CN112079775A - Synthesis method of 5-trifluoromethyl isoquinoline-8-formic acid - Google Patents
Synthesis method of 5-trifluoromethyl isoquinoline-8-formic acid Download PDFInfo
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- CN112079775A CN112079775A CN202011049648.XA CN202011049648A CN112079775A CN 112079775 A CN112079775 A CN 112079775A CN 202011049648 A CN202011049648 A CN 202011049648A CN 112079775 A CN112079775 A CN 112079775A
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- XXTQFFGNGYFTGG-UHFFFAOYSA-N 5-(trifluoromethyl)isoquinoline-8-carboxylic acid Chemical compound FC(C1=C2C=CN=CC2=C(C=C1)C(=O)O)(F)F XXTQFFGNGYFTGG-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000001308 synthesis method Methods 0.000 title claims abstract description 15
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000002994 raw material Substances 0.000 claims abstract description 19
- BFXXUPORXKYIBL-UHFFFAOYSA-N 5-(trifluoromethyl)isoquinoline Chemical compound N1=CC=C2C(C(F)(F)F)=CC=CC2=C1 BFXXUPORXKYIBL-UHFFFAOYSA-N 0.000 claims abstract description 17
- TZQJDWTZVNKDBO-UHFFFAOYSA-N 8-bromo-5-(trifluoromethyl)isoquinoline Chemical compound C1=CC(=C2C=NC=CC2=C1C(F)(F)F)Br TZQJDWTZVNKDBO-UHFFFAOYSA-N 0.000 claims abstract description 14
- HMFOBPNVAAAACP-UHFFFAOYSA-N 2-[4-(trifluoromethyl)phenyl]ethanamine Chemical compound NCCC1=CC=C(C(F)(F)F)C=C1 HMFOBPNVAAAACP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000005893 bromination reaction Methods 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- 238000003780 insertion Methods 0.000 claims abstract description 6
- 230000037431 insertion Effects 0.000 claims abstract description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 4
- 238000007256 debromination reaction Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 81
- 238000003786 synthesis reaction Methods 0.000 claims description 46
- 230000015572 biosynthetic process Effects 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 239000012074 organic phase Substances 0.000 claims description 33
- 239000000243 solution Substances 0.000 claims description 32
- 239000011259 mixed solution Substances 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 24
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 claims description 22
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 22
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000012071 phase Substances 0.000 claims description 13
- CFIUVUZTXDZNTN-UHFFFAOYSA-N 5-(trifluoromethyl)-3,4-dihydroisoquinoline Chemical compound C1=NCCC2=C1C=CC=C2C(F)(F)F CFIUVUZTXDZNTN-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 10
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 10
- RZJMQDDFHIHYIY-UHFFFAOYSA-N methyl 5-(trifluoromethyl)isoquinoline-8-carboxylate Chemical compound COC(=O)C=1C=CC(=C2C=CN=CC12)C(F)(F)F RZJMQDDFHIHYIY-UHFFFAOYSA-N 0.000 claims description 10
- 238000000746 purification Methods 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000004440 column chromatography Methods 0.000 claims description 9
- 239000012043 crude product Substances 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 6
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 5
- 229920002866 paraformaldehyde Polymers 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- QSUYNRUIBVETBC-UHFFFAOYSA-N 2,2,2-trifluoro-1-[5-(trifluoromethyl)-3,4-dihydro-1h-isoquinolin-2-yl]ethanone Chemical compound C1=CC=C(C(F)(F)F)C2=C1CN(C(=O)C(F)(F)F)CC2 QSUYNRUIBVETBC-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- -1 phenylacetamide 4-trifluoromethyl phenethylamine Chemical compound 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 238000002390 rotary evaporation Methods 0.000 claims description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 101150003085 Pdcl gene Proteins 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 238000005899 aromatization reaction Methods 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- 238000000643 oven drying Methods 0.000 claims description 2
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 6
- 230000031709 bromination Effects 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 4
- 230000003321 amplification Effects 0.000 abstract description 3
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 150000001336 alkenes Chemical class 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 102000005936 beta-Galactosidase Human genes 0.000 description 2
- 108010005774 beta-Galactosidase Proteins 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- AMVYAIXPAGBXOM-AATRIKPKSA-N (E)-2-(trifluoromethyl)cinnamic acid Chemical compound OC(=O)\C=C\C1=CC=CC=C1C(F)(F)F AMVYAIXPAGBXOM-AATRIKPKSA-N 0.000 description 1
- VTLLEQMXSWJONO-UHFFFAOYSA-N 1-chloro-5-(trifluoromethyl)isoquinoline Chemical compound N1=CC=C2C(C(F)(F)F)=CC=CC2=C1Cl VTLLEQMXSWJONO-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- FDRKXRFTGRZXJN-UHFFFAOYSA-N N1N=C(C=C1)NC1=NC=CC=C1.C1=NC=CC2=CC=CC=C12 Chemical class N1N=C(C=C1)NC1=NC=CC=C1.C1=NC=CC2=CC=CC=C12 FDRKXRFTGRZXJN-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 229920002978 Vinylon Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
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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
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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 discloses a synthesis method of 5-trifluoromethyl isoquinoline-8-formic acid, which comprises the steps of taking 4-trifluoromethyl phenethylamine as a raw material, carrying out amino protection, ring closing, hydrolysis, bromination, debromination and alkene insertion, dehydroaromatization on the 4-trifluoromethyl phenethylamine and TFAA to obtain 5-trifluoromethyl isoquinoline, carrying out 8-bit bromination on the 5-trifluoromethyl isoquinoline and NBS to obtain 8-bromo-5-trifluoromethyl isoquinoline, and carrying out carbonyl insertion and hydrolysis to obtain 5-trifluoromethyl isoquinoline-8-formic acid. The method has the advantages of simple synthetic route, reasonable process selection, low raw material cost, simple and easily obtained raw materials, convenient operation and post-treatment, high total yield, no use of highly toxic reagents, easy amplification and large-scale production.
