CN113072493A - Novel synthesis method of 1-fluoromethyl-tetrahydroisoquinoline derivative - Google Patents
Novel synthesis method of 1-fluoromethyl-tetrahydroisoquinoline derivative Download PDFInfo
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- tetrahydroisoquinoline
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- DXXASTAWFOYKGR-UHFFFAOYSA-N 1-(fluoromethyl)-1,2,3,4-tetrahydroisoquinoline Chemical class C1=CC=C2C(CF)NCCC2=C1 DXXASTAWFOYKGR-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000001308 synthesis method Methods 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 239000002904 solvent Substances 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000007800 oxidant agent Substances 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 230000001590 oxidative effect Effects 0.000 claims abstract description 10
- 238000005859 coupling reaction Methods 0.000 claims abstract description 9
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 claims abstract description 9
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 8
- 230000008878 coupling Effects 0.000 claims abstract description 8
- 238000010168 coupling process Methods 0.000 claims abstract description 8
- 125000005605 benzo group Chemical group 0.000 claims abstract description 7
- AFZFSFXGGOJVCU-UHFFFAOYSA-N FC1S(CCS1(=O)=O)(=O)=O Chemical compound FC1S(CCS1(=O)=O)(=O)=O AFZFSFXGGOJVCU-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052751 metal Inorganic materials 0.000 claims abstract description 6
- 239000002184 metal Substances 0.000 claims abstract description 6
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- -1 di-tert-butyl peroxy ether Chemical compound 0.000 claims description 30
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- MJGFBOZCAJSGQW-UHFFFAOYSA-N mercury sodium Chemical compound [Na].[Hg] MJGFBOZCAJSGQW-UHFFFAOYSA-N 0.000 claims description 12
- 229910001023 sodium amalgam Inorganic materials 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 12
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 11
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical group Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- 229910000761 Aluminium amalgam Inorganic materials 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 229960003280 cupric chloride Drugs 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- UAWABSHMGXMCRK-UHFFFAOYSA-L samarium(ii) iodide Chemical compound I[Sm]I UAWABSHMGXMCRK-UHFFFAOYSA-L 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 238000006356 dehydrogenation reaction Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 18
- 239000003480 eluent Substances 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 18
- 238000000746 purification Methods 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 8
- 229940008718 metallic mercury Drugs 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- JYJLQWZDRMDUNW-UHFFFAOYSA-N 2-phenyl-3,4,4a,5-tetrahydro-1h-isoquinoline Chemical compound C1C2=CC=CCC2CCN1C1=CC=CC=C1 JYJLQWZDRMDUNW-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- IBXGVMBSWBGRRB-UHFFFAOYSA-N FCC1N(CCC2=CC=CC=C12)C1=CC2=CC=CC=C2C=C1 Chemical compound FCC1N(CCC2=CC=CC=C12)C1=CC2=CC=CC=C2C=C1 IBXGVMBSWBGRRB-UHFFFAOYSA-N 0.000 description 2
- CPDNOPPCPOJRJD-UHFFFAOYSA-N FCC1N(CCC2=CC=CC=C12)C1=CC=C(C=C1)OC Chemical compound FCC1N(CCC2=CC=CC=C12)C1=CC=C(C=C1)OC CPDNOPPCPOJRJD-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
- 229940079593 drug Drugs 0.000 description 2
- 238000005799 fluoromethylation reaction Methods 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QPILYVQSKNWRDD-UHFFFAOYSA-N 1-methyl-1,2,3,4-tetrahydroisoquinoline Chemical class C1=CC=C2C(C)NCCC2=C1 QPILYVQSKNWRDD-UHFFFAOYSA-N 0.000 description 1
- GNVXOIRECQQWBJ-UHFFFAOYSA-N 2-(4-methoxyphenyl)-3,4-dihydro-1h-isoquinoline Chemical compound C1=CC(OC)=CC=C1N1CC2=CC=CC=C2CC1 GNVXOIRECQQWBJ-UHFFFAOYSA-N 0.000 description 1
