CN104860975B - A kind of preparation method of bortezomib synthetic intermediate - Google Patents
A kind of preparation method of bortezomib synthetic intermediate Download PDFInfo
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- CN104860975B CN104860975B CN201410058782.4A CN201410058782A CN104860975B CN 104860975 B CN104860975 B CN 104860975B CN 201410058782 A CN201410058782 A CN 201410058782A CN 104860975 B CN104860975 B CN 104860975B
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- nhc
- ether
- boric acid
- hours
- dehydrating agent
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- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 title claims abstract description 20
- 229960001467 bortezomib Drugs 0.000 title claims abstract description 18
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims abstract description 28
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 24
- 229910052786 argon Inorganic materials 0.000 claims abstract description 14
- 239000007789 gas Substances 0.000 claims abstract description 14
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000002170 ethers Chemical class 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 238000005935 nucleophilic addition reaction Methods 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 106
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- 238000006243 chemical reaction Methods 0.000 claims description 54
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- 239000000243 solution Substances 0.000 claims description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 21
- 239000012024 dehydrating agents Substances 0.000 claims description 20
- -1 isopentyl aldehyde Chemical class 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 235000019441 ethanol Nutrition 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 13
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 11
- 238000010790 dilution Methods 0.000 claims description 10
- 239000012895 dilution Substances 0.000 claims description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 9
- 238000007259 addition reaction Methods 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- 150000001298 alcohols Chemical class 0.000 claims description 7
- 150000001348 alkyl chlorides Chemical class 0.000 claims description 6
- 239000004327 boric acid Substances 0.000 claims description 6
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- XGZNHFPFJRZBBT-UHFFFAOYSA-N ethanol;titanium Chemical compound [Ti].CCO.CCO.CCO.CCO XGZNHFPFJRZBBT-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 150000003141 primary amines Chemical class 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium(IV) ethoxide Substances [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 claims description 4
- HHSNIRLXHJNXAK-UHFFFAOYSA-N 1,3-di(propan-2-yl)-2h-imidazole Chemical class CC(C)N1CN(C(C)C)C=C1 HHSNIRLXHJNXAK-UHFFFAOYSA-N 0.000 claims description 3
- YQZCSEVPKQVTQP-UHFFFAOYSA-N 1,3-dicyclohexyl-2h-imidazole Chemical class C1N(C2CCCCC2)C=CN1C1CCCCC1 YQZCSEVPKQVTQP-UHFFFAOYSA-N 0.000 claims description 3
- LNUWTZONQTVTFH-UHFFFAOYSA-N 4,5-bis(1-adamantyl)-1H-imidazole Chemical class C12(CC3CC(CC(C1)C3)C2)C2=C(N=CN2)C23CC1CC(CC(C2)C1)C3 LNUWTZONQTVTFH-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 229940015043 glyoxal Drugs 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 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 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims description 2
- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 claims description 2
- POHBENQQTGHXQY-UHFFFAOYSA-N OC(C)(C)C(C)(C)O.NC(CC(C)C)OB(O)O Chemical compound OC(C)(C)C(C)(C)O.NC(CC(C)C)OB(O)O POHBENQQTGHXQY-UHFFFAOYSA-N 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000001119 stannous chloride Substances 0.000 claims description 2
- 235000011150 stannous chloride Nutrition 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- 150000001299 aldehydes Chemical class 0.000 claims 1
- 150000003851 azoles Chemical class 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- POHBENQQTGHXQY-QDXATWJZSA-N OC(C)(C)C(C)(C)O.N[C@@H](CC(C)C)OB(O)O Chemical compound OC(C)(C)C(C)(C)O.N[C@@H](CC(C)C)OB(O)O POHBENQQTGHXQY-QDXATWJZSA-N 0.000 abstract description 29
