CN109384664A - A kind of Ai Le replaces the preparation method of Buddhist nun's intermediate - Google Patents
A kind of Ai Le replaces the preparation method of Buddhist nun's intermediate Download PDFInfo
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- CN109384664A CN109384664A CN201811370734.3A CN201811370734A CN109384664A CN 109384664 A CN109384664 A CN 109384664A CN 201811370734 A CN201811370734 A CN 201811370734A CN 109384664 A CN109384664 A CN 109384664A
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- Prior art keywords
- compound
- ethyl
- buddhist nun
- iodine
- phenyl
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 98
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 95
- 239000011630 iodine Substances 0.000 claims abstract description 95
- 238000006243 chemical reaction Methods 0.000 claims abstract description 92
- YYEROYLAYAVZNW-UHFFFAOYSA-N 2-methyl-2-phenylpropanoic acid Chemical compound OC(=O)C(C)(C)C1=CC=CC=C1 YYEROYLAYAVZNW-UHFFFAOYSA-N 0.000 claims abstract description 87
- 239000002904 solvent Substances 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 37
- 239000012535 impurity Substances 0.000 claims abstract description 14
- 238000012805 post-processing Methods 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 156
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- 239000003054 catalyst Substances 0.000 claims description 46
- 239000003153 chemical reaction reagent Substances 0.000 claims description 32
- 239000002585 base Substances 0.000 claims description 30
- 229910052751 metal Inorganic materials 0.000 claims description 25
- 239000002184 metal Substances 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 22
- 239000003513 alkali Substances 0.000 claims description 21
- 230000002378 acidificating effect Effects 0.000 claims description 15
- 125000002346 iodo group Chemical group I* 0.000 claims description 13
- 230000001035 methylating effect Effects 0.000 claims description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 9
- 229960000583 acetic acid Drugs 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 8
- 150000004820 halides Chemical class 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000005859 coupling reaction Methods 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 238000007069 methylation reaction Methods 0.000 claims description 5
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 3
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 3
- 229960004217 benzyl alcohol Drugs 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- 150000002170 ethers Chemical class 0.000 claims 1
- 238000005303 weighing Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 19
- 230000008569 process Effects 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 7
- 230000001681 protective effect Effects 0.000 abstract description 7
- 239000013067 intermediate product Substances 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 3
- 238000012797 qualification Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 86
- 238000003756 stirring Methods 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 238000010792 warming Methods 0.000 description 20
- 239000007788 liquid Substances 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 17
- 238000000926 separation method Methods 0.000 description 15
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 11
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 11
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 10
- 229940127554 medical product Drugs 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 7
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 229910001385 heavy metal Inorganic materials 0.000 description 5
- 238000005457 optimization Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 230000003321 amplification Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000005998 bromoethyl group Chemical group 0.000 description 4
- 231100001261 hazardous Toxicity 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 238000003199 nucleic acid amplification method Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000000108 ultra-filtration Methods 0.000 description 4
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 3
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000004140 cleaning Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 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 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000005554 pickling Methods 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000010865 sewage Substances 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- -1 washing Substances 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- 235000010894 Artemisia argyi Nutrition 0.000 description 1
- WOVSUSZMYLDKRM-UHFFFAOYSA-N C(OC(C)(C)C)(OC(C)(C)C)=O.C(CC(=O)O)(=O)O Chemical compound C(OC(C)(C)C)(OC(C)(C)C)=O.C(CC(=O)O)(=O)O WOVSUSZMYLDKRM-UHFFFAOYSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- JHRRZPXFDKRWJS-UHFFFAOYSA-N [K]C=C Chemical compound [K]C=C JHRRZPXFDKRWJS-UHFFFAOYSA-N 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N acetic acid;palladium Chemical compound [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 229960001611 alectinib Drugs 0.000 description 1
- KDGFLJKFZUIJMX-UHFFFAOYSA-N alectinib Chemical compound CCC1=CC=2C(=O)C(C3=CC=C(C=C3N3)C#N)=C3C(C)(C)C=2C=C1N(CC1)CCC1N1CCOCC1 KDGFLJKFZUIJMX-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 244000030166 artemisia Species 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- YKYMGFHOJJOSEB-UHFFFAOYSA-N butan-1-ol;potassium Chemical compound [K].CCCCO YKYMGFHOJJOSEB-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- INQOMBQAUSQDDS-BJUDXGSMSA-N iodomethane Chemical group I[11CH3] INQOMBQAUSQDDS-BJUDXGSMSA-N 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- FKBSHNBSEUWDAC-UHFFFAOYSA-L lithium sodium dihydroxide Chemical compound [Li+].[OH-].[OH-].[Na+] FKBSHNBSEUWDAC-UHFFFAOYSA-L 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229940073584 methylene chloride Drugs 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- 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
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of Ai Le to replace Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method, preparation method of the present invention passes through Optimal improvements preparation route method, optimize reaction condition, improve post-processing and purification process, reduces operational hazards grade and production cost；It is low to the anticorrosive class requirement of reaction tankage, good operation safety, it post-processes environmentally protective, obtained Ai Le is low for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid impurity content, the purity and quality that intermediate product is substantially increased while improving yield improve Ai Le for the difficulty of technology controlling and process during Buddhist nun's production of raw medicine and improve Ai Le for the bulk pharmaceutical chemicals quality and qualification rate of Buddhist nun；Each step operation of this preparation method is simple, and solvent and process conditions are easy safely, realizes environment-friendly and green production, has broad application prospects.
Description
Technical field
The present invention relates to pharmaceutical intermediate synthesis technical fields, more particularly, are related to a kind of Ai Le for Buddhist nun's intermediate
Preparation method.
