3,66.3,34.4(t,J＝19.5Hz),33.5, 26.2.HRMS(ESI)([M+Na]+)Calcd.for C17H16DClO2:312.0872；found:312.0878。According to the general operation procedure, 0.5 mmol m-chlorostyrene, 1.5 mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) were used, and the reaction solvent was a mixed solvent of ethyl acetate and deuterium water (6 mL, V :V=2:1). After the reaction was completed, 109 mg of colorless liquid was obtained after treatment and purification, which was the product with a yield of 75% and a deuteration rate of 84%. NMR and mass spectrometry data: 1 H NMR (400MHz, CDCl 3 ) δ 7.44-7.28(m, 5H), 7.24-7.08(m, 3H), 7.07-6.97(m, 1H), 5.12(s, 2H), 2.66-2.55 (m, 1H), 2.37 (t, J=7.4 Hz, 2H), 2.01-1.89 (m, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 173.1, 143.4, 136.0, 134.2, 129.7, 128.6 , 128.3, 126.7, 126.3, 66.3, 34.4 (t, J=19.5Hz), 33.5, 26.2.HRMS(ESI)([M+Na] + )Calcd.for C 17 H 16 DClO 2 : 312.0872; found: 312.0878 .
实施例9Example 9
按照一般操作流程使用0.5mmol茚、1.5mmol巯基乙酸苄酯、PPh3(4.0equiv.)、DTBP (4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得119mg无色液体，即为产物，产率89％，氘代率86％。核磁和质谱数据：1HNMR(400MHz,CDCl3)δ7.43-7.27(m,5H),7.22-7.15(m,2H),7.15 -7.07(m,2H),5.14(s,2H),3.12(dd,J＝15.6,7.8Hz,1.5H),2.99-2.80 (m,1H),2.64(dd,J＝15.5,7.2Hz,1.5H),2.54(dd,J＝7.5,1.7Hz,2H).13C NMR(101MHz,CDCl3)δ172.8,142.7,136.0,128.6,128.2,128.2,126.3,124.5, 66.2,40.0,39.0,38.7(t,J＝20.3Hz),36.1.HRMS(ESI)([M+Na]+)Calcd.for C18H17DO2:290.1262；found:290.1265。Use 0.5mmol indene, 1.5mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) according to the general operation procedure, and the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6 mL, V:V= 2:1). After the reaction was completed, 119 mg of colorless liquid was obtained after treatment and purification, which was the product with a yield of 89% and a deuteration rate of 86%. NMR and mass spectrometry data: 1 HNMR (400MHz, CDCl 3 ) δ 7.43-7.27(m, 5H), 7.22-7.15(m, 2H), 7.15-7.07(m, 2H), 5.14(s, 2H), 3.12 (dd, J＝15.6, 7.8Hz, 1.5H), 2.99-2.80 (m, 1H), 2.64 (dd, J＝15.5, 7.2Hz, 1.5H), 2.54 (dd, J＝7.5, 1.7Hz, 2H) ). 13 C NMR (101MHz, CDCl 3 )δ172.8, 142.7, 136.0, 128.6, 128.2, 128.2, 126.3, 124.5, 66.2, 40.0, 39.0, 38.7(t, J=20.3Hz), 36.1.HRMS(ESI)( [M+Na] + ) Calcd. for C18H17DO2 : 290.1262 ; found: 290.1265 .
实施例10Example 10
按照一般操作流程使用0.5mmol N-乙烯基吡咯烷酮、1.5mmol巯基乙酸苄酯、PPh3(4.0 equiv.)、DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得127mg无色液体，即为产物，产率97％，氘代率93％。核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.46-7.28(m,5H),5.12(s,2H), 3.37(t,J＝7.0Hz,2H),3.34-3.24(m,1H),2.44-2.31(m,4H),2.06-1.95 (m,2H),1.92-1.83(m,2H).13C NMR(101MHz,CDCl3)δ175.2,172.9,135.9, 128.6,128.3,128.3,66.4,47.1,41.6(t,J＝21.1Hz),31.5,31.0,22.5,17.9. HRMS(ESI)([M+H]+)Calcd.for C15H18DNO3:263.1500；found:263.1506。0.5mmol N-vinylpyrrolidone, 1.5mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) were used according to the general operation procedure, and the reaction solvent was a mixed solvent of ethyl acetate and deuterium water (6 mL, V:V=2:1). After the reaction was completed, 127 mg of colorless liquid was obtained after treatment and purification, which was the product with a yield of 97% and a deuteration rate of 93%. NMR and mass spectrometry data: 1 H NMR (400 MHz, CDCl 3 ) δ 7.46-7.28 (m, 5H), 5.12 (s, 2H), 3.37 (t, J=7.0 Hz, 2H), 3.34-3.24 (m, 1H), 2.44-2.31 (m, 4H), 2.06-1.95 (m, 2H), 1.92-1.83 (m, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 175.2, 172.9, 135.9, 128.6, 128.3, 128.3 , 66.4, 47.1, 41.6 (t, J=21.1 Hz), 31.5, 31.0, 22.5, 17.9. HRMS(ESI) ([M+H] + ) Calcd. for C 15 H 18 DNO 3 : 263.1500; found: 263.1506 .
