CN116375556B - A kind of alpha-chlorodifluoromethylstyrene derivative and preparation method thereof - Google Patents
A kind of alpha-chlorodifluoromethylstyrene derivative and preparation method thereof Download PDFInfo
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- CN116375556B CN116375556B CN202310239882.6A CN202310239882A CN116375556B CN 116375556 B CN116375556 B CN 116375556B CN 202310239882 A CN202310239882 A CN 202310239882A CN 116375556 B CN116375556 B CN 116375556B
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- chlorodifluoromethylstyrene
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- -1 alpha-chlorodifluoromethylstyrene derivative Chemical class 0.000 title claims abstract description 79
- 238000002360 preparation method Methods 0.000 title abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 16
- 150000003841 chloride salts Chemical class 0.000 claims abstract description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 42
- 238000004440 column chromatography Methods 0.000 claims description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- 239000012043 crude product Substances 0.000 claims description 23
- 239000003208 petroleum Substances 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 17
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 16
- 238000004821 distillation Methods 0.000 claims description 14
- 239000003480 eluent Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 8
- 229940045803 cuprous chloride Drugs 0.000 claims description 8
- 235000005074 zinc chloride Nutrition 0.000 claims description 8
- 239000011592 zinc chloride Substances 0.000 claims description 8
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 7
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 7
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- 229960003280 cupric chloride Drugs 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 239000001103 potassium chloride Substances 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- RFVHKBGPIPZPOW-UHFFFAOYSA-N 3,3-difluoroprop-1-en-2-ylbenzene Chemical class FC(F)C(=C)C1=CC=CC=C1 RFVHKBGPIPZPOW-UHFFFAOYSA-N 0.000 claims 1
- 229940032296 ferric chloride Drugs 0.000 claims 1
- 229940073577 lithium chloride Drugs 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 229960001939 zinc chloride Drugs 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 21
- 230000015572 biosynthetic process Effects 0.000 abstract description 19
- 239000003814 drug Substances 0.000 abstract description 6
- LTVOKYUPTHZZQH-UHFFFAOYSA-N difluoromethane Chemical group F[C]F LTVOKYUPTHZZQH-UHFFFAOYSA-N 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 4
- 238000005660 chlorination reaction Methods 0.000 abstract description 3
- 150000002429 hydrazines Chemical class 0.000 abstract description 3
- 230000001404 mediated effect Effects 0.000 abstract description 3
- 238000011112 process operation Methods 0.000 abstract description 3
- 230000004048 modification Effects 0.000 abstract description 2
- 238000012986 modification Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 96
- 238000001228 spectrum Methods 0.000 description 48
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 33
- 239000000047 product Substances 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 16
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 16
- 238000012512 characterization method Methods 0.000 description 16
- 239000011737 fluorine Substances 0.000 description 16
- 229910052731 fluorine Inorganic materials 0.000 description 16
- 229910052739 hydrogen Inorganic materials 0.000 description 16
- 239000001257 hydrogen Substances 0.000 description 16
- 238000001819 mass spectrum Methods 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- 238000004293 19F NMR spectroscopy Methods 0.000 description 15
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 14
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 8
- 239000000243 solution Substances 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- 125000005605 benzo group Chemical group 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- UCZQXJKDCHCTAI-UHFFFAOYSA-N 4h-1,3-dioxine Chemical compound C1OCC=CO1 UCZQXJKDCHCTAI-UHFFFAOYSA-N 0.000 description 2
- LJUSIZYFGCPWFQ-UHFFFAOYSA-N FC(C(=C)C1=CC=C(C=C1)C1=CC=CC=C1)F Chemical group FC(C(=C)C1=CC=C(C=C1)C1=CC=CC=C1)F LJUSIZYFGCPWFQ-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- OWIUPIRUAQMTTK-UHFFFAOYSA-N carbazic acid Chemical compound NNC(O)=O OWIUPIRUAQMTTK-UHFFFAOYSA-N 0.000 description 2
- 238000003682 fluorination reaction Methods 0.000 description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229910020257 Cl2F2 Inorganic materials 0.000 description 1
- 229910020323 ClF3 Inorganic materials 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001804 chlorine Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000006692 trifluoromethylation reaction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C22/00—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom
- C07C22/02—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings
- C07C22/04—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings
- C07C22/08—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings containing fluorine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/24—Halogenated aromatic hydrocarbons with unsaturated side chains
- C07C25/28—Halogenated styrenes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/14—Acetic acid esters of monohydroxylic compounds
- C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
- C07C69/157—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/52—Radicals substituted by halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/12—Radicals substituted by halogen atoms or nitro or nitroso radicals
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention discloses an alpha-chloro difluoro methyl styrene derivative and a preparation method thereof. The preparation method of the alpha-chlorodifluoromethyl styrene derivative comprises the following steps of adding a 3, 3-difluoroallyl hydrazine derivative and a chloride salt into a solvent for reaction to obtain the alpha-chlorodifluoromethyl styrene derivative, wherein the structural formula of the alpha-chlorodifluoromethyl styrene derivative is shown as the formula (I). The preparation method adopts the 3, 3-difluoroallylhydrazine derivative as a raw material, and the alpha-chlorodifluoromethylstyrene derivative is obtained through the dehydrazide chlorination reaction mediated by chloride salt, so that the preparation method has wide substrate application range, simple process operation and mild conditions, and successfully prepares the alpha-chlorodifluoromethylstyrene derivative containing chloro-gem difluoromethylene structural unit and double bond structural unit, thereby providing a novel method for the preparation process of the alpha-chlorodifluoromethylstyrene derivative serving as a medicine modification synthesis process.
