CN112047829B - Synthesis method of alcaine intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid - Google Patents
Synthesis method of alcaine intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid Download PDFInfo
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- CN112047829B CN112047829B CN202010895334.5A CN202010895334A CN112047829B CN 112047829 B CN112047829 B CN 112047829B CN 202010895334 A CN202010895334 A CN 202010895334A CN 112047829 B CN112047829 B CN 112047829B
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- ethylphenyl
- solvent
- methylpropanoic acid
- ethyl
- propane
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- RUVGXZCQYVEAKQ-UHFFFAOYSA-N 2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid Chemical compound CCC1=CC=C(C(C)(C)C(O)=O)C=C1I RUVGXZCQYVEAKQ-UHFFFAOYSA-N 0.000 title claims abstract description 58
- 238000001308 synthesis method Methods 0.000 title claims abstract description 14
- KCLANYCVBBTKTO-UHFFFAOYSA-N Proparacaine Chemical compound CCCOC1=CC=C(C(=O)OCCN(CC)CC)C=C1N KCLANYCVBBTKTO-UHFFFAOYSA-N 0.000 title abstract description 8
- 229940087458 alcaine Drugs 0.000 title abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 72
- ZTABWPDSXBXQMV-UHFFFAOYSA-N 2-(4-ethylphenyl)-2-methylpropanoic acid Chemical compound CCC1=CC=C(C(C)(C)C(O)=O)C=C1 ZTABWPDSXBXQMV-UHFFFAOYSA-N 0.000 claims abstract description 61
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 28
- NODGRWCMFMEGJH-UHFFFAOYSA-N p-ethylacetophenone Chemical compound CCC1=CC=C(C(C)=O)C=C1 NODGRWCMFMEGJH-UHFFFAOYSA-N 0.000 claims abstract description 25
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000006192 iodination reaction Methods 0.000 claims abstract description 23
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000011261 inert gas Substances 0.000 claims abstract description 22
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 22
- 239000011630 iodine Substances 0.000 claims abstract description 22
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 14
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 14
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 126
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 98
- 239000002904 solvent Substances 0.000 claims description 90
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 77
- 238000006243 chemical reaction Methods 0.000 claims description 69
- 239000000243 solution Substances 0.000 claims description 66
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 59
- -1 2- (4-ethylphenyl) propyl magnesium halide Chemical class 0.000 claims description 56
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 48
- 239000007864 aqueous solution Substances 0.000 claims description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 44
- 239000012074 organic phase Substances 0.000 claims description 44
- 238000002360 preparation method Methods 0.000 claims description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 32
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 238000005406 washing Methods 0.000 claims description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 24
- 239000003054 catalyst Substances 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 24
- 238000010438 heat treatment Methods 0.000 claims description 24
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 22
- 238000010992 reflux Methods 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 22
- 239000003999 initiator Substances 0.000 claims description 21
- 239000007800 oxidant agent Substances 0.000 claims description 21
- 230000001590 oxidative effect Effects 0.000 claims description 21
- 230000026045 iodination Effects 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 239000000047 product Substances 0.000 claims description 20
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 20
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 19
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 18
- 239000003208 petroleum Substances 0.000 claims description 18
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 16
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 16
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 16
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000011780 sodium chloride Substances 0.000 claims description 13
- 239000007789 gas Substances 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 11
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 9
- 239000012286 potassium permanganate Substances 0.000 claims description 9
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 9
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- FNYBGQNKLJVUDD-UHFFFAOYSA-N 1-ethyl-4-(2-iodopropan-2-yl)benzene Chemical compound CCC1=CC=C(C(C)(C)I)C=C1 FNYBGQNKLJVUDD-UHFFFAOYSA-N 0.000 claims description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 8
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 230000002140 halogenating effect Effects 0.000 claims description 8
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 8
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 8
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 claims description 8
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 8
- 229910017604 nitric acid Inorganic materials 0.000 claims description 8
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000011777 magnesium Substances 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 14
- 238000009776 industrial production Methods 0.000 abstract description 5
- OWFMATBOEUOZNJ-UHFFFAOYSA-N 2-(4-ethylphenyl)propan-2-ol Chemical compound CCC1=CC=C(C(C)(C)O)C=C1 OWFMATBOEUOZNJ-UHFFFAOYSA-N 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 7
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 7
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 238000004821 distillation Methods 0.000 description 5
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 2
- 229960005061 crizotinib Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- AKVOQXBQLXOEEF-UHFFFAOYSA-N 2-(4-bromophenyl)-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)C1=CC=C(Br)C=C1 AKVOQXBQLXOEEF-UHFFFAOYSA-N 0.000 description 1
- QMBLXRHXCGJOGU-UHFFFAOYSA-N 2-(4-ethylphenyl)acetic acid Chemical compound CCC1=CC=C(CC(O)=O)C=C1 QMBLXRHXCGJOGU-UHFFFAOYSA-N 0.000 description 1
- XXSPGBOGLXKMDU-UHFFFAOYSA-N 2-bromo-2-methylpropanoic acid Chemical compound CC(C)(Br)C(O)=O XXSPGBOGLXKMDU-UHFFFAOYSA-N 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 1
- WCOCYZXXISYZLN-UHFFFAOYSA-N B(F)(F)F.C=C.[K] Chemical compound B(F)(F)F.C=C.[K] WCOCYZXXISYZLN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 231100000206 health hazard Toxicity 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007886 mutagenicity Effects 0.000 description 1
- 231100000299 mutagenicity Toxicity 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000010865 sewage Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
- C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/15—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction of organic compounds with carbon dioxide, e.g. Kolbe-Schmitt synthesis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of an alcaine intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid, which is characterized in that: under the protection of inert gas, reacting 4-ethylacetophenone with a methyl format reagent to obtain 2- (4-ethylphenyl) -2-propanol, and then treating with a halogenated reagent to obtain 2-halogen-2- (4-ethylphenyl) propane; preparing 2-halogen-2- (4-ethylphenyl) propane into a format reagent, and introducing carbon dioxide to obtain 2- (4-ethylphenyl) -2-methylpropanoic acid; iodination reaction is carried out between elemental iodine or N-iodinated succinimide and 2- (4-ethyl phenyl) -2-methylpropanoic acid to prepare the intermediate of the alcaine, namely 2- (4-ethyl-3-iodiphenyl) -2-methylpropanoic acid. The invention has the characteristics of cheap and easily obtained raw materials, high yield, no existence of highly toxic reagents and the like, is easy for industrial production and has strong practicability.
Description
Technical Field
The invention belongs to the preparation of organic compounds, and relates to a synthetic method of an anetinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid. The 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid prepared by the invention is particularly suitable for being used as an intermediate of the bulk drug of the alcaine.
Background
Lung cancer is one of the most serious malignant tumors that have the highest incidence and death rate at present and are most threatening to human health and life. The albezene hydrochloride is a new anaplastic lymphoma kinase (ALK for short) inhibitor, is mainly used for treating ALK positive non-small cell lung cancer patients, and has curative effect especially on patients who are deteriorated or intolerant to the patients treated by crizotinib. Clinical data indicate that the alatinib-treated group (34.8 months) is 3 times more than the crizotinib-treated group (10.9 months) in terms of progression free survival (PFS for short); therefore, it is important to study the synthesis method of the intermediate.