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 abstract description 5
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 3
- 238000003756 stirring Methods 0.000 description 42
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 18
- 229910052796 boron Inorganic materials 0.000 description 18
- 238000012544 monitoring process Methods 0.000 description 16
- 239000006227 byproduct Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 238000004090 dissolution Methods 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 10
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 10
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- UOFFEDRAIFYOBS-UHFFFAOYSA-N butan-1-imine Chemical compound CCCC=N UOFFEDRAIFYOBS-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000004519 grease Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 6
- 238000006219 Matteson homologation reaction Methods 0.000 description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000002153 concerted effect Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- MOILFCKRQFQVFS-BDNRQGISSA-N (1r,3s,4r,5r)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@@H]2C(C)(C)[C@H]1C[C@H](O)[C@@]2(O)C MOILFCKRQFQVFS-BDNRQGISSA-N 0.000 description 2
- MOILFCKRQFQVFS-OORONAJNSA-N (1s,3r,4s,5s)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@H]2C(C)(C)[C@@H]1C[C@@H](O)[C@]2(O)C MOILFCKRQFQVFS-OORONAJNSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 108010016626 Dipeptides Proteins 0.000 description 2
- XBAPKIMFLPKGJW-RXMQYKEDSA-N N[C@@H](CC(C)C)OB(O)O Chemical compound N[C@@H](CC(C)C)OB(O)O XBAPKIMFLPKGJW-RXMQYKEDSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- XOKSLPVRUOBDEW-UHFFFAOYSA-N pinane Chemical compound CC1CCC2C(C)(C)C1C2 XOKSLPVRUOBDEW-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- QPKFVRWIISEVCW-UHFFFAOYSA-N 1-butane boronic acid Chemical compound CCCCB(O)O QPKFVRWIISEVCW-UHFFFAOYSA-N 0.000 description 1
- XVPMVAZVQKAVOV-UHFFFAOYSA-N 3-methylbutoxyboronic acid Chemical compound CC(C)CCOB(O)O XVPMVAZVQKAVOV-UHFFFAOYSA-N 0.000 description 1
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 229910004039 HBF4 Inorganic materials 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- KMWLUGSVWULTHR-UHFFFAOYSA-N [4-(aminomethyl)phenyl]boronic acid Chemical compound NCC1=CC=C(B(O)O)C=C1 KMWLUGSVWULTHR-UHFFFAOYSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- VRWQZWUZGDOTKM-UHFFFAOYSA-N butoxy(methoxy)borinic acid Chemical compound COB(OCCCC)O VRWQZWUZGDOTKM-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 150000004699 copper complex Chemical class 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229930006728 pinane Natural products 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
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- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of bortezomib synthetic intermediate --- the preparation process of (R) 1- amino -3- methyl butyl boric acid pinacol ester hydrochloride.Preparation process of the present invention; the following steps are included: in ethers and/or benzene kind solvent; (R) -1-N-(terf-butylsulfinyl) -3- methyl butyl imines and connection borate at tertiary fourth oxygen copper complex (NHC) CuOt-Bu of N-heterocyclic carbine and proton donor co-catalysis; in the reactor full of argon gas or nitrogen, (R) -1-N-(terf-butylsulfinyl is obtained in 0-30 DEG C of nucleophilic addition) -3- methylbutylamine -1- boric acid pinacol ester.
Description
Technical field:
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of bortezomib synthetic intermediate --- (R) 1- ammonia
The preparation process of base -3- methyl butyl boric acid pinacol ester hydrochloride.
Background technique:
Bortezomib (Bortezomib), chemical name are [(1R)-3- methyl-1-[[(2S)-1- oxo-3- phenyl-2-
[(pyrazine formyl)-amino] propyl] amino] boric acid, trade name Bortezomib (Velcade), chemical structural formula is as follows:
Bortezomib is a kind of proteasome inhibitor researched and developed by Millennium company, the U.S., is first dipeptides boron
Pepsin body inhibitor can reversibly be combined with 26S proteasome, and blocks protein degradation prevents tumour cell malignant proliferation,
Clinically for treating Huppert's disease (MM).
