CN113292493A - Preparation method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline - Google Patents
Preparation method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline Download PDFInfo
- Publication number
- CN113292493A CN113292493A CN202110701495.0A CN202110701495A CN113292493A CN 113292493 A CN113292493 A CN 113292493A CN 202110701495 A CN202110701495 A CN 202110701495A CN 113292493 A CN113292493 A CN 113292493A
- Authority
- CN
- China
- Prior art keywords
- dichloro
- reducing agent
- gas
- tetrahydroisoquinoline
- dihydroisoquinoline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- QCSLOZFEMQTPJA-UHFFFAOYSA-N 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline Chemical compound C1CNCC2=CC(Cl)=CC(Cl)=C21 QCSLOZFEMQTPJA-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 68
- QCECTJBUZDVDFR-UHFFFAOYSA-N ClC1=CC(Cl)=C(CCN=C2)C2=C1 Chemical compound ClC1=CC(Cl)=C(CCN=C2)C2=C1 QCECTJBUZDVDFR-UHFFFAOYSA-N 0.000 claims abstract description 51
- VHJKDOLGYMULOP-UHFFFAOYSA-N 2-(2,4-dichlorophenyl)ethanamine Chemical compound NCCC1=CC=C(Cl)C=C1Cl VHJKDOLGYMULOP-UHFFFAOYSA-N 0.000 claims abstract description 41
- PDZMYPGQGYYDNK-UHFFFAOYSA-N n-[2-(2,4-dichlorophenyl)ethyl]formamide Chemical compound ClC1=CC=C(CCNC=O)C(Cl)=C1 PDZMYPGQGYYDNK-UHFFFAOYSA-N 0.000 claims abstract description 40
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 35
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 25
- 238000006482 condensation reaction Methods 0.000 claims abstract description 22
- 230000001603 reducing effect Effects 0.000 claims abstract description 19
- PWKJMPFEQOHBAC-UHFFFAOYSA-N 4-Ethyloctanoic acid Chemical compound CCCCC(CC)CCC(O)=O PWKJMPFEQOHBAC-UHFFFAOYSA-N 0.000 claims abstract description 14
- 235000019253 formic acid Nutrition 0.000 claims abstract description 13
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000004675 formic acid derivatives Chemical class 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 35
- 230000008569 process Effects 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 27
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 26
- VJARIBGMDPJLCL-UHFFFAOYSA-N 2-(2,4-dichlorophenyl)acetonitrile Chemical compound ClC1=CC=C(CC#N)C(Cl)=C1 VJARIBGMDPJLCL-UHFFFAOYSA-N 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 239000002841 Lewis acid Substances 0.000 claims description 17
- 150000007517 lewis acids Chemical class 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000012279 sodium borohydride Substances 0.000 claims description 16
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims description 15
- 230000002829 reductive effect Effects 0.000 claims description 15
- 230000009467 reduction Effects 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- 229910000085 borane Inorganic materials 0.000 claims description 13
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 13
- 239000012448 Lithium borohydride Substances 0.000 claims description 12
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 12
- 229910052700 potassium Inorganic materials 0.000 claims description 12
- 239000011591 potassium Substances 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 239000007868 Raney catalyst Substances 0.000 claims description 8
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 8
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 230000018044 dehydration Effects 0.000 claims description 8
- 238000006297 dehydration reaction Methods 0.000 claims description 8
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 8
- 150000007522 mineralic acids Chemical class 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 4
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- NCPHGZWGGANCAY-UHFFFAOYSA-N methane;ruthenium Chemical compound C.[Ru] NCPHGZWGGANCAY-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 238000011946 reduction process Methods 0.000 claims description 4
- RMOUBSOVHSONPZ-UHFFFAOYSA-N Isopropyl formate Chemical compound CC(C)OC=O RMOUBSOVHSONPZ-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- DIQMPQMYFZXDAX-UHFFFAOYSA-N Pentyl formate Chemical compound CCCCCOC=O DIQMPQMYFZXDAX-UHFFFAOYSA-N 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims 20
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 description 63
- 238000006243 chemical reaction Methods 0.000 description 44
- 238000004128 high performance liquid chromatography Methods 0.000 description 25
- 238000006722 reduction reaction Methods 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000000605 extraction Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000012263 liquid product Substances 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000011261 inert gas Substances 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 229910052987 metal hydride Inorganic materials 0.000 description 5
- 150000004681 metal hydrides Chemical class 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 238000005265 energy consumption Methods 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000003912 environmental pollution Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229920000137 polyphosphoric acid Polymers 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- IOEPOEDBBPRAEI-UHFFFAOYSA-N 1,2-dihydroisoquinoline Chemical compound C1=CC=C2CNC=CC2=C1 IOEPOEDBBPRAEI-UHFFFAOYSA-N 0.000 description 2
- CASRSOJWLARCRX-UHFFFAOYSA-N 3,5-dichlorobenzaldehyde Chemical compound ClC1=CC(Cl)=CC(C=O)=C1 CASRSOJWLARCRX-UHFFFAOYSA-N 0.000 description 2
- 238000006407 Bischler-Napieralski reaction Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical class NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-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
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 230000005732 intercellular adhesion Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- VPKAHUMPZYVNIV-UHFFFAOYSA-N 1,4-dihydroisoquinoline Chemical compound C1=CC=C2CC=NCC2=C1 VPKAHUMPZYVNIV-UHFFFAOYSA-N 0.000 description 1
- HJKLEAOXCZIMPI-UHFFFAOYSA-N 2,2-diethoxyethanamine Chemical compound CCOC(CN)OCC HJKLEAOXCZIMPI-UHFFFAOYSA-N 0.000 description 1
- YSFBEAASFUWWHU-UHFFFAOYSA-N 2,4-dichlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C(Cl)=C1 YSFBEAASFUWWHU-UHFFFAOYSA-N 0.000 description 1
- ONRREFWJTRBDRA-UHFFFAOYSA-N 2-chloroethanamine;hydron;chloride Chemical compound [Cl-].[NH3+]CCCl ONRREFWJTRBDRA-UHFFFAOYSA-N 0.000 description 1
- 102000015271 Intercellular Adhesion Molecule-1 Human genes 0.000 description 1
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000003948 formamides Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 229960005381 lifitegrast Drugs 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a preparation method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline, which comprises the following steps: reducing the 2, 4-dichlorobenzyl cyanide by a first reducing agent to generate 2, 4-dichlorophenethylamine; carrying out condensation reaction on the 2, 4-dichlorophenethylamine and formic acid compounds to prepare N- (2, 4-dichlorophenethyl) formamide, wherein the formic acid compounds comprise formic acid and/or formate compounds; subjecting said N- (2, 4-dichlorophenethyl) carboxamide to a cyclization reaction to produce 5, 7-dichloro-3, 4-dihydroisoquinoline; reducing the 5, 7-dichloro-3, 4-dihydroisoquinoline by a second reducing agent to produce the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline. The invention can obviously improve the preparation efficiency of the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline and has the advantages of low cost and the like.