Background technique
It is a kind of inhibitor of new anaplastic lymphoma kinase (ALK) that new anticancer drug Ai Le, which replaces Buddhist nun (Alectinib),
For treating advanced stage or metastatic ALK positive non-small cell lung cancer, suitable for being disliked after gram azoles not being resistant to and treated for Buddhist nun
The patient of change.
Synthesize the key intermediate that Ai Le replaces Buddhist nun, 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid, molecular formula are as follows:
C12H15IO2, English name are as follows: 2- (4-Ethyl-3-idodophenyl) -2-methylpropanoic acid, structural formula are as follows
Shown in formula:
Existing disclosed 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method, WO2004/046080 document
Using 2- (4- bromophenyl) -2 Methylpropionic acid as starting material, pass through the hydrogenation of Suzuki coupling, the palladium carbon catalysis of acetic acid palladium chtalyst
It restores double bond two-step reaction and introduces ethyl in the position of phenyl ring bromine, obtain intermediate product 2- (4- ethyl -3- finally by iodo
Iodine) phenyl -2 Methylpropionic acid, preparation method route is as follows；
This preparation method raw material and reagent 2- (4- bromophenyl) -2 Methylpropionic acid, vinyl potassium trifluoborate, palladium acetate second
Base palladium carbon is expensive, and operating condition needs strict control anaerobic, increases operation difficulty, and 2- (4- ethyl -3- iodine) is prepared
Heavy metal palladium is easy residual in phenyl -2 Methylpropionic acid product, is unfavorable for amplification production and industrialization promotion；Also, intermediate
The residual of heavy metal palladium easily leads to Ai Le during storage for Buddhist nun in 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid product
Key intermediate, 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid purity reduces, and is carrying out subsequent synthesis Ai Le for Buddhist nun
When product, that brings heavy metal palladium into remains on Ai Le for its not easy purification is made in Buddhist nun's product, is unfavorable for Ai Le for Buddhist nun's product quality
Raising.
CN106946650A document is starting material through chloro, F-K reaction, rearrangement using 2 bromo 2 methyl propionic acid
Totally 5 steps react to obtain intermediate product 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid for reaction, iodo and hydrolysis, preparation
Method route is as follows；
This preparation method route is long, uses a large amount of thionyl chloride, alchlor hazardous reagents in the process, uses reaction
There are corrosion harmfulnesses for tankage, and post-processing, which generates, largely has corrosive sewage, is unfavorable for environmentally protective industrial metaplasia
It produces.
In conclusion Ai Le disclosed in the prior art produces for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid
That there are preparation routes is long for the preparation method of product, and raw material and expensive reagents preparation cost are high, heavy-metal residual in target product, product
Quality is bad, and generates a large amount of acid gas and waste water in post-processing stages, can not achieve environmentally protective industrialized production, Huo Zheyuan
Material and reagent are hazardous agents, and operational safety is poor, improves the security level and production cost of production, is unfavorable for industrializing
Popularization and application.
Therefore, Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation side is replaced to exploitation optimization Ai Le
Method can especially carry out workshop amplification and realize the preparation method of environment protection requirement there are demands.
Summary of the invention
In order to solve the problems in the existing technology, the object of the present invention is to provide a kind of preparation method process is short, behaviour
Make simply, low in cost, the Ai Le of environmentally protective suitable industrialized production replaces Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2-
The preparation method of methylpropanoic acid.
An aspect of of the present present invention provides a kind of Ai Le for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid
The preparation method of (formula A),
The preparation method comprises the following steps:
Compound A-1 and A-2 is carried out coupling reaction by step 1 in the presence of catalyst and alkali, and hydrolysis obtains compound A-
3；
Step 2, by compound A-3 in the presence of acidic with R2OH carries out esterification, obtains compound A-4；
Compound A-4 and methylating reagent are carried out double methylation reactions by step 3 in the presence of a base, and hydrolysis obtains chemical combination
Object A-5；
Compound A-5 is carried out iodide reaction by step 4, obtains Ai Le for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -
2 Methylpropionic acid (formula A).
Preparation route is as follows:
Wherein, R1For C1~C10 alkyl；R2For C1~C10 alkyl or aryl alkyl.