Description
Technical Field
The invention belongs to the technical field of synthesis of drug intermediates, and particularly relates to a synthesis method of 5-trifluoromethyl isoquinoline-8-formic acid.
Background
5-trifluoromethyl isoquinoline-8-formic acid is a medical intermediate of , and the carboxyl at the 8-position is a good modifying group and is widely applied to the design of the prior medicine. The lipid solubility of the original medicine is enhanced, the oral absorption effect is improved and the blood concentration is increased by preparing the esterified prodrug. Trifluoromethyl, as one of the fluorine-containing substituent groups, also has many excellent properties in terms of improvement of the pharmacodynamic structure. 5-trifluoromethylisoquinoline-8-carboxylic acid is therefore frequently used as a modifying group to improve the activity of drug candidate molecules. Wherein Garcia Collazo et al developed a heteroaryl aminoisoquinoline structure. The main role is to bind to the variant β -galactosidase protein, to form a stable protein-chaperone complex, to enable stable presence at neutral pH and safe degradation of the incoming lysosome (WO 2016120808 Al. 2016). Wherein the introduction of the 5-trifluoromethyl isoquinoline can effectively enhance the binding force with beta-galactosidase protein. Steinig AG et al synthesized a novel isoquinoline pyrazolylaminopyridine derivative for inhibiting tyrosine kinase. For the prevention and treatment of various diseases and disorders, such as cancer, and the like. The novel compounds can also be used for the treatment and prevention of diseases associated with meschymal-epithelial transition (MET). The introduction of trifluoromethyl at the 5-position of isoquinoline can also effectively improve the inhibitory activity. (US 8178668B 2) because 5-trifluoromethyl isoquinoline-8-carboxylic acid is an excellent medical intermediate, it has attracted considerable attention in the organic synthesis community, especially in the medicinal chemistry community. The synthesis of 5-trifluoromethyl isoquinoline-8-formic acid, which is used as a modifying group to improve the properties of the original lead compound, and the research and development work of obtaining efficient drug candidate molecules is also being carried out orderly. Therefore, the development of a simple and efficient synthesis method of 5-trifluoromethyl isoquinoline-8-formic acid is particularly important.
At present, no synthetic route of 5-trifluoromethyl isoquinoline-8-formic acid exists, but only a synthetic route of 5-trifluoromethyl isoquinoline is provided, 2-trifluoromethyl cinnamic acid and azido diphenyl phosphonate react to generate 1-chloro-5-trifluoromethyl isoquinoline through a ring closing reaction, but a subsequent synthetic step is lacked, so that the subsequent synthetic method needs to be expanded and extended.
Disclosure of Invention
The invention aims to provide a method for synthesizing 5-trifluoromethyl isoquinoline-8-formic acid, which fills the blank of synthesizing 5-trifluoromethyl isoquinoline-8-formic acid in the market. The synthetic method avoids the defects of unavailable synthetic route reagents, troublesome post-treatment, difficult amplification, high cost and the like.