Description
Technical Field
The invention belongs to the technical fields of medical intermediates and organic synthesis, and in particular relates to an alpha-chlorodifluoromethyl styrene derivative and a preparation method thereof.
Background
In recent years, the importance of fluorinated compounds in agrochemicals, pharmaceuticals and materials science has led to an explosive growth of research efforts to develop new efficient methods for introducing fluorinated functional groups into organic molecules. Difluoromethylene groups are generally considered bioisosteres of oxygen or carbonyl groups, which result in increased dipole moment, increased acidity of adjacent groups, and conformational changes. The introduction of fluorinated substituents can significantly affect pKa, lipophilicity, permeability and/or metabolic stability of a cellular bioactive molecule, generally resulting in significant improvements in its pharmacological and/or pharmacokinetic properties. Alpha-chlorodifluoromethyl styrene is an important synthetic intermediate, and its unique convertibility provides opportunities for synthesizing various fluorinated molecules, and thus has been widely used.
Although considerable progress has been made in the present science in the fluorination, trifluoromethylation and difluoromethylation of organic substrates, so far, the synthetic strategies for α -chlorodifluoromethyl styrene derivatives have been explored very little. Although a small amount has been reported for the preparation of alpha-chlorodifluoromethyl derivatives, the use of expensive fluorination reagents, as well as harsh, strong base and ultra-low temperature conditions severely limits their wide synthetic applications. Therefore, the exploration of a preparation method for synthesizing a novel alpha-chlorodifluoromethyl styrene derivative by adopting cheap raw materials and mild process conditions is very important, and has great significance in the field of biological medicine and the field of organic synthesis.
Disclosure of Invention
The invention aims to provide an alpha-chlorodifluoromethyl styrene derivative and a preparation method thereof aiming at the defects of the prior art.
The preparation method of the alpha-chlorodifluoromethyl styrene derivative comprises the following steps of adding a3, 3-difluoroallyl hydrazine derivative and chloride salt into a solvent to react to obtain the alpha-chlorodifluoromethyl styrene derivative, wherein the structural formula of the alpha-chlorodifluoromethyl styrene derivative is shown as a formula (I):
In the formula (I), n is the number of H on the benzene ring substituted by a substituent R 1, n is a natural number of 1-5, when n=2-5, a plurality of hydrogens on the benzene ring are substituted by a plurality of substituents R 1, substituents on different substituted positions are the same or different groups, and R 1 is one of phenyl, methyl, tert-butyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, acetyl, benzodiazole, naphthyl and thienyl.
The preparation method adopts the 3, 3-difluoroallylhydrazine derivative as a raw material, and the alpha-chlorodifluoromethylstyrene derivative is obtained through the dehydrazide chlorination reaction mediated by chloride salt, and the preparation method has wide substrate application range, is simple in process operation, successfully prepares the alpha-chlorodifluoromethylstyrene derivative containing chloro-gem difluoromethylene structural unit and double bond structural unit, and provides a novel method for the preparation method in the process of synthesizing the alpha-chlorodifluoromethylstyrene derivative as a medicine modification.
As a preferred embodiment of the present invention, the structural formula of the 3, 3-difluoroallylhydrazine derivative is shown as formula (II):
in the formula (II), n is the number of H on the benzene ring substituted by a substituent R 1, n is a natural number of 1-5, when n=2-5, a plurality of hydrogens on the benzene ring are substituted by a plurality of substituents R 1, substituents on different substituted positions are the same or different groups, and R 1 is one of phenyl, methyl, tert-butyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, acetyl, benzodiazole, naphthyl and thienyl.
As a preferred embodiment of the present invention, the chloride salt is one of lithium chloride, zinc chloride, ferric chloride, cuprous chloride, cupric chloride, nickel chloride, potassium chloride, and sodium chloride.
As a preferred embodiment of the present invention, the solvent is one of methanol, ethanol, tetrahydrofuran, N-dimethylformamide, acetonitrile, 1, 4-dioxane, toluene, 1, 2-dichloroethane, and dimethylsulfoxide.