Description
Technical Field
The invention relates to a preparation method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline, belonging to the field of pharmaceutical chemical synthesis.
Background
5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline is widely applied, for example, it can be used as intermediate or raw material for synthesizing medicine, take ritystast (Lifitegrast) as an example, its structural formula is shown in formula A below, ritystast is a new inhibitor of intercellular adhesion factor, can act by blocking the combination between intercellular adhesion factor (ICAM-1) and integrin protein lymphocyte function-related antigen (LFA-1), mainly used for the treatment of Dry Eye Disease (DED) symptoms and signs, and 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline is an important intermediate for synthesizing ritystast.
At present, the preparation process of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline generally has the defects of high cost, low yield and the like, and is not beneficial to industrial growth. For example, patent document WO2014018748a1 discloses a synthetic route shown in the following reaction formula 1, wherein 3, 5-dichlorobenzaldehyde is used as a raw material, and is reacted with 2-chloroethylamine hydrochloride for reductive amination, and then the reaction is melted at 185 ℃ for cyclization to obtain a target compound, the raw material used in the process is expensive, the production cost is high, the cyclization reaction under high temperature conditions is harsh on equipment, and the problems of low yield, large amount of three wastes, heavy environmental pollution and the like exist; CN111057003a1 discloses a synthetic route shown in the following reaction formula 2, which takes 2, 4-dichlorobenzaldehyde as an initial raw material, and obtains a target compound through the processes of elimination by nitryl-alcohol condensation, reduction, amino protection, cyclization, deprotection and the like, the process route is long, the yield is low, nitromethane condensation is used at a high temperature of 140 ℃, the potential safety hazard is large, lithium aluminum hydride is used for reducing double bonds and nitro groups, the post-treatment is complicated, a large amount of acid reagents such as sulfuric acid, nitric acid and the like are required in the cyclization process, a large amount of three wastes are easily generated, and the environmental pollution is serious; the document "Journal of Medicinal Chemistry,1980, vol.23(5), p.506-511" discloses a synthetic route shown in the following reaction formula 3, wherein 3, 5-dichlorobenzaldehyde is used as a raw material, and is condensed with 2, 2-diethoxyethylamine, and then the condensation is sequentially carried out, and the target compound is obtained by catalytic hydrogenation reduction under the condition of platinum dioxide.
Therefore, optimizing the preparation process of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline, reducing the cost and improving the preparation efficiency still remains a technical problem to be solved by those skilled in the art.
Disclosure of Invention
The invention provides a preparation method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline, which can obviously improve the preparation efficiency of the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline, has the advantages of low cost and the like, and can effectively overcome the defects in the prior art.
The invention provides a preparation method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline, which comprises the following steps: reducing the 2, 4-dichlorobenzyl cyanide by a first reducing agent to generate 2, 4-dichlorophenethylamine; carrying out condensation reaction on the 2, 4-dichlorophenethylamine and formic acid compounds to prepare N- (2, 4-dichlorophenethyl) formamide, wherein the formic acid compounds comprise formic acid and/or formate compounds; subjecting said N- (2, 4-dichlorophenethyl) carboxamide to a cyclization reaction to produce 5, 7-dichloro-3, 4-dihydroisoquinoline; reducing the 5, 7-dichloro-3, 4-dihydroisoquinoline by a second reducing agent to produce the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline.
According to an embodiment of the present invention, the first reducing agent includes at least one of hydrogen, sodium borohydride, potassium borohydride, lithium borohydride, borane, and lithium aluminum hydride; and/or the 2, 4-dichlorobenzyl cyanide is reduced by a first reducing agent in a first solvent, wherein the first solvent comprises at least one of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran and water; and/or the reduction process of the 2, 4-dichlorobenzyl cyanide by the first reducing agent is carried out under the catalysis of a first catalyst, and the first catalyst comprises at least one of palladium carbon, ruthenium carbon, platinum carbon, raney nickel and Lewis acid.
According to one embodiment of the present invention, the mass ratio of the 2, 4-dichlorophenylacetonitrile to the first catalyst is 1: (0.01 to 1.0); and/or the first reducing agent comprises hydrogen, and the pressure of the hydrogen is maintained to be 0.1-1.0 MPa in the process of reducing the 2, 4-dichlorobenzyl cyanide by the first reducing agent.
According to one embodiment of the present invention, the temperature of the 2, 4-dichlorophenylacetonitrile is-50 to 100 ℃ during the reduction process by the first reducing agent.
According to one embodiment of the invention, the molar ratio of the 2, 4-dichlorophenethylamine to the formic acid compound is 1: (1.0-3.0); and/or, the condensation reaction is carried out in the presence of a base, and the molar ratio of the 2, 4-dichlorophenethylamine to the base is 1: (0.1 to 1.0); and/or the formate compound comprises at least one of methyl formate, ethyl formate, amyl formate and isopropyl formate; and/or the temperature of the condensation reaction is-50 to 100 ℃.
According to an embodiment of the present invention, the cyclization reaction process comprises: mixing N- (2, 4-dichlorophenethyl) formamide, a dehydration reagent, a second solvent and Lewis acid, reacting at-50-100 ℃, and then adding inorganic acid into the mixture to prepare the 5, 7-dichloro-3, 4-dihydroisoquinoline.
According to an embodiment of the present invention, the second solvent includes at least one of dichloromethane, 1, 2-dichloroethane, chloroform, benzene, toluene, ethylbenzene, xylene, chlorobenzene; and/or the dehydration reagent comprises at least one of phosphorus pentachloride, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, PPA, concentrated sulfuric acid, phosphoric acid and methanesulfonic acid; and/or the Lewis acid comprises at least one of ferric chloride, aluminum chloride and zinc chloride; and/or the molar ratio of the N- (2, 4-dichlorophenethyl) formamide to the dehydrating reagent is 1: (1.0-5.0); and/or the molar ratio of the N- (2, 4-dichlorophenethyl) formamide to the Lewis acid is 1: (1.0-5.0).
According to an embodiment of the present invention, the second reducing agent includes at least one of hydrogen, sodium borohydride, potassium borohydride, lithium aluminum hydride, lithium borohydride, and borane; and/or, the 5, 7-dichloro-3, 4-dihydroisoquinoline is reduced by a second reducing agent in a third solvent, and the third solvent comprises at least one of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran and water.