- JTNHLXYPLDFKAP-UHFFFAOYSA-N 2-naphthalen-2-yl-3,4-dihydro-1H-isoquinoline Chemical compound C1=CC=CC2=CC(=CC=C12)N1CC2=CC=CC=C2CC1 JTNHLXYPLDFKAP-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- TUZGMBZILYZZRU-UHFFFAOYSA-N [benzenesulfonyl(fluoro)methyl]sulfonylbenzene Chemical compound C=1C=CC=CC=1S(=O)(=O)C(F)S(=O)(=O)C1=CC=CC=C1 TUZGMBZILYZZRU-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000006326 desulfonation Effects 0.000 description 1
- 238000005869 desulfonation reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- ORPNPOLCSMQLNJ-UHFFFAOYSA-N n-(4-fluorophenyl)-2,2-dimethyl-3-methylidenebicyclo[2.2.1]heptane-4-carboxamide Chemical compound C=C1C(C)(C)C(C2)CCC21C(=O)NC1=CC=C(F)C=C1 ORPNPOLCSMQLNJ-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 238000007514 turning Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a novel method for synthesizing a 1-fluoromethyl-tetrahydroisoquinoline derivative. The method adopts tetrahydroisoquinoline derivatives as raw materials, and in the presence of a metal catalyst and an oxidant, the tetrahydroisoquinoline derivatives and benzo (2-fluoro-1, 3-dithiolane-1, 1, 3, 3-tetraoxide) react in a solvent to obtain a dehydrogenation coupling product, and then the dehydrogenation coupling product and a reducing agent undergo a desulfonyl reaction to obtain the 1-fluoromethyl-tetrahydroisoquinoline derivatives. The method has the advantages of simple operation, cheap and easily obtained catalyst and oxidant, high reaction yield and high practical value for the production of the 1-fluoromethyl-tetrahydroisoquinoline derivative.
Description
Technical Field
The invention relates to a new synthesis method of a 1-fluoromethyl-tetrahydroisoquinoline derivative, belonging to the field of fine chemical engineering and drug synthesis.
Background
The 1-methyl tetrahydroisoquinoline derivative has various biological activities and is widely applied to a large number of synthetic drugs. The 1-fluoromethyl-tetrahydroisoquinoline derivative obtained by substituting methyl with fluoromethyl can obviously improve the pharmacodynamic and pharmacokinetic properties of the compound under many conditions, and has high value for the research of new drugs (J.Med.chem.2011, 54, 2529-.
Although various fluoromethylation reactions and reagents (Angew. chem. int. Ed.2020, 59, 12268-12281) have been developed, few methods have been reported for introducing a fluoromethyl group directly at the α -position of a tertiary amine. In 2013, Hu et al developed a dehydrogenation coupling reaction of N-methyl tertiary amine and fluoro-bisphenylsulfonyl methane, and adopted azodicarboxylic acid ester as an oxidant, and the product was subjected to reductive desulfonation to obtain an alpha-fluoromethylamine product (New J.chem.2013, 37, 1684-1687), but the method is only suitable for fluoromethylation reaction on N-methyl and cannot be used for tertiary amines with other structures. Shibata et al reported the addition reaction of fluorobisphenylsulfone methane with an active imine followed by removal of the sulfone group to give α -fluoromethylamine (J.Am.chem.Soc.2007, 129, 6394-6395), but this method is only suitable for the synthesis of α -fluoromethylsylamine. Therefore, for tetrahydroisoquinoline derivatives, a method for introducing a fluoromethyl group at the 1-position is lacking at present, and the application of the compounds in the research and production of medicaments is limited.
Disclosure of Invention
The invention aims to provide a novel synthesis method of a 1-fluoromethyl-tetrahydroisoquinoline derivative. The method adopts tetrahydroisoquinoline derivatives as raw materials, and in the presence of a metal catalyst and an oxidant, the tetrahydroisoquinoline derivatives and benzo (2-fluoro-1, 3-dithiolane-1, 1, 3, 3-tetraoxide) react in a solvent to obtain a dehydrogenation coupling product, and then the dehydrogenation coupling product and a reducing agent undergo a desulfonyl reaction to obtain the 1-fluoromethyl-tetrahydroisoquinoline derivatives. The method has the advantages of simple operation, cheap and easily obtained catalyst and oxidant, high reaction yield and high practical value for preparing the 1-fluoromethyl-tetrahydroisoquinoline derivative.