In order to achieve the purpose, the invention provides the following technical scheme:
the synthesis method of 5-trifluoromethyl isoquinoline-8-formic acid comprises the following steps:
(1) synthesis of 2,2, 2-trifluoro-N- (2-trifluoromethyl) phenylacetamide
4-trifluoromethyl phenethylamine and trifluoroacetic anhydride are taken as raw materials to carry out dehydration condensation reaction to synthesize 2,2, 2-trifluoro-N- (2-trifluoromethyl) phenylacetamide;
(2) synthesis of 2,2, 2-trifluoro-1- [5- (trifluoromethyl) -3, 4-dihydroisoquinolin-2 (1H) -yl ] ethan-1-one
Taking the 2,2, 2-trifluoro-N- (2-trifluoromethyl) phenylacetamide synthesized in the step (1) and paraformaldehyde as raw materials to carry out a ring closing reaction to synthesize 2,2, 2-trifluoro-1- [5- (trifluoromethyl) -3, 4-dihydroisoquinoline-2 (1H) -yl ] ethane-1-ketone;
(3) synthesis of 5- (trifluoromethyl) -1-tetrahydroisoquinoline
Adding the 2,2, 2-trifluoro-1- [5- (trifluoromethyl) -3, 4-dihydroisoquinoline-2 (1H) -yl ] ethane-1-ketone synthesized in the step (2) into an ethanol solution, adding a potassium carbonate aqueous solution, heating and refluxing to perform amide hydrolysis reaction, and synthesizing 5- (trifluoromethyl) -1-tetrahydroisoquinoline;
(4) synthesis of 5- (trifluoromethyl) -3, 4-dihydroisoquinoline
The compound 5- (trifluoromethyl) -1-tetrahydroisoquinoline and N-bromosuccinimide are taken as raw materials to carry out bromination reaction, and then the compound is subjected to debromination reaction in 30 percent sodium hydroxide aqueous solution to synthesize 5- (trifluoromethyl) -3, 4-dihydroisoquinoline;
(5) synthesis of 5-trifluoromethyl isoquinoline
Taking a compound 5- (trifluoromethyl) -3, 4-dihydroisoquinoline as a raw material and manganese dioxide as a reaction reagent to perform oxidative dehydrogenation and aromatization to synthesize 5-trifluoromethyl isoquinoline;
(6) synthesis of 8-bromo-5-trifluoromethyl isoquinoline
Taking a compound 5-trifluoromethyl isoquinoline as a raw material, N-bromosuccinimide as a reaction reagent and concentrated sulfuric acid as a reaction solvent, and carrying out selective bromination reaction at a 5-position to synthesize 8-bromo-5-trifluoromethyl isoquinoline;
(7) synthesis of 5-trifluoromethyl isoquinoline-8-carboxylic acid methyl ester
Taking a compound 8-bromo-5-trifluoromethyl isoquinoline as a raw material, taking N, N-dimethylformamide and methanol as solvents to perform an insertion carbonyl reaction, and synthesizing 5-trifluoromethyl isoquinoline-8-carboxylic acid methyl ester;
(8) synthesis of 5-trifluoromethyl isoquinoline-8-formic acid
5-trifluoromethyl isoquinoline-8-carboxylic acid methyl ester is subjected to hydrolysis reaction to synthesize the 5-trifluoromethyl isoquinoline-8-formic acid.
Further, the specific synthesis steps of the step (1) are as follows:
adding DCM, 4-trifluoromethyl phenethylamine and TEA into a three-necked bottle, slowly cooling the mixed solution to 5 ℃, slowly dropwise adding TFAA trifluoroacetic anhydride, controlling the temperature to be below 10 ℃, after dropwise adding, slowly heating the mixed solution to normal temperature and stirring for reaction; after the reaction is finished, adding 10% hydrochloric acid solution, uniformly stirring, separating the mixed solution, adding saturated sodium carbonate aqueous solution into the organic phase, washing, concentrating and drying to obtain the 2,2, 2-trifluoro-N- (2-trifluoromethyl) phenylacetamide.
Further, the specific synthesis steps of the step (2) are as follows:
respectively adding acetic acid and concentrated sulfuric acid into a three-neck flask, adding a compound 2,2, 2-trifluoro-N- (2-trifluoromethyl) phenylacetamide and paraformaldehyde when the temperature of a reaction solution is reduced to below 15 ℃, and stirring the mixed solution at normal temperature for reaction; after the reaction is finished, adding ice water, extracting the water phase by using ethyl acetate, combining the organic phases, and adding a saturated sodium carbonate aqueous solution for washing; separating organic phase, drying with anhydrous sodium sulfate, concentrating, and oven drying to obtain 2,2, 2-trifluoro-1- [5- (trifluoromethyl) -3, 4-dihydroisoquinoline-2 (1H) -yl ] ethane-1-ketone.
Further, the specific synthesis steps of the step (3) are as follows:
respectively adding ethanol, a compound 2,2, 2-trifluoro-1- [5- (trifluoromethyl) -3, 4-dihydroisoquinoline-2 (1H) -yl ] ethane-1-ketone and a potassium carbonate aqueous solution into a three-necked bottle, and heating the mixed solution to reflux and stir for reaction; after the reaction is finished, the ethanol is removed by rotary evaporation, the water phase is extracted by DCM, the organic phases are combined, dried by anhydrous sodium sulfate, dried by rotary drying and dried, and the synthesis of the 5- (trifluoromethyl) -1-tetrahydroisoquinoline is obtained.