According to an embodiment of the present invention, the second reducing agent includes at least one of sodium borohydride, potassium borohydride, lithium aluminum hydride, lithium borohydride and borane, and the molar ratio of the 5, 7-dichloro-3, 4-dihydroisoquinoline to the second reducing agent is 1: (1.0-5.0); or, the second reducing agent comprises hydrogen, and the pressure of the hydrogen is maintained to be 0.1-1.0 MPa in the process of reducing the 5, 7-dichloro-3, 4-dihydroisoquinoline by the second reducing agent.
According to one embodiment of the present invention, the temperature of the 5, 7-dichloro-3, 4-dihydroisoquinoline during the reduction process by the second reducing agent is-50 to 100 ℃.
In the invention, 2, 4-dichlorobenzyl cyanide is used as a raw material and is reduced into 2, 4-dichlorophenethylamine, then the dihydroisoquinoline product (namely 5, 7-dichloro-3, 4-dihydroisoquinoline) is prepared through condensation and cyclization (cyclization), and the dihydroisoquinoline is reduced into 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline, and the raw material used in the process is cheap and easy to obtain, has low cost, high yield and purity and high atom economic utilization rate, and better conforms to the green concept of the production process; in addition, the invention prepares the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline by the route, also has the advantages of short route, simple operation, mild reaction condition, no rigor to equipment, safety, less three wastes, small environmental pollution and the like, and has important significance for practical industrial production.
Drawings
FIG. 1 shows the NMR spectra of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline product in one embodiment of the invention (1H-NMR) chart.
Detailed Description
The present invention is described in further detail below in order to enable those skilled in the art to better understand the aspects of the present invention. The following detailed description is merely illustrative of the principles and features of the present invention, and the examples are intended to be illustrative of the invention and not limiting of the scope of the invention. All other embodiments obtained by a person of ordinary skill in the art based on the embodiments of the present invention without any creative effort belong to the protection scope of the present invention.
The preparation method of the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline provided by the invention comprises the following steps: reducing 2, 4-dichlorophenylacetonitrile (formula II) by a first reducing agent to generate 2, 4-dichlorophenethylamine (formula III); carrying out condensation reaction on 2, 4-dichlorophenethylamine and formic acid compounds to prepare N- (2, 4-dichlorophenethyl) formamide (formula IV), wherein the formic acid compounds comprise formic acid and/or formic ester compounds; cyclizing N- (2, 4-dichlorophenethyl) formamide to generate 5, 7-dichloro-3, 4-dihydroisoquinoline (formula V); reducing the 5, 7-dichloro-3, 4-dihydroisoquinoline by a second reducing agent to generate the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline (formula I). The reaction process is schematically shown as follows:
in the above preparation process, the first reducing agent is used to reduce 2, 4-dichlorobenzyl cyanide into 2, 4-dichlorophenethylamine, which may include at least one of hydrogen gas, borane, metal hydride with reducing property, for example, lithium aluminum hydride, and metal borohydride with reducing property, for example, alkali metal borohydride, such as sodium borohydride, potassium borohydride, lithium borohydride, and the like. In some embodiments, the first reducing agent may specifically include at least one of hydrogen, sodium borohydride, potassium borohydride, lithium borohydride, borane, and lithium aluminum hydride.
To further improve the reduction efficiency of 2, 4-dichlorophenylacetonitrile, in some embodiments, the reduction of 2, 4-dichlorophenylacetonitrile by the first reducing agent may be performed under the catalysis of a first catalyst, and even if the reduction of 2, 4-dichlorophenylacetonitrile by the first reducing agent is performed under the catalysis of the first catalyst, the first catalyst may include at least one of palladium carbon, ruthenium carbon, platinum carbon, Raney nickel (Raney-Ni), and lewis acid.
In general, the mass ratio of 2, 4-dichlorophenylacetonitrile to the first catalyst may be 1: (0.01 to 1.0), for example, 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1 or a range consisting of any two of them.
When the first reducing agent comprises a metal hydride and/or a metal borohydride, the molar ratio to 2, 4-dichlorophenylacetonitrile is generally not less than 5:1, the first catalyst used generally comprises a lewis acid, and the yield of 2, 4-dichlorophenethylamine is not less than 40%, for example, 40% to 70% can be achieved.
In contrast, when the first reducing agent comprises hydrogen, the yield and the purity of the 2, 4-dichlorophenethylamine can be improved more remarkably, the yield of the 2, 4-dichlorophenethylamine is basically close to 100%, and the purity is more than 96%, so that the subsequent processes of condensation reaction, cyclization reaction, reduction and the like are facilitated, and the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline product with high yield and purity is obtained. Meanwhile, when the first reducing agent comprises hydrogen, the first catalyst is preferably at least one of palladium carbon, ruthenium carbon, platinum carbon and raney nickel, and compared with lewis acid, the catalyst is more beneficial to post-treatment such as purification of 2, 4-dichlorophenethylamine, and is not easy to generate a large amount of wastewater, and has the advantages of higher yield of target products, simpler and more convenient operation, higher safety and environmental protection, and the like.
Further, when the first reducing agent comprises hydrogen, it is more preferable that the first catalyst comprises palladium on carbon and/or raney nickel. In contrast, the use of raney nickel is beneficial to further cost saving and can achieve excellent yield and purity of the target product.
In some preferred embodiments, the first reducing agent comprises hydrogen, and the pressure of the hydrogen is maintained at 0.1 to 1.0MPa, such as 0.1MPa, 0.2MPa, 0.3MPa, 0.4MPa, 0.5MPa, 0.6MPa, 0.7MPa, 0.8MPa, 0.9MPa, 1.0MPa or any combination thereof during the reduction of the 2, 4-dichlorophenylacetonitrile by the first reducing agent, and generally preferably 0.2 to 0.3 MPa.
In the above preparation process, the reduction of 2, 4-dichlorophenylacetonitrile by the first reducing agent may be specifically performed in the first solvent, and the first solvent may include water and/or an organic solvent, the organic solvent may include at least one of an alcohol solvent, an ester solvent, a furan-based solvent, and the like, the alcohol solvent may include at least one of monohydric alcohols of C1 to C3, such as methanol, ethanol, and isopropanol, the ester solvent may include ethyl acetate, and the furan-based solvent may include tetrahydrofuran, and the like. In some embodiments, the first solvent may comprise at least one of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, and water, and generally more preferably comprises methanol in consideration of cost and reduction efficiency.