Further, the R1For methyl, ethyl or tert-butyl；
Further, the R2For methyl, ethyl, tert-butyl or benzyl；
Further, in the step 1, the catalyst is cuprous halide；The alkali is metal base；
Further, in the step 1, the catalyst be one of cuprous iodide, cuprous bromide, stannous chloride or
It is a variety of；The alkali is one of sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide, sodium tert-butoxide or a variety of；
Further, in the step 1, the molar ratio of compound A-1 and A-2 are 1:1.5~1:2.5；
Further, in the step 1, the molar ratio of compound A-1 and catalyst is 1:0.2~1:0.6；
Further, in the step 1, the molar ratio of compound A-1 and alkali is 1:1.5~1:2.5；
Further, in the step 1, the reaction dissolvent of the coupling reaction is ether solvent；
Further, the ether solvent be glycol dimethyl ether, Isosorbide-5-Nitrae-one of dioxane or tetrahydrofuran or
It is a variety of；
Further, in the step 1, the reaction temperature of the coupling reaction is 60~80 DEG C, the reaction time is 10~
14 hours；
Further, the step 1 specifically: compound A-1 and A-2 in cuprous halide as catalyst, deposit by metal base
Under, using ether solvent as solvent, reaction temperature is to react 10~14 hours at 60~80 DEG C, is hydrolyzed, and post-processing obtains chemical combination
Object A-3；
Wherein, compound A-1, A-2, cuprous halide, the molar ratio between metal base are 1:(1.5-2.5): (0.2-
0.6):(1.5-2.5)；
Further, in the step 2, the acidic catalyst be one of the concentrated sulfuric acid, chloroacetic chloride, thionyl chloride or
It is a variety of；
Further, in the step 2, the R2OH be methanol, ethyl alcohol, the tert-butyl alcohol, in benzylalcohol it is a kind of；
Further, in the step 2, the molar ratio of the compound A-3 and acidic catalyst is 1:0.05~1:
0.3；
Further, in the step 2, the compound A-3 and R2The w/v (g/mL) of OH is 1:1~1:
10；
Further, in the step 2, the reaction temperature of the esterification is 40~65 DEG C, and the reaction time is 4~5 small
When；
Further, the step 2 specifically: compound A-3 in the presence of acidic with R2OH is at 40~65 DEG C
Lower reaction 4~5 hours, post-processing obtains compound A-4；
Wherein, the molar ratio of compound A-3 and acidic catalyst is 1:0.05~1:0.3；Compound A-3 and R2The weight of OH
Measuring volume ratio (g/mL) is 1:1~1:10；
Further, in the step 3, the methylating reagent is iodomethane；The alkali is metal base；
Further, the metal base be one of sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide, sodium tert-butoxide or
It is a variety of；
Further, in the step 3, the reaction dissolvent of double methylation reactions is non-protonic solvent；
Further, the non-protonic solvent is n,N-Dimethylformamide, n,N-dimethylacetamide, Isosorbide-5-Nitrae-dioxy
One of six rings are a variety of；
Further, in the step 3, the molar ratio of the compound A-4 and methylating reagent is 1:2~1:4；
Further, in the step 3, the molar ratio of the compound A-4 and metal base is 1:2~1:4；
Further, in the step 3, the w/v (g/mL) of the compound A-4 and non-protonic solvent is
1:5~1:15；
Further, in the step 3, the reaction temperatures of double methylation reactions is -10~25 DEG C, and the reaction time is
5~7 hours；
Further, the step 3 specifically: compound A-4 and methylating reagent are in the presence of metal base, with non-proton
Property solvent be solvent, reaction temperature be -10~25 DEG C at react 5~7 hours, hydrolyze and post-process to obtain compound A-5；
Wherein, compound A-4, methylating reagent, metal base molar ratio be 1:(2~4): (2~4)；Compound A-4 with
The w/v (g/mL) of non-protonic solvent is 1:5~1:15；
Further, in the step 4, the iodo reagent of the iodide reaction is N- N-iodosuccinimide, elemental iodine
One of or it is a variety of；
Further, in the step 4, the catalyst of the iodide reaction is the concentrated sulfuric acid；
Further, in the step 4, the reaction dissolvent of the iodide reaction is glacial acetic acid, methylene chloride, acetic acid second
One of ester, tetrahydrofuran are a variety of；
Further, in the step 4, the molar ratio of compound A-5 and iodo reagent is 1:(1.1~1.5)；
Further, in the step 4, the w/v (g/mL) of compound A-5 and solvent is 1:(3~5)；
Further, in the step 4, the bulking value (g/mL) of compound A-5 and catalyst is than being 1:(1~2)；
Further, in the step 4, the reaction temperature of the iodide reaction is 20~30 DEG C, and the reaction time is 2~4
Hour；
Further, the step 4 specifically: compound A-5 exists in iodo reagent, catalyst and reaction dissolvent
Under, 20~30 DEG C are reacted 2~4 hours, and post-processing obtains Ai Le for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2- methyl-prop
Sour (formula A)；
Wherein, the molar ratio of compound A-5 and iodo reagent is 1:(1.1~1.5)；The weight of compound A-5 and solvent
Volume ratio (g/mL) is 1:(3~5)；The w/v (g/mL) of compound A-5 and catalyst is 1:(1~2).