Further, the specific synthesis steps of the step (4) are as follows:
dissolving a compound 5- (trifluoromethyl) -1-tetrahydroisoquinoline in a DCM solution in a three-necked bottle, adding N-bromosuccinimide, cooling a reaction system to 0 ℃, stirring for reaction, returning the temperature to room temperature, adding a 30% NaOH solution, and stirring for reaction at room temperature; after the reaction is finished, extracting an organic phase, and adding 10% hydrochloric acid to separate a mixed solution; and adjusting the pH of the water phase to be 7-9 by using saturated sodium carbonate aqueous solution, extracting by using DCM, combining organic phases, drying by using anhydrous sodium sulfate, concentrating and drying to obtain the 5- (trifluoromethyl) -3, 4-dihydroisoquinoline.
Further, the specific synthesis steps of the step (5) are as follows:
dissolving the compound 5- (trifluoromethyl) -3, 4-dihydroisoquinoline in a toluene solution in a three-neck flask, adding manganese dioxide, heating the mixed solution to 110 ℃, and stirring for reaction; after the reaction is finished, filtering the reaction solution by using diatomite, leaching a filter cake by using ethyl acetate, concentrating an organic phase to obtain a crude product, and further performing column chromatography purification to obtain the 5-trifluoromethyl isoquinoline.
Further, the specific synthesis steps of the step (6) are as follows:
dissolving a compound 5-trifluoromethyl isoquinoline in a concentrated sulfuric acid solution in a three-necked bottle, heating the mixed solution to 75 ℃, adding N-bromosuccinimide in batches, and stirring for reaction after the addition is finished; and after the reaction is finished, cooling the mixed solution to room temperature, pouring the cooled mixed solution into ice, adjusting the pH of a water phase to be 7-9 by using ammonia water, extracting the water phase by using ethyl acetate, combining organic phases, drying and filtering the combined organic phases through anhydrous sodium sulfate, concentrating the combined organic phases to obtain a crude product, and further performing column chromatography purification to obtain the 8-bromo-5-trifluoromethyl isoquinoline.
Further, the specific synthesis steps of the step (7) are as follows:
dissolving the compound 8-bromo-5-trifluoromethyl isoquinoline in methanol and DMF in a three-necked flask, and adding PdCl respectively2(dppf) and TEA, introducing CO into the mixed solution at 75 ℃, and stirring and reacting under the pressure of 0.8 MPa; after the reaction is completed, the reaction solution is dried by spinning, and water and acetic acid B are poured into the reaction solutionAnd (3) extracting the water phase by using the ester, combining the organic phases, drying by using anhydrous sodium sulfate, carrying out spin drying to obtain a crude product, and further carrying out column chromatography purification to obtain the 5-trifluoromethyl isoquinoline-8-carboxylic acid methyl ester.
Further, the specific synthesis steps of the step (8) are as follows:
pouring a 10% sodium hydroxide aqueous solution and a methanol mixed solution into a three-necked bottle, adding a compound 5-trifluoromethyl isoquinoline-8-carboxylic acid methyl ester, and stirring at normal temperature for reaction; and after the reaction is completed, spin-drying methanol, adjusting the pH value of the solution to be weakly acidic by using 10% hydrochloric acid, performing suction filtration to separate out a solid, and drying to obtain the 5-trifluoromethyl isoquinoline-8-formic acid.
Has the advantages that: the invention provides a method for synthesizing 5-trifluoromethyl isoquinoline-8-formic acid, which takes 4-trifluoromethyl phenethylamine as a raw material, has simple synthetic route, reasonable process selection, low raw material cost, simple and easily obtained raw materials, convenient operation and post-treatment, high total yield, no use of highly toxic reagents, easy amplification and large-scale production.
Drawings
FIG. 1 shows a reaction scheme for synthesizing 5-trifluoromethylisoquinoline-8-carboxylic acid.
Detailed Description
The present invention is further described below with reference to specific examples, which are only exemplary and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
The synthesis process of the 5-trifluoromethyl isoquinoline-8-formic acid comprises the steps of carrying out amino protection, ring closing, hydrolysis, bromination, debromination and vinylon insertion on a 4-trifluoromethyl phenethylamine raw material and TFAA, carrying out dehydroaromatization to obtain 5-trifluoromethyl isoquinoline, carrying out 8-bit bromination on NBS to obtain 8-bromo-5-trifluoromethyl isoquinoline, and carrying out carbonyl insertion and hydrolysis to obtain 5-trifluoromethyl isoquinoline-8-formic acid, wherein the reaction formula is shown in figure 1.