Bortezomib is dipeptide chipal compounds, and the key for synthesizing bortezomib is chiral intermediate (R) 1- amino -3-
The synthesis of methyl butyl borate, there are mainly two types of preparation method, that is, Matteson methods (CN20058001764.5) for the intermediate
With Ellman method (J.Am.Chem.Soc, 2008,130,6910-6911).
Matteson method is to generate isobutyl group boron by isobutyric acid and the reaction of (1S, 2S, 3R, 5S)-(+) -2,3- pinane diol
Acid esters reacts in -60 DEG C with methylene chloride under lithium diisopropylamine effect, dichloromethyl is introduced in boron atom,
ZnCl2The lower Matteson that occurs of effect is reset, and stereoselectivity generates β-chloro borate (ee ﹥ 94%), then with two (trimethyls
Silicon substrate) lithium amide (LiHMDS) generation nucleophilic displacement of fluorine introducing amino, then (R) 1- amino-is hydrolyzed under trifluoroacetic acid effect
3- methyl butyl boric acid pinane diol ester trifluoroacetate.
Ellman method is to be condensed to yield the tertiary fourth of (R) 1-N-(using isopentyl aldehyde and R- t-butyl sulfonamide as starting material
Base sulfinyl) -3- methyl butyl imines, then under N- heterocycle carbine (NHC) copper complex ((NHC) CuOt-Bu) catalysis,
Asymmetric addition is carried out at room temperature with connection boric acid pinacol ester, then obtains (R) 1- amino -3- methyl fourth through de- sulfonyl
Ylboronic acid pinacol ester hydrochloride (I).
It is induction agent that Matteson method, which is the original enterprise of bortezomib in Matteson et al. using chiral pinane diol,
On the basis of preparing alpha-amido borine acid esters, bortezomib key intermediate (R) 1- amino -3- methyl butyl boric acid pinane of research and development
The preparation method of alkane diol ester trifluoroacetate, this method technology maturation, stable product quality have been applied to large-scale production.
But starting material (1S, 2S, 3R, 5S)-(+) -2,3- pinane diol is expensive, at high cost, severe reaction conditions, and boron removal
By-products content is higher, separation is difficult, influences end product quality.
Ellman method is condensed by isopentyl aldehyde and chiral ligand R- t-butyl sulfonamide, is then urged in (NHC) CuOt-Bu
Change it is lower carry out asymmetric addition with pinacol connection borate, then hydrolyzed prepare (R) 1- amino -3- methyl butyl boric acid frequently that
A kind of method of alcohol ester hydrochloride (I), this method are catalyzed using the single tertiary fourth oxygen copper of N- heterocycle carbine, and catalytic activity is low, adds
At reaction time it is longer, lead in reaction solution that boron removal by-products content is high, yield is low, stereoselectivity is poor, need by column
Chromatography improves purity to meet the next step demand, thus this method only exists in the laboratory research stage, technique not at
It is ripe, it is unsuitable for industrialized production.
The present invention is to be urged by the way that proton donor collaboration is added on the basis of prior art Ellman method process modification
Change, improve selectivity, the yield of addition reaction, shortens the reaction time to prepare (R) 1- amino -3- methyl butyl boric acid pinacol
A kind of method of ester hydrochloride (I).
Summary of the invention:
The present invention provides a kind of improved bortezomib key intermediate (R) -1- amino -3- methyl butyl boric acid pinacol
The preparation method of ester hydrochloride (I), preparation method of the invention include the following steps:
Step (2), in ethers and/or benzene kind solvent, (R) -1-N-(terf-butylsulfinyl) -3- methyl butyl imines
(b3) with connection borate (b4) at tertiary fourth oxygen copper complex (NHC) CuOt-Bu of N-heterocyclic carbine and proton donor co-catalysis,
In the reactor full of argon gas or nitrogen, (R) -1-N-(terf-butylsulfinyl is obtained in 0-30 DEG C of nucleophilic addition) -3- first
Base butylamine -1- boric acid pinacol ester (b5).