The compound with chemical name of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid is a key intermediate in the synthesis of alcaine. The English name of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid is: 2- (4-Ethyl-3-iodophenyl) -2-methylpropanoic acid, the molecular formula is: c (C) 12 H 15 IO 2 The chemical structural formula is as follows:
in the prior art, the synthesis method of the intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid mainly comprises four methods: firstly, carrying out Suzuki coupling on 2- (4-bromophenyl) -2-methylpropanoic acid and ethylene potassium trifluoroborate disclosed in US2012083488A1 under the condition of a palladium catalyst, and carrying out hydrogenation reduction and iodination to obtain a target compound; the method needs to use an expensive palladium catalyst for two continuous steps, heavy metal impurities are not easy to remove in the product, and the cost is very high due to the use of expensive raw materials and the palladium catalyst, so the synthetic method has little industrial production value, and the chemical reaction process is as follows:
Secondly, CN106946650A discloses a synthesis method of an intermediate of Alfitinib hydrochloride, which takes cheap 2-bromoisobutyric acid as a raw material to obtain a target compound through chlorination, friedel-crafts acylation, rearrangement, iodination and hydrolysis; the synthesis method needs to use a large amount of dangerous reagents such as thionyl chloride, anhydrous aluminum trichloride and the like, can generate a large amount of acid gas and corrosive sewage, is easy to corrode production equipment, and does not meet the requirements of environmental protection in industry. The chemical reaction process is as follows:
thirdly, CN109384664A discloses a preparation method of an intermediate of the Airotinib, wherein the reaction of bromoethylbenzene and malonic acid diester in cuprous halide is used for obtaining 4-ethylphenylacetic acid, and then the target compound is obtained through esterification, methylation, hydrolysis and iodination processes; the method has the advantages of low raw material cost, simple operation and the like. However, the used methyl iodide has the defects of strong volatility, low boiling point (41 ℃), germ cell mutagenicity, possible carcinogenesis and the like, and has potential health hazard to operators when being used in large quantities in industrial production. The chemical reaction process is as follows:
fourthly, CN109438218A discloses a method for synthesizing a Ai Leti Ni intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid by taking ethylbenzene and 3-chloro-2-methyl-1-propylene as raw materials and obtaining a target product through Friedel-crafts alkylation, format reaction, oxidation and iodination. The method has the advantages of cheap and easily available raw materials, simple post-treatment and the like, but the synthetic method has the defects of repeated distillation purification, long reaction steps and the like. The chemical reaction process is as follows:
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a synthesis method of an alatinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid. Thereby providing the synthesis method of the aletinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid, which has the advantages of low price and easy obtainment of raw materials, simple and convenient operation, easy post-treatment, high yield, low cost and little pollution to the environment, and is suitable for industrial production
The invention comprises the following steps: a method for synthesizing an anetinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid is characterized by comprising the following steps:
a. preparation of 2-halo-2- (4-ethylphenyl) propane:
under the protection of inert gas, 4-ethyl acetophenone reacts with a methyl format reagent to obtain 2- (4-ethylphenyl) -2-propanol; then treating with halogenated reagent to obtain 2-halogen-2- (4-ethylphenyl) propane (shown in formula 1, wherein X represents halogen atom and comprises chlorine, bromine and iodine); the chemical reaction process is as follows:
b. preparation of 2- (4-ethylphenyl) -2-methylpropanoic acid:
preparing the obtained 2-halogen-2- (4-ethylphenyl) propane into a format reagent, and then introducing carbon dioxide to obtain 2- (4-ethylphenyl) -2-methylpropanoic acid (shown in formula 2); the chemical reaction process is as follows:
c. Preparation of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid:
iodination reaction is carried out between elemental iodine or N-iodosuccinimide (NIS for short) and 2- (4-ethylphenyl) -2-methylpropanoic acid to prepare the intermediate of the alcaine, namely 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid (shown in formula 3), wherein the chemical reaction process is as follows:
the invention relates to a synthesis method of an anetinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid, which is characterized by comprising the following specific steps of:
a. preparation of 2-halo-2- (4-ethylphenyl) propane:
under the protection of inert gas, dissolving 4-ethyl acetophenone into a solvent to form a solution, cooling to-5 ℃, dropwise adding a methyl format reagent into the solution (slowly), reacting between-5 ℃ and room temperature (taking a certain value temperature) for 1-10 hours after the dropwise adding is finished, adding water and an organic solvent after the reaction is finished, separating a liquid, washing an organic phase by a saturated sodium chloride solution, drying by anhydrous sodium sulfate, concentrating the organic phase to obtain an oily intermediate, adding a halogenated reagent, reacting at room temperature or by heating, distilling (purifying) after the reaction is finished, and collecting fractions to obtain the prepared 2-halogen-2- (4-ethylphenyl) propane (shown in formula 1);
the methyl format reagent is one or a mixture of more than two of methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide;
The solvent is one or more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, 1, 4-dioxane and toluene;
the halogenating reagent is any one of trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, hydrochloric acid, hydrobromic acid and thionyl chloride;
b. preparation of 2- (4-ethylphenyl) -2-methylpropanoic acid:
under the protection of inert gas, adding magnesium metal, an initiator and a solvent A into a reactor provided with a condensing device, heating and refluxing for 0.5-2 hours, then (slowly) dropwise adding a solution prepared by 2-halogen-2- (4-ethylphenyl) propane (shown in formula 1) and the solvent A, and reacting for 2-5 hours at 50-80 ℃ to obtain a solution containing 2- (4-ethylphenyl) propyl magnesium halide intermediate; cooling the intermediate solution containing 2- (4-ethylphenyl) propyl magnesium halide to-20-0 ℃, introducing dry carbon dioxide gas, controlling the reaction temperature to be not higher than 35 ℃, reacting for about 5-10 hours, adding (proper amount of) saturated ammonium chloride aqueous solution, then adjusting the pH value of the reaction system to 2-3 by hydrochloric acid, washing an organic phase by saturated sodium chloride aqueous solution, drying by anhydrous sodium sulfate, distilling (removing the organic solvent), and recrystallizing the obtained residue by the solvent B to obtain 2- (4-ethylphenyl) -2-methylpropanoic acid;
The 2-halo-2- (4-ethylphenyl) propane may be any of 2-chloro-2- (4-ethylphenyl) propane, 2-bromo-2- (4-ethylphenyl) propane, 2-iodo-2- (4-ethylphenyl) propane;
the solvent A is one or a mixture of more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and toluene;
the solvent B is one or more than two of petroleum ether, n-hexane, cyclohexane, n-heptane, ethyl acetate, dichloromethane, methanol, ethanol and water;
the initiator is one or a mixture of more than two of elemental iodine, bromine, 1, 2-dibromoethane, methyl magnesium halide and ethyl magnesium halide;
c. preparation of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid:
adding 2- (4-ethylphenyl) -2-methylpropanoic acid, a solvent C, a catalyst, an oxidant and an iodination reagent into a reactor with a condensing reflux device at normal temperature, reacting for 6-24 hours at 0-100 ℃, then dropwise adding a (proper amount) of saturated sodium sulfite aqueous solution until the brown color of the reaction solution is completely removed to be colorless, adding a (proper amount) of ethyl acetate, stirring and standing, washing the organic phase with a (proper amount) of saturated sodium chloride aqueous solution and a (proper amount) of sodium chloride aqueous solution respectively for one time, drying with a (proper amount) of anhydrous sodium sulfate, filtering, distilling the filtrate to remove the ethyl acetate, and then recrystallizing with a (proper amount) of solvent D to obtain a product 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid;
The solvent C is one or a mixture of more than two of acetic acid, acetonitrile, methanol and ethanol;
the solvent D is petroleum ether, C 5 ～C 10 One or more of linear, branched and cyclic hydrocarbons, ethyl acetate, methylene chloride methanol, ethanol and water;
the catalyst is sulfuric acid or methanesulfonic acid;
the oxidant is one or a mixture of more than two of nitric acid, periodic acid, potassium permanganate, manganese dioxide and hydrogen peroxide;
the iodination reagent is elemental iodine or N-iodinated succinimide.
In the content of the invention: the molar ratio of the 4-ethylacetophenone to the methyl format reagent in the step a is 1:1-1:3.
In the content of the invention: the molar ratio of the 4-ethylacetophenone to the halogenated reagent in the step a is 1:1-1:10.