Further, the reduction of 2, 4-dichlorophenylacetonitrile by the first reducing agent may be performed in an alkaline system, for example, in a mixed system formed by an alkaline substance and the first solvent, wherein the alkaline substance includes, for example, ammonia water, which is advantageous for further improving the efficiency of the preparation of the target product.
In the above preparation process, the 2, 4-dichlorophenylacetonitrile (formula II) is reacted with the first reducing agent, so that the 2, 4-dichlorophenylacetonitrile (formula II) is reduced by the first reducing agent, in some embodiments, the temperature of the reaction between the 2, 4-dichlorophenylacetonitrile (formula II) and the first reducing agent is-50 to 100 ℃, i.e., the reaction temperature of the 2, 4-dichlorophenylacetonitrile (formula II) and the first reducing agent is-50 to 100 ℃, for example, -50 ℃, -30 ℃, -100 ℃, 0 ℃,5 ℃, 10 ℃, 20 ℃, 30 ℃, 50 ℃, 70 ℃, 90 ℃, 100 ℃ or any two thereof, preferably 20 to 30 ℃ (room temperature), the reaction conditions are milder, and the target product with high yield and purity can be prepared.
In addition, the reduction of 2, 4-dichlorophenylacetonitrile (formula II) by the first reducing agent may be performed under the protection of an inert gas, which includes, but is not limited to, nitrogen, and the like, and may be other inert gases conventional in the art.
In some embodiments, the process of reducing 2, 4-dichlorophenylacetonitrile with a first reducing agent comprises: dissolving 2, 4-dichlorobenzyl cyanide in a first solvent, adding ammonia water, then adding a first catalyst under the protection of inert gas, introducing hydrogen into the first solvent for reaction, and maintaining the pressure of the hydrogen at 0.1-1.0 MPa in the reaction process to reduce the 2, 4-dichlorobenzyl cyanide into 2, 4-dichlorophenethylamine by the hydrogen.
In specific implementation, the reaction of 2, 4-dichlorophenylacetonitrile with the first reducing agent can be followed by High Performance Liquid Chromatography (HPLC), that is, the 2, 4-dichlorophenylacetonitrile in the reaction system is detected by HPLC, and after the 2, 4-dichlorophenylacetonitrile is substantially completely reacted (the ratio of the peak area of the 2, 4-dichlorophenylacetonitrile in the system after the reaction to the peak area of the 2, 4-dichlorophenylacetonitrile in the system before the reaction is less than or equal to 2%), that is, the reaction is finished (the reaction time is generally not higher than 20h), the obtained first product system can be purified, which specifically includes: and (3) carrying out solid-liquid separation on the first product system by filtration and the like, and then carrying out alkali liquor concentration on the obtained liquid product to obtain the 2, 4-dichlorophenethylamine product (usually light yellow oily), which is directly used for the next condensation reaction.
In the condensation reaction process, 2, 4-dichlorophenethylamine and formic acid compounds are condensed to generate formamide compounds (namely N- (2, 4-dichlorophenethyl) formamide), the condensation reaction process has mild conditions and low energy consumption, the condensation reaction temperature can be generally-50-100 ℃, such as-50 ℃, 30 ℃, 100 ℃, 0 ℃,5 ℃, 10 ℃, 20 ℃, 30 ℃, 50 ℃, 60 ℃, 70 ℃, 90 ℃, 100 ℃ or the range of any two of the two, the factors such as reaction efficiency, energy consumption and the like are further comprehensively considered, and the condensation reaction process is generally preferably 50-60 ℃.
The formate compound may include formic acid and/or formate compounds, which are generally in a liquid state, and in some embodiments, the formate compound may specifically include at least one of methyl formate, ethyl formate, pentyl formate, and isopropyl formate. Generally, when the formic acid compound comprises formic acid, the condensation reaction temperature can be between 80 and 100 ℃, and when the formic acid compound comprises the formic acid ester compound, the reaction temperature is relatively lower (can be lower than 80 ℃), which is beneficial to further saving energy consumption and simultaneously can further improve the conversion rate of raw materials (generally more than 99%), and particularly, methyl formate and/or ethyl formate can be selected, and ethyl formate with large market supply quantity and low cost is more preferable.
In some embodiments, the molar ratio of 2, 4-dichlorophenethylamine to formic acid is 1: (1.0-3.0), for example, 1:1, 1:1.5, 1:2, 1:2.5, 1:3 or any two thereof.
In some embodiments, the condensation reaction may be carried out in the presence of a base, which may include inorganic bases, including, for example, sodium hydroxide and the like, and the amount of base may be controlled to be: the molar ratio of 2, 4-dichlorophenethylamine to base is 1: (0.1-1.0), for example, 1:0.2, 1:0.4, 1:0.6, 1:0.8, 1:1 or a combination of any two thereof.
In some embodiments, the condensation reaction may be performed under reflux, and in particular, 2, 4-dichlorophenethylamine, a formic acid compound and a base may be mixed and then heated to allow the system to perform the condensation reaction under reflux.
In specific implementation, the condensation reaction may be followed by HPLC, that is, 2, 4-dichlorophenethylamine in the reaction system is detected by HPLC, after the 2, 4-dichlorophenethylamine is substantially completely reacted (the ratio of the peak area of 2, 4-dichlorophenethylamine in the system after the reaction to the peak area of 2, 4-dichlorophenethylamine in the system before the reaction is less than or equal to 2%), that is, the condensation reaction is finished (the condensation reaction time is generally 0.5 to 2 hours, for example, 1 hour), and then the obtained second product system may be purified, which specifically includes: adding water into the second product system for extraction, separating a water phase and an organic phase, washing and drying the organic phase, and then performing reduced pressure concentration to obtain an N- (2, 4-dichlorophenethyl) formamide product, wherein the molar yield of the N- (2, 4-dichlorophenethyl) formamide product is generally over 97 percent, the purity of the N- (2, 4-dichlorophenethyl) formamide product is over 97 percent, and the N- (2, 4-dichlorophenethyl) formamide product can be directly used for the next cyclization reaction; wherein, organic solvent can be added into the water phase for one or more times of extraction to extract the residual N- (2, 4-dichlorophenethyl) formamide in the water phase, and finally all the organic phases are combined and then washed, dried, decompressed and concentrated and the like, specifically, the organic solvent can be washed by saturated salt water and dried by anhydrous sodium sulfate, and the used organic solvent can comprise methyl tert-butyl ether and the like.