实施例11Example 11
按照一般操作流程使用0.5mmol环己基乙烯醚、1.5mmol巯基乙酸苄酯、PPh3(4.0equiv.)、DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V:V＝2: 1)。反应结束后，经处理和纯化得136mg无色液体，即为产物，产率98％，氘代率96％。核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.46-7.28(m,5H),5.11(s,2H), 3.50-3.39(m,1H),3.24-3.10(m,1H),2.46(t,J＝7.4Hz,2H),1.94-1.86 (m,2H),1.87-1.78(m,2H),1.76-1.63(m,2H),1.57-1.46(m,1H),1.32 -1.09(m,5H).13C NMR(101MHz,CDCl3)δ173.5,136.1,128.5,128.2,128.2, 77.4,66.1(t,J＝21.5Hz),66.1,32.2,31.2,25.8,25.4,24.1.HRMS(ESI)([M+H]+) Calcd.for C17H23DO3:278.1861；found:278.1863。According to the general operation procedure, 0.5 mmol cyclohexyl vinyl ether, 1.5 mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) were used, and the reaction solvent was a mixed solvent of ethyl acetate and deuterium water (6 mL, V :V=2:1). After the reaction was completed, 136 mg of colorless liquid was obtained after treatment and purification, which was the product with a yield of 98% and a deuteration rate of 96%. NMR and mass spectrometry data: 1 H NMR (400MHz, CDCl 3 ) δ 7.46-7.28(m, 5H), 5.11(s, 2H), 3.50-3.39(m, 1H), 3.24-3.10(m, 1H), 2.46(t,J＝7.4Hz,2H),1.94-1.86(m,2H),1.87-1.78(m,2H),1.76-1.63(m,2H),1.57-1.46(m,1H),1.32 - 1.09 (m, 5H). 13 C NMR (101 MHz, CDCl 3 ) δ 173.5, 136.1, 128.5, 128.2, 128.2, 77.4, 66.1 (t, J=21.5 Hz), 66.1, 32.2, 31.2, 25.8, 25.4, 24.1. HRMS(ESI)([M+H] + ) Calcd. for C17H23DO3 : 278.1861 ; found: 278.1863 .
实施例12Example 12
按照一般操作流程使用0.5mmol苯甲酸乙烯酯、1.5mmol巯基乙酸苄酯、PPh3(4.0equiv.)、DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V:V＝2: 1)。反应结束后，经处理和纯化得112mg无色液体，即为产物，产率75％，氘代率93％。核磁和质谱数据：1H NMR(400MHz,CDCl3)δ8.03(dd,J＝8.3,1.2Hz,2H),7.55 (tt,J＝7.4,1.2Hz,1H),7.43(dd,J＝10.8,4.5Hz,2H),7.39-7.27(m,5H), 5.11(s,2H),4.43-4.27(m,1H),2.55(t,J＝7.4Hz,2H),2.19-2.08(m, 2H).13C NMR(101MHz,CDCl3)δ172.7,166.5,135.8,133.0,130.2,129.6,128.6, 128.4,128.3,128.3,66.4,63.6(t,J＝22.8Hz),31.0,24.1.HRMS(ESI)([M+Na]+) Calcd.for C18H17DO4:322.1160；found:322.1163。According to the general operation procedure, 0.5 mmol vinyl benzoate, 1.5 mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) were used, and the reaction solvent was a mixed solvent of ethyl acetate and deuterium water (6 mL, V :V=2:1). After the reaction was completed, 112 mg of colorless liquid was obtained after treatment and purification, which was the product with a yield of 75% and a deuteration rate of 93%. NMR and mass spectrometry data: 1 H NMR (400 MHz, CDCl 3 ) δ 8.03 (dd, J=8.3, 1.2 Hz, 2H), 7.55 (tt, J=7.4, 1.2 Hz, 1H), 7.43 (dd, J= 10.8, 4.5Hz, 2H), 7.39-7.27(m, 5H), 5.11(s, 2H), 4.43-4.27(m, 1H), 2.55(t, J=7.4Hz, 2H), 2.19-2.08(m , 2H). 13 C NMR(101MHz, CDCl 3 )δ172.7,166.5,135.8,133.0,130.2,129.6,128.6,128.4,128.3,128.3,66.4,63.6(t,J=22.8Hz),31.0,24.1.HRMS (ESI)([M+Na] + ) Calcd. for C 18 H 17 DO 4 :322.1160; found: 322.1163.