In the content of the invention: the molar ratio of the 2-halogen-2- (4-ethylphenyl) propane to the metal magnesium in the step b is 1:1-1:2.
In the content of the invention: the molar ratio of the 2-halogen-2- (4-ethylphenyl) propane to the initiator in the step b is 100:0.3-100:5.
In the content of the invention: in the step c, the molar ratio of the 2- (4-ethylphenyl) -2-methylpropanoic acid (shown in the formula 3) to the elemental iodine is 1:0.5-1:1.5, and the molar ratio of the 2- (4-ethylphenyl) -2-methylpropanoic acid to the N-iodosuccinimide (NIS for short) is 1:1-1:2.
In the content of the invention: the molar ratio of the catalyst to the 2- (4-ethylphenyl) -2-methylpropanoic acid (shown in formula 3) in the step c is 1:1-1:10.
In the content of the invention: the molar ratio of the oxidant to the 2- (4-ethylphenyl) -2-methylpropanoic acid (shown in formula 3) in the step c is 1:0.1-1:2.
In the content of the invention: the inert gas is nitrogen or argon.
In the content of the invention: the amount of the solvent used in each step may be 2 to 10 times the total mass amount of the other raw materials used in the step, and the appropriate amount may be determined as required, as will be understood and practiced by those skilled in the art.
Compared with the prior art, the invention has the following characteristics and beneficial effects:
(1) The invention takes the cheap 4-ethyl acetophenone as the initial raw material, the initial raw material can be prepared from ethylbenzene and acetyl chloride with lower price, and the whole synthesis method has no expensive reagent, thus greatly reducing the production cost;
(2) The raw materials and the reagents used in the invention have no reagents with high toxicity and great harm to the environment, are easier for industrial production, are beneficial to environmental protection and are beneficial to human health;
(3) In the whole synthesis method, the post-treatment is very easy; only synthesizing the compound shown in the formula 1 requires distillation purification, and the target compound can be obtained only by recrystallization in the other two steps, so that the energy consumption and the requirements on industrialized equipment are reduced;
(4) The preparation method of the invention has the advantages of simple preparation process, simple and convenient working procedure, easy operation, low-cost and easily obtained raw materials, low cost, high yield and strong practicability.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid prepared in example 1;
FIG. 2 is a nuclear magnetic carbon spectrum of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid produced in example 1.
The successful preparation of the intermediate, 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid, of april hydrochloride according to the present invention can be illustrated in conjunction with figures 1 and 2.
Detailed Description
The following examples are intended to further illustrate the present invention but are not to be construed as limiting its scope, as many insubstantial modifications and adaptations of the invention that are within the scope of the invention as described above would be within the skill of the art.
The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
The chemical reaction procedure for the following examples is as follows:
example 1:
a method for synthesizing an anetinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid comprises the following steps:
a. preparation of 2-chloro-2- (4-ethylphenyl) propane:
4-Ethylacetophenone (148 g,1 mol) was dissolved in tetrahydrofuran (500 mL) under nitrogen protection, cooled to-5℃and methyl magnesium chloride (550 mL,2 mol/L) was slowly added dropwise to the above solution, stirred at-5℃for 1 hour after the addition was completed, and then allowed to react at room temperature for 3 hours. After the reaction, water and ethyl acetate were added, and the organic phase was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating the organic phase to obtain an oily intermediate, adding concentrated hydrochloric acid (150 mL), heating to 80 ℃ for reaction for 2 hours, distilling and purifying after the reaction is completed, and collecting fractions to obtain colorless oily compound 1 (149 g), wherein the yield is 82%;
b. preparation of 2- (4-ethylphenyl) -2-methylpropanoic acid:
to a reactor equipped with a condensing unit under nitrogen protection were added magnesium metal (25 g,1.04 mol), iodine (0.76 g,3 mmol) and tetrahydrofuran (800 mL), and after refluxing under heating for 1 hour, a solution of 1- (2-chloropropane-2-yl) -4-ethylbenzene (182 g,1 mol) and tetrahydrofuran (500 mL) was slowly added dropwise, followed by initiation of the reaction by heating after about 50mL, and then dropwise addition under an ice water bath. After the completion of the dropwise addition, the reaction was carried out at 60℃for 3 hours. The above solution was cooled to-10 ℃, dried carbon dioxide gas was introduced, and after about 5 hours of reaction, saturated aqueous ammonium chloride and ethyl acetate were added, then the pH of the reaction system was adjusted to 2-3 with hydrochloric acid, the organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, the organic solvent was removed by distillation, and the obtained residue was recrystallized from petroleum ether to give 2- (4-ethylphenyl) -2-methylpropanoic acid (150 g) as a white solid, yield: 78%;
c. Preparation of the product 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid:
an aqueous solution of 2- (4-ethylphenyl) -2-methylpropanoic acid (192.3 g,1.0 mol), glacial acetic acid (500 mL), elemental iodine (126.9 g,0.5 mol), concentrated sulfuric acid (15 mL) and periodic acid (22.7 g,100 mmol) was charged into a reactor equipped with a condensing reflux apparatus at ordinary temperature. Heating to 75 ℃ for reaction for 6 hours, dropwise adding a proper amount of saturated sodium sulfite aqueous solution, then distilling under reduced pressure to remove acetic acid, adding a proper amount of ethyl acetate into residues, stirring, standing, washing an organic phase with a proper amount of saturated sodium bicarbonate aqueous solution and sodium chloride aqueous solution sequentially, and distilling to remove ethyl acetate to obtain a product 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid crude product; recrystallizing with water and ethanol (1:2), filtering, and washing with water and ethanol (1:2)Washing to obtain 268g of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid as a product, yield: 84% purity 98.6%. 1 H NMR:(400MHz,CDCl 3 ):δ＝11.76(s,1H),7.87(d,J＝2Hz,1H),7.37(dd,J＝8Hz,1.6Hz,1H),7.22(d,J＝8Hz,1H),2.74(q,J＝7.2Hz,2H),1.61(s,6H),1.23(t,J＝7.6Hz,3H)； 13 C NMR:(400MHz,CDCl 3 ):δ＝14.6,26.2,33.8,45.7,100.8,126.4,128.4,136.8,143.2,145.3,183.2.
Example 2:
a method for synthesizing an anetinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid comprises the following steps:
a. preparation of 2-chloro-2- (4-ethylphenyl) propane:
4-Ethylacetophenone (222 g,1.5 mol) was dissolved in diethyl ether (750 mL) under nitrogen protection, cooled to-5℃and methyl magnesium chloride (1L, 2 mol/L) was slowly added dropwise to the above solution, stirred at-5℃for 1 hour after the dropwise addition was completed, and then allowed to react at room temperature for 10 hours. After the reaction, water and diethyl ether were added, and the organic phase was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating the organic phase to obtain an oily intermediate, adding trimethylchlorosilane (252 mL,2 mol), reacting at room temperature for 24 hours, distilling and purifying after the reaction is completed, and collecting fractions to obtain colorless oily compound 1 (235 g), wherein the yield is 86%;
b. Preparation of 2- (4-ethylphenyl) -2-methylpropanoic acid:
to a reactor equipped with a condensing unit under argon gas protection, magnesium metal (25 g,1.04 mol), iodine (2.5 g,10 mmol) and tetrahydrofuran (600 mL) were added, and after refluxing under heating for 1 hour, a solution of 1- (2-chloropropane-2-yl) -4-ethylbenzene (182 g,1 mol) and tetrahydrofuran (300 mL) was slowly added dropwise, and the reaction was initiated by heating after about 50mL was added dropwise, followed by dropwise addition under ice water bath. After the completion of the dropwise addition, the mixture was refluxed for 5 hours. The above solution was cooled to-20 ℃, dried carbon dioxide gas was introduced, and after about 5 hours of reaction, saturated aqueous ammonium chloride and ethyl acetate were added, then the pH of the reaction system was adjusted to 2-3 with hydrochloric acid, the organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, the organic solvent was removed by distillation, and the obtained residue was recrystallized from petroleum ether and ethyl acetate to give 2- (4-ethylphenyl) -2-methylpropanoic acid (160 g) as a white solid, yield: 83%;
c. preparation of the product 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid:
2- (4-ethylphenyl) -2-methylpropanoic acid (96.2 g,0.5 mol), glacial acetic acid (300 mL), elemental iodine (76.1 g, 0.3 mol), concentrated sulfuric acid (35 mL) and potassium permanganate (79.0 g,0.5 mol) were charged into a reactor equipped with a condensing reflux apparatus at normal temperature. Heating to 100 ℃ for reaction for 6 hours, dropwise adding a proper amount of saturated sodium sulfite aqueous solution, adding a proper amount of ethyl acetate and water, stirring, standing, washing an organic phase with a proper amount of saturated sodium bicarbonate aqueous solution and sodium chloride aqueous solution sequentially, and distilling to remove ethyl acetate to obtain a product 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid crude product; recrystallisation with water and ethanol (1:2), filtration and washing with water and ethanol (1:2) gave the product, 142g, yield of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid: 89%.