The specific synthetic steps are as follows:
the first step is as follows: synthesis of 2,2, 2-trifluoro-N- (2-trifluoromethyl) phenylacetamide
100 mL of DCM was added into a 200 mL three-necked flask, 4-trifluoromethylphenethylamine (9.52 g, 50.4 mmol) and 14 mL of TEA were added respectively, the mixture was slowly cooled to 5 ℃, TFAA (13.8 g,65.7 mmol) trifluoroacetic anhydride was slowly added dropwise, the temperature was controlled below 10 ℃, the dropwise addition was completed, the mixture was slowly warmed to room temperature and stirred for reaction. And monitoring the reaction by TLC, adding 100 mL of 10% hydrochloric acid solution after the reaction is finished, uniformly stirring, separating the mixed solution, adding saturated sodium carbonate aqueous solution into the organic phase, washing, concentrating and drying to obtain 14.0 g of a light yellow solid compound with the yield of 97.5%. The product was used in the next reaction without purification.
1H NMR (400 MHz, DMSO-d6) 9.59 (s, 1H,-NH), 7.70 (d, J = 7.9 Hz, 1H, ArH), 7.63 (t, J = 7.5 Hz, 1H, ArH), 7.45 (t, J = 7.9 Hz, 2H, ArH), 3.46 (dd, J = 13.5, 6.8 Hz, 2H,-CH2), 2.98 (t, J = 7.2 Hz, 2H, -CH2).ESI + -MS, m /z: 286.1[M+H]+。
The second step is that: synthesis of 2,2, 2-trifluoro-1- [5- (trifluoromethyl) -3, 4-dihydroisoquinolin-2 (1H) -yl ] ethan-1-one
50 mL of acetic acid and 50 mL of concentrated sulfuric acid are respectively added into a 200 mL three-neck flask, after the temperature of a reaction solution is reduced to below 15 ℃, a compound 2,2, 2-trifluoro-N- (2-trifluoromethyl) phenylacetamide (14.2 g, 49.8 mmol) and paraformaldehyde (2.24 g,74.7 mmol) are added, the mixed solution is stirred at normal temperature for reaction, TLC is used for monitoring the reaction, after the reaction is finished, 500 mL of ice water is added, an aqueous phase is extracted by ethyl acetate (300 mL multiplied by 3), an organic phase is combined, and saturated aqueous sodium carbonate solution is added for washing. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated and dried to give 13.1 g of the compound as yellow crystals in 88.5% yield. The product was used in the next reaction without purification.
1H NMR (400 MHz, DMSO-d6) 7.62 (dd, J = 16.5, 8.3 Hz, 2H, ArH), 7.45 (t, J = 7.8 Hz, 1H, ArH), 4.85 (d, J = 14.5 Hz, 2H, -CH2), 3.93 – 3.77 (m, 2H, -CH2), 3.13 – 2.99 (m, 2H, -CH2).ESI + -MS, m /z: 298.1[M+H]+。
The third step: synthesis of 5- (trifluoromethyl) -1-tetrahydroisoquinoline
In a 500 mL three-necked flask, 200 mL of ethanol, the compound 2,2, 2-trifluoro-1- [5- (trifluoromethyl) -3, 4-dihydroisoquinolin-2 (1H) -yl ] ethan-1-one (13.1 g, 44.1 mmol) and 50 mL of an aqueous potassium carbonate solution (520 g/L) were added, respectively, and the mixture was heated to reflux and stirred for reaction. The reaction was monitored by TLC and, after completion of the reaction, the ethanol was removed by rotary evaporation and the aqueous phase was extracted with DCM (100 mL × 3), the organic phases were combined, dried over anhydrous sodium sulphate, dried by rotary evaporation and dried to give 8.51 g of the compound as a pale yellow liquid with a yield of 95.9%. The product was used in the next reaction without purification.
1H NMR (400 MHz, DMSO-d6) 7.48 (dd, J = 8.6, 5.7 Hz, 1H, ArH), 7.35 – 7.25 (m, 2H, ArH), 3.91 (s, 2H, -CH2), 2.96 (t, J = 5.9 Hz, 2H, -CH2), 2.79 (t, J = 5.8 Hz, 2H, -CH2), 2.57 (d, J = 41.9 Hz, 1H, -NH).ESI + -MS, m /z: 202.1[M+H]+。
The fourth step: synthesis of 5- (trifluoromethyl) -3, 4-dihydroisoquinoline
In a 500 mL three-necked flask, the compound 5- (trifluoromethyl) -1-tetrahydroisoquinoline (9.42 g, 46.8 mmol) was dissolved in 100 mL of a solution of EDCM, NBS (9.18 g, 51.6 mmol) was added, the reaction system was cooled to 0 ℃ and stirred for reaction for 2 hours, the temperature was returned to room temperature, 30 mL of a 30% NaOH solution was added, and the reaction was stirred at room temperature. Monitoring the reaction by TLC, after the reaction is finished, extracting an organic phase, adding 100 mL of 10% hydrochloric acid, and separating a mixed solution; the aqueous phase was adjusted to pH = 7-9 with saturated aqueous sodium carbonate solution, extracted with DCM (200 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and dried to give the compound as an orange solid 8.61 g. The yield was 92.3%. The product was used in the next reaction without purification.