实施例13Example 13
按照一般操作流程使用0.5mmol 1-丁烯-3-醇、1.5mmol巯基乙酸苄酯、PPh3(4.0equiv.)、DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V:V＝2: 1)。反应结束后，经处理和纯化得61mg无色液体，即为产物，产率55％，氘代率86％。核磁和质谱数据：1H NMR(400MHz,CD3OD)δ7.44-7.24(m,5H),5.11(s,2H), 3.76-3.63(m,1H),2.38(t,J＝7.4Hz,2H),1.82-1.68(m,1H),1.68-1.55 (m,1H),1.48-1.34(m,1H),1.13(d,J＝6.2Hz,3H).13C NMR(101MHz,CD3OD) δ175.2,137.7,129.6,129.2,129.2,68.1,67.2,39.0(t,J＝19.2Hz),35.0, 23.5,22.3.HRMS(ESI)([M+Na]+)Calcd.for C13H17DO3:246.1211；found:246.1212。Use 0.5mmol 1-buten-3-ol, 1.5mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) according to the general operation procedure, and the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6 mL, V:V=2:1). After the reaction was completed, 61 mg of colorless liquid was obtained after treatment and purification, which was the product, with a yield of 55% and a deuteration rate of 86%. NMR and mass spectrometry data: 1 H NMR (400MHz, CD 3 OD) δ 7.44-7.24 (m, 5H), 5.11 (s, 2H), 3.76-3.63 (m, 1H), 2.38 (t, J=7.4Hz) , 2H), 1.82-1.68(m, 1H), 1.68-1.55 (m, 1H), 1.48-1.34(m, 1H), 1.13(d, J=6.2Hz, 3H). 13 C NMR(101MHz, CD 3 OD) δ175.2,137.7,129.6,129.2,129.2,68.1,67.2,39.0(t,J=19.2Hz),35.0,23.5,22.3.HRMS(ESI)([M+Na] + )Calcd.for C 13 H 17 DO 3 : 246.1211; found: 246.1212.
实施例14Example 14
按照一般操作流程使用0.5mmol N-烯丙基氨基甲酸叔丁酯、1.5mmol巯基乙酸苄酯、 PPh3(4.0equiv.)、DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得61mg无色液体，即为产物，产率80％，氘代率83％。核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.45-7.29(m,5H),5.11 (s,2H),4.57(br s,1H),3.11(t,J＝6.0Hz,2H),2.38(t,J＝7.4Hz,2H), 1.71-1.62(m,2H),1.55-1.38(m,1H),1.44(s,9H).13C NMR(101MHz,CDCl3) δ173.3,156.0,136.0,128.6,128.2,128.2,79.2,66.2,40.1,33.8,29.1(t, J＝19.3Hz),28.4,22.0.HRMS(ESI)([M+Na]+)Calcd.for C17H24DNO4:331.1739； found:331.1740。According to the general operation procedure, 0.5 mmol N-allyl carbamate tert-butyl ester, 1.5 mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) were used, and the reaction solvent was ethyl acetate and deuterium water. Mixed solvent (6 mL, V:V=2:1). After the reaction was completed, 61 mg of colorless liquid was obtained after treatment and purification, which was the product, the yield was 80%, and the deuteration rate was 83%. NMR and mass spectrometry data: 1 H NMR (400MHz, CDCl 3 ) δ 7.45-7.29 (m, 5H), 5.11 (s, 2H), 4.57 (br s, 1H), 3.11 (t, J=6.0Hz, 2H) ), 2.38(t, J=7.4Hz, 2H), 1.71-1.62(m, 2H), 1.55-1.38(m, 1H), 1.44(s, 9H). 13 C NMR(101MHz, CDCl 3 ) δ173. 3, 156.0, 136.0, 128.6, 128.2, 128.2, 79.2, 66.2, 40.1, 33.8, 29.1(t, J=19.3Hz), 28.4, 22.0.HRMS(ESI)([M+Na] + )Calcd.for C 17 H 24 DNO 4 :331.1739; found:331.1740.