In a preferred embodiment of the present invention, the molar ratio of the 3, 3-difluoroallylhydrazine derivative, the chlorine salt and the solvent is 3, 3-difluoroallylhydrazine derivative/chlorine salt/solvent=1 (1-4): 10-100.
As a preferred embodiment of the present invention, the reaction temperature is 50-90 ℃ and the reaction time is 2-5 hours.
As a preferred embodiment of the invention, the preparation method of the alpha-chlorodifluoromethyl styrene derivative further comprises the steps of carrying out reduced pressure distillation on the reaction solution after the reaction of the 3, 3-difluoroallyl hydrazine derivative and the chloride salt in the solvent is finished to obtain a crude product, and then carrying out column chromatography to obtain the alpha-chlorodifluoromethyl styrene derivative.
As a preferred embodiment of the invention, the temperature of the reduced pressure distillation is 30-40 ℃, and the eluent of the column chromatography is a mixed solution or petroleum ether with the volume ratio of petroleum ether to ethyl acetate being 10:1.
The invention also claims the alpha-chlorodifluoromethyl styrene derivative prepared by the preparation method of the alpha-chlorodifluoromethyl styrene derivative.
The alpha-chlorodifluoromethyl styrene derivative prepared by the preparation method disclosed by the invention contains a chloro gem difluoromethylene structural unit and a double bond structural unit, can be used as a potential pharmaceutical lead compound or a pharmaceutical active molecule synthesis intermediate, and provides opportunities for synthesizing macromolecular drugs.
Compared with the prior art, the invention has the following beneficial effects that the 3, 3-difluoroallylhydrazine derivative is used as a raw material, and the alpha-chlorodifluoromethyl styrene derivative which has high yield, novel structure and difficult synthesis by the existing method and contains chloro-gem difluoromethylene and double bond structural units is successfully prepared by the dehydrazide chlorination reaction mediated by chloride, so that a novel method is provided for the process of modifying and synthesizing the alpha-chlorodifluoromethyl styrene derivative as a medicament. The preparation method has the advantages of wide substrate application range, simple process operation, mild preparation conditions, high product yield and high purity.
Detailed Description
For a better description of the objects, technical solutions and advantages of the present invention, the present invention will be further described with reference to the following specific examples.
Example 1
The synthesis of 4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) -1,1' -biphenyl described in this example comprises the steps of:
According to the molar ratio of 1- (2- ([ 1,1' -biphenyl ] -4-yl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester to cuprous chloride to acetonitrile=1:3:100, adding 0.4mmol of 1- (2- ([ 1,1' -biphenyl ] -4-yl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester, 1.2mmol of cuprous chloride and 40mmol of acetonitrile into a reactor, reacting for 2 hours at the temperature of 85 ℃, distilling under reduced pressure at 40 ℃ to remove the solvent to obtain a crude product, then using petroleum ether as eluent for column chromatography, wherein silica gel of column chromatography is 300 meshes, and 75mg of 4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) -1,1' -biphenyl is obtained, and the yield is 71%.
The reaction equation is as follows:
The nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(600MHz,CDCl3)δ7.74–7.65(m,4H),7.62(d,J＝7.8Hz,2H),7.52(t,J＝7.8Hz,2H),7.44(m,1H),6.00(s,1H),5.73(d,J＝1.2Hz,1H).13C NMR(151MHz,CDCl3)δ143.71(t,J＝23.8Hz),141.87,140.36,133.38,129.00,128.58,127.81,127.24,127.22,125.93(t,J＝291.2Hz),119.06(t,J＝7.0Hz).19F NMR(471MHz,CDCl3)δ-50.83(s,2F).HRMS(ESI):mass found:287.0411,calculated mass for C15H11ClF2Na+[M+Na+]:287.0410.
Example 2
The synthesis of 1- (3-chloro-3, 3-difluoroprop-1-en-2-yl) -4-methylbenzene described in this example comprises the steps of:
According to the mol ratio of 1- (3, 3-difluoro-2- (p-tolyl) allyl) hydrazine-1-carboxylic acid tert-butyl ester to lithium chloride to methyl alcohol=1:3:100, 0.4mmol of 1- (3, 3-difluoro-2- (p-tolyl) allyl) hydrazine-1-carboxylic acid tert-butyl ester, 1.2mmol of copper chloride and 40mmol of methyl alcohol are sequentially added into a reactor to react for 3 hours at the temperature of 75 ℃, the solvent is removed by reduced pressure distillation at the temperature of 40 ℃ to obtain a crude product, then petroleum ether is used as eluent to carry out column chromatography, silica gel of the column chromatography is 300 meshes, and 45mg of 1- (3-chloro-3, 3-difluoro-1-en-2-yl) -4-methylbenzene is obtained, and the yield is 56%.