1H NMR (400 MHz, DMSO-d6) 8.43 (t, J = 2.2 Hz, 1H, ArH), 7.78 (d, J= 7.9 Hz, 1H, ArH), 7.72 (d, J = 7.5 Hz, 1H, ArH), 7.56 (t, J = 7.6 Hz, 1H, ArH), 3.74 – 3.66 (m, 2H, -CH2), 2.81 (t, J = 7.8 Hz, 2H, -CH2).ESI + -MS, m /z: 200.1[M+H]+。
The fifth step: synthesis of 5-trifluoromethyl isoquinoline
In a 500 mL three-necked flask, the compound 5- (trifluoromethyl) -3, 4-dihydroisoquinoline (25.7 g, 129 mmol) was dissolved in 250 mL of a toluene solution, manganese dioxide (89.9 g,1.03 mol) was added, and the mixture was heated to 110 ℃ and stirred for reaction. The reaction was monitored by TLC, after the reaction was completed, the reaction solution was filtered with celite, the filter cake was rinsed with ethyl acetate, the organic phase was concentrated to give a crude product, which was further purified by column chromatography (eluent: V (petroleum ether) = 40/1), yielding 11.58 g of a compound as a yellow solid. The yield was 45.5%.
1H NMR (400 MHz, CDCl3) : 9.36 (d, J = 0.6 Hz, 1H, ArH), 8.68 (t, J = 5.2 Hz, 1H, ArH), 8.18 (d, J = 8.3 Hz, 1H, ArH), 8.09 (d, J = 7.3 Hz, 1H, ArH), 8.00 – 7.93 (m, 1H, ArH), 7.68 (t, J = 7.8 Hz, 1H, ArH). ESI + -MS, m /z: 198.0[M+H]+。
And a sixth step: synthesis of 8-bromo-5-trifluoromethyl isoquinoline
In a 250 mL three-necked flask, compound 5-trifluoromethylisoquinoline (10.2 g, 51.5 mmol) was dissolved in 100 mL concentrated sulfuric acid solution, the mixture was warmed to 75 ℃, NBS (11.9 g, 66.9 mmol) was added in portions, and the reaction was stirred after the addition. And monitoring the reaction by TLC, cooling the mixed solution to room temperature after the reaction is finished, pouring the cooled mixed solution into ice, and adjusting the water phase to pH = 7-9 by using ammonia water. Ethyl acetate (100 mL × 3) extracts the aqueous phase, combines the organic phases, dries over anhydrous sodium sulfate, filters, concentrates to give a crude product, which is further purified by column chromatography [ eluent; v (petroleum ether): v (ethyl acetate) =50/1] gave 7.29 g of the compound as a pale yellow solid with a yield of 51.0%.
1H NMR (400 MHz, CDCl3) : 9.36 (d, J = 0.8 Hz, 1H, ArH), 8.68 (d, J = 6.4 Hz, 1H, ArH), 8.18 (d, J = 8.0 Hz, 1H, ArH), 8.09 (d, J = 7.2 Hz, 1H, ArH), 8.00 – 7.93 (m, 1H, ArH), 7.68 (t, J = 7.6 Hz, 1H, ArH). ESI + -MS, m /z: 277.0[M+H]+。
The seventh step: synthesis of 5-trifluoromethyl isoquinoline-8-carboxylic acid methyl ester
In a 500 mL three-necked flask, the compound 8-bromo-5-trifluoromethylisoquinoline (20.1 g,74.5 mmol) was dissolved in methanol 140 mL and DMF 60 mL, and PdCl was added separately2(dppf) (2.01 g, 2.75 mmol) and TEA (11.0 g, 108.7 mmol), the mixture was stirred at 0.8MPA pressure with CO bubbling at 75 ℃. The reaction was monitored by TLC, after completion of the reaction, the reaction solution was spin-dried, water was poured in 250 mL, the aqueous phase was extracted with ethyl acetate (250 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, spin-dried to give a crude product, which was further purified by column chromatography [ eluent: v (petroleum ether): v (ethyl acetate) =20/1]14.7 g of a white solid of the compound was obtained in 78.9% yield.