实施例15Example 15
按照一般操作流程使用0.5mmol烯丙基苯、1.5mmol巯基乙酸苄酯、PPh3(4.0equiv.)、 DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得89mg无色液体，即为产物，产率66％，氘代率84％。核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.41-7.29(m,5H),7.29-7.22(m, 2H),7.21-7.09(m,3H),5.11(s,2H),2.70-2.56(m,2H),2.38(t,J＝7.3 Hz,2H),1.76-1.60(m,3H).13C NMR(101MHz,CDCl3)δ173.5,142.1,136.1, 128.6,128.4,128.3,128.2,125.8,66.2,35.5,34.2,30.5(t,J＝19.5Hz),24.5. HRMS(ESI)([M+Na]+)Calcd.for C18H19DO2:292.1418；found:292.1419。Use 0.5 mmol allyl benzene, 1.5 mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) according to the general operation procedure, and the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6 mL, V :V=2:1). After the reaction was completed, 89 mg of colorless liquid was obtained after treatment and purification, which was the product, with a yield of 66% and a deuteration rate of 84%. NMR and mass spectrometry data: 1 H NMR (400MHz, CDCl 3 ) δ 7.41-7.29(m, 5H), 7.29-7.22(m, 2H), 7.21-7.09(m, 3H), 5.11(s, 2H), 2.70-2.56 (m, 2H), 2.38 (t, J=7.3 Hz, 2H), 1.76-1.60 (m, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 173.5, 142.1, 136.1, 128.6, 128.4, 128.3 , 128.2, 125.8, 66.2, 35.5, 34.2, 30.5 (t, J=19.5Hz), 24.5. HRMS(ESI)([M+Na] + )Calcd.for C 18 H 19 DO 2 :292.1418;found:292.1419 .
实施例16Example 16
按照一般操作流程使用0.5mmol 4-苯基-1-丁烯、1.5mmol巯基乙酸苄酯、PPh3(4.0 equiv.)、DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得113mg无色液体，即为产物，产率80％，氘代率84％。核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.42-7.30(m,5H),7.30-7.22(m, 2H),7.20-7.10(m,3H),5.10(s,2H),2.59(t,J＝7.8Hz,2H),2.35(t,J ＝7.5Hz,2H),1.73-1.57(m,4H),1.40-1.30(m,1H).13C NMR(101MHz,CDCl3) δ173.6,142.5,136.1,128.6,128.4,128.3,128.2,125.7,66.1,35.7,34.2, 31.0,28.4(t,J＝19.2Hz),24.7.HRMS(ESI)([M+Na]+)Calcd.forC19H21DO2: 306.1575；found:306.1574。Use 0.5mmol 4-phenyl-1-butene, 1.5mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) according to the general operation procedure, the reaction solvent is a mixture of ethyl acetate and deuterium water Solvent (6 mL, V:V=2:1). After the reaction, 113 mg of colorless liquid was obtained after treatment and purification, which was the product, and the yield was 80% and the deuteration rate was 84%. NMR and mass spectrometry data: 1 H NMR (400MHz, CDCl 3 ) δ 7.42-7.30(m, 5H), 7.30-7.22(m, 2H), 7.20-7.10(m, 3H), 5.10(s, 2H), 2.59 (t, J=7.8Hz, 2H), 2.35 (t, J=7.5Hz, 2H), 1.73-1.57 (m, 4H), 1.40-1.30 (m, 1H). 13 C NMR (101MHz, CDCl 3 ) δ173.6,142.5,136.1,128.6,128.4,128.3,128.2,125.7,66.1,35.7,34.2, 31.0,28.4(t,J=19.2Hz),24.7.HRMS(ESI)([M+Na] + )Calcd .forC 19 H 21 DO 2 : 306.1575; found: 306.1574.
实施例17Example 17
按照一般操作流程使用0.5mmol 2,4,6-三甲基苯乙烯、1.5mmol 2-巯基丙酸乙酯、PPh3 (4.0equiv.)、DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得113mg无色液体，即为产物，产率91％，氘代率87％。核磁和质谱数据：1H NMR(400MHz,CDCl3)δ6.82(s,2H),4.17(q,J＝7.1 Hz,2H),2.63-2.45(m,2H),2.27(s,6H),2.24(s,3H),1.84-1.70(m,1H), 1.61-1.50(m,1H),1.28(t,J＝7.1Hz,3H),1.23(d,J＝7.0Hz,3H).13C NMR (101MHz,CDCl3)δ176.5,135.9,135.5,135.1,128.9,60.3,40.1,33.0,26.7 (t,J＝19.5Hz),20.8,19.5,17.1,14.3.HRMS(ESI)([M+H]+)Calcd.for C16H23DO2: 250.1912；found:250.1912。Use 0.5mmol 2,4,6-trimethylstyrene, 1.5mmol ethyl 2-mercaptopropionate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) according to the general operation procedure, the reaction solvent is ethyl acetate and a mixed solvent of deuterium water (6 mL, V:V=2:1). After the reaction was completed, 113 mg of colorless liquid was obtained after treatment and purification, which was the product. The yield was 91% and the deuteration rate was 87%. NMR and mass spectral data: 1 H NMR (400 MHz, CDCl 3 ) δ 6.82 (s, 2H), 4.17 (q, J=7.1 Hz, 2H), 2.63-2.45 (m, 2H), 2.27 (s, 6H) ,2.24(s,3H),1.84-1.70(m,1H), 1.61-1.50(m,1H),1.28(t,J＝7.1Hz,3H),1.23(d,J＝7.0Hz,3H). 13 C NMR (101 MHz, CDCl 3 ) δ 176.5, 135.9, 135.5, 135.1, 128.9, 60.3, 40.1, 33.0, 26.7 (t, J=19.5 Hz), 20.8, 19.5, 17.1, 14.3. HRMS (ESI) ([M +H] + ) Calcd.for C16H23DO2 : 250.1912 ; found: 250.1912.