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the catalyst is cuprous iodide；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the catalyst is cuprous bromide；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the catalyst is the mixed catalyst of cuprous iodide and cuprous bromide；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the molar ratio of cuprous iodide and cuprous bromide is 1:1~1:3 in the mixed catalyst；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the alkali is sodium methoxide；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the alkali is sodium hydride；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the alkali is potassium tert-butoxide；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the molar ratio of compound A-1 and A-2 are 1:1.5；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the molar ratio of compound A-1 and A-2 are 1:2；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the molar ratio of compound A-1 and A-2 are 1:2.5；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the molar ratio of compound A-1 and catalyst is 1:0.2；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the molar ratio of compound A-1 and catalyst is 1:0.4；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the molar ratio of compound A-1 and catalyst is 1:0.6；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the molar ratio of compound A-1 and alkali is 1:1.5；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the molar ratio of compound A-1 and alkali is 1:2；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the molar ratio of compound A-1 and alkali is 1:2.5；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, compound A-1, A-2, catalyst, alkali molar ratio be 1:2:0.4:2；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the molar ratio of cuprous iodide and cuprous bromide is 1:1 in the mixed catalyst；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the molar ratio of cuprous iodide and cuprous bromide is 1:2 in the mixed catalyst；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 1, the molar ratio of cuprous iodide and cuprous bromide is 1:3 in the mixed catalyst；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 2, the molar ratio of compound A-3 and acidic catalyst is 1:0.05；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 2, the molar ratio of compound A-3 and acidic catalyst is 1:0.1；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 2, the molar ratio of compound A-3 and acidic catalyst is 1:0.3；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 2, compound A-3 and R2The w/v (g/mL) of OH is 1:1；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 2, compound A-3 and R2The w/v (g/mL) of OH is 1:5；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 2, compound A-3 and R2The w/v (g/mL) of OH is 1:10；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 3, the molar ratio of compound A-4 and methylating reagent is 1:2；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 3, the molar ratio of compound A-4 and methylating reagent is 1:3；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 3, the molar ratio of compound A-4 and methylating reagent is 1:4
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 3, the molar ratio of compound A-4 and metal base is 1:2；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 3, the molar ratio of compound A-4 and metal base is 1:3；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 3, the molar ratio of compound A-4 and metal base is 1:4；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 3, the w/v (g/mL) of compound A-4 and non-protonic solvent is 1:5；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 3, the w/v (g/mL) of compound A-4 and non-protonic solvent is 1:10；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 3, the w/v (g/mL) of compound A-4 and non-protonic solvent is 1:15；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 3, compound A-4, iodomethane, metal base molar ratio be 1:3:3；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 4, the molar ratio of compound A-5 and iodo reagent is 1:1.1；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 4, the molar ratio of compound A-5 and iodo reagent is 1:1.2；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 4, the molar ratio of compound A-5 and iodo reagent is 1:1.5；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 4, the w/v (g/mL) of compound A-5 and solvent is 1:3；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 4, the w/v (g/mL) of compound A-5 and solvent is 1:4；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 4, the w/v (g/mL) of compound A-5 and solvent is 1:5；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 4, the w/v (g/mL) of compound A-5 and catalyst is 1:1.0；
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 4, the w/v (g/mL) of compound A-5 and catalyst is 1:1.5
Ai Le is according to the present invention for the excellent of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Select embodiment, in the step 4, the w/v (g/mL) of compound A-5 and catalyst is 1:2.0.
Technical parameter feature in present invention method made above can be in any combination.
In aforesaid operations, post-processing include but is not limited to stirring, the transfer of liquid or solid, washing, alkali cleaning, pickling,
Adjust the operation such as pH value, filtering, ultrafiltration, loop ultrafiltration, suction filtration, dilution, concentration, drying, recrystallization, freeze-drying, or stirring, liquid
The transfer of body or solid, washing, alkali cleaning, pickling, adjust pH value, filtering, ultrafiltration, loop ultrafiltration, suction filtration, dilution, concentration, drying,
The combination of one or more of the operations such as recrystallization, freeze-drying.
In the synthesis field of medicine intermediate organic compound molecule, the purity of midbody compound and wherein maximum list
Miscellaneous content all strong influences the quality of final medical product.Since chemically synthesized reaction has reaction site not single
One, impurity reaction simultaneously progress and inevitable feature.Under normal conditions, it is reacted by optimum synthesis method and optimization
Condition, medical product compound on the basis of reaching certain purity, then improve its purity to the higher stage be extremely difficult
's.On the other hand, it is applied to human body or the living individual of other animals as treating disease, in order to reduce medical product
The middle issuable toxic side effect of impurity, medical product have high requirement in terms of purity and content.So that can expire
The demand of sufficient industry's enlarging production, and medical product purity can be improved, reduce the content of largest single impurity, and do not reducing yield
On the basis of, to the preparation method of different medical products improve it is not regular follow, also not ready-made warp
Testing and enlightening can use for reference.
Specific to the present invention, Ai Le replaces Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid purity and quality
It is affected to finished product Ai Le for the quality of Buddhist nun, purity replaces the influence of Buddhist nun's purity in subsequent preparation process final product Ai Le
In be further amplified.Therefore, compound 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid (formula A) replaces the key of Buddhist nun as Ai Le
Intermediate, it is necessary to carry out stringenter quality control.
Compared with prior art, Ai Le of the invention replaces Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid
Preparation method has the following beneficial effects:
Ai Le of the invention replaces Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method, and optimization changes
System is for route methods, without using expensive raw material and metal palladium catalyst, while greatly reducing preparation cost, and behaviour
Make mild condition, without controlling oxygen free condition, reduces operation difficulty, be conducive to amplification production and industrialization promotion；It avoids
Ai Le improves intermediate for the residual of the heavy metal palladium in Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid
The quality of object is closed, provides reliable guarantee for the subsequent Ai Le for preparing for the quality of Buddhist nun's product；
Ai Le of the invention replaces Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method, and optimization changes
System is for route methods, without using hazardous reagents such as thionyl chloride, alchlors, to the anticorrosive etc. of reaction tankage
Grade requires low, good operation safety, reduces the potential threat grade to the harm of production line employee's life, post-processes green ring
It protects, not generating largely has corrosive sewage, reduces the security level and production cost of production, is conducive to environmentally protective
Industrialized production application；
Ai Le of the invention replaces Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method, and optimization changes
For system for route methods, each step reaction post-processing is conventional treatment, easy to operate without using purification process such as column chromatographies,
Each step reaction yield is high, and side reaction is few, and raw materials required for the reaction is cheap and easy to get, and reaction condition is mild, is suitble to industrialized production；
Ai Le of the invention replaces the preparation of Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
Impurity is few in 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid product of method preparation, and especially largest single impurity content is less than
0.1%, substantially increase intermediate product purity and product quality；Using the Ai Le that this preparation method obtains for Buddhist nun's intermediate 2-
(4- ethyl -3- iodine) phenyl -2 Methylpropionic acid produces Ai Le as key intermediate for Buddhist nun, improves the purity that Ai Le replaces Buddhist nun
And quality, reduce the toxic side effect that Ai Le replaces Buddhist nun to use as drug；
The Ai Le that preparation method of the invention is prepared replaces Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2- methyl-prop
Sour purity is increased to 99.5% or more, and largest single impurity content is 0.1% hereinafter, each step intermediate easy purification, post-processing are simple
Facilitate easy to operate；
The Ai Le of preparation method preparation of the invention is steady for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid
It is qualitative good, purity is placed under harsh conditions without substantially changeing, and convenient for storage and transport, is substantially reduced as Ai Le in Buddhist nun's key
The introducing of plurality of impurities when mesosome is reacted is conducive to improve the Ai Le of preparation for the quality and purity of Buddhist nun's drug, reduces Chinese mugwort
The happy use medicine toxicity for replacing Buddhist nun, improves drug safety.