The purpose of the invention is realized by the following technical scheme:
a method for synthesizing 1-fluoromethyl-tetrahydroisoquinoline derivatives represented by formula (I) is characterized in that tetrahydroisoquinoline derivatives represented by formula (II) are used as raw materials, and react with benzo (2-fluoro-1, 3-dithiolane-1, 1, 3, 3-tetraoxide) represented by formula (III) in a solvent in the presence of a metal catalyst and an oxidant to obtain coupling products represented by formula (IV), and then the coupling products undergo a desulfonyl reaction with a reducing agent to obtain 1-fluoromethyl-tetrahydroisoquinoline derivatives represented by formula (I); the metal catalyst is cuprous bromide, cuprous chloride, cupric bromide, cupric chloride and ferric chloride; the oxidant is di-tert-butyl peroxy ether, tert-butyl hydroperoxide and hydrogen peroxide; the solvent is acetonitrile, methanol, toluene, tetrahydrofuran and N, N-dimethylformamide; the reducing agent is magnesium, sodium amalgam, aluminum amalgam and samarium diiodide; the compounds with the structures of the formula (I), the formula (II), the formula (III) and the formula (IV) are as follows:
wherein:
r represents hydrogen, C1～C6Alkyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, cyano, acetyl, methoxycarbonyl, ethoxycarbonyl;
ar represents phenyl, naphthyl, pyridyl, pyrimidyl or substituted phenyl, and the substituent is C1～C6Alkyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, acetyl, methoxycarbonyl, ethoxycarbonyl.
Preferably, the catalyst is cuprous bromide.
Preferably, the oxidizing agent is tert-butyl hydroperoxide.
Preferably, the solvent is acetonitrile.
Preferably, the reducing agent is sodium amalgam.
Preferably, the molar ratio of the tetrahydroisoquinoline derivative shown in the formula (II) to the benzo (2-fluoro-1, 3-dithiolane-1, 1, 3, 3-tetraoxide) shown in the formula (III) is 1.2: 1.
The novel method for synthesizing the 1-fluoromethyl-tetrahydroisoquinoline derivative has the advantages of simple and convenient operation, cheap and easily obtained catalyst and oxidant, high reaction yield and the like, and has high practical value for synthesizing the 1-fluoromethyl-tetrahydroisoquinoline derivative.
Detailed Description
The present invention is further described below with reference to examples, but the embodiments of the present invention are not limited thereto.
Example 11 Synthesis of fluoromethyl-2-phenyl-1, 2, 3, 4-tetrahydroisoquinoline
A250 mL round bottom flask was charged with 2-phenyltetrahydroisoquinoline (2.51g, 0.012mol), benzo 2-fluoro-1, 3-dithiolane-1, 1, 3, 3-tetraoxide (2.36g, 0.01mol), cuprous bromide (0.22g, 0.0015mol), and anhydrous acetonitrile (100 mL). T-butyl hydroperoxide (2mL, 0.013mol, 6.5M n-hexane solution) was added at room temperature, and the reaction was stirred for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. Purification by column chromatography (eluent: petroleum ether/ethyl acetate 4: 1) gave intermediate IVa (4.16g, 94% yield). IVa was transferred to a 250mL round bottom flask, 6% by mass sodium amalgam (107.97g, 0.28mol net sodium content), anhydrous disodium hydrogen phosphate (39.75g, 0.28mol) was added, the flask was purged with nitrogen three times, anhydrous methanol (100mL) was added with ice-cooling, and the reaction was continued for 2 hours, then warmed to room temperature and reacted for 2 hours. After the reaction, the reaction suspension and metallic mercury were removed by suction filtration, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (eluent: petroleum ether) to give 1-fluoromethyl-2-phenyl-1, 2, 3, 4-tetrahydroisoquinoline (1.45g, yield 64%).