实施例18Example 18
按照一般操作流程使用0.5mmol苯乙烯、1.5mmol 2-巯基-1-(对甲苯基)丙-1-酮、PPh3(4.0equiv.)、DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(6mL， V:V＝2:1)。反应结束后，经处理和纯化得86mg无色液体，即为产物，产率68％，氘代率87％。核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.1Hz,2H), 7.31-7.17(m,5H),7.15(d,J＝7.2Hz,2H),3.50-3.36(m,1H),2.71-2.54 (m,1H),2.41(s,3H),2.21-2.08(m,1H),1.80-1.68(m,1H),1.22(d,J＝ 6.9Hz,3H).13C NMR(101MHz,CDCl3)δ203.8,143.7,141.9,134.1,129.3,128.5, 128.5,128.4,125.9,39.6,35.2,33.2(t,J＝19.6Hz),21.6,17.4.HRMS(ESI) ([M+H]+)Calcd.for C18H19DO:254.1650；found:254.1650。Use 0.5mmol styrene, 1.5mmol 2-mercapto-1-(p-tolyl)propan-1-one, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) according to the general operation procedure, and the reaction solvent is ethyl acetate and a mixed solvent of deuterium water (6 mL, V:V=2:1). After the reaction was completed, 86 mg of colorless liquid was obtained after treatment and purification, which was the product, the yield was 68%, and the deuteration rate was 87%. NMR and mass spectrometry data: 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (d, J=8.1 Hz, 2H), 7.31-7.17 (m, 5H), 7.15 (d, J=7.2 Hz, 2H), 3.50 -3.36(m,1H),2.71-2.54(m,1H),2.41(s,3H),2.21-2.08(m,1H),1.80-1.68(m,1H),1.22(d,J=6.9Hz , 3H). 13 C NMR (101MHz, CDCl 3 )δ203.8, 143.7, 141.9, 134.1, 129.3, 128.5, 128.5, 128.4, 125.9, 39.6, 35.2, 33.2 (t, J=19.6Hz), 21.6, 17.4.HRMS (ESI) ([M+H] + )Calcd. for C 18 H 19 DO: 254.1650; found: 254.1650.
实施例19Example 19
按照一般操作流程使用0.5mmol苯乙烯、1.5mmol 3-巯基-2-戊酮、PPh3(4.0equiv.)、 DTBP(4.5equiv.)，反应溶剂为二氯甲烷和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得60mg无色液体，即为产物，产率63％，氘代率85％。核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.32-7.26(m,2H),7.22-7.11(m, 3H),2.59-2.48(m,1H),2.43(tt,J＝8.0,5.6Hz,1H),2.12(s,3H),1.98 -1.88(m,1H),1.77-1.68(m,1H),1.68-1.59(m,1H),1.59-1.47(m,1H), 0.87(t,J＝7.5Hz,3H).13C NMR(101MHz,CDCl3)δ212.5,141.8,128.4,128.4, 126.0,54.0,33.3(t,J＝19.4Hz),32.6,28.9,24.6,11.6.HRMS(ESI)([M+H]+) Calcd.for C13H17DO:192.1493；found:192.1492。Use 0.5mmol styrene, 1.5mmol 3-mercapto-2-pentanone, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) according to the general operation procedure, and the reaction solvent is a mixed solvent of dichloromethane and deuterium water (6 mL , V:V=2:1). After the reaction was completed, 60 mg of colorless liquid was obtained after treatment and purification, which was the product with a yield of 63% and a deuteration rate of 85%. NMR and mass spectrometry data: 1 H NMR (400 MHz, CDCl 3 ) δ 7.32-7.26 (m, 2H), 7.22-7.11 (m, 3H), 2.59-2.48 (m, 1H), 2.43 (tt, J=8.0 ,5.6Hz,1H),2.12(s,3H),1.98-1.88(m,1H),1.77-1.68(m,1H),1.68-1.59(m,1H),1.59-1.47(m,1H), 0.87 (t, J=7.5Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 212.5, 141.8, 128.4, 128.4, 126.0, 54.0, 33.3 (t, J=19.4 Hz), 32.6, 28.9, 24.6, 11.6 .HRMS(ESI)([M+H] + ) Calcd. for C 13 H 17 DO: 192.1493; found: 192.1492.