In conclusion the present invention prepares Ai Le for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation
Method, Optimal improvements preparation route method do not use thionyl chloride, three without using expensive raw material and metal palladium catalyst
The hazardous reagents such as aluminium chloride；Reduce operational hazards grade and production cost；To the anticorrosive grade of reaction tankage
It is required that low, good operation safety, post-processing is environmentally protective, and obtained Ai Le replaces Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2-
Methylpropanoic acid impurity content is low, and the purity and quality of intermediate product are substantially increased while improving yield, so as to improve
Ai Le replaces the bulk pharmaceutical chemicals quality and qualification rate of Buddhist nun for the difficulty and raising Ai Le of technology controlling and process during Buddhist nun's production of raw medicine；Each step
Rapid method is simple and easy, and solvent and process conditions safety are inexpensively, it can be achieved that environment-friendly and green industrialized production, has wide application
Prospect.
Specific embodiment
All features disclosed in this specification or disclosed all methods or in the process the step of, in addition to mutually exclusive
Feature and/or step other than, can combine in any way.
Any feature disclosed in this specification unless specifically stated can be equivalent or with similar purpose by other
Alternative features are replaced.That is, unless specifically stated, each feature is an example in a series of equivalent or similar characteristics
?.
Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation successively will be replaced to Ai Le of the present invention below
Method is described in more detail.
An exemplary embodiment of the present invention, the Ai Le replace Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2- methyl
The preparation method of propionic acid includes following following steps:
Compound A-2 feeds intake with metal base, ether solvent and mixes, and cuprous halide and compound A- is added after reaction solution heating
1, compound A-1, A-2, cuprous halide, the molar ratio between metal base are 1:2:0.4:2；Reaction solution reacts at 60~80 DEG C
10~14 hours；Successively alkali process, acid processing, filter, washing, dry, are recrystallized to give compound A-3；
Compound A-3, R2OH and acidic catalyst feed intake mixing, and the molar ratio of compound A-3 and acidic catalyst is 1:
0.1；Compound A-3 and R2The w/v (g/mL) of OH is 1:5；It is reacted 4~5 hours at 40~65 DEG C of reaction solution heating；
Concentration, washing, alkali cleaning, concentrate drying obtain compound A-4；
Compound A-4, methylating reagent, metal base and non-protonic solvent are solvent mixed material feeding, compound A-4, first
Base reagent, metal base molar ratio be 1:3:3；The w/v (g/mL) of compound A-4 and non-protonic solvent is 1:
10；Reaction solution reacts 5~7 hours at -10~25 DEG C；Alkali process, concentration, is dried to obtain compound A-5；
Compound A-5, iodo reagent, catalyst and reaction dissolvent mixed material feeding, mole of compound A-5 and iodo reagent
Than for 1:1.1；The w/v (g/mL) of compound A-5 and solvent is 1:3；The bulking value of compound A-5 and catalyst
It is 1:1.5 than (g/mL)；Reaction solution, which heats up 20~30 DEG C, to react 2~4 hours；Washing filters, and is dried to obtain Ai Le among Buddhist nun
Body 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid (formula A).
The Ai Le that the preparation method of present embodiment is prepared replaces Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2- first
The purity of base propionic acid (formula A) is 99.5% or more, and largest single impurity content is 0.1% or less.
Largest single impurity is the impurity of the highest single component of content in medical product, in medical synthesis and preparation process method
In, usual largest single impurity is the quality control index of medical product key.
Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2- methyl is replaced to Ai Le of the present invention below in conjunction with specific embodiment
The preparation method of propionic acid is described further.
The preparation route of the embodiment of the present invention is as follows:
Embodiment 1, Ai Le replace Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method
1) reaction flask is added in 64.0g diethyl malonate (compound A-2a) and 640mL glycol dimethyl ether, be added
21.6g sodium methoxide after being warming up to 70-75 DEG C of reaction 0.5h, is added 7.6g cuprous iodide and 5.8g cuprous bromide, stirs 1h；Add
Enter 37.0g bromo ethyl phenenyl (compound A-1), keeps 70-75 DEG C of reaction 10-12h.50% sodium hydrate aqueous solution is added, protects
It holds after pH > 12 stirs 4h and filters, be concentrated under reduced pressure and remove solvent；Water is added and salt acid for adjusting pH is 1-2, filters, wash after stirring,
It is dry, it is recrystallized to give compound A-3 (25.0g, yield 76%).
2) reaction flask is added in 20.0g compound A-3,100mL methanol and the 4mL concentrated sulfuric acid, is warming up to back flow reaction 4-5h,
It is concentrated under reduced pressure and removes methanol, sequentially add water and ethyl acetate, liquid separation merges organic layer, saturated sodium bicarbonate washing, organic layer
It is concentrated under reduced pressure and removes ethyl acetate, obtain compound A-4a (18.2g, yield 93%).