In the cyclization reaction process, N- (2, 4-dichlorophenethyl) formamide dehydrates and cyclizes to generate 5, 7-dichloro-3, 4-dihydroisoquinoline, 5, 7-dichloro-3, 4-dihydroisoquinoline can be generated through Bischler-Napieralski reaction, and the Bischler-Napieralski reaction process mainly comprises the following steps: the substituted phenethylamine is dehydrated under the action of a dehydrating reagent to form imine positive ions, then the ring is closed through electrophilic substitution reaction of an aromatic ring, and then dehydrogenation is carried out to prepare the isoquinoline compounds.
In some embodiments of the present invention, the cyclization reaction process may specifically include: mixing N- (2, 4-dichlorophenethyl) formamide, a dehydration reagent, a second solvent and Lewis acid, reacting at-50-100 ℃ (cyclization reaction temperature), and adding inorganic acid to prepare the 5, 7-dichloro-3, 4-dihydroisoquinoline; the cyclization reaction temperature may be, for example, in the range of-50 ℃, -30 ℃, -100 ℃, 0 ℃,5 ℃, 10 ℃, 20 ℃, 30 ℃, 50 ℃, 60 ℃, 70 ℃, 90 ℃, 100 ℃ or any two thereof, preferably 20 to 30 ℃. In the process, N- (2, 4-dichlorophenethyl) formamide is dehydrated to form imine under the action of a dehydration reagent, then is cyclized under the catalysis of Lewis acid to obtain an unstable intermediate, and is hydrolyzed under the action of inorganic acid to obtain 5, 7-dichloro-3, 4-dihydroisoquinoline, in the cyclization process, the cyclization reaction temperature is not more than 100 ℃, the condition is mild, the energy consumption is low, meanwhile, the yield and the purity of the 5, 7-dichloro-3, 4-dihydroisoquinoline product are high, the molar yield is generally more than 77%, and the purity is more than 98.1%.
Further, the N- (2, 4-dichlorophenethyl) formamide may be contacted with the dehydrating reagent for a period of time, then the lewis acid may be added thereto, and then the reaction may be carried out at the above cyclization reaction temperature, for example, in some embodiments, the cyclization reaction process may include: mixing N- (2, 4-dichlorophenethyl) formamide, a dehydration reagent and a second solvent, reacting at room temperature for 1.0-3.0 h, cooling the system to-10 +/-5 ℃, adding Lewis acid into the system, reacting at-50-100 ℃ for 5.0-30.0 h, adding inorganic acid into the system, and stirring for 1.0-3.0 h to obtain the 5, 7-dichloro-3, 4-dihydroisoquinoline. Wherein, the inorganic acid can comprise hydrochloric acid, and the inorganic acid can be added and stirred for 1.0-3.0 h at room temperature.
Further, the cyclization reaction may be performed under the protection of an inert gas, which may include, but is not limited to, nitrogen, and the like, and may be other inert gases conventional in the art.
In some embodiments, the dehydration reagent may include phosphorus pentachloride (PCl)5) Phosphorus oxychloride (POCl)3) Phosphorus trichloride, thionyl chloride (SOCl)2) At least one of oxalyl chloride, polyphosphoric acid (PPA), concentrated sulfuric acid, phosphoric acid, and methanesulfonic acid, and when the dehydrating reagent contains oxalyl chloride, the cyclization reaction temperature can be lowered (to below 80 ℃) and the yield and purity of 5, 7-dichloro-3, 4-dihydroisoquinoline can be further improved.
In some embodiments, the lewis acid comprises at least one of ferric chloride, aluminum chloride, zinc chloride, with ferric chloride generally preferred.
In some embodiments, the molar ratio of N- (2, 4-dichlorophenethyl) formamide to dehydrating reagent is 1: (1.0-5.0), for example, 1:1, 1:2, 1:3, 1:4, 1:5 or any two thereof. The molar ratio of N- (2, 4-dichlorophenethyl) formamide to Lewis acid is 1: (1.0-5.0), for example, 1:1, 1:2, 1:3, 1:4, 1:5 or any two thereof.
In some embodiments, the second solvent comprises at least one of dichloromethane, 1, 2-dichloroethane, chloroform, benzene, toluene, ethylbenzene, xylene, chlorobenzene, preferably dichloromethane.
In specific implementation, after the cyclization reaction is finished (for example, in the above embodiment, after the inorganic acid is added thereto and stirred for 1.0 to 3.0 hours, that is, the cyclization reaction is finished), the obtained third product system may be purified, specifically including: and standing the third product system, removing the solvent, adding saturated sodium bicarbonate solution into the obtained residue to adjust the pH of the system to be more than 7, extracting by using organic solvents such as ethyl acetate and the like, washing, drying and concentrating under reduced pressure the obtained organic phase to obtain the 5, 7-dichloro-3, 4-dihydroisoquinoline product which can be directly used in the next step. The reaction mixture may be washed with brine and dried over anhydrous sodium sulfate.
In the above preparation process, the second reducing agent is used to reduce the 5, 7-dichloro-3, 4-dihydroisoquinoline to 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline, which may include at least one of hydrogen, borane, a metal hydride having reducibility, a metal borohydride having reducibility, a metal hydride including, for example, lithium aluminum hydride, and a metal borohydride including, for example, an alkali metal borohydride, such as sodium borohydride, potassium borohydride, lithium borohydride, and the like. In some embodiments, the second reducing agent includes at least one of hydrogen, sodium borohydride, potassium borohydride, lithium aluminum hydride, lithium borohydride, and borane, and relatively speaking, when the second reducing agent includes sodium borohydride, the reaction efficiency is further improved, the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline with high yield and purity is obtained, the reaction conditions are mild, and at the same time, the sodium borohydride is cheap and easy to obtain, and the cost can be further saved.
In general, when the second reducing agent comprises at least one of borane, metal hydride, and metal borohydride, for example, at least one of sodium borohydride, potassium borohydride, lithium aluminum hydride, lithium borohydride, and borane, the molar ratio of the 5, 7-dichloro-3, 4-dihydroisoquinoline to the second reducing agent is 1: (1.0-5.0), for example, 1:1, 1:2, 1:3, 1:4, 1:5, or any two thereof; when the second reducing agent comprises hydrogen, the pressure of the hydrogen gas can be maintained at 0.1 to 1.0MPa, for example, 0.1MPa, 0.3MPa, 0.5MPa, 0.6MPa, 0.7MPa, 1.0MPa or any two of them, during the reduction of the 5, 7-dichloro-3, 4-dihydroisoquinoline by the second reducing agent.