Preparation method of the invention, further includes following steps:
Step (1), in chloro alkanes and/or ether solvent, excessive isopentyl aldehyde (b1) and (R)-tert-butyl sulfenyl
Amine (b2) in the presence of a dehydrating agent, (R) -1-N-(terf-butylsulfinyl is condensed to yield in 40-50 DEG C) -3- methyl butyl imines
(b3)。
Step (3), in alcohols and/or ether solvent, (R) -1-N-(terf-butylsulfinyl) -3- methylbutylamine -1-
Boric acid pinacol ester (b5) in 0-30 DEG C after sour water solution, then through solvent dilution, washing, concentration, crystallization, obtain high-purity
(R) hydrochloride (I) of -1- amino -3- methyl butyl boric acid pinacol ester.
Preparation method of the invention is the combination of following steps:
Step (1), in chloro alkanes and/or ether solvent, excessive isopentyl aldehyde (b1) and (R)-tert-butyl sulfenyl
Amine (b2) in the presence of a dehydrating agent, (R) -1-N-(terf-butylsulfinyl is condensed to yield in 40-50 DEG C) -3- methyl butyl imines
(b3)。
Step (2), in ethers and/or benzene kind solvent, (R) -1-N-(terf-butylsulfinyl) -3- methyl butyl imines
(b3) with connection borate (b4) at tertiary fourth oxygen copper complex (NHC) CuOt-Bu of N-heterocyclic carbine and proton donor co-catalysis,
In the reactor full of argon gas or nitrogen, (R) -1-N-(terf-butylsulfinyl is obtained in 0-30 DEG C of nucleophilic addition) -3- first
Base butylamine -1- boric acid pinacol ester (b5).
Step (3), in alcohols and/or ether solvent, (R) -1-N-(terf-butylsulfinyl) -3- methylbutylamine -1-
Boric acid pinacol ester (b5) in 0-30 DEG C after sour water solution, then through solvent dilution, washing, concentration, crystallization, obtain high-purity
(R) hydrochloride (I) of -1- amino -3- methyl butyl boric acid pinacol ester.
Preparation method of the invention, wherein
In step (1):
Chloro alkanes/or ether solvent are one of methylene chloride, dichloroethanes, tetrahydrofuran, dioxane or several
Kind.
Preferably methylene chloride.
Dehydrating agent is the mixture (PPTS/MgSO of p-methyl benzenesulfonic acid pyridiniujm and anhydrous magnesium sulfate4), tetraethyl titanate
(Ti (OEt)4), cesium carbonate (Cs2CO4One of).
Preferably PPTS/MgSO4。
More preferably PPTS:MgSO4=(0.01~0.1): 5.
The molar ratio of isopentyl aldehyde (b1), R- t-butyl sulfonamide (b2) and dehydrating agent is (1~1.5): 1:(0.01
~5.1).
Specifically,
When dehydrating agent is PPTS/MgSO4When, the molar ratio of b1, b2 and dehydrating agent is (1~1.5): 1:(5.01~
5.1), wherein PPTS and MgSO4Ratio be (0.01~0.1): 5；
When dehydrating agent is tetraethyl titanate, the molar ratio of b1, b2 and dehydrating agent is (1~1.5): 1:(0.9~
1.1)；
When dehydrating agent is cesium carbonate, the molar ratio of b1, b2 and dehydrating agent is (1~1.5): 1:(0.01~0.1).
In the step (2):
Ethers and/or benzene kind solvent are tetrahydrofuran, dioxane, ether, isopropyl ether, methyl tertiary butyl ether(MTBE), benzene, toluene
One or more of.
NHC is selected from catalyst (NHC) CuOt-Bu: 1,3- dicyclohexyl imidazoles (Icy), 1,3- be bis--(2,6- diisopropyls
Base phenyl) imidazoles (Ipr), 1,3- diisopropyl imidazoles (Ipp) or 1, bis- adamantyl imidazoles (Iad) of 3-.
Preferably Icy.
Proton donor is selected from alcohol, organic acid, acetonitrile etc..