Example 3:
a method for synthesizing an anetinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid comprises the following steps:
a. preparation of 2-chloro-2- (4-ethylphenyl) propane:
4-Ethylacetophenone (148 g,1 mol) was dissolved in tetrahydrofuran (500 mL) under argon, cooled to-5℃and methyl magnesium chloride (550 mL,2 mol/L) was slowly added dropwise to the above solution, stirred at-5℃for 1 hour after the addition was completed, and then allowed to react at room temperature for 3 hours. After the reaction, water and ethyl acetate were added, and the organic phase was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase was concentrated to give an oily intermediate, which was added with a dichloromethane solution of thionyl chloride (109 mL,1.5 mol) and heated under reflux for 2 hours. After the completion of the reaction, water and ethyl acetate were added, and the organic phase was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The resulting mixture was purified by distillation, and fractions were collected to give 2-chloro-2- (4-ethylphenyl) propane (140 g) as a colorless oily compound in 77% yield.
b. Preparation of 2- (4-ethylphenyl) -2-methylpropanoic acid:
magnesium (25 g,1.04 mol), bromine (1.6 g,10 mmol) and diethyl ether (800 mL) were added to a reactor equipped with a condensing unit under nitrogen protection, and after refluxing for 1 hour, a solution of 1- (2-chloropropane-2-yl) -4-ethylbenzene (182 g,1 mol) and diethyl ether (500 mL) was slowly added dropwise, followed by initiation of the reaction by heating after about 50mL was added dropwise, and then dropwise under an ice-water bath. After the completion of the dropwise addition, the mixture was refluxed for 5 hours. The above solution was cooled to-20 ℃, dried carbon dioxide was introduced, and after about 5 hours of reaction, a saturated aqueous ammonium chloride solution was added, then the pH of the reaction system was adjusted to 2-3 with hydrochloric acid, the organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, the organic solvent was distilled off, and the obtained residue was recrystallized from water and ethanol to give 2- (4-ethylphenyl) -2-methylpropanoic acid (152 g) as a white solid, yield: 79%;
c. Preparation of the product 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid:
2- (4-ethylphenyl) -2-methylpropanoic acid (38.4 g,0.2 mol), glacial acetic acid (100 mL) and N-iodosuccinimide (56.2 g,0.25 mol) were added to the reaction flask at room temperature, the temperature was lowered to about 5℃and concentrated sulfuric acid (10 mL) was added dropwise, followed by reaction at room temperature for 5 hours after the completion of the dropwise addition. After the reaction is finished, a proper amount of saturated sodium sulfite aqueous solution is dropwise added, a proper amount of ice water is added, a large amount of white solid is separated out, the mixture solution of water and ethanol (1:1) is filtered and washed, the crude product of the product 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid is obtained, and 59g of the product 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid is obtained by recrystallization with petroleum ether, and the yield is obtained: 92%.
Example 4:
a synthesis method of an anetinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid comprises the following steps:
a. preparation of 2-halo-2- (4-ethylphenyl) propane:
under the protection of inert gas, 4-ethyl acetophenone reacts with a methyl format reagent to obtain 2- (4-ethylphenyl) -2-propanol; then treating with halogenated reagent to obtain 2-halogen-2- (4-ethylphenyl) propane (shown in formula 1, wherein X represents halogen atom and comprises chlorine, bromine and iodine); the chemical reaction process is as follows:
b. Preparation of 2- (4-ethylphenyl) -2-methylpropanoic acid:
preparing the obtained 2-halogen-2- (4-ethylphenyl) propane into a format reagent, and then introducing carbon dioxide to obtain 2- (4-ethylphenyl) -2-methylpropanoic acid (shown in formula 2); the chemical reaction process is as follows:
c. preparation of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid:
iodination reaction is carried out between elemental iodine or N-iodosuccinimide (NIS for short) and 2- (4-ethylphenyl) -2-methylpropanoic acid to prepare the intermediate of the alcaine, namely 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid (shown in formula 3), wherein the chemical reaction process is as follows:
example 5:
a method for synthesizing an anetinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid comprises the following steps:
a. preparation of 2-halo-2- (4-ethylphenyl) propane:
under the protection of inert gas, dissolving 4-ethyl acetophenone into a solvent to form a solution, cooling to-5 ℃, dropwise adding a methyl format reagent (slowly) into the solution, reacting at-5 ℃ for 10 hours after dropwise adding, adding water and an organic solvent after reaction, washing an organic phase by a saturated sodium chloride solution after liquid separation, drying by anhydrous sodium sulfate, concentrating the organic phase to obtain an oily intermediate, adding a halogenated reagent, reacting at room temperature or under heating, distilling (purifying) after the reaction is finished, and collecting fractions to obtain the prepared 2-halogen-2- (4-ethyl phenyl) propane (shown in formula 1);
The methyl format reagent is one or a mixture of more than two of methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide;
the solvent is one or more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, 1, 4-dioxane and toluene;
the halogenating reagent is any one of trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, hydrochloric acid, hydrobromic acid and thionyl chloride;
b. preparation of 2- (4-ethylphenyl) -2-methylpropanoic acid:
under the protection of inert gas, adding magnesium metal, an initiator and a solvent A into a reactor provided with a condensing device, heating and refluxing for 0.5 hour, then (slowly) dropwise adding a solution prepared by 2-halogen-2- (4-ethylphenyl) propane (shown in formula 1) and the solvent A, and reacting at 50 ℃ for 5 hours after the dropwise adding is finished to obtain a solution containing 2- (4-ethylphenyl) propyl magnesium halide intermediate; cooling the intermediate solution containing 2- (4-ethylphenyl) propyl magnesium halide to-20 ℃, introducing dry carbon dioxide gas, controlling the reaction temperature to be not more than 35 ℃, reacting for about 5 hours, adding (proper amount of) saturated ammonium chloride aqueous solution, then adjusting the pH value of the reaction system to 2 by hydrochloric acid, washing an organic phase by saturated sodium chloride aqueous solution, drying by anhydrous sodium sulfate, distilling (removing the organic solvent), and recrystallizing the obtained residue by the solvent B to obtain 2- (4-ethylphenyl) -2-methylpropanoic acid;
The 2-halogen-2- (4-ethylphenyl) propane is any one of 2-chloro-2- (4-ethylphenyl) propane, 2-bromo-2- (4-ethylphenyl) propane and 2-iodo-2- (4-ethylphenyl) propane;
the solvent A is one or a mixture of more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and toluene;
the solvent B is one or more than two of petroleum ether, n-hexane, cyclohexane, n-heptane, ethyl acetate, dichloromethane, methanol, ethanol and water;
the initiator is one or a mixture of more than two of elemental iodine, bromine, 1, 2-dibromoethane, methyl magnesium halide and ethyl magnesium halide;
c. preparation of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid:
adding 2- (4-ethylphenyl) -2-methylpropanoic acid, a solvent C, a catalyst, an oxidant and an iodination reagent into a reactor with a condensing reflux device at normal temperature, reacting for 24 hours at 0 ℃, dropwise adding a (proper amount) of saturated sodium sulfite aqueous solution until the brown color of the reaction liquid is completely removed to be colorless, adding a (proper amount) of ethyl acetate, stirring, standing, washing the organic phase with a (proper amount) of saturated sodium chloride aqueous solution and a (proper amount) of sodium chloride aqueous solution respectively for one time, drying with a (proper amount) of anhydrous sodium sulfate, filtering, distilling the filtrate to remove ethyl acetate, and recrystallizing with a (proper amount) of solvent D to obtain a product 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid;
The solvent C is one or a mixture of more than two of acetic acid, acetonitrile, methanol and ethanol;
the solvent D is petroleum ether, C 5 ～C 10 One or more of linear, branched and cyclic hydrocarbons, ethyl acetate, methylene chloride methanol, ethanol and water;
the catalyst is sulfuric acid or methanesulfonic acid;
the oxidant is one or a mixture of more than two of nitric acid, periodic acid, potassium permanganate, manganese dioxide and hydrogen peroxide;
the iodination reagent is elemental iodine or N-iodinated succinimide.