3) reaction flask is added in the DMF of 17.8g compound A-4a and 178mL, is cooled to 0-10 DEG C, 60wt% hydrogenation is added
Sodium 12g is added 42.6g iodomethane, is warming up to 15-25 DEG C of reaction 5-6h after stirring.Water, ethyl acetate are sequentially added, liquid separation is closed
And organic layer, it is concentrated under reduced pressure and removes solvent ethyl acetate, lithium hydroxide aqueous solution and 24mL methanol, 20-30 DEG C of stirring 10- is added
Water and ethyl acetate are added after 12h, salt acid for adjusting pH is 1-2, and liquid separation, organic layer concentration is dry, obtain compound A-5 (15.6g,
Yield 81%).
4) 12.0g compound A-5 and 36mL acetic acid is added in reaction flask, is cooled to 0-5 DEG C, 15.5g N- iodo is added
Succimide and the 18mL concentrated sulfuric acid are warming up to 20-30 DEG C of reaction 2-3h.Saturation aqueous solution of sodium bisulfite and water is added, stirs
Filtered after mixing 1h, filter cake dry get Ai Le for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid (formula A) (17.0g,
Yield 85%).
Embodiment 2
1) reaction flask is added in 48.0g diethyl malonate (compound A-2a) and 640mL Isosorbide-5-Nitrae-dioxane, be added
The 60wt% sodium hydride of 12g after being warming up to 70-75 DEG C of reaction 0.5h, is added 7.6g cuprous iodide, 37.0g bromine is added after stirring
Ethylo benzene (compound A-1) keeps 70-75 DEG C of reaction 10-12h.50% sodium hydrate aqueous solution is added, pH > 12 is kept to stir
It is filtered after mixing 4h, is concentrated under reduced pressure and removes solvent；Water is added in residue and salt acid for adjusting pH is 1-2, filters, wash after stirring,
It is dry, it is recrystallized to give compound A-3 (24.7g, yield 75%).
2) reaction flask is added in 20.0g compound A-3,20mL methanol and the 3.5mL concentrated sulfuric acid, is warming up to back flow reaction 4-
5h is concentrated under reduced pressure and removes methanol, sequentially adds water and ethyl acetate, and liquid separation merges organic layer, and saturated sodium bicarbonate washing has
Machine layer is concentrated under reduced pressure to give compound A-4a (18.0g, yield 92%).
3) reaction flask is added in the THF of 17.8g compound A-4a and 89mL.It is cooled to 0-10 DEG C, sodium methoxide 11g is added,
28.4g iodomethane is added after stirring, is warming up to 15-25 DEG C of reaction 5-6h.Water, ethyl acetate are sequentially added, liquid separation merges organic
Layer is concentrated under reduced pressure and removes solvent ethyl acetate.Lithium hydroxide aqueous solution and methanol, 20-30 DEG C of stirring 10- are added in residue
Water and ethyl acetate are added after 12h, salt acid for adjusting pH is 1-2, and liquid separation, organic layer concentration is dry, obtain compound A-5 (15.0g,
Yield 80%).
4) 12.0g compound A-5 and 48mL acetic acid is added in reaction flask, is cooled to 0-5 DEG C, 15.5g N- iodo is added
Succimide and the 12mL concentrated sulfuric acid are warming up to 20-30 DEG C of reaction 2-3h, and saturation aqueous solution of sodium bisulfite and water is added, stirs
It is filtered after mixing 1h, Washing of Filter Cake, dry get Ai Le replaces Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid (formula A)
(16.8g, yield 84%).
Embodiment 3
1) reaction flask is added in 80.0g diethyl malonate (compound A-2a) and 640mL tetrahydrofuran, uncle 56g is added
Butanol potassium after being warming up to 65-70 DEG C of reaction 0.5h, is added 17.2g cuprous bromide, 37.0g bromo ethyl phenenyl (chemical combination is added after stirring
Object A-1), keep 65-70 DEG C of reaction 10-12h.Then 50% sodium hydrate aqueous solution is added, pH > 12 is kept to stir mistake after 4h
Filter is concentrated under reduced pressure and removes solvent；Water is added in residue and salt acid for adjusting pH is 1-2, filters, wash after stirring, dry, weight
Crystallization obtains compound A-3 (23.6g, yield 72%).
2) reaction flask is added in 20.0g compound A-3,200mL methanol and 4mL chloroacetic chloride, is warming up to back flow reaction 4-5h,
It is concentrated under reduced pressure and removes methanol, sequentially add water and ethyl acetate, liquid separation merges organic layer, saturated sodium bicarbonate washing, organic layer
It is concentrated under reduced pressure and removes ethyl acetate, obtain compound A-4a (17.6g, yield 90%).
3) reaction flask is added in 17.8g compound A-4a and 267mL DMF.It is cooled to 0-10 DEG C, enters 60wt% sodium hydride
16g is added 56.8g iodomethane, is warming up to 15-25 DEG C of reaction 5-6h after stirring.Water, ethyl acetate are sequentially added, liquid separation merges
Organic layer is concentrated under reduced pressure and removes solvent ethyl acetate, and lithium hydroxide sodium water solution and 24mL methanol, 20-30 is added in residue
Water and ethyl acetate is added after DEG C stirring 10-12h, salt acid for adjusting pH is 1-2, and liquid separation, organic layer concentration is dry, obtains compound
A-5 (15.2g, yield 81%).
4) 12.0g compound A-5 and 60mL acetic acid is added in reaction flask, is cooled to 0-5 DEG C, 21.1g N- iodo is added
Succimide and the 24mL concentrated sulfuric acid are warming up to 20-30 DEG C of reaction 2-3h, and saturation aqueous solution of sodium bisulfite and water is added, stirs
Filtered after mixing 1h, filter cake dry get Ai Le for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid (formula A) (17.8g,
Yield 89%).