The reaction equation is as follows:
The nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(600MHz,CDCl3)δ7.39(d,J＝7.8Hz,2H),7.21(d,J＝7.8Hz,2H),5.89(s,1H),5.60(t,J＝1.8Hz,1H),2.39(s,3H).13C NMR(151MHz,CDCl3)δ143.97(t,J＝23.6Hz),139.05,131.69,129.26,128.08,126.03(t,J＝291.2Hz),118.56(t,J＝7.0Hz),21.36.19F NMR(471MHz,CDCl3)δ-51.06(s,2F).HRMS(ESI):mass found:225.0252,calculated mass for C10H9ClF2Na+[M+Na+]:225.0253.
Example 3
The synthesis of 1- (tert-butyl) -4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) benzene described in this example comprises the steps of:
According to the mol ratio of 1- (2- (4- (tert-butyl) phenyl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester to copper chloride in the ratio of tetrahydrofuran=1:3:100, adding 0.4 mmole of 1- (2- (4- (tert-butyl) phenyl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester, 1.2 mmole of copper chloride and 40 mmole of tetrahydrofuran into a reactor, reacting for 4 hours at 65 ℃, distilling under reduced pressure at 40 ℃ to remove the solvent to obtain a crude product, then using petroleum ether as eluent to carry out column chromatography, wherein the silica gel of the column chromatography is 300 meshes, and the yield of 69mg of 1- (tert-butyl) -4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) benzene is 70%.
The reaction equation is as follows:
The nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(600MHz,CDCl3)δ7.44(d,J＝9.0Hz,2H),7.43–7.40(m,2H),5.89(s,1H),5.63(t,J＝1.8Hz,1H),1.36(s,9H).13C NMR(151MHz,CDCl3)δ152.14,143.90(t,J＝23.7Hz),131.54,127.83,126.03(t,J＝291.2Hz),125.51,118.56(t,J＝7.0Hz),34.78,31.37.19F NMR(471MHz,CDCl3)δ-50.91(s,2F).HRMS(ESI):mass found:245.0903,calculated mass for C13H15ClF2H+[M+H+]:245.0903.
Example 4
The synthesis of 1- (3-chloro-3, 3-difluoroprop-1-en-2-yl) -3-methylbenzene described in this example comprises the steps of:
According to the mol ratio of 1- (3, 3-difluoro-2- (m-tolyl) allyl) hydrazine-1-carboxylic acid tert-butyl ester to ferric chloride, wherein 1, 4-dioxane=1:3:100, 0.4mmol of 1- (3, 3-difluoro-2- (m-tolyl) allyl) hydrazine-1-carboxylic acid tert-butyl ester, 1.2mmol of ferric chloride and 40mmol of 1, 4-dioxane are sequentially added into a reactor to react for 2 hours at the temperature of 90 ℃, the solvent is removed by reduced pressure distillation at the temperature of 40 ℃ to obtain a crude product, petroleum ether is taken as eluent to carry out column chromatography, and silica gel of the column chromatography is 300 meshes to obtain 41mg of 1- (3-chloro-3, 3-difluoro-1-en-2-yl) -3-methylbenzene, wherein the yield is 51%.
The reaction equation is as follows:
the nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(500MHz,CDCl3)δ7.30(d,J＝4.5Hz,3H),7.23(d,J＝4.5Hz,1H),5.92(s,1H),5.61(s,1H),2.41(s,3H).13C NMR(126MHz,CDCl3)δ144.37(t,J＝23.7Hz),138.23,134.63,129.81,128.98,128.43,126.03(t,J＝291.1Hz),125.38,119.04(dd,J＝6.9,5.6Hz),21.57(d,J＝1.5Hz).19F NMR(471MHz,CDCl3)δ-50.94(s,2F).HRMS(ESI):mass found:225.0255,calculatedmass for C10H9ClF2Na+[M+Na+]:225.0253.
Example 5
The synthesis of 1- (3-chloro-3, 3-difluoroprop-1-en-2-yl) -4-methoxybenzene described in this example comprises the steps of:
According to the mol ratio of 1- (3, 3-difluoro-2- (4-methoxyphenyl) allyl) hydrazine-1-carboxylic acid tert-butyl ester to zinc chloride to toluene=1:3:100, 0.4mmol of 1- (3, 3-difluoro-2- (4-methoxyphenyl) allyl) hydrazine-1-carboxylic acid tert-butyl ester, 1.2mmol of zinc chloride and 40mmol of toluene are sequentially added into a reactor to react for 5 hours at 65 ℃, the solvent is removed by reduced pressure distillation at 40 ℃ to obtain a crude product, then the petroleum ether/ethyl acetate eluent is used for column chromatography, the silica gel of the column chromatography is 300 meshes, and 53mg of 1- (3-chloro-3, 3-difluoroprop-1-en-2-yl) -4-methoxybenzene is obtained, and the yield is 60%.