Example 6:
a method for synthesizing an anetinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid comprises the following steps:
a. preparation of 2-halo-2- (4-ethylphenyl) propane:
under the protection of inert gas, dissolving 4-ethyl acetophenone into a solvent to form a solution, cooling to 5 ℃, dropwise adding a methyl format reagent into the solution (slowly), reacting for 1 hour at room temperature after the dropwise adding is finished, adding water and an organic solvent after the reaction is finished, washing an organic phase by a saturated sodium chloride solution, drying by anhydrous sodium sulfate, concentrating the organic phase to obtain an oily intermediate, adding a halogenated reagent, reacting at room temperature or by heating, distilling (purifying) after the reaction (finishing), and collecting fractions to obtain the prepared 2-halogen-2- (4-ethylphenyl) propane (shown in formula 1);
The methyl format reagent is one or a mixture of more than two of methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide;
the solvent is one or more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, 1, 4-dioxane and toluene;
the halogenating reagent is any one of trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, hydrochloric acid, hydrobromic acid and thionyl chloride;
b. preparation of 2- (4-ethylphenyl) -2-methylpropanoic acid:
under the protection of inert gas, adding magnesium metal, an initiator and a solvent A into a reactor provided with a condensing device, heating and refluxing for 2 hours, and then (slowly) dropwise adding a solution prepared by 2-halogen-2- (4-ethylphenyl) propane (shown in formula 1) and the solvent A, and reacting at 80 ℃ for 2 hours after the dropwise adding is finished to obtain a solution containing 2- (4-ethylphenyl) propyl magnesium halide intermediate; cooling the intermediate solution containing 2- (4-ethylphenyl) propyl magnesium halide to 0 ℃, introducing dry carbon dioxide gas, controlling the reaction temperature to be not higher than 35 ℃, reacting for about 5 hours, adding (proper amount of) saturated ammonium chloride aqueous solution, then adjusting the pH value of the reaction system to 3 by hydrochloric acid, washing an organic phase by saturated sodium chloride aqueous solution, drying by anhydrous sodium sulfate, distilling (removing the organic solvent), and recrystallizing the obtained residue by the solvent B to obtain 2- (4-ethylphenyl) -2-methylpropanoic acid;
The 2-halogen-2- (4-ethylphenyl) propane is any one of 2-chloro-2- (4-ethylphenyl) propane, 2-bromo-2- (4-ethylphenyl) propane and 2-iodo-2- (4-ethylphenyl) propane;
the solvent A is one or a mixture of more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and toluene;
the solvent B is one or more than two of petroleum ether, n-hexane, cyclohexane, n-heptane, ethyl acetate, dichloromethane, methanol, ethanol and water;
the initiator is one or a mixture of more than two of elemental iodine, bromine, 1, 2-dibromoethane, methyl magnesium halide and ethyl magnesium halide;
c. preparation of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid:
adding 2- (4-ethylphenyl) -2-methylpropanoic acid, a solvent C, a catalyst, an oxidant and an iodination reagent into a reactor with a condensing reflux device at normal temperature, reacting for 6 hours at 100 ℃, dropwise adding a (proper amount) of saturated sodium sulfite aqueous solution until the brown color of the reaction liquid is completely removed to be colorless, adding a (proper amount) of ethyl acetate, stirring, standing, washing the organic phase with a (proper amount) of saturated sodium chloride aqueous solution and a (proper amount) of sodium chloride aqueous solution respectively for one time, drying with a (proper amount) of anhydrous sodium sulfate, filtering, distilling the filtrate to remove ethyl acetate, and recrystallizing with a (proper amount) of solvent D to obtain a product 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid;
The solvent C is one or a mixture of more than two of acetic acid, acetonitrile, methanol and ethanol;
the solvent D is petroleum ether, C 5 ～C 10 One or more of linear, branched and cyclic hydrocarbons, ethyl acetate, methylene chloride methanol, ethanol and water;
the catalyst is sulfuric acid or methanesulfonic acid;
the oxidant is one or a mixture of more than two of nitric acid, periodic acid, potassium permanganate, manganese dioxide and hydrogen peroxide;
the iodination reagent is elemental iodine or N-iodinated succinimide.