1H NMR (400 MHz, DMSO-d6) 9.71 (s, 1H, ArH), 9.12 (s, 1H, ArH), 8.83 (d, J = 6.0 Hz, 1H, ArH), 8.50 (s, 1H, ArH), 7.95 (d, J = 4.2 Hz, 1H, ArH), 3.98 (s, 3H, -OCH3).m/z: 256.0 [M + H]+。
Eighth step: synthesis of 5-trifluoromethyl isoquinoline-8-formic acid
In a 250 mL three-necked flask, a mixed solution of 40 mL of a 10% aqueous solution of sodium hydroxide and 120 mL of methanol was poured, and the compound methyl 5-trifluoromethylisoquinoline-8-carboxylate (12.5 g, 49.0 mmol) was added. Stirring and reacting at normal temperature. And monitoring the reaction by TLC, after the reaction is completed, spin-drying methanol, adjusting the pH of the solution to weak acidity by using 10% hydrochloric acid, performing suction filtration to separate out a solid, and drying to obtain 11.3 g of a compound white solid with the yield of 95.5%.1H NMR (400 MHz, DMSO-d6) 14.17 – 13.35 (m, 1H, -COOH), 9.74 (s, 1H, ArH), 9.14 (s, 1H, ArH), 8.84 (d, J = 6.4 Hz, 1H, ArH), 8.56 (s, 1H, ArH), 8.00 (d, J = 4.0 Hz, 1H, ArH). m/z: 242.0 [M + H]+。
Claims (9)
- The synthesis method of the 1.5-trifluoromethyl isoquinoline-8-formic acid is characterized by comprising the following steps:(1) synthesis of 2,2, 2-trifluoro-N- (2-trifluoromethyl) phenylacetamide4-trifluoromethyl phenethylamine and trifluoroacetic anhydride are taken as raw materials to carry out dehydration condensation reaction to synthesize 2,2, 2-trifluoro-N- (2-trifluoromethyl) phenylacetamide;(2) synthesis of 2,2, 2-trifluoro-1- [5- (trifluoromethyl) -3, 4-dihydroisoquinolin-2 (1H) -yl ] ethan-1-oneTaking the 2,2, 2-trifluoro-N- (2-trifluoromethyl) phenylacetamide synthesized in the step (1) and paraformaldehyde as raw materials to carry out a ring closing reaction to synthesize 2,2, 2-trifluoro-1- [5- (trifluoromethyl) -3, 4-dihydroisoquinoline-2 (1H) -yl ] ethane-1-ketone;(3) synthesis of 5- (trifluoromethyl) -1-tetrahydroisoquinolineAdding the 2,2, 2-trifluoro-1- [5- (trifluoromethyl) -3, 4-dihydroisoquinoline-2 (1H) -yl ] ethane-1-ketone synthesized in the step (2) into an ethanol solution, adding a potassium carbonate aqueous solution, heating and refluxing to perform amide hydrolysis reaction, and synthesizing 5- (trifluoromethyl) -1-tetrahydroisoquinoline;(4) synthesis of 5- (trifluoromethyl) -3, 4-dihydroisoquinolineThe compound 5- (trifluoromethyl) -1-tetrahydroisoquinoline and N-bromosuccinimide are taken as raw materials to carry out bromination reaction, and then the compound is subjected to debromination reaction in 30 percent sodium hydroxide aqueous solution to synthesize 5- (trifluoromethyl) -3, 4-dihydroisoquinoline;(5) synthesis of 5-trifluoromethyl isoquinolineTaking a compound 5- (trifluoromethyl) -3, 4-dihydroisoquinoline as a raw material and manganese dioxide as a reaction reagent to perform oxidative dehydrogenation and aromatization to synthesize 5-trifluoromethyl isoquinoline;(6) synthesis of 8-bromo-5-trifluoromethyl isoquinolineTaking a compound 5-trifluoromethyl isoquinoline as a raw material, N-bromosuccinimide as a reaction reagent and concentrated sulfuric acid as a reaction solvent, and carrying out selective bromination reaction at a 5-position to synthesize 8-bromo-5-trifluoromethyl isoquinoline;(7) synthesis of 5-trifluoromethyl isoquinoline-8-carboxylic acid methyl esterTaking a compound 8-bromo-5-trifluoromethyl isoquinoline as a raw material, taking N, N-dimethylformamide and methanol as solvents to perform an insertion carbonyl reaction, and synthesizing 5-trifluoromethyl isoquinoline-8-carboxylic acid methyl ester;(8) synthesis of 5-trifluoromethyl isoquinoline-8-formic acid5-trifluoromethyl isoquinoline-8-carboxylic acid methyl ester is subjected to hydrolysis reaction to synthesize the 5-trifluoromethyl isoquinoline-8-formic acid.
- 2. The synthesis method according to claim 1, wherein the specific synthesis steps of the step (1) are as follows:adding DCM, 4-trifluoromethyl phenethylamine and TEA into a three-necked bottle, slowly cooling the mixed solution to 5 ℃, slowly dropwise adding TFAA trifluoroacetic anhydride, controlling the temperature to be below 10 ℃, after dropwise adding, slowly heating the mixed solution to normal temperature and stirring for reaction; after the reaction is finished, adding 10% hydrochloric acid solution, uniformly stirring, separating the mixed solution, adding saturated sodium carbonate aqueous solution into the organic phase, washing, concentrating and drying to obtain the 2,2, 2-trifluoro-N- (2-trifluoromethyl) phenylacetamide.