Specifically, the reduction of the 5, 7-dichloro-3, 4-dihydroisoquinoline by the second reducing agent may be performed in a third solvent, which may include water and/or an organic solvent, for example, including at least one of an alcohol solvent, for example, a monohydric alcohol of C1 to C3, for example, including at least one of methanol, ethanol, isopropanol, a nitrile solvent, for example, acetonitrile, etc., a furan solvent, for example, including tetrahydrofuran, etc. In some embodiments, the third solvent comprises at least one of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, water, preferably methanol.
In the above process, the 5, 7-dichloro-3, 4-dihydroisoquinoline reacts with the second reducing agent to reduce the 5, 7-dichloro-3, 4-dihydroisoquinoline by the second reducing agent, and in some embodiments, the temperature of the reaction of the 5, 7-dichloro-3, 4-dihydroisoquinoline with the second reducing agent is-50 to 100 ℃, i.e., the temperature of the reaction of the 5, 7-dichloro-3, 4-dihydroisoquinoline with the second reducing agent is-50 to 100 ℃, such as-50 ℃, 30 ℃, 100 ℃, 0 ℃,5 ℃, 10 ℃, 20 ℃, 30 ℃, 50 ℃, 70 ℃, 90 ℃, 100 ℃ or any two thereof, preferably 0 to 5 ℃, so as to obtain the target product with high yield and purity.
In some embodiments, the second reducing agent includes at least one of sodium borohydride, potassium borohydride, lithium aluminum hydride, lithium borohydride, and borane, and in specific implementation, the 5, 7-dichloro-3, 4-dihydroisoquinoline and the third solvent are mixed, the temperature of the system is reduced to 0 to 5 ℃, and then the second reducing agent is added to the mixture in portions, for example, the second reducing agent is added in 3 to 5 portions, the adding time can be about 0.5 hour, after the adding is completed, the temperature of the system is maintained to be 0 to 5 ℃ for reaction, and the reaction is followed by HPLC, that is, the 5, 7-dichloro-3, 4-dihydroisoquinoline in the reaction system is detected by HPLC, after the 5, 7-dichloro-3, 4-dihydroisoquinoline is substantially completely reacted (5, 7-dichloro-3, the ratio of the peak area of the 4-dihydroisoquinoline to the peak area of the 5, 7-dichloro-3, 4-dihydroisoquinoline in the system before the reaction is less than or equal to 2%, and the reaction time is generally about 1 hour), adding water to the solution to quench the reaction, and then purifying the obtained fourth product system, which specifically comprises: adding organic solvent into the fourth product system for extraction, washing and drying the obtained organic phase, and then carrying out reduced pressure concentration to obtain the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline product (usually white solid), wherein the molar yield can generally reach more than 94 percent, and the purity can reach more than 98 percent.
In the present invention, unless otherwise specified, the washing may be carried out by washing with a saturated saline solution; the drying can be drying by adopting anhydrous sodium sulfate; the solvent used in the vacuum concentration process (i.e., crystallization process) may include at least one of petroleum ether, ethyl acetate, n-hexane, n-heptane, toluene, chlorobenzene, 1, 2-dichloroethane, dichloromethane, acetonitrile, acetone, ethanol, methanol; the solvent in each step can be recycled.
To make the objects, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to specific embodiments, and it is obvious that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
1. Preparation of 2, 4-dichlorophenethylamine
Adding 100g of 2, 4-dichlorobenzyl cyanide (537.52mmol, 1.00eq) and 1000mL of anhydrous methanol into a 2000mL hydrogenation reaction bottle, stirring for dissolving, adding 225.75g of 25% ammonia water, adding Raney nickel (10.0g) into the hydrogenation reaction bottle under the protection of nitrogen, replacing the mixture with nitrogen and hydrogen for three times respectively, maintaining the hydrogen pressure at 0.2-0.3 MPa, and stirring for reacting at room temperature for 16-20 hours (TLC and HPLC detection reaction are complete) to obtain a first product system; filtering the first product system by using a Buchner funnel padded with diatomite to remove insoluble solids, and concentrating the obtained liquid product under reduced pressure to obtain a 2, 4-dichlorophenethylamine product (101.15g) which is directly used for the next condensation reaction; the reaction process is shown as follows
The structure of the 2, 4-dichlorophenethylamine product is shown in the formula III by the analysis of nuclear magnetic resonance hydrogen spectrum, carbon spectrum and liquid chromatography-Mass spectrum (LCMS-ESI), wherein the molecular weight (Exact Mass) of the 2, 4-dichlorophenethylamine is 189.01, and the LCMS-ESI (m/z) analysis result of the 2, 4-dichlorophenethylamine product is as follows: [ M +1 ]]+＝190.0，[M+3]+＝192.0。
The HPLC purity of the 2, 4-dichlorophenethylamine product was found to be 96.87% with a molar yield of 99.0%;
(1) the molar yield w ═ x1/x2, x1 is the actual moles calculated by dividing the mass of the 2, 4-dichlorophenethylamine product obtained by the above preparation process (101.15g) by the molecular weight of 2, 4-dichlorophenethylamine, and x2 is the theoretical moles of 2, 4-dichlorophenethylamine converted from the amount of 2, 4-dichlorophenylacetonitrile used (moles).