The reaction equation is as follows:
The nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(600MHz,CDCl3)δ7.42(d,J＝9.0Hz,2H),6.95–6.87(m,2H),5.85(s,1H),5.56(t,J＝1.8Hz,1H),3.84(s,3H).13C NMR(151MHz,CDCl3)δ160.16,143.53(t,J＝23.6Hz),129.47,126.89,126.09(t,J＝291.1Hz),117.97(t,J＝7.0Hz),113.90,55.41.19F NMR(471MHz,CDCl3)δ-51.07(s,2F).HRMS(ESI):mass found:219.0383,calculated mass for C10H9ClF2OH+[M+H+]:219.0383.
Example 6
The synthesis of 1- (3-chloro-3, 3-difluoroprop-1-en-2-yl) -4-fluorobenzene described in this example comprises the steps of:
Adding 0.4mmol of tert-butyl 1- (3, 3-difluoro-2- (4-fluorophenyl) allyl) hydrazine-1-carboxylate, 1.2mmol of potassium chloride and 40mmol of 1, 2-dichloroethane into a reactor according to the proportion of 1- (3, 3-difluoro-2- (4-fluorophenyl) allyl) hydrazine-1-carboxylate to 1, 2-dichloroethane of 1:1:3:100, reacting for 3 hours at 75 ℃, distilling under reduced pressure at 40 ℃ to remove the solvent to obtain a crude product, and carrying out column chromatography on silica gel with 300 meshes by petroleum ether leacheate, wherein the column chromatography is carried out to obtain 37mg of 1- (3-chloro-3, 3-difluoroprop-1-en-2-yl) -4-fluorobenzene, and the yield is 45%.
The reaction equation is as follows:
The nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(600MHz,CDCl3)δ7.46(dd,J＝8.4,5.4Hz,2H),7.16–7.01(m,2H),5.92(s,1H),5.59(d,J＝1.2Hz,1H).13C NMR(126MHz,CDCl3)δ163.26(d,J＝248.8Hz),143.26(t,J＝24.1Hz),130.67(d,J＝3.4Hz),130.22(d,J＝8.2Hz),125.81(t,J＝290.9Hz),119.36(t,J＝6.7Hz),115.60(d,J＝21.6Hz).19F NMR(471MHz,CDCl3)δ-51.53(s,2F),-112.50(dq,J＝8.6,5.3Hz,1F).HRMS(ESI):mass found:207.0183,calculated mass for C9H6ClF3H+[M+H+]:207.0183.
Example 7
The synthesis of 1-chloro-4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) benzene described in this example specifically comprises the following steps:
According to the mol ratio of 1- (2- (4-chlorophenyl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester to sodium chloride to N, N-dimethylformamide=1:3:100, 0.4mmol of 1- (2- (4-chlorophenyl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester, 1.2mmol of sodium chloride and 40mmol of N, N-dimethylformamide are sequentially added into a reactor to react for 4 hours at 80 ℃, the solvent is removed by reduced pressure distillation at 40 ℃ to obtain a crude product, then petroleum ether eluent is used for column chromatography, silica gel of column chromatography is 300 meshes, and 44mg of 1-chloro-4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) benzene is obtained, and the yield is 49%.
The reaction equation is as follows:
The nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(600MHz,CDCl3)δ7.41(d,J＝9.0Hz,2H),7.39–7.34(m,2H),5.94(t,J＝1.2Hz,1H),5.62(t,J＝1.8Hz,1H).13C NMR(151MHz,CDCl3)δ143.11(t,J＝24.2Hz),135.22,132.97,129.61,128.82,125.62(t,J＝291.0Hz),119.64(t,J＝6.9Hz).19FNMR(471MHz,CDCl3)δ-51.39(s,2F).HRMS(ESI):mass found:244.9707,calculated mass for C9H6Cl2F2Na+[M+Na+]:244.9707.
Example 8
The synthesis of 1-bromo-4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) benzene described in this example specifically comprises the steps of:
According to the mol ratio of 1- (2- (4-bromophenyl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester to cupric chloride, dimethyl sulfoxide=1:3:100, 0.4mmol of 1- (2- (4-bromophenyl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester, 1.2mmol of cupric chloride and 40mmol of dimethyl sulfoxide are sequentially added into a reactor to react for 3.5 hours at the temperature of 85 ℃, the solvent is removed by reduced pressure distillation at the temperature of 40 ℃ to obtain a crude product, then the crude product is subjected to column chromatography by petroleum ether eluent, and the silica gel of the column chromatography is 300 meshes, thus obtaining 49mg of 1-bromo-4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) benzene, and the yield is 46%.