Example 7:
a method for synthesizing an anetinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid comprises the following steps:
a. preparation of 2-halo-2- (4-ethylphenyl) propane:
under the protection of inert gas, dissolving 4-ethyl acetophenone into a solvent to form a solution, cooling to 2 ℃, dropwise adding a methyl format reagent into the solution (slowly), reacting for 4 hours at room temperature after the dropwise adding is finished, adding water and an organic solvent after the reaction is finished, washing an organic phase by a saturated sodium chloride solution, drying by anhydrous sodium sulfate, concentrating the organic phase to obtain an oily intermediate, adding a halogenated reagent, reacting at room temperature or heating, distilling (purifying) after the reaction (finishing), and collecting fractions to obtain the prepared 2-halogen-2- (4-ethylphenyl) propane (shown in formula 1);
The methyl format reagent is one or a mixture of more than two of methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide;
the solvent is one or more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, 1, 4-dioxane and toluene;
the halogenating reagent is any one of trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, hydrochloric acid, hydrobromic acid and thionyl chloride;
b. preparation of 2- (4-ethylphenyl) -2-methylpropanoic acid:
under the protection of inert gas, adding magnesium metal, an initiator and a solvent A into a reactor provided with a condensing device, heating and refluxing for 1 hour, and then (slowly) dropwise adding a solution prepared by 2-halogen-2- (4-ethylphenyl) propane (shown in formula 1) and the solvent A, and reacting at 70 ℃ for 3 hours after the dropwise adding is finished to obtain a solution containing 2- (4-ethylphenyl) propyl magnesium halide intermediate; cooling the intermediate solution containing 2- (4-ethylphenyl) propyl magnesium halide to-9 ℃, introducing dry carbon dioxide gas, controlling the reaction temperature to be not higher than 35 ℃, reacting for about 7 hours, adding (proper amount of) saturated ammonium chloride aqueous solution, then adjusting the pH value of the reaction system to 2.5 by hydrochloric acid, washing an organic phase by saturated sodium chloride aqueous solution, drying by anhydrous sodium sulfate, distilling (removing the organic solvent), and recrystallizing the obtained residue by the solvent B to obtain 2- (4-ethylphenyl) -2-methylpropanoic acid;
The 2-halogen-2- (4-ethylphenyl) propane is any one of 2-chloro-2- (4-ethylphenyl) propane, 2-bromo-2- (4-ethylphenyl) propane and 2-iodo-2- (4-ethylphenyl) propane;
the solvent A is one or a mixture of more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and toluene;
the solvent B is one or more than two of petroleum ether, n-hexane, cyclohexane, n-heptane, ethyl acetate, dichloromethane, methanol, ethanol and water;
the initiator is one or a mixture of more than two of elemental iodine, bromine, 1, 2-dibromoethane, methyl magnesium halide and ethyl magnesium halide;
c. preparation of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid:
adding 2- (4-ethylphenyl) -2-methylpropanoic acid, a solvent C, a catalyst, an oxidant and an iodination reagent into a reactor with a condensing reflux device at normal temperature, reacting for 15 hours at 50 ℃, dropwise adding a (proper amount) of saturated sodium sulfite aqueous solution until the brown color of the reaction liquid is completely removed to be colorless, adding a (proper amount) of ethyl acetate, stirring, standing, washing the organic phase with a (proper amount) of saturated sodium chloride aqueous solution and a (proper amount) of sodium chloride aqueous solution respectively for one time, drying with a (proper amount) of anhydrous sodium sulfate, filtering, distilling the filtrate to remove ethyl acetate, and recrystallizing with a (proper amount) of solvent D to obtain a product 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid;
The solvent C is one or a mixture of more than two of acetic acid, acetonitrile, methanol and ethanol;
the solvent D is petroleum ether, C 5 ～C 10 One or more of linear, branched and cyclic hydrocarbons, ethyl acetate, methylene chloride methanol, ethanol and water;
the catalyst is sulfuric acid or methanesulfonic acid;
the oxidant is one or a mixture of more than two of nitric acid, periodic acid, potassium permanganate, manganese dioxide and hydrogen peroxide;
the iodination reagent is elemental iodine or N-iodinated succinimide.
Example 8:
a method for synthesizing an anetinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid comprises the following steps:
a. preparation of 2-halo-2- (4-ethylphenyl) propane:
under the protection of inert gas, dissolving 4-ethyl acetophenone into a solvent to form a solution, cooling to-5 ℃, dropwise adding a methyl format reagent (slowly) into the solution, reacting at-5 ℃ for 10 hours after dropwise adding, adding water and an organic solvent after reaction, washing an organic phase by a saturated sodium chloride solution after liquid separation, drying by anhydrous sodium sulfate, concentrating the organic phase to obtain an oily intermediate, adding a halogenated reagent, reacting at room temperature or under heating, distilling (purifying) after the reaction is finished, and collecting fractions to obtain the prepared 2-halogen-2- (4-ethyl phenyl) propane (shown in formula 1);
The molar ratio of the 4-ethylacetophenone to the methyl format reagent is 1:1;
the molar ratio of the 4-ethylacetophenone to the halogenated reagent is 1:1;
the methyl format reagent is one or a mixture of more than two of methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide;
the solvent is one or more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, 1, 4-dioxane and toluene;
the halogenating reagent is any one of trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, hydrochloric acid, hydrobromic acid and thionyl chloride;
b. preparation of 2- (4-ethylphenyl) -2-methylpropanoic acid:
under the protection of inert gas, adding magnesium metal, an initiator and a solvent A into a reactor provided with a condensing device, heating and refluxing for 0.5 hour, then (slowly) dropwise adding a solution prepared by 2-halogen-2- (4-ethylphenyl) propane (shown in formula 1) and the solvent A, and reacting at 50 ℃ for 5 hours after the dropwise adding is finished to obtain a solution containing 2- (4-ethylphenyl) propyl magnesium halide intermediate; cooling the intermediate solution containing 2- (4-ethylphenyl) propyl magnesium halide to-20 ℃, introducing dry carbon dioxide gas, controlling the reaction temperature to be not higher than 35 ℃, reacting for about 5 hours, adding (proper amount of) saturated ammonium chloride aqueous solution, then adjusting the pH value of the reaction system to 3 by hydrochloric acid, washing an organic phase by saturated sodium chloride aqueous solution, drying by anhydrous sodium sulfate, distilling (removing the organic solvent), and recrystallizing the obtained residue by the solvent B to obtain 2- (4-ethylphenyl) -2-methylpropanoic acid;
The molar ratio of the 2-halogen-2- (4-ethylphenyl) propane to the metal magnesium is 1:1;
the molar ratio of the 2-halogen-2- (4-ethylphenyl) propane to the initiator is 100:0.3;
the 2-halogen-2- (4-ethylphenyl) propane is any one of 2-chloro-2- (4-ethylphenyl) propane, 2-bromo-2- (4-ethylphenyl) propane and 2-iodo-2- (4-ethylphenyl) propane;
the solvent A is one or a mixture of more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and toluene;
the solvent B is one or more than two of petroleum ether, n-hexane, cyclohexane, n-heptane, ethyl acetate, dichloromethane, methanol, ethanol and water;
the initiator is one or a mixture of more than two of elemental iodine, bromine, 1, 2-dibromoethane, methyl magnesium halide and ethyl magnesium halide;
c. preparation of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid:
adding 2- (4-ethylphenyl) -2-methylpropanoic acid, a solvent C, a catalyst, an oxidant and an iodination reagent into a reactor with a condensing reflux device at normal temperature, reacting for 24 hours at 0 ℃, dropwise adding a (proper amount) of saturated sodium sulfite aqueous solution until the brown color of the reaction liquid is completely removed to be colorless, adding a (proper amount) of ethyl acetate, stirring, standing, washing the organic phase with a (proper amount) of saturated sodium chloride aqueous solution and a (proper amount) of sodium chloride aqueous solution respectively for one time, drying with a (proper amount) of anhydrous sodium sulfate, filtering, distilling the filtrate to remove ethyl acetate, and recrystallizing with a (proper amount) of solvent D to obtain a product 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid;
The molar ratio of the 2- (4-ethylphenyl) -2-methylpropanoic acid (shown in the formula 3) to the elemental iodine is 1:0.5, and the molar ratio of the 2- (4-ethylphenyl) -2-methylpropanoic acid to the N-iodosuccinimide (NIS for short) is 1:1;
the molar ratio of the catalyst to the 2- (4-ethylphenyl) -2-methylpropanoic acid is 1:1;
the molar ratio of the oxidant to the 2- (4-ethylphenyl) -2-methylpropanoic acid is 1:0.1;
the solvent C is one or a mixture of more than two of acetic acid, acetonitrile, methanol and ethanol;
the solvent D is stoneOil ether, C 5 ～C 10 One or more of linear, branched and cyclic hydrocarbons, ethyl acetate, methylene chloride methanol, ethanol and water;
the catalyst is sulfuric acid or methanesulfonic acid;
the oxidant is one or a mixture of more than two of nitric acid, periodic acid, potassium permanganate, manganese dioxide and hydrogen peroxide;
the iodination reagent is elemental iodine or N-iodinated succinimide.