Nuclear magnetic hydrogen spectrum (400MHz, CDCl)3) δ 7.26(t, J ═ 7.9Hz, 2H), 7.21-7.13(m, 4H), 6.94(d, J ═ 8.3Hz, 2H), 6.78(t, J ═ 7.2Hz, 1H), 5.00-4.94(m, 1H), 4.68(ddd, J ═ 47.8, 9.4, 6.4Hz, 1H), 4.52(ddd, J ═ 47.3, 9.3, 6.1Hz, 1H), 3.66-3.49(m, 2H), 3.05-2.98(m, 1H), 2.89-2.80(m, 1H); nuclear magnetic carbon spectrum (101MHz, CDCl3) delta 149.52, 135.99, 133.89(d, J)C-C-C-F＝4.1Hz)，129.41，128.61，127.80，127.47，126.33，118.22，114.23，84.95(d，JC-F＝178.4Hz)，59.32(d，JC-C-F20.8Hz), 42.72, 27.82; high resolution mass spectrum HRMS (ESI) calculated for C16H17NF(M+H)+：242.1340，found：242.1328.
Example 21 Synthesis of fluoromethyl-2- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydroisoquinoline
Into a 250mL round bottom flask was added 2- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydroisoquinoline (2.87g, 0)012mol), benzo 2-fluoro-1, 3-dithiolane-1, 1, 3, 3-tetraoxide (2.36g, 0.01mol), cuprous bromide (0.22g, 0.0015mol), and anhydrous acetonitrile (100 mL). T-butyl hydroperoxide (2ml, 0.013mol, 6.5M n-hexane solution) was added thereto at room temperature, and the reaction was stirred for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. Purification by column chromatography (eluent: petroleum ether/ethyl acetate 4: 1) gave intermediate IVb (2.46g, 52% yield). IVb was transferred to a 250mL round bottom flask, 6% by mass sodium amalgam (61.33g, 0.16mol net sodium content), anhydrous disodium hydrogen phosphate (22.71g, 0.16mol) was added, the flask was purged with nitrogen three times, anhydrous methanol (55mL) was added with ice cooling, and the reaction was continued for 2 hours and then allowed to warm to room temperature for 2 hours. After the reaction, the reaction suspension and metallic mercury were removed by suction filtration, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (eluent: petroleum ether) to give 1-fluoromethyl-2- (4-methoxy-phenyl) -1, 2, 3, 4-tetrahydroisoquinoline (1.23g, yield 87%). Nuclear magnetic hydrogen spectrum (400MHz, CDCl)3) δ 7.25-7.13(m, 4H), 6.93(d, J ═ 8.9Hz, 2H), 6.84(d, J ═ 9.0Hz, 2H), 4.83(m, 1H), 4.76-4.60(m, 1H), 4.60-4.44(m, 1H), 3.75(s, 3H), 3.63-3.55(m, 1H), 3.53-3.45(m, 1H), 3.04-2.94(m, 1H), 2.79(m, J ═ 16.1, 4.6Hz, 1H); nuclear magnetic carbon spectrum (101MHz, CDCl)3)δ153.12，144.21，135.99，133.75(d，JC-C-C-F＝4.5Hz)，128.79，127.68，127.25，126.19，117.50，114.73，85.20(d，JC-F＝178.0Hz)，60.15(d，JC-C-F20.1Hz), 55.70, 43.79, 27.38; high resolution mass spectrum HRMS (ESI) calculated for C17H20FNO(M+H)+：272.1445，found：272.1443.