The reaction equation is as follows:
the nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(600MHz,CDCl3)δ7.56–7.48(m,2H),7.35(d,J＝8.4Hz,2H),5.94(s,1H),5.62(t,J＝1.8Hz,1H).13C NMR(151MHz,CDCl3)δ143.16(t,J＝24.2Hz),133.44,131.78,129.88,125.55(t,J＝291.0Hz),123.47,119.66(t,J＝6.9Hz).19F NMR(471MHz,CDCl3)δ-51.39(s,2F).HRMS(ESI):mass found:288.9202,calculated mass for C9H6BrClF2Na+[M+Na+]:288.9202.
Example 9
The synthesis of 1- (3-chloro-3, 3-difluoroprop-1-en-2-yl) -4- (trifluoromethyl) benzene described in this example comprises the steps of:
According to the mol ratio of 1- (3, 3-difluoro-2- (4- (trifluoromethyl) phenyl) allyl) hydrazine-1-carboxylic acid tert-butyl ester to nickel chloride to acetonitrile=1:3:100, 0.4mmol of 1- (3, 3-difluoro-2- (4- (trifluoromethyl) phenyl) allyl) hydrazine-1-carboxylic acid tert-butyl ester, 1.2mmol of nickel chloride and 40mmol of acetonitrile are sequentially added into a reactor to react for 5 hours at 50 ℃,40 ℃ is reduced pressure distilled to remove the solvent, the crude product is obtained, then petroleum ether leacheate is used for column chromatography, silica gel of column chromatography is 300 meshes, and 49mg of 1- (3-chloro-3, 3-difluoro-1-en-2-yl) -4- (trifluoromethyl) benzene is obtained, and the yield is 48%.
The reaction equation is as follows:
The nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(600MHz,CDCl3)δ7.66(d,J＝8.4Hz,2H),7.60(d,J＝8.4Hz,2H),6.02(s,1H),5.68(t,J＝1.8Hz,1H).13C NMR(151MHz,CDCl3)δ143.16(t,J＝24.4Hz),138.10,131.16(q,J＝32.7Hz),128.73,125.58(q,J＝3.7Hz),125.45(t,J＝290.9Hz),124.04(q,J＝272.2Hz),120.67(t,J＝6.8Hz).19F NMR(85MHz,CDCl3)δ-133.99(s,3F),-145.48(s,2F).HRMS(ESI):mass found:257.0151,calculated mass for C10H6ClF5H+[M+H+]:257.0151.
Example 10
The synthesis of 1- (4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) phenyl) ethan-1-one described in this example comprises the steps of:
According to the mol ratio of 1- (2- (4-acetyl phenyl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester to zinc chloride to toluene=1:3:100, 0.4mmol of 1- (2- (4-acetyl phenyl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester, 1.2mmol of zinc chloride and 40mmol of toluene are sequentially added into a reactor to react for 4.5 hours at the temperature of 60 ℃, the solvent is removed by reduced pressure distillation at the temperature of 40 ℃ to obtain a crude product, then the crude product is subjected to column chromatography by petroleum ether/ethyl acetate 10:1 (volume ratio) leacheate, and silica gel of the column chromatography is 300 meshes to obtain 65mg of 1- (4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) phenyl) ethane-1-ketone, wherein the yield is 70%.
The reaction equation is as follows:
The nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(600MHz,CDCl3)δ8.02–7.92(m,2H),7.57(d,J＝8.4Hz,2H),6.00(s,1H),5.70(t,J＝1.8Hz,1H),2.62(s,3H).13C NMR(151MHz,CDCl3)δ197.63,143.28(t,J＝24.3Hz),138.98,137.25,128.53,128.44,125.45(t,J＝291.1Hz),120.47(t,J＝6.9Hz),26.82.19F NMR(471MHz,CDCl3)δ-51.12(s,2F).HRMS(ESI):mass found:231.0383,calculated mass for C11H9ClF2OH+[M+H+]:231.0383.
Example 11
The synthesis of 4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) benzonitrile in this example comprises the following steps:
According to the mol ratio of 1- (2- (4-cyanophenyl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester to copper chloride in the ratio of acetonitrile=1:3:100, 0.4mmol of 1- (2- (4-cyanophenyl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester, 1.2mmol of copper chloride and 40mmol of acetonitrile are sequentially added into a reactor to react for 2.5 hours at the temperature of 55 ℃, the solvent is removed by reduced pressure distillation at the temperature of 40 ℃ to obtain a crude product, then the crude product is subjected to column chromatography by petroleum ether/ethyl acetate eluent with the volume ratio of 10:1, and the silica gel of the column chromatography is 300 meshes, thus obtaining 40mg of 4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) benzonitrile with the yield of 47 percent.
The reaction equation is as follows:
The nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(600MHz,CDCl3)δ7.78–7.63(m,2H),7.59(d,J＝8.4Hz,2H),6.04(s,1H),5.71(t,J＝1.2Hz,1H).13C NMR(151MHz,CDCl3)δ142.74(t,J＝24.6Hz),138.91,132.37,128.94,125.15(t,J＝291.0Hz),121.25(t,J＝6.8Hz),118.43,112.94.19F NMR(85MHz,CDCl3)δ-145.72(s,2F).HRMS(ESI):mass found:214.0230,calculated mass for C10H6ClF2NH+[M+H+]:214.0230.