(2) HPLC purity was determined as follows: carrying out HPLC detection on the 2, 4-dichlorophenethylamine product to obtain peak areas of all components, and calculating the sum of the peak areas of all the components to be AGeneral assemblyWherein the peak area of the 2, 4-dichlorophenethylamine is A1Then, HPLC purity is equal to A1/AGeneral assembly；
2. Preparation of N- (2, 4-dichlorophenethyl) formamide
Adding 12.6g of 2, 4-dichlorophenethylamine product (0.066mol, 1.00eq), 5.38g of ethyl formate (0.073mol, 1.10eq) and 0.26g of sodium hydroxide (0.007mol, 0.1eq) into a 100mL three-port reaction bottle, and after the addition is finished, heating to enable the system to react for 1.0 hour under a reflux state (HPLC tracking reaction is finished) to obtain a second product system; adding 50mL of water into the second product system for extraction, separating the liquid to obtain an aqueous phase and an organic phase respectively, adding 100mL of methyl tert-butyl ether into the aqueous phase for further extraction, combining the organic phases obtained by two extractions, adding 50g of saturated saline into the combined organic phase for washing, then adding anhydrous sodium sulfate for drying, filtering again, and concentrating the obtained liquid product under reduced pressure to obtain an N- (2, 4-dichlorophenethyl) formamide product (about 12.9 g). The reaction process is schematically shown as follows:
the structure of the N- (2, 4-dichlorophenethyl) formamide product is shown in a formula IV by analyzing a hydrogen spectrum, a carbon spectrum and a liquid chromatography-Mass spectrum (LCMS-ESI) of nuclear magnetic resonance, wherein the molecular weight (Exact Mass) of the N- (2, 4-dichlorophenethyl) formamide is 217.01, and the LCMS-ESI (m/z) analysis result of the N- (2, 4-dichlorophenethyl) formamide product is as follows: [ M +1 ]]+＝218.02，[M+3]+＝220.0。
The molar yield of the N- (2, 4-dichlorophenethyl) formamide product was 97.3% and the HPLC purity was 97.8% as follows:
(1) molar yield w ═ x3/x4, x3 is the actual moles calculated by dividing the mass of the N- (2, 4-dichlorophenethyl) carboxamide product obtained by the above preparation process (about 12.9 g) by the molecular weight of N- (2, 4-dichlorophenethyl) carboxamide, x4 is the theoretical moles of N- (2, 4-dichlorophenethyl) carboxamide calculated as moles of 2, 4-dichlorophenethylamine product (0.066 mol);
(2) HPLC purity was calculated as follows: carrying out HPLC detection on the N- (2, 4-dichlorophenethyl) formamide product to obtain peak areas of all components, and calculating the sum of the peak areas of all the components as BGeneral assemblyWherein the peak area of the N- (2, 4-dichlorophenethyl) formamide is B1Then, HPLC purity is equal to B1/BGeneral assembly。
3. Preparation of 5, 7-dichloro-3, 4-dihydroisoquinoline
Under the protection of nitrogen, adding 21.8g N- (2, 4-dichlorophenethyl) formamide products (0.1mol, 1.0eq) and 200mL dichloromethane into a 500mL four-mouth reaction bottle, stirring and dissolving, dropwise adding oxalyl chloride at room temperature, adding 13.96 g (0.11mol, 1.1eq) of oxalyl chloride, stirring and reacting at room temperature for 1.0 hour after dropwise adding, then cooling the system to-10 degrees, adding 19.46g anhydrous ferric trichloride (0.12mol,1.2eq) into the system, slowly heating the system to 20-25 ℃, stirring for 20 hours, adding 250mL 4M hydrochloric acid (1.0mol, 10eq) into the system, and stirring at room temperature for 1 hour to obtain a third product system; standing the third product system for a period of time, removing the solvent, and adding saturated NaHCO to the residue3Aqueous solution to adjust system pH>And 7, extracting twice with ethyl acetate, wherein each extraction is performed by using 100mL of ethyl acetate, combining organic phases obtained by two extractions, washing the organic phase with brine, adding anhydrous sodium sulfate, drying, filtering, and concentrating the obtained liquid product under reduced pressure to obtain the 5, 7-dichloro-3, 4-dihydroisoquinoline product (about 16.8 g). The reaction process is schematically shown as follows:
the structure of the 5, 7-dichloro-3, 4-dihydroisoquinoline product is shown in a formula V by nuclear magnetic resonance hydrogen spectrum, carbon spectrum and liquid chromatography-Mass spectrum (LCMS-ESI) analysis, wherein the LCMS-ESI (m/z) analysis result of the 5, 7-dichloro-3, 4-dihydroisoquinoline product is that the molecular weight (Exact Mass) of the 5, 7-dichloro-3, 4-dihydroisoquinoline product is 199.00: [ M +1 ]]+＝199.9，[M+3]+＝201.9。
The molar yield of the 5, 7-dichloro-3, 4-dihydroisoquinoline product was 77.0% and the HPLC purity was 98.1% as follows:
(1) the molar yield w ═ x5/x6, x5 is the actual moles calculated by dividing the mass of the 5, 7-dichloro-3, 4-dihydroisoquinoline product (about 16.8 g) obtained by the above preparation process by the molecular weight of 5, 7-dichloro-3, 4-dihydroisoquinoline, x6 is the theoretical moles of 5, 7-dichloro-3, 4-dihydroisoquinoline calculated from the moles (0.1mol) of the N- (2, 4-dichlorophenethyl) carboxamide product;
(2) HPLC purity was calculated as follows: HPLC detection is carried out on the 5, 7-dichloro-3, 4-dihydroisoquinoline product to obtain peak areas of all the components, and the sum of the peak areas of all the components is CGeneral assemblyWherein the peak area of the 5, 7-dichloro-3, 4-dihydroisoquinoline is C1Then, HPLC purity is equal to C1/CGeneral assembly。
4. Preparation of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline
20g of 5, 7-dichloro-3, 4-dihydroisoquinoline (0.10mol, 1.0eq) and 200mL of methanol are added into a 500mL four-mouth reaction bottle, then the temperature is reduced to 0-5 ℃ through an ice water bath, and sodium borohydride (NaBH) is added into the reaction bottle in batches4) Adding 4.54g (0.12mol,1.2eq) of sodium borohydride, completing the addition within about 0.5 hour, maintaining the system temperature at 0-5 ℃, stirring and reacting for 1.0 hour (after HPLC tracking reaction), and adding 100mL of water to quench the reaction to obtain a fourth product system; extracting the fourth product system twice with dichloromethane, each time with 100mL of dichloromethane, combining the organic phases obtained by two extractions, washing the organic phase with 100mL of saturated saline solution, adding anhydrous sodium sulfate, drying, filtering, and filteringThe liquid product is reduced pressure concentration, concentrated to the system volume is 0.2 times of the initial liquid product volume, added into heptane and continued to reduce pressure concentration, this process precipitates a large amount of white solid, then the vacuum concentration product suction filtration, vacuum drying, 5, 7-dichloro-1, 2,3, 4-four hydrogen isoquinoline product (about 18.99 g). The reaction process is schematically shown as follows:
the structure of the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline product is shown in the formula I by analyzing hydrogen nuclear magnetic resonance spectrum, carbon spectrum and liquid chromatography-mass spectrum (LCMS-ESI), wherein the structure of the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline product is shown in the formula I1The H-NMR spectrum is shown in figure 1,1the results of H-NMR analysis were as follows:1H NMR(400MHz,CDCl3) δ 7.22(s, 1H),6.94(s, 1H),3.95(s, 2H),3.14(t, 2H),2.71(t, 2H),1.66(s, 1H); the molecular weight (Exact Mass) of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline is 201.01, and LCMS-ESI (m/z) analysis result of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline product is as follows: [ M +1 ]]+＝201.9，[M+3]+＝203.9。
According to the following process determination of 5, 7-dichloro-1, 2,3, 4-four hydrogen isoquinoline product molar yield of 94.0%, HPLC purity 98.6%:
(1) molar yield w ═ x7/x8, x7 is the actual number of moles calculated by dividing the mass of the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline product obtained by the above-mentioned preparation process (about 18.99g) by the molecular weight of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline, x8 is the theoretical number of moles of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline converted from the number of moles of 5, 7-dichloro-3, 4-dihydroisoquinoline (0.10 mol);
(2) HPLC purity was calculated as follows: HPLC detection is carried out on the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline product to obtain the peak areas of all the components, and the sum of the peak areas of all the components is DGeneral assemblyWherein the peak area of the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline is D1Then, HPLC purity is equal to D1/DGeneral assembly。
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline is characterized by comprising the following steps:
reducing the 2, 4-dichlorobenzyl cyanide by a first reducing agent to generate 2, 4-dichlorophenethylamine;
carrying out condensation reaction on the 2, 4-dichlorophenethylamine and formic acid compounds to prepare N- (2, 4-dichlorophenethyl) formamide, wherein the formic acid compounds comprise formic acid and/or formate compounds;
subjecting said N- (2, 4-dichlorophenethyl) carboxamide to a cyclization reaction to produce 5, 7-dichloro-3, 4-dihydroisoquinoline;
reducing the 5, 7-dichloro-3, 4-dihydroisoquinoline by a second reducing agent to produce the 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline.