Example 31 Synthesis of fluoromethyl-2- (2-naphthyl) -1, 2, 3, 4-tetrahydroisoquinoline
Into a 250mL round bottom flask was added 2- (2-naphthyl) -1, 2, 3, 4-tetrahydroisoquinoline (3.11g, 0.012mol), benzo 2-fluoro-1, 3-dithioheterocyclePentane-1, 1, 3, 3-tetraoxide (2.36g, 0.01mol), cuprous bromide (0.22g, 0.0015mol), and anhydrous acetonitrile (100 mL). T-butyl hydroperoxide (2ml, 0.013mol, 6.5M n-hexane solution) was added thereto at room temperature, and the reaction was stirred for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. Purification by column chromatography (eluent: petroleum ether/ethyl acetate 4: 1) gave intermediate IVc (4.34g, 88% yield). IVc was transferred to a 250mL round bottom flask, 6% by mass sodium amalgam (99.67g, 0.26mol net sodium content), anhydrous disodium hydrogen phosphate (36.91g, 0.26mol) was added, the flask was purged with nitrogen three times, anhydrous methanol (100mL) was added with ice cooling, and the reaction was continued for 2 hours and then allowed to warm to room temperature for 2 hours. After the reaction, the reaction suspension and metallic mercury were removed by suction filtration, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (eluent: petroleum ether) to give 1-fluoromethyl-2- (2-naphthyl) -1, 2, 3, 4-tetrahydroisoquinoline (1.87g, yield 73%). Nuclear magnetic hydrogen spectrum (400MHz, CDCl)3) δ 7.74(d, J ═ 9.1Hz, 1H), 7.70(d, J ═ 8.1Hz, 1H), 7.66(d, J ═ 8.2Hz, 1H), 7.40-7.32(m, 2H), 7.28-7.16(m, 6H), 5.14(m, 1H), 4.76(ddd, J ═ 44.7, 8.0, 5.0Hz, 1H), 4.61(ddd, J ═ 15.0, 8.0, 4.2Hz, 1H.), 3.78-3.69(m, 2H), 3.14-3.05(m, 1H), 2.91(m, 1H); nuclear magnetic carbon spectrum (126MHz, CDCl)3)δ147.26，135.83，134.80，133.52(d，JC-C-C-F＝4.4Hz)，129.04，128.71，127.72，127.45，127.40，126.43，126.32，126.30，122.79，117.64，108.78，84.98(d，JC-F＝178.5Hz)，59.35(d，JC-C-F20.5Hz), 42.84, 27.66; high resolution mass spectrum HRMS (ESI) calculated for C20H19NF(M+H)+：292.1496，found：292.1488.
Example 41 Synthesis of fluoromethyl-2-phenyl-1, 2, 3, 4-tetrahydroisoquinoline
Into a 250mL round bottom flask was charged 2-phenyltetrahydroisoquinoline (2.51g, 0.012mol), benzo 2-fluoro-1, 3-dithiolane-1, 1, 3, 3-tetraoxide (2.36g, 0.01mol), cuprous chloride (0.15g, 0.0015mol), and anhydrous acetonitrile (100 mL). T-butyl hydroperoxide (2ml, 0.013mol, 6.5M n-hexane solution) was added thereto at room temperature, and the reaction was stirred for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. Purification by column chromatography (eluent: petroleum ether/ethyl acetate 4: 1) gave IVa (3.90g, 88% yield). IVa was transferred to a 250mL round bottom flask, 6% by mass sodium amalgam (99.67g, 0.26mol net sodium content), anhydrous disodium hydrogen phosphate (36.91g, 0.26mol) was added, the flask was purged with nitrogen three times, anhydrous methanol (100mL) was added with ice cooling, and the reaction was continued for 2 hours and then allowed to warm to room temperature for 2 hours. After the reaction, the reaction suspension and metallic mercury were removed by suction filtration, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (eluent: petroleum ether) to give 1-fluoromethyl-2-phenyl-1, 2, 3, 4-tetrahydroisoquinoline (1.32g, yield 62%).
Example 51 Synthesis of fluoromethyl-2-phenyl-1, 2, 3, 4-tetrahydroisoquinoline
Into a 250mL round bottom flask were charged 2-phenyltetrahydroisoquinoline (2.51g, 0.012mol), benzo 2-fluoro-1, 3-dithiolane-1, 1, 3, 3-tetraoxide (2.36g, 0.01mol), copper bromide (0.34g, 0.0015mol), and anhydrous acetonitrile (100 mL). T-butyl hydroperoxide (2ml, 0.013mol, 6.5M n-hexane solution) was added thereto at room temperature, and the reaction was stirred for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. Purification by column chromatography (eluent: petroleum ether/ethyl acetate 4: 1) gave IVa (3.72g, 84% yield). IVa was transferred to a 250mL round bottom flask, 6% by mass sodium amalgam (95.83g, 0.25mol net sodium content), anhydrous disodium hydrogen phosphate (35.49g, 0.25mol) was added, the flask was purged with nitrogen three times, anhydrous methanol (100mL) was added with ice-cooling, and the reaction was continued for 2 hours and then allowed to warm to room temperature for 2 hours. After the reaction, the reaction suspension and metallic mercury were removed by suction filtration, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (eluent: petroleum ether) to give 1-fluoromethyl-2-phenyl-1, 2, 3, 4-tetrahydroisoquinoline (1.30g, yield 64%).