Example 12
The synthesis of 5- (3-chloro-3, 3-difluoroprop-1-en-2-yl) benzo [ d ] [1,3] dioxin described in this example comprises the following steps:
Adding 0.4mmol of 1- (2- (benzo [ d ] [1,3] dioxygen-5-yl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester, 1.2mmol of ferric chloride and 40mmol of 1, 4-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester into a reactor according to the mol ratio of 1- (2- (benzo [ d ] [1,3] dioxygen-5-yl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester to ferric chloride to be 1.4 mmol of ferric chloride in a ratio of 1, 4-dioxane to be 1:3:100, reacting for 3 hours at 80 ℃, distilling under reduced pressure at 40 ℃ to remove the solvent to obtain a crude product, and carrying out column chromatography on petroleum ether/ethyl acetate 10:1 (volume ratio) liquid to obtain 47mg of 5- (3-chloro-3, 3-difluoroprop-1-en-2-yl) benzo [ d ] [1,3] dioxin with the yield of 50%.
The reaction equation is as follows:
the nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(600MHz,CDCl3)δ7.02–6.90(m,2H),6.87–6.76(m,1H),6.00(s,2H),5.85(s,1H),5.55(t,J＝1.8Hz,1H).13C NMR(126MHz,CDCl3)δ148.30,147.76,143.65(t,J＝23.8Hz),128.40,125.94(t,J＝291.1Hz),122.39,118.67(t,J＝6.9Hz),108.73,108.36,101.51.19F NMR(471MHz,CDCl3)δ-51.16(s,2F).HRMS(ESI):mass found:254.9996,calculated mass for C10H7ClF2O2Na+[M+Na+]:254.9995.
Example 13
The synthesis of 2- (3-chloro-3, 3-difluoroprop-1-en-2-yl) naphthalene described in this example comprises the following steps:
according to the mol ratio of 1- (3, 3-difluoro-2- (naphthalene-2-yl) allyl) hydrazine-1-carboxylic acid tert-butyl ester to cupric chloride in the ratio of ethyl alcohol=1:3:100, 0.4mmol of 1- (3, 3-difluoro-2- (naphthalene-2-yl) allyl) hydrazine-1-carboxylic acid tert-butyl ester, 1.2mmol of cupric chloride and 40mmol of ethyl alcohol are added into a reactor in turn to react for 5 hours at 75 ℃, the solvent is removed by reduced pressure distillation at 40 ℃ to obtain a crude product, then the crude product is subjected to column chromatography by petroleum ether leacheate, the silica gel of the column chromatography is 300 meshes, and 62mg of 2- (3-chloro-3, 3-difluoro-1-en-2-yl) naphthalene is obtained, and the yield is 65%.
The reaction equation is as follows:
The nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(600MHz,CDCl3)δ8.00(s,1H),7.96–7.79(m,3H),7.60(d,J＝8.4Hz,1H),7.55(dq,J＝6.6,3.4Hz,2H),6.04(s,1H),5.76(s,1H).13C NMR(151MHz,CDCl3)δ144.10(t,J＝23.8Hz),133.32,133.06,131.89,128.54,128.23,127.81,127.76,126.92,126.69,126.01(t,J＝291.2Hz),125.64,119.54(t,J＝7.0Hz).19F NMR(471MHz,CDCl3)δ-50.71(s,2F).HRMS(ESI):mass found:261.0253,calculated mass for C13H9ClF2Na+[M+Na+]:261.0253.
Example 14
The synthesis of 3- (3-chloro-3, 3-difluoroprop-1-en-2-yl) thiophene in this example comprises the following steps:
According to the mol ratio of 1- (3, 3-difluoro-2- (thiophene-3-yl) allyl) hydrazine-1-carboxylic acid tert-butyl ester to lithium chloride to methyl alcohol=1:3:100, 0.4mmol of 1- (3, 3-difluoro-2- (thiophene-3-yl) allyl) hydrazine-1-carboxylic acid tert-butyl ester, 1.2mmol of lithium chloride and 40mmol of methyl alcohol are sequentially added into a reactor to react for 4 hours at the temperature of 70 ℃, the solvent is removed by reduced pressure distillation at the temperature of 40 ℃ to obtain a crude product, then a petroleum ether leacheate is used for carrying out column chromatography, silica gel with the size of 300 meshes is subjected to column chromatography, and 33mg of 3- (3-chloro-3, 3-difluoro-1-alkene-2-yl) thiophene is obtained, and the yield is 42%.