Embodiment 4
1) reaction flask is added in 48.0g diethyl malonate (compound A-2a) and 640mL glycol dimethyl ether, added
27.0g sodium methoxide after being warming up to 60-65 DEG C of reaction 0.5h, is added 3.8g cuprous iodide and 8.7g cuprous bromide, stirs 1h；Again
It is added 37.0g bromo ethyl phenenyl (compound A-1), keeps 60-65 DEG C of reaction 10-12h.Then the sodium hydroxide of addition 50% is water-soluble
Liquid filters after keeping pH > 12 to stir 4h, is concentrated under reduced pressure and removes solvent.Water is added in residue and salt acid for adjusting pH is 1-2, stirs
It filters, wash after mixing, it is dry, it is recrystallized to give compound A-3 (24.3g, yield 74%).
2) reaction flask is added in 20.0g compound A-3,100mL methanol and 4mL thionyl chloride, is warming up to back flow reaction 4-
5h is concentrated under reduced pressure and removes methanol, sequentially adds water and ethyl acetate, and liquid separation merges organic layer, and saturated sodium bicarbonate washing has
Machine layer, which is concentrated under reduced pressure, removes ethyl acetate, obtains compound A-4a (17.4g, yield 89%).
3) reaction flask is added in 17.8g compound A-4a and 178mL DMF, is cooled to 0-10 DEG C, 60wt% hydrogenation is added
Sodium 12g is added 42.6g iodomethane, is warming up to 15-25 DEG C of reaction 5-6h after stirring.Water, ethyl acetate are sequentially added, liquid separation is closed
And organic layer, it is concentrated under reduced pressure and removes solvent ethyl acetate, lithium hydroxide aqueous solution and 24mL methanol, 20-30 is added in residue
Water and ethyl acetate is added after DEG C stirring 10-12h, salt acid for adjusting pH is 1-2, and liquid separation, organic layer concentration is dry, obtains compound
A-5 (16.0g, yield 82%).
4) 12.0g compound A-5 and 36mL acetic acid is added in reaction flask, is cooled to 0-5 DEG C, 16.9g N- iodo is added
Succimide and the 18mL concentrated sulfuric acid are warming up to 20-30 DEG C of reaction 2-3h.Saturation aqueous solution of sodium bisulfite and water is added, stirs
Filtered after mixing 1h, filter cake dry get Ai Le for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid (formula A) (18.0g,
Yield 90%).
Embodiment 5
1) reaction flask is added in 64.0g diethyl malonate (compound A-2a) and 640mL glycol dimethyl ether, added
21.6g sodium methoxide after being warming up to 70-75 DEG C of reaction 0.5h, is added 3.8g cuprous iodide and 5.8g cuprous bromide, stirs 1h；Again
It is added 37.0g bromo ethyl phenenyl (compound A-1), keeps 70-75 DEG C of reaction 10-12h.Then the sodium hydroxide of addition 50% is water-soluble
Liquid filters after keeping pH > 12 to stir 4h, is concentrated under reduced pressure and removes solvent；Water is added and salt acid for adjusting pH is 1-2, filtered after stirring,
Washing, it is dry, it is recrystallized to give compound A-3 (24.0g, yield 73%).
2) reaction flask is added in 20.0g compound A-3,100mL methanol and the 4.5mL concentrated sulfuric acid, is warming up to back flow reaction 4-
5h is concentrated under reduced pressure and removes methanol, sequentially adds water and ethyl acetate, and liquid separation merges organic layer, and saturated sodium bicarbonate washing has
Machine layer, which is concentrated under reduced pressure, removes ethyl acetate, obtains compound A-4a (18.0g, yield 92%).
3) reaction flask is added in 17.8g compound A-4a and 178mL DMF.It is cooled to 0-10 DEG C, 60wt% hydrogenation is added
Sodium 12g is added 42.6g iodomethane, is warming up to 15-25 DEG C of reaction 5-6h after stirring.Water, ethyl acetate are sequentially added, liquid separation is closed
And organic layer, it is concentrated under reduced pressure and removes solvent ethyl acetate, lithium hydroxide aqueous solution and 24mL methanol, 20-30 is added in residue
Water and ethyl acetate is added after DEG C stirring 10-12h, salt acid for adjusting pH is 1-2, and liquid separation, organic layer concentration is dry, obtains compound
A-5 (16.6g, yield 82%).
4) 12.0g compound A-5 and 36mL acetic acid is added in reaction flask, is cooled to 0-5 DEG C, 15.5g N- iodo is added
Succimide and the 24mL concentrated sulfuric acid are warming up to 20-30 DEG C of reaction 2-3h.Saturation aqueous solution of sodium bisulfite and water is added, stirs
Filtered after mixing 1h, filter cake dry get Ai Le for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid (formula A) (18.2g,
Yield 86%).
Under other similar performances,
In above-mentioned steps 1, diethyl malonate (compound A-2a) can use dimethyl malenate, malonic acid di tert butyl carbonate
Instead of；
In above-mentioned steps 2, methanol can be replaced with ethyl alcohol, the tert-butyl alcohol, benzylalcohol.
Test example 6:
The Ai Le that above-described embodiment is prepared (is changed for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid
Close object A) Stability Determination is carried out, sample is placed six months in room temperature sealing, sampling observation appearance and detection purity, compound
The purity of A is 99.5% or more.