2. The process for producing 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline according to claim 1, wherein the reaction mixture,
the first reducing agent comprises at least one of hydrogen, sodium borohydride, potassium borohydride, lithium borohydride, borane and lithium aluminum hydride; and/or the presence of a gas in the gas,
the process of reducing the 2, 4-dichlorobenzyl cyanide by the first reducing agent is carried out in a first solvent, and the first solvent comprises at least one of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran and water; and/or the presence of a gas in the gas,
the process of reducing the 2, 4-dichlorobenzyl cyanide by the first reducing agent is carried out under the catalysis of a first catalyst, and the first catalyst comprises at least one of palladium carbon, ruthenium carbon, platinum carbon, raney nickel and Lewis acid.
3. The method for producing 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline according to claim 2,
the mass ratio of the 2, 4-dichlorophenylacetonitrile to the first catalyst is 1: (0.01 to 1.0); and/or the presence of a gas in the gas,
the first reducing agent comprises hydrogen, and in the process of reducing the 2, 4-dichlorobenzyl cyanide by the first reducing agent, the pressure of the hydrogen is maintained to be 0.1-1.0 MPa.
4. The method for producing 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline according to claim 1 or 2, wherein the temperature of the 2, 4-dichlorophenylacetonitrile during the reduction with the first reducing agent is-50 to 100 ℃.
5. The process for producing 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline according to claim 1, wherein the reaction mixture,
the mol ratio of the 2, 4-dichlorophenethylamine to the formic acid compound is 1: (1.0-3.0); and/or the presence of a gas in the gas,
the condensation reaction is carried out in the presence of a base, and the molar ratio of the 2, 4-dichlorophenethylamine to the base is 1: (0.1 to 1.0); and/or the presence of a gas in the gas,
the formate compound comprises at least one of methyl formate, ethyl formate, amyl formate and isopropyl formate; and/or the presence of a gas in the gas,
the condensation reaction temperature is-50-100 ℃.
6. The method for preparing 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline according to claim 1, wherein the cyclization reaction process comprises: mixing N- (2, 4-dichlorophenethyl) formamide, a dehydration reagent, a second solvent and Lewis acid, reacting at-50-100 ℃, and then adding inorganic acid into the mixture to prepare the 5, 7-dichloro-3, 4-dihydroisoquinoline.
7. The process for producing 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline according to claim 6,
the second solvent comprises at least one of dichloromethane, 1, 2-dichloroethane, chloroform, benzene, toluene, ethylbenzene, xylene and chlorobenzene; and/or the presence of a gas in the gas,
the dehydration reagent comprises at least one of phosphorus pentachloride, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, PPA, concentrated sulfuric acid, phosphoric acid and methanesulfonic acid; and/or the presence of a gas in the gas,
the Lewis acid comprises at least one of ferric chloride, aluminum chloride and zinc chloride; and/or the presence of a gas in the gas,
the molar ratio of the N- (2, 4-dichlorophenethyl) formamide to the dehydrating reagent is 1: (1.0-5.0); and/or the molar ratio of the N- (2, 4-dichlorophenethyl) formamide to the Lewis acid is 1: (1.0-5.0).
8. The process for producing 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline according to claim 1, wherein the reaction mixture,
the second reducing agent comprises at least one of hydrogen, sodium borohydride, potassium borohydride, lithium aluminum hydride, lithium borohydride and borane; and/or the presence of a gas in the gas,
the reduction process of the 5, 7-dichloro-3, 4-dihydroisoquinoline by the second reducing agent is carried out in a third solvent, wherein the third solvent comprises at least one of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran and water.
9. The method for producing 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline according to claim 1 or 8,
the second reducing agent comprises at least one of sodium borohydride, potassium borohydride, lithium aluminum hydride, lithium borohydride and borane, and the molar ratio of the 5, 7-dichloro-3, 4-dihydroisoquinoline to the second reducing agent is 1: (1.0-5.0); or,
the second reducing agent comprises hydrogen, and the pressure of the hydrogen is maintained to be 0.1-1.0 MPa in the process of reducing the 5, 7-dichloro-3, 4-dihydroisoquinoline by the second reducing agent.
10. The method for preparing 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline according to claim 1, wherein the temperature of the 5, 7-dichloro-3, 4-tetrahydroisoquinoline is-50 to 100 ℃ in the process of being reduced by the second reducing agent.
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| CN1238764A (en) * | 1996-11-27 | 1999-12-15 | 美国辉瑞有限公司 | ApoB-secretion/MTP inhibitory amides |
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| CN109863145A (en) * | 2016-11-03 | 2019-06-07 | 豪夫迈·罗氏有限公司 | Novel tetrahydroisoquinoline and tetrahydronaphthalene compounds for the treatment and prevention of hepatitis B virus infection |
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| CN1238764A (en) * | 1996-11-27 | 1999-12-15 | 美国辉瑞有限公司 | ApoB-secretion/MTP inhibitory amides |
| CN103880745A (en) * | 2014-02-26 | 2014-06-25 | 南通大学 | Chemical synthesis method of 6-bromo-1,2,3,4-tetrahydroisoquinolyl-1-formic acid |
| CN109863145A (en) * | 2016-11-03 | 2019-06-07 | 豪夫迈·罗氏有限公司 | Novel tetrahydroisoquinoline and tetrahydronaphthalene compounds for the treatment and prevention of hepatitis B virus infection |
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