It is preferred that the mixing of alcohols solvent methanol, ethyl alcohol, isopropanol or alcohol and other several proton donors.
Most preferably methanol.
The molar ratio of b3 and b4, (NHC) CuOt-Bu and proton donor are 1:(1~1.5): (0.01~0.1):
(0.3~10).
It is preferred that 1:(1~1.2): (0.03~0.06): (0.5~5).
Most preferably 1:(1~1.2): (0.03~0.06): (1~3).
The addition reaction time is 2-10 hours.
It is preferred that 2-6 hours.
Catalyst (NHC) CuOt-Bu can be prepared via a method which: NHC.BF4 is reacted with stannous chloride, highly basic.It rubs
You are than being 1:1:(2~8), reaction temperature is 0-40 DEG C.
The highly basic, preferably potassium tert-butoxide or sodium tert-butoxide.
Wherein NHC.BF4 can be prepared via a method which: in organic solvent, be added molar ratio be 2:1:1:1 primary amine,
Paraformaldehyde, glyoxal, tetrafluoro boric acid treat different things alike for 0-60 DEG C and generate NHC.BF4 crude product；Again through methylene chloride and/or acetic acid second
Ester is recrystallized to give NHC.BF4.
The organic solvent is selected from: one or more of methylene chloride, tetrahydrofuran, dioxane or toluene, described
Primary amine is R-NH2, wherein R substituent is selected from: cyclohexyl, 2,6- diisopropyl phenyls, adamantyl, diisopropyl.
In the step (3):
Alcohols and/or ether solvent are methanol, ethyl alcohol, tetrahydrofuran, dioxane, ether, isopropyl ether, methyl tertbutyl
One or more of ether.
Acid used in hydrolysis is the organic solution containing HCl, preferably the ether of HCl, isopropyl ether, methyl tertiary butyl ether(MTBE)
Or dioxane solution.
Retarder thinner is methylene chloride or ethyl acetate, recrystallisation solvent be ether, isopropyl ether, methyl tertiary butyl ether(MTBE), just oneself
One or more of alkane, normal heptane.
A kind of embodiment of synthesis (R) 1- amino -3- methyl butyl boric acid pinacol ester hydrochloride (I) of the invention
Reaction equation is as follows:
By (R) 1- amino -3- methyl butyl boric acid pinacol ester hydrochloride (I) prepared by the present invention further by following
Bortezomib can be obtained in method.
Illustrate advantages of the present invention by the parsing of following mechanism:
The present invention passes through the addition reaction of (NHC) CuOt-Bu and proton donor concerted catalysis b3 and b4, reaction mechanism
Be: due to the addition of proton donor, such as methanol, the proton in proton donor will be in the addition product of copper ligand and imines
Copper ligand is replaced as (NHC)-Cu-OMe, and then the reaction was continued by the PinB-BPin in it and reaction system, carries out circulation catalysis,
Reaction is accelerated to carry out, reaction process is as follows:
The present invention also screens catalyst type, the usage amount of proton donor and reaction dissolvent, screening experiment
It is as follows:
The different methanol additional amounts of table 1, under the conditions of the reaction time, (R) 1- amino -3- methyl butyl boric acid pinacol ester hydrochloride
The stereoselectivity and yield of salt (I) compare
Wherein, the dosage of (NHC) CuOt-Bu and methanol is relative to (R) -1-N-(terf-butylsulfinyl) -3- methyl
The molar percentage of butylimine (b3).Similarly hereinafter.
The different amount of alcohol added of table 2, under the conditions of the reaction time, (R) 1- amino -3- methyl butyl boric acid pinacol ester hydrochloride
The stereoselectivity and yield of salt (I) compare
The different quantity of isopropanol of table 3, under the conditions of the reaction time, (R) 1- amino -3- methyl butyl boric acid pinacol ester salt
The stereoselectivity and yield of hydrochlorate (I) compare
Conclusion: in table 1, the 2nd~7 row be not added methanol part be according to the prior art (J.Am.Chem.Soc, 2008,
130,6910-6911) Ellman method operates in, is reacted using the catalysis that single (NHC) CuOt-Bu is carried out, as can be seen from the results,
The addition reaction time is longer (16~18h), and stereoselectivity is poor (96:4), and formula (I) yield is lower (23%~32%), boron removal pair
Product assay height (20% or so).