Compared with the sample before placement, significant change does not occur for appearance after Compound A sample is placed 6 months, and purity is not
It significantly reduces.Illustrate the Ai Le that preparation method of the present invention is prepared for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2-
Methylpropanoic acid compound A stability is good, is conducive to store and transport.
Show the Ai Le of preparation method preparation of the invention for Buddhist nun's intermediate 2- (4- second by above embodiments and test example
Base -3- iodine) phenyl -2 Methylpropionic acid compound A purity is 99.5% or more, and product stability is good.Each step operation letter
Just, easy purification, post-processing is simple and convenient, environmentally protective easy to operate, and solvent and condition safe and feasible are good for the environment green industry
Change amplification production, has broad application prospects.
The invention is not limited to specific embodiments above-mentioned.The present invention, which expands to, any in the present specification to be disclosed
New feature or any new combination, and disclose any new method or process the step of or any new combination.
Claims (10)
1. a kind of Ai Le replaces Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid preparation method, which is characterized in that
The preparation method includes following preparation route and step:
The Ai Le is for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid as shown in formula A:
Preparation route is as follows:
Wherein, R1For C1~C10 alkyl；R2For C1~C10 alkyl or aryl alkyl；
Compound A-1 and A-2 is carried out coupling reaction by step 1 in the presence of catalyst and alkali, and hydrolysis obtains compound A-3；
Step 2, by compound A-3 in the presence of acidic with R2OH carries out esterification, obtains compound A-4；
Compound A-4 and methylating reagent are carried out double methylation reactions by step 3 in the presence of a base, and hydrolysis obtains compound A-
5；
Compound A-5 is carried out iodide reaction by step 4, obtains Ai Le for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2- first
Base propionic acid.
2. method according to claim 1, which is characterized in that in the step 1,
The catalyst is cuprous halide；The alkali is metal base；
The molar ratio of the compound A-1 and A-2 is 1:1.5~1:2.5；
The molar ratio of the compound A-1 and catalyst is 1:0.2~1:0.6；
The molar ratio of the compound A-1 and alkali is 1:1.5~1:2.5；
The reaction dissolvent of the coupling reaction is ether solvent.
3. method according to claim 1, which is characterized in that in the step 2,
The acidic catalyst is one of the concentrated sulfuric acid, chloroacetic chloride, thionyl chloride or a variety of；
The R2OH is one of methanol, ethyl alcohol, the tert-butyl alcohol, benzylalcohol；
The molar ratio of the compound A-3 and acidic catalyst is 1:0.05~1:0.3；
The compound A-3 and R2The w/v of OH is 1:1~1:10.
4. method according to claim 1, which is characterized in that in the step 3,
The alkali is metal base；The reaction dissolvent of double methylation reactions is non-protonic solvent；
The molar ratio of the compound A-4 and methylating reagent is 1:2~1:4；
The molar ratio of the compound A-4 and metal base is 1:2~1:4；
The w/v of the compound A-4 and non-protonic solvent is 1:5~1:15.
5. method according to claim 1, which is characterized in that in the step 4,
The iodo reagent of the iodide reaction is one of N- N-iodosuccinimide, elemental iodine or a variety of；
The catalyst of the iodide reaction is the concentrated sulfuric acid；
The reaction dissolvent of the iodide reaction is one of glacial acetic acid, methylene chloride, ethyl acetate, tetrahydrofuran or a variety of.
6. method according to claim 2, which is characterized in that
The step 1 specifically: compound A-1 and A-2 in cuprous halide as catalyst, it is molten with ethers in the presence of metal base
Agent is solvent, and reaction temperature is to react 10~14 hours at 60~80 DEG C, is hydrolyzed, post-processing obtains compound A-3；
Wherein, compound A-1, A-2, cuprous halide, the molar ratio between metal base are 1:(1.5-2.5): (0.2-0.6):
(1.5-2.5)。
7. method according to claim 3, which is characterized in that
The step 2 specifically: compound A-3 in the presence of acidic with R2OH reacts 4~5 hours at 40~65 DEG C,
Post-processing obtains compound A-4；
Wherein, the molar ratio of compound A-3 and acidic catalyst is 1:0.05~1:0.3；Compound A-3 and R2The weighing body of OH
Product is than being 1:1~1:10.
8. method according to claim 4, which is characterized in that
The step 3 specifically: compound A-4 and methylating reagent are in the presence of metal base, using non-protonic solvent as solvent,
Reaction temperature is to react 5~7 hours at -10~25 DEG C, hydrolyzes and post-processes to obtain compound A-5；
Wherein, compound A-4, methylating reagent, metal base molar ratio be 1:(2~4): (2~4)；Compound A-4 and non-matter
The w/v of sub- property solvent is 1:5~1:15.
9. method according to claim 5, which is characterized in that
The step 4 specifically: compound A-5 is in the presence of iodo reagent, catalyst and reaction dissolvent, 20~30 DEG C of reactions
2~4 hours, post-processing obtained Ai Le for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid；
Wherein, the molar ratio of compound A-5 and iodo reagent is 1:(1.1~1.5)；The bulking value of compound A-5 and solvent
Than for 1:(3~5)；The w/v of compound A-5 and catalyst is 1:(1~2).
10. the Ai Le that a kind of any one of claim 1~9 the method is prepared is for Buddhist nun's intermediate 2- (4- ethyl -3- iodine)
Phenyl -2 Methylpropionic acid, which is characterized in that
The Ai Le is 99.5% or more for Buddhist nun's intermediate 2- (4- ethyl -3- iodine) phenyl -2 Methylpropionic acid purity, largest single impurity
Content is 0.1% or less.
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