实施例20Example 20
按照一般操作流程使用0.5mmol苯乙烯、1.5mmol 2-巯基-N-甲基乙酰胺、PPh3(4.0 equiv.)、DTBP(4.5equiv.)，反应溶剂为二氯甲烷和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得61mg无色液体，即为产物，产率69％，氘代率88％。核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.33-7.26(m,2H),7.24-7.13(m, 3H),5.39(br s,1H),2.80(d,J＝4.8Hz,3H),2.70-2.58(m,1H),2.17(t, J＝7.5Hz,2H),2.04-1.90(m,2H).13CNMR(101MHz,CDCl3)δ173.4,141.5, 128.5,128.4,126.0,35.8,34.9(t,J＝19.4Hz),27.0,26.3.HRMS(ESI)([M+H]+) Calcd.for C11H14DNO:179.1289；found:179.1290。According to the general operation procedure, 0.5mmol styrene, 1.5mmol 2-mercapto-N-methylacetamide, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) were used, and the reaction solvent was a mixed solvent of dichloromethane and deuterium water (6 mL, V:V=2:1). After the reaction was completed, 61 mg of colorless liquid was obtained after treatment and purification, which was the product with a yield of 69% and a deuteration rate of 88%. NMR and mass spectrometry data: 1 H NMR (400 MHz, CDCl 3 ) δ 7.33-7.26 (m, 2H), 7.24-7.13 (m, 3H), 5.39 (br s, 1H), 2.80 (d, J=4.8Hz , 3H), 2.70-2.58(m, 1H), 2.17(t, J=7.5Hz, 2H), 2.04-1.90(m, 2H). 13 CNMR(101MHz, CDCl 3 )δ173.4,141.5, 128.5,128.4, 126.0, 35.8, 34.9 (t, J=19.4 Hz), 27.0, 26.3. HRMS (ESI) ([M+H] + ) Calcd. for C 11 H 14 DNO: 179.1289; found: 179.1290.
实施例21Example 21
按照一般操作流程使用0.5mmol苯乙烯、1.5mmol巯基乙酸苄酯、PPh3(4.0equiv.)、 DTBP(4.5equiv.)，反应溶剂为氘代甲醇和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得70mg无色液体，即为产物，产率55％，氘代率93％。核磁数据与实施例1一致。According to the general operation procedure, 0.5 mmol styrene, 1.5 mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) were used, and the reaction solvent was a mixed solvent of deuterated methanol and deuterium water (6 mL, V:V = 2:1). After the reaction was completed, 70 mg of colorless liquid was obtained after treatment and purification, which was the product with a yield of 55% and a deuteration rate of 93%. The NMR data were consistent with Example 1.
实施例22Example 22
按照一般操作流程使用0.5mmol对三氟甲基苯乙烯、1.5mmol巯基乙酸苄酯、PPh3(4.0 equiv.)、DTBP(4.5equiv.)，反应溶剂为二氯甲烷和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得123mg无色液体，即为产物，产率76％，氘代率89％。核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.52(d,J＝8.1Hz,2H),7.43-7.29 (m,5H),7.26(d,J＝8.0Hz,2H),5.12(s,2H),2.78-2.61(m,1H),2.38(t, J＝7.4Hz,2H),2.03-1.94(m,2H).13CNMR(101MHz,CDCl3)δ173.1,145.4, 136.0,128.8,128.6,128.3,128.3,125.4(q,J＝3.7Hz),66.3,34.5(t,J＝19.3Hz),33.5,26.1.19F NMR(377MHz,CDCl3)δ-62.34.HRMS(ESI)([M+Na]+) Calcd.for C18H16DF3O2:346.1136；found:346.1136。According to the general operation procedure, 0.5mmol p-trifluoromethylstyrene, 1.5mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) were used, and the reaction solvent was a mixed solvent of dichloromethane and deuterium water ( 6 mL, V:V=2:1). After the reaction was completed, 123 mg of colorless liquid was obtained after treatment and purification, which was the product with a yield of 76% and a deuteration rate of 89%. NMR and mass spectral data: 1 H NMR (400 MHz, CDCl 3 ) δ 7.52 (d, J=8.1 Hz, 2H), 7.43-7.29 (m, 5H), 7.26 (d, J=8.0 Hz, 2H), 5.12 (s, 2H), 2.78-2.61 (m, 1H), 2.38 (t, J=7.4Hz, 2H), 2.03-1.94 (m, 2H). 13 CNMR (101 MHz, CDCl 3 ) δ 173.1, 145.4, 136.0, 128.8, 128.6, 128.3, 128.3, 125.4 (q, J=3.7 Hz), 66.3, 34.5 (t, J=19.3 Hz), 33.5, 26.1. 19 F NMR (377 MHz, CDCl 3 ) δ-62.34.HRMS (ESI )([M+Na] + ) Calcd. for C 18 H 16 DF 3 O 2 : 346.1136; found: 346.1136.