Example 9:
a method for synthesizing an anetinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid comprises the following steps:
a. preparation of 2-halo-2- (4-ethylphenyl) propane:
under the protection of inert gas, dissolving 4-ethyl acetophenone into a solvent to form a solution, cooling to 5 ℃, dropwise adding a methyl format reagent into the solution (slowly), reacting for 1 hour at room temperature after the dropwise adding is finished, adding water and an organic solvent after the reaction is finished, washing an organic phase by a saturated sodium chloride solution, drying by anhydrous sodium sulfate, concentrating the organic phase to obtain an oily intermediate, adding a halogenated reagent, reacting at room temperature or by heating, distilling (purifying) after the reaction (finishing), and collecting fractions to obtain the prepared 2-halogen-2- (4-ethylphenyl) propane (shown in formula 1);
The molar ratio of the 4-ethylacetophenone to the methyl format reagent is 1:3;
the molar ratio of the 4-ethylacetophenone to the halogenated reagent is 1:10;
the methyl format reagent is one or a mixture of more than two of methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide;
the solvent is one or more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, 1, 4-dioxane and toluene;
the halogenating reagent is any one of trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, hydrochloric acid, hydrobromic acid and thionyl chloride;
b. preparation of 2- (4-ethylphenyl) -2-methylpropanoic acid:
under the protection of inert gas, adding magnesium metal, an initiator and a solvent A into a reactor provided with a condensing device, heating and refluxing for 2 hours, and then (slowly) dropwise adding a solution prepared by 2-halogen-2- (4-ethylphenyl) propane (shown in formula 1) and the solvent A, and reacting at 80 ℃ for 2 hours after the dropwise adding is finished to obtain a solution containing 2- (4-ethylphenyl) propyl magnesium halide intermediate; cooling the intermediate solution containing 2- (4-ethylphenyl) propyl magnesium halide to 0 ℃, introducing dry carbon dioxide gas, controlling the reaction temperature to be not higher than 35 ℃, reacting for about 10 hours, adding (proper amount of) saturated ammonium chloride aqueous solution, then adjusting the pH value of the reaction system to 2 by hydrochloric acid, washing an organic phase by saturated sodium chloride aqueous solution, drying by anhydrous sodium sulfate, distilling (removing the organic solvent), and recrystallizing the obtained residue by the solvent B to obtain 2- (4-ethylphenyl) -2-methylpropanoic acid;
The molar ratio of the 2-halogen-2- (4-ethylphenyl) propane to the metal magnesium is 1:2;
the molar ratio of the 2-halogen-2- (4-ethylphenyl) propane to the initiator is 100:5;
the 2-halogen-2- (4-ethylphenyl) propane is any one of 2-chloro-2- (4-ethylphenyl) propane, 2-bromo-2- (4-ethylphenyl) propane and 2-iodo-2- (4-ethylphenyl) propane;
the solvent A is one or a mixture of more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and toluene;
the solvent B is one or more than two of petroleum ether, n-hexane, cyclohexane, n-heptane, ethyl acetate, dichloromethane, methanol, ethanol and water;
the initiator is one or a mixture of more than two of elemental iodine, bromine, 1, 2-dibromoethane, methyl magnesium halide and ethyl magnesium halide;
c. preparation of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid:
adding 2- (4-ethylphenyl) -2-methylpropanoic acid, a solvent C, a catalyst, an oxidant and an iodination reagent into a reactor with a condensing reflux device at normal temperature, reacting for 6 hours at 100 ℃, dropwise adding a (proper amount) of saturated sodium sulfite aqueous solution until the brown color of the reaction liquid is completely removed to be colorless, adding a (proper amount) of ethyl acetate, stirring, standing, washing the organic phase with a (proper amount) of saturated sodium chloride aqueous solution and a (proper amount) of sodium chloride aqueous solution respectively for one time, drying with a (proper amount) of anhydrous sodium sulfate, filtering, distilling the filtrate to remove ethyl acetate, and recrystallizing with a (proper amount) of solvent D to obtain a product 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid;
The molar ratio of the 2- (4-ethylphenyl) -2-methylpropanoic acid to the elemental iodine is 1:1.5, and the molar ratio of the 2- (4-ethylphenyl) -2-methylpropanoic acid to the N-iodosuccinimide (NIS for short) is 1:2;
the molar ratio of the catalyst to the 2- (4-ethylphenyl) -2-methylpropanoic acid is 1:10;
the molar ratio of the oxidant to the 2- (4-ethylphenyl) -2-methylpropanoic acid is 1:2;
the solvent C is one or a mixture of more than two of acetic acid, acetonitrile, methanol and ethanol;
the solvent D is petroleum ether, C 5 ～C 10 One or more of linear, branched and cyclic hydrocarbons, ethyl acetate, methylene chloride methanol, ethanol and water;
the catalyst is sulfuric acid or methanesulfonic acid;
the oxidant is one or a mixture of more than two of nitric acid, periodic acid, potassium permanganate, manganese dioxide and hydrogen peroxide;
the iodination reagent is elemental iodine or N-iodinated succinimide.
Example 10:
a method for synthesizing an anetinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid comprises the following steps:
a. preparation of 2-halo-2- (4-ethylphenyl) propane:
under the protection of inert gas, dissolving 4-ethyl acetophenone into a solvent to form a solution, cooling to 3 ℃, dropwise adding a methyl format reagent into the solution (slowly), reacting for 5 hours at room temperature after the dropwise adding is finished, adding water and an organic solvent after the reaction is finished, washing an organic phase by a saturated sodium chloride solution, drying by anhydrous sodium sulfate, concentrating the organic phase to obtain an oily intermediate, adding a halogenated reagent, reacting at room temperature or by heating, distilling (purifying) after the reaction (finishing), and collecting fractions to obtain the prepared 2-halogen-2- (4-ethylphenyl) propane (shown in formula 1);
The molar ratio of the 4-ethylacetophenone to the methyl format reagent is 1:2;
the molar ratio of the 4-ethylacetophenone to the halogenated reagent is 1:5;
the methyl format reagent is one or a mixture of more than two of methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide;
the solvent is one or more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, 1, 4-dioxane and toluene;
the halogenating reagent is any one of trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, hydrochloric acid, hydrobromic acid and thionyl chloride;
b. preparation of 2- (4-ethylphenyl) -2-methylpropanoic acid:
under the protection of inert gas, adding magnesium metal, an initiator and a solvent A into a reactor provided with a condensing device, heating and refluxing for 1 hour, then (slowly) dropwise adding a solution prepared by 2-halogen-2- (4-ethylphenyl) propane and the solvent A, and reacting at 75 ℃ for 3.5 hours after the dropwise adding is finished to obtain a solution containing 2- (4-ethylphenyl) propyl magnesium halide intermediate; cooling the intermediate solution containing 2- (4-ethylphenyl) propyl magnesium halide to-10 ℃, introducing dry carbon dioxide gas, controlling the reaction temperature to be not higher than 35 ℃, reacting for about 7.5 hours, adding (proper amount of) saturated ammonium chloride aqueous solution, then adjusting the pH value of the reaction system to 2.5 by hydrochloric acid, washing an organic phase by saturated sodium chloride aqueous solution, drying by anhydrous sodium sulfate, distilling (removing the organic solvent), and recrystallizing the obtained residue by the solvent B to obtain 2- (4-ethylphenyl) -2-methylpropanoic acid;
The molar ratio of the 2-halogen-2- (4-ethylphenyl) propane to the metal magnesium is 1:1.5;
the molar ratio of the 2-halogen-2- (4-ethylphenyl) propane to the initiator is 100:2.6;
the 2-halo-2- (4-ethylphenyl) propane may be any of 2-chloro-2- (4-ethylphenyl) propane, 2-bromo-2- (4-ethylphenyl) propane, 2-iodo-2- (4-ethylphenyl) propane;
the solvent A is one or a mixture of more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and toluene;
the solvent B is one or more than two of petroleum ether, n-hexane, cyclohexane, n-heptane, ethyl acetate, dichloromethane, methanol, ethanol and water;
the initiator is one or a mixture of more than two of elemental iodine, bromine, 1, 2-dibromoethane, methyl magnesium halide and ethyl magnesium halide;
c. preparation of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid:
adding 2- (4-ethylphenyl) -2-methylpropanoic acid, a solvent C, a catalyst, an oxidant and an iodination reagent into a reactor with a condensing reflux device at normal temperature, reacting for 15 hours at 50 ℃, dropwise adding a (proper amount) of saturated sodium sulfite aqueous solution until the brown color of the reaction liquid is completely removed to be colorless, adding a (proper amount) of ethyl acetate, stirring, standing, washing the organic phase with a (proper amount) of saturated sodium chloride aqueous solution and a (proper amount) of sodium chloride aqueous solution respectively for one time, drying with a (proper amount) of anhydrous sodium sulfate, filtering, distilling the filtrate to remove ethyl acetate, and recrystallizing with a (proper amount) of solvent D to obtain a product 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid;
The molar ratio of the 2- (4-ethylphenyl) -2-methylpropanoic acid to the elemental iodine is 1:1, and the molar ratio of the 2- (4-ethylphenyl) -2-methylpropanoic acid to the N-iodosuccinimide (NIS for short) is 1:1.5;
the molar ratio of the catalyst to the 2- (4-ethylphenyl) -2-methylpropanoic acid is 1:5;
the molar ratio of the oxidant to the 2- (4-ethylphenyl) -2-methylpropanoic acid is 1:1;
the solvent C is one or a mixture of more than two of acetic acid, acetonitrile, methanol and ethanol;
the solvent D is petroleum ether, C 5 ～C 10 Straight chain, branched chain and ring of (2)One or more of ethyl acetate, dichloromethane methanol, ethanol and water;
the catalyst is sulfuric acid or methanesulfonic acid;
the oxidant is one or a mixture of more than two of nitric acid, periodic acid, potassium permanganate, manganese dioxide and hydrogen peroxide;
the iodination reagent is elemental iodine or N-iodinated succinimide.