The reaction equation is as follows:
The nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(500MHz,CDCl3)δ7.48(d,J＝1.5Hz,1H),7.33(dd,J＝5.0,3.0Hz,1H),7.25(m,1H),5.82(s,1H),5.71(s,1H).13C NMR(126MHz,CDCl3)δ139.01(t,J＝24.7Hz),134.19,126.87,125.96,125.55(t,J＝290.8Hz),124.29(t,J＝2.1Hz),116.67(t,J＝7.1Hz).19F NMR(471MHz,CDCl3)δ-52.08(s,2F).HRMS(ESI):mass found:194.9841,calculated mass for C7H5ClF2SH+[M+H+]:194.9841.
Example 15
The synthesis of 4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) -1,1' -biphenyl described in this example comprises the steps of:
According to the molar ratio of 1- (2- ([ 1,1' -biphenyl ] -4-yl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester to cuprous chloride to acetonitrile=1:1:50, adding 0.4mmol of 1- (2- ([ 1,1' -biphenyl ] -4-yl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester, 0.4mmol of cuprous chloride and 20mmol of acetonitrile into a reactor, reacting for 2 hours at the temperature of 85 ℃, distilling under reduced pressure at 40 ℃ to remove the solvent to obtain a crude product, then using petroleum ether as eluent for column chromatography, wherein silica gel of column chromatography is 300 meshes, and 51mg of 4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) -1,1' -biphenyl is obtained, and the yield is 48%.
The reaction equation is as follows:
The nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(600MHz,CDCl3)δ7.74–7.65(m,4H),7.62(d,J＝7.8Hz,2H),7.52(t,J＝7.8Hz,2H),7.44(m,1H),6.00(s,1H),5.73(d,J＝1.2Hz,1H).13C NMR(151MHz,CDCl3)δ143.71(t,J＝23.8Hz),141.87,140.36,133.38,129.00,128.58,127.81,127.24,127.22,125.93(t,J＝291.2Hz),119.06(t,J＝7.0Hz).19F NMR(471MHz,CDCl3)δ-50.83(s,2F).HRMS(ESI):mass found:287.0411,calculated mass for C15H11ClF2Na+[M+Na+]:287.0410.
Example 16
The synthesis of 4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) -1,1' -biphenyl described in this example comprises the steps of:
According to the molar ratio of 1- (2- ([ 1,1' -biphenyl ] -4-yl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester to cuprous chloride to acetonitrile=1:4:10, adding 0.4mmol of 1- (2- ([ 1,1' -biphenyl ] -4-yl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester, 1.6mmol of cuprous chloride and 4mmol of acetonitrile into a reactor, reacting for 2 hours at the temperature of 85 ℃, distilling under reduced pressure at 40 ℃ to remove the solvent to obtain a crude product, then using petroleum ether as eluent for column chromatography, wherein silica gel of column chromatography is 300 meshes, and 56mg of 4- (3-chloro-3, 3-difluoroprop-1-en-2-yl) -1,1' -biphenyl is obtained, and the yield is 53%.
The reaction equation is as follows:
The nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum characterization data of the product are as follows ：1HNMR(600MHz,CDCl3)δ7.74–7.65(m,4H),7.62(d,J＝7.8Hz,2H),7.52(t,J＝7.8Hz,2H),7.44(m,1H),6.00(s,1H),5.73(d,J＝1.2Hz,1H).13C NMR(151MHz,CDCl3)δ143.71(t,J＝23.8Hz),141.87,140.36,133.38,129.00,128.58,127.81,127.24,127.22,125.93(t,J＝291.2Hz),119.06(t,J＝7.0Hz).19F NMR(471MHz,CDCl3)δ-50.83(s,2F).HRMS(ESI):mass found:287.0411,calculated mass for C15H11ClF2Na+[M+Na+]:287.0410.
Comparative example 1
The preparation of 4- (3, 3-difluoroprop-1-en-2-yl) -1,1' -biphenyl described in this example comprises the steps of:
According to the mol ratio of 1- (2- ([ 1,1 '-biphenyl ] -4-yl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester to zinc dichloride to N, N-diisopropylethylamine to 2-methyltetrahydrofuran=1:3:1:100, adding 0.4mmol of 1- (2- ([ 1,1' -biphenyl ] -4-yl) -3, 3-difluoroallyl) hydrazine-1-carboxylic acid tert-butyl ester, 1.2mmol of zinc dichloride, 0.4 mmole of N, N '-diisopropylethylamine and 40mmol of tetrahydrofuran into a reactor in turn, reacting for 2 hours at 60 ℃, carrying out reduced pressure distillation at 40 ℃ to remove the solvent to obtain a crude product, carrying out column chromatography by taking petroleum ether as eluent, wherein the silica gel of column chromatography is 200-300 meshes, and the yield is 30 percent, thus obtaining 32mg of 4- (3, 3-difluoroprop-1-en-2-yl) -1,1' -biphenyl.
The above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted without departing from the spirit and scope of the technical solution of the present invention.
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