实施例23Example 23
按照一般操作流程使用0.5mmol苯乙烯、1.5mmol巯基乙酸苄酯、PPh3(4.0equiv.)、 DTBP(4.5equiv.)，反应溶剂为乙腈和氘水的混合溶剂(6mL，V:V＝2:1)。反应结束后，经处理和纯化得82mg无色液体，即为产物，产率64％，氘代率82％。核磁数据与实施例1一致。According to the general operation procedure, 0.5 mmol styrene, 1.5 mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) were used, and the reaction solvent was a mixed solvent of acetonitrile and deuterium water (6 mL, V:V=2 :1). After the reaction was completed, 82 mg of colorless liquid was obtained after treatment and purification, which was the product. The yield was 64% and the deuteration rate was 82%. The NMR data were consistent with Example 1.
对比例1Comparative Example 1
依据文献报道，使用0.5mmol洛索洛芬、10mol％B(C6F5)3，反应溶剂为氯仿(1.0mL)和氘水(50equiv.)，在100℃油浴下反应12小时。反应结束后，经处理和纯化得 116mg白色固体，即为产物，产率94％，两处位点氘代率分别为87％和73％。核磁数据：1H NMR(400MHz,CDCl3)δ7.23(d,J＝7.7Hz,2H),7.12(d,J＝7.7Hz,2H), 3.70(q,J＝7.2Hz,1H),3.11(d,J＝13.9Hz,1H),2.50(d,J＝14.0Hz,1H), 2.37–2.28(m,0.27H),2.13–2.04(m,1.13H),2.00–1.90(m,1H),1.77 –1.67(m,1H),1.58–1.51(m,1H),1.49(d,J＝7.2Hz,3H).13C NMR(101 MHz,CDCl3)δ220.6,180.3,139.1,137.6,129.1,127.6,51.0,50.5,50.3,44.9,37.6,35.1,35.1,29.0,20.4,20.4,20.3,18.1。According to literature reports, 0.5 mmol loxoprofen, 10 mol% B(C 6 F 5 ) 3 were used, and the reaction solvent was chloroform (1.0 mL) and deuterium water (50 equiv.), and the reaction was carried out in an oil bath at 100° C. for 12 hours. After the reaction, 116 mg of white solid was obtained after treatment and purification, which was the product, and the yield was 94%. The deuteration rates of the two sites were 87% and 73%, respectively. Nuclear magnetic data: 1 H NMR (400 MHz, CDCl 3 ) δ 7.23 (d, J=7.7 Hz, 2H), 7.12 (d, J=7.7 Hz, 2H), 3.70 (q, J=7.2 Hz, 1H), 3.11(d, J＝13.9Hz, 1H), 2.50(d, J＝14.0Hz, 1H), 2.37-2.28(m, 0.27H), 2.13-2.04(m, 1.13H), 2.00-1.90(m, 1H), 1.77-1.67(m, 1H), 1.58-1.51(m, 1H), 1.49(d, J=7.2Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 220.6, 180.3, 139.1, 137.6 ,129.1,127.6,51.0,50.5,50.3,44.9,37.6,35.1,35.1,29.0,20.4,20.4,20.3,18.1.
对比例2Comparative Example 2
根据文献报道，使用0.5mmol喹啉、1mol％图示铁催化剂、D2(4atm)，反应溶剂为四氢呋喃(2mL)，在45℃油浴下反应24小时。反应结束后，经处理得50mg无色液体，即为产物，产率76％，两处位点氘代率分别为91％和34％。核磁数据：1H NMR(400MHz, CDCl3)δ8.77(m,0.09H),8.01(d,J＝8.5Hz,1H),7.91–7.89(m,1H),7.59 (d,J＝8Hz,1H),7.54(ddd,J＝8.5,6.9,1.5Hz,1H),7.34(ddd,J＝8.5, 6.9,1.5Hz,1H),7.15(d,J＝8.4Hz,0.66H).13CNMR(101MHz,CDCl3)δ150.1, 148.0,135.7,129.2,129.1,128.0,127.5,126.2,120.7。According to literature reports, using 0.5 mmol quinoline, 1 mol % iron catalyst, D 2 (4 atm), the reaction solvent was tetrahydrofuran (2 mL), and the reaction was carried out in an oil bath at 45° C. for 24 hours. After the reaction was completed, 50 mg of colorless liquid was obtained after treatment, which was the product, and the yield was 76%. The deuteration rates of the two sites were 91% and 34%, respectively. Nuclear magnetic data: 1 H NMR (400MHz, CDCl 3 )δ8.77(m, 0.09H), 8.01(d, J=8.5Hz, 1H), 7.91-7.89(m, 1H), 7.59 (d, J=8Hz) ,1H),7.54(ddd,J＝8.5,6.9,1.5Hz,1H),7.34(ddd,J＝8.5,6.9,1.5Hz,1H),7.15(d,J＝8.4Hz,0.66H). 13 CNMR (101 MHz, CDCl3 ) δ 150.1, 148.0, 135.7, 129.2, 129.1, 128.0, 127.5, 126.2, 120.7.