In examples 4-10 above: the inert gas is nitrogen or argon.
In examples 4-10 above: the amount of the solvent used in each step may be 2 to 10 times the total mass amount of the other raw materials used in the step, and the appropriate amount may be determined as required, as will be understood and practiced by those skilled in the art.
In the above embodiment: the percentages used are not particularly indicated, and are all percentages by mass (weight) or percentages known to those skilled in the art; the proportions used are not particularly specified, but are mass (weight) proportions; the parts by weight may all be g or kg.
In the above embodiment: the process parameters (temperature, time, concentration, etc.) and the amount of each component in each step are within the range, and any point is applicable.
The technical contents of the invention and the technical contents not specifically described in the above embodiments are the same as the prior art, and the raw materials are all commercial products.
The present invention is not limited to the above-described embodiments, and the present invention can be implemented with the above-described advantageous effects.
Claims (2)
1. A synthesis method of an anetinib hydrochloride intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid is characterized by comprising the following steps:
a. preparation of 2-halo-2- (4-ethylphenyl) propane:
under the protection of inert gas, dissolving 4-ethyl acetophenone into a solvent to form a solution, cooling to-5 ℃, dropwise adding a methyl format reagent into the solution, reacting for 1-10 hours at-5 ℃ and room temperature after the dropwise adding is finished, adding water and an organic solvent after the reaction is finished, washing an organic phase by a saturated sodium chloride solution, drying by anhydrous sodium sulfate, concentrating the organic phase to obtain an oily intermediate, adding a halogenated reagent, reacting at room temperature or by heating, distilling after the reaction, and collecting fractions to obtain the prepared 2-halogen-2- (4-ethylphenyl) propane;
The methyl format reagent is one or a mixture of more than two of methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide;
the solvent is one or more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, 1, 4-dioxane and toluene;
the halogenating reagent is any one of trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, hydrochloric acid, hydrobromic acid and thionyl chloride;
the molar ratio of the 4-ethylacetophenone to the methyl format reagent is 1:1-1:3;
the molar ratio of the 4-ethylacetophenone to the halogenated reagent is 1:1-1:10;
b. preparation of 2- (4-ethylphenyl) -2-methylpropanoic acid:
under the protection of inert gas, adding magnesium metal, an initiator and a solvent A into a reactor provided with a condensing device, heating and refluxing for 0.5-2 hours, then dropwise adding a solution prepared by 2-halogen-2- (4-ethylphenyl) propane and the solvent A, and reacting at 50-80 ℃ for 2-5 hours after the dropwise adding is finished to obtain a solution containing 2- (4-ethylphenyl) propyl magnesium halide intermediate; cooling the intermediate solution containing 2- (4-ethylphenyl) propyl magnesium halide to-20-0 ℃, introducing dry carbon dioxide gas, controlling the reaction temperature to be not higher than 35 ℃, reacting for 5-10 hours, adding saturated ammonium chloride aqueous solution, then adjusting the pH value of the reaction system to 2-3 by hydrochloric acid, washing an organic phase by saturated sodium chloride aqueous solution, drying by anhydrous sodium sulfate, distilling, and recrystallizing the obtained residue by a solvent B to obtain 2- (4-ethylphenyl) -2-methylpropanoic acid;
The 2-halogen-2- (4-ethylphenyl) propane is any one of 2-chloro-2- (4-ethylphenyl) propane, 2-bromo-2- (4-ethylphenyl) propane and 2-iodo-2- (4-ethylphenyl) propane;
the solvent A is one or a mixture of more than two of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and toluene;
the solvent B is one or more than two of petroleum ether, n-hexane, cyclohexane, n-heptane, ethyl acetate, dichloromethane, methanol, ethanol and water;
the initiator is one or a mixture of more than two of elemental iodine, bromine, 1, 2-dibromoethane, methyl magnesium halide and ethyl magnesium halide;
the molar ratio of the 2-halogen-2- (4-ethylphenyl) propane to the metal magnesium is 1:1-1:2;
the molar ratio of the 2-halogen-2- (4-ethylphenyl) propane to the initiator is 100:0.3-100:5;
c. preparation of 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid:
adding 2- (4-ethylphenyl) -2-methylpropanoic acid, a solvent C, a catalyst, an oxidant and an iodination reagent into a reactor with a condensing reflux device at normal temperature, reacting for 6-24 hours at 0-100 ℃, dropwise adding a saturated sodium sulfite aqueous solution until the brown color of the reaction liquid is completely removed to be colorless, adding ethyl acetate, stirring, standing, washing an organic phase with a saturated sodium chloride aqueous solution and a sodium chloride aqueous solution respectively for one time, drying with anhydrous sodium sulfate, filtering, distilling the filtrate to remove the ethyl acetate, and recrystallizing with a solvent D to obtain the product 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid;
The solvent C is one or a mixture of more than two of acetic acid, acetonitrile, methanol and ethanol;
the solvent D is petroleum ether, C 5 ～C 10 One or more of linear, branched and cyclic hydrocarbons, ethyl acetate, methylene chloride, methanol, ethanol and water;
the catalyst is sulfuric acid or methanesulfonic acid
The oxidant is one or a mixture of more than two of nitric acid, periodic acid, potassium permanganate, manganese dioxide and hydrogen peroxide;
the iodination reagent is elemental iodine or N-iodinated succinimide;
the molar ratio of the 2- (4-ethylphenyl) -2-methylpropanoic acid to the elemental iodine is 1:0.5-1:1.5, and the molar ratio of the 2- (4-ethylphenyl) -2-methylpropanoic acid to the N-iodosuccinimide is 1:1-1:2;
the mol ratio of the catalyst to the 2- (4-ethylphenyl) -2-methylpropanoic acid is 1:1-1:10;
the mol ratio of the oxidant to the 2- (4-ethylphenyl) -2-methylpropanoic acid is 1:0.1-1:2.
2. A process for the synthesis of the intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid, as defined in claim 1, wherein: the inert gas is nitrogen or argon.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202010895334.5A CN112047829B (en) | 2020-08-31 | 2020-08-31 | Synthesis method of alcaine intermediate 2- (4-ethyl-3-iodophenyl) -2-methylpropanoic acid |
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