- 3. The synthesis method according to claim 1, wherein the specific synthesis steps of the step (2) are as follows:respectively adding acetic acid and concentrated sulfuric acid into a three-neck flask, adding a compound 2,2, 2-trifluoro-N- (2-trifluoromethyl) phenylacetamide and paraformaldehyde when the temperature of a reaction solution is reduced to below 15 ℃, and stirring the mixed solution at normal temperature for reaction; after the reaction is finished, adding ice water, extracting the water phase by using ethyl acetate, combining the organic phases, and adding a saturated sodium carbonate aqueous solution for washing; separating organic phase, drying with anhydrous sodium sulfate, concentrating, and oven drying to obtain 2,2, 2-trifluoro-1- [5- (trifluoromethyl) -3, 4-dihydroisoquinoline-2 (1H) -yl ] ethane-1-ketone.
- 4. The synthesis method according to claim 1, wherein the specific synthesis steps of the step (3) are as follows:respectively adding ethanol, a compound 2,2, 2-trifluoro-1- [5- (trifluoromethyl) -3, 4-dihydroisoquinoline-2 (1H) -yl ] ethane-1-ketone and a potassium carbonate aqueous solution into a three-necked bottle, and heating the mixed solution to reflux and stir for reaction; after the reaction is finished, the ethanol is removed by rotary evaporation, the water phase is extracted by DCM, the organic phases are combined, dried by anhydrous sodium sulfate, dried by rotary drying and dried, and the synthesis of the 5- (trifluoromethyl) -1-tetrahydroisoquinoline is obtained.
- 5. The synthesis method according to claim 1, wherein the specific synthesis steps of the step (4) are as follows:dissolving a compound 5- (trifluoromethyl) -1-tetrahydroisoquinoline in a DCM solution in a three-necked bottle, adding N-bromosuccinimide, cooling a reaction system to 0 ℃, stirring for reaction, returning the temperature to room temperature, adding a 30% NaOH solution, and stirring for reaction at room temperature; after the reaction is finished, extracting an organic phase, and adding 10% hydrochloric acid to separate a mixed solution; and adjusting the pH of the water phase to be 7-9 by using saturated sodium carbonate aqueous solution, extracting by using DCM, combining organic phases, drying by using anhydrous sodium sulfate, concentrating and drying to obtain the 5- (trifluoromethyl) -3, 4-dihydroisoquinoline.
- 6. The synthesis method according to claim 1, wherein the specific synthesis steps of the step (5) are as follows:dissolving the compound 5- (trifluoromethyl) -3, 4-dihydroisoquinoline in a toluene solution in a three-neck flask, adding manganese dioxide, heating the mixed solution to 110 ℃, and stirring for reaction; after the reaction is finished, filtering the reaction solution by using diatomite, leaching a filter cake by using ethyl acetate, concentrating an organic phase to obtain a crude product, and further performing column chromatography purification to obtain the 5-trifluoromethyl isoquinoline.
- 7. The synthesis method according to claim 1, wherein the specific synthesis steps of the step (6) are as follows:dissolving a compound 5-trifluoromethyl isoquinoline in a concentrated sulfuric acid solution in a three-necked bottle, heating the mixed solution to 75 ℃, adding N-bromosuccinimide in batches, and stirring for reaction after the addition is finished; and after the reaction is finished, cooling the mixed solution to room temperature, pouring the cooled mixed solution into ice, adjusting the pH of a water phase to be 7-9 by using ammonia water, extracting the water phase by using ethyl acetate, combining organic phases, drying and filtering the combined organic phases through anhydrous sodium sulfate, concentrating the combined organic phases to obtain a crude product, and further performing column chromatography purification to obtain the 8-bromo-5-trifluoromethyl isoquinoline.
- 8. The synthesis method according to claim 1, wherein the specific synthesis steps of the step (7) are as follows:dissolving the compound 8-bromo-5-trifluoromethyl isoquinoline in methanol and DMF in a three-necked flask, and adding PdCl respectively2(dppf) and TEA, introducing CO into the mixed solution at 75 ℃, and stirring and reacting under the pressure of 0.8 MPa; and after the reaction is completed, spin-drying the reaction solution, pouring water and ethyl acetate into the reaction solution to extract a water phase, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, spin-drying the organic phases to obtain a crude product, and further performing column chromatography purification to obtain the 5-trifluoromethyl isoquinoline-8-carboxylic acid methyl ester.
- 9. The synthesis method according to claim 1, wherein the specific synthesis steps of the step (8) are as follows:pouring a 10% sodium hydroxide aqueous solution and a methanol mixed solution into a three-necked bottle, adding a compound 5-trifluoromethyl isoquinoline-8-carboxylic acid methyl ester, and stirring at normal temperature for reaction; and after the reaction is completed, spin-drying methanol, adjusting the pH value of the solution to be weakly acidic by using 10% hydrochloric acid, performing suction filtration to separate out a solid, and drying to obtain the 5-trifluoromethyl isoquinoline-8-formic acid.
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