对比例3Comparative Example 3
按照一般操作流程使用0.5mmol苯乙烯、1.5mmol巯基乙酸苄酯、PPh3(4.0equiv.)、 DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(14mL，V:V＝0.4:1)。反应结束后，经处理和纯化得66mg无色液体，即为产物，产率52％，氘代率95％。核磁数据与实施例1一致。According to the general operation procedure, 0.5 mmol styrene, 1.5 mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) were used, and the reaction solvent was a mixed solvent of ethyl acetate and deuterium water (14 mL, V:V = 0.4:1). After the reaction, 66 mg of colorless liquid was obtained after treatment and purification, which was the product, the yield was 52%, and the deuteration rate was 95%. The NMR data were consistent with Example 1.
对比例4Comparative Example 4
按照一般操作流程使用0.5mmol苯乙烯、1.5mmol巯基乙酸苄酯、PPh3(4.0equiv.)、 DTBP(4.5equiv.)，反应溶剂为乙酸乙酯和氘水的混合溶剂(4.5mL，V:V＝8:1)。反应结束后，经处理和纯化得116mg无色液体，即为产物，产率91％，氘代率35％。核磁数据与实施例1一致。According to the general operation procedure, 0.5 mmol styrene, 1.5 mmol benzyl thioglycolate, PPh 3 (4.0 equiv.), DTBP (4.5 equiv.) were used, and the reaction solvent was a mixed solvent of ethyl acetate and deuterium water (4.5 mL, V: V=8:1). After the reaction was completed, 116 mg of colorless liquid was obtained after treatment and purification, which was the product with a yield of 91% and a deuteration rate of 35%. The NMR data were consistent with Example 1.
表1实施例1-23以及对比例1-4产物产率与氘代率Table 1 Example 1-23 and Comparative Example 1-4 Product yield and deuteration rate
实施例1-23可以看出本发明底物选择范围广，通过表1发现优选有机溶剂为乙酸乙酯时产物产率与氘代率都较为优异，且与对比例1-2对比实验条件简单。对比例1与对比例2为现有的氘取代化合物合成技术，可以发现需要加热油浴，对反应条件要求严格且氘取代率不稳定。从表1对比可以发现对比例3与对比例4的乙酸乙酯与氘水的混合溶剂体积比超出范围0.5～5：1，可以看出对比例3产率明显降低，对比例4氘代率明显降低。Embodiment 1-23 can be seen that the substrate selection range of the present invention is wide, and it is found through Table 1 that when the preferred organic solvent is ethyl acetate, the product yield and the deuteration rate are both excellent, and the experimental conditions are simple compared with Comparative Examples 1-2. . Comparative example 1 and comparative example 2 are the existing deuterium substitution compound synthesis technology, it can be found that the oil bath needs to be heated, the reaction conditions are strict and the deuterium substitution rate is unstable. From the comparison of Table 1, it can be found that the volume ratio of the mixed solvent of ethyl acetate and deuterium water in Comparative Example 3 and Comparative Example 4 exceeds the range of 0.5 to 5:1. It can be seen that the yield of Comparative Example 3 is significantly reduced, and the deuterium rate of Comparative Example 4 is significantly reduced. Obvious reduction.
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变化或修改，这并不影响本发明的实质内容。在不冲突的情况下，本申请的实施例和实施例中的特征可以任意相互组合。Specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the above-mentioned specific embodiments, and those skilled in the art can make various changes or modifications within the scope of the claims, which do not affect the essential content of the present invention. The embodiments of the present application and features in the embodiments may be combined with each other arbitrarily, provided that there is no conflict.
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| ANEESH TAZHE VEETIL ET AL.: "Photochemistry of S-Phenacyl Xanthates", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| LUISA BENATI ET AL.: "A Novel Tin-Free Procedure for Alkyl Radical Reactions", 《ANGEWANDTE CHEMIE INTERNATIONAL EDITION》 * |
| LUMIN ZHANG ET AL.: "Reductive C−C Coupling by Desulfurizing Gold-Catalyzed Photoreactions", 《ACS CATALYSIS》 * |
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