And using technical solutions according to the invention, i.e. (NHC) CuOt-Bu and alcohols proton donor concerted catalysis addition are anti-
It answers, the addition reaction time is obviously shortened (2~8h), and stereoselectivity and yield significantly improve, especially the addition effect of methanol
It is more obvious, and as the increase formula (I) yield of methanol additional amount also significantly improves, when methanol and (R) -1-N-(tert-butyl
Sulfinyl) when increasing to 1:1, formula (I) yield has been up to 67% for the molar ratio of -3- methyl butyl imines (b3), if after
The continuous methanol usage formula (I) yield that increases declines instead, directly methanol is used to be reacted as solvent, is then unable to get formula at all
(I) product.It can be seen that the inventory of methanol has a great impact to reaction time, product yield, only when methanol usage is
When 0.3 to 10 molar equivalent, preferably 0.5 to 5 molar equivalent, the reaction time is shorter, yield and purity are higher.
Using technical solutions according to the invention, boron removal by-products content can be made to fall below 1% by the prior art 20%
Hereinafter, stereoselectivity has been increased to 99.6:0.4, formula (I) yield can reach 67%.
Beneficial effects of the present invention:
The present invention carries out Ellman method synthesis (R) -1- amino -3- methyl butyl boric acid pinacol ester hydrochloride (I)
Improve, innovation is that (R) 1-N-(terf-butylsulfinyl) -3- methyl butyl imines (b3) and connection boric acid frequency that
Alcohol ester (b4) carries out asymmetric addition, has used the tertiary fourth oxygen copper complex of generated in-situ N-heterocyclic carbine ((NHC) CuOt-Bu)
It is acted on proton donor concerted catalysis, greatly improves catalytic activity, shorten the time of addition reaction, reduce boron removal pair
Product improves stereoselectivity, and the yield of formula (I), which has, significantly to be improved.And due to after addition reaction product purity compared with
Height, without the column separating purification process of former Ellman method, directly progress the next step.It is synthesized with improved Ellman method
(R) 1- amino -3- methyl butyl boric acid pinacol ester hydrochloride (I) through preparation bortezomib verifying, the results showed that product
Quality is high, at low cost, easy to operation to be suitable for preparation of industrialization.
Specific embodiment:
The present invention is further illustrated by the following examples.Method in the embodiment of the present invention is only used for illustrating this
Invention, rather than limiting the invention.
The preparation of 1 Icy.BF4 of embodiment
Paraformaldehyde (12.6g), toluene (400ml), cyclohexylamine (39.6g) are added in 1000ml reaction flask, room temperature
Reaction 1.5 hours, be warming up to 40 DEG C, another cyclohexylamine (39.6g) be added, then be added dropwise tetrafluoro boric acid (40%HBF4,
88g) aqueous solution finishes for about 0.5 hour, stirs 10 minutes, is cooled to 0 DEG C, is added glyoxal (58g), and 0-5 DEG C is stirred 2 hours,
20 DEG C are warming up to, 20-25 DEG C is stirred 3 hours, and a large amount of solids are precipitated, and it cools to 0-5 DEG C of stirring and filters for 2 hours, solid washing two
Secondary, ether is washed twice, is drained, room-dry, and Icy.BF4 crude product 82g is obtained.
By Icy.BF4 crude product (82g), methylene chloride (500ml), ethyl acetate (500ml) is added in 2000ml reaction flask,
Being warming up to reflux dissolves solid material, filters out insoluble substance, and filtrate is stirred at room temperature 1 hour, and 0-5 DEG C is stirred 1 hour, is filtered, and is used
Ethyl acetate is washed, and is