Example 61 Synthesis of fluoromethyl-2-phenyl-1, 2, 3, 4-tetrahydroisoquinoline
A250 mL round bottom flask was charged with 2-phenyltetrahydroisoquinoline (2.51g, 0.012mol), benzo 2-fluoro-1, 3-dithiolane-1, 1, 3, 3-tetraoxide (2.36g, 0.01mol), cuprous bromide (0.22g, 0.0015mol), and anhydrous acetonitrile (100 mL). Di-tert-butylperoxyether (2.39ml, 0.013mol, 6.5M n-hexane solution) was added thereto at room temperature, and the reaction was stirred for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. Purification by column chromatography (eluent: petroleum ether/ethyl acetate 4: 1) gave IVa (3.94g, 89% yield). IVa was transferred to a 250mL round bottom flask, 6% by mass sodium amalgam (103.50g, 0.27mol net sodium content), anhydrous disodium hydrogen phosphate (38.33g, 0.27mol) was added, the flask was purged with nitrogen three times, anhydrous methanol (100mL) was added with ice cooling, and the reaction was continued for 2 hours and then allowed to warm to room temperature for 2 hours. After the reaction, the reaction suspension and metallic mercury were removed by suction filtration, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (eluent: petroleum ether) to give 1-fluoromethyl-2-phenyl-1, 2, 3, 4-tetrahydroisoquinoline (1.35g, yield 63%).
Example 71 Synthesis of fluoromethyl-2-phenyl-1, 2, 3, 4-tetrahydroisoquinoline
Into a 250mL round bottom flask was charged 2-phenyltetrahydroisoquinoline (2.51g, 0.012mol), benzo 2-fluoro-1, 3-dithiolane-1, 1, 3, 3-tetraoxide (2.36g, 0.01mol), cuprous bromide (0.22g, 0.0015mol), and anhydrous methanol (100 mL). T-butyl hydroperoxide (2ml, 0.013mol, 6.5M n-hexane solution) was added thereto at room temperature, and the reaction was stirred for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. Purification by column chromatography (eluent: petroleum ether/ethyl acetate 4: 1) gave IVa (3.54g, 80% yield). IVa was transferred to a 250mL round bottom flask, added with 6% mass fraction of sodium amalgam (92.00g, 0.24mol net sodium content), anhydrous disodium hydrogen phosphate (34.07g, 0.24mol), the flask was purged with nitrogen three times, added with anhydrous methanol (100mL) with ice-bath cooling, and allowed to react for 2 hours, then warmed to room temperature for 2 hours. After the reaction, the reaction suspension and metallic mercury were removed by suction filtration, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (eluent: petroleum ether) to give 1-fluoromethyl-2-phenyl-1, 2, 3, 4-tetrahydroisoquinoline (1.21g, yield 63%).
Example 81 Synthesis of fluoromethyl-2-phenyl-1, 2, 3, 4-tetrahydroisoquinoline
Into a 250mL round bottom flask was charged 2-phenyltetrahydroisoquinoline (2.51g, 0.012mol), benzo 2-fluoro-1, 3-dithiolane-1, 1, 3, 3-tetraoxide (2.36g, 0.01mol), cuprous bromide (0.22g, 0.0015mol), and anhydrous toluene (100 mL). T-butyl hydroperoxide (2ml, 0.013mol, 6.5M n-hexane solution) was added thereto at room temperature, and the reaction was stirred for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. Purification by column chromatography (eluent: petroleum ether/ethyl acetate 4: 1) gave IVa (3.23g, 73% yield). IVa was transferred to a 250mL round bottom flask, added with 6% mass fraction of sodium amalgam (83.33g, 0.22mol net sodium content), anhydrous disodium hydrogen phosphate (31.23g, 0.22mol), the flask was purged with nitrogen three times, added with anhydrous methanol (100mL) with ice-bath cooling and allowed to react for 2 hours, then warmed to room temperature for 2 hours. After the reaction, the reaction suspension and metallic mercury were removed by suction filtration, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (eluent: petroleum ether) to give 1-fluoromethyl-2-phenyl-1, 2, 3, 4-tetrahydroisoquinoline (1.13g, yield 64%).
Example 91 Synthesis of fluoromethyl-2-phenyl-1, 2, 3, 4-tetrahydroisoquinoline
A250 mL round bottom flask was charged with 2-phenyltetrahydroisoquinoline (2.51g, 0.012mol), benzo 2-fluoro-1, 3-dithiolane-1, 1, 3, 3-tetraoxide (2.36g, 0.01mol), cuprous bromide (0.22g, 0.0015mol), and anhydrous acetonitrile (100 mL). T-butyl hydroperoxide (2ml, 0.013mol, 6.5M n-hexane solution) was added thereto at room temperature, and the reaction was stirred for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. Purification by column chromatography (eluent: petroleum ether/ethyl acetate 4: 1) gave IVa (4.16g, 94% yield). IVa was transferred to a 100mL round bottom flask, magnesium metal turnings (6.85g, 0.28mol) were added, the flask was purged with nitrogen three times, at which time anhydrous methanol (50mL) was added, and the temperature was raised to 50 ℃ for 2 hours. After the reaction, added water (50ml) and ethyl acetate (50ml x 2) extraction, combined extract with saturated salt water washing, anhydrous sodium sulfate drying, decompression to remove solvent, residue by column chromatography purification (eluent: petroleum ether), 1-fluoromethyl-2-phenyl-1, 2, 3, 4-four hydrogen isoquinoline (0.75g, yield 33%).
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (6)
1. A method for synthesizing 1-fluoromethyl-tetrahydroisoquinoline derivatives represented by formula (I) is characterized in that tetrahydroisoquinoline derivatives represented by formula (II) are used as raw materials, and react with benzo (2-fluoro-1, 3-dithiolane-1, 1, 3, 3-tetraoxide) represented by formula (III) in a solvent in the presence of a metal catalyst and an oxidant to obtain coupling products represented by formula (IV), and then the coupling products undergo a desulfonyl reaction with a reducing agent to obtain 1-fluoromethyl-tetrahydroisoquinoline derivatives represented by formula (I); the metal catalyst is cuprous bromide, cuprous chloride, cupric bromide, cupric chloride and ferric chloride; the oxidant is di-tert-butyl peroxy ether, tert-butyl hydroperoxide and hydrogen peroxide; the solvent is acetonitrile, methanol, toluene, tetrahydrofuran and N, N-dimethylformamide; the reducing agent is magnesium, sodium amalgam, aluminum amalgam and samarium diiodide; the structures of the compounds of formula (I), formula (II), formula (III) and formula (IV) are as follows:
wherein:
r represents hydrogen, C1～C6Alkyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, cyano, acetyl, methoxycarbonyl, ethoxycarbonyl;
ar represents phenyl, naphthyl, pyridyl, pyrimidyl or substituted phenyl, and the substituent is C1～C6Alkyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, acetyl, methoxycarbonyl, ethoxycarbonyl.
2. The synthesis method according to claim 1, wherein the catalyst is cuprous bromide.
3. The method of claim 1, wherein the oxidizing agent is t-butyl hydroperoxide.
4. The method of claim 1, wherein the solvent is acetonitrile.
5. The method of synthesis of claim 1, wherein the reducing agent is sodium amalgam.
6. The synthesis method according to claim 1, wherein the molar ratio of the tetrahydroisoquinoline derivative represented by the formula (II) to the benzo (2-fluoro-1, 3-dithiolane-1, 1, 3, 3-tetraoxide) represented by the formula (III) is 0.5: 1 to 2: 1, preferably 1.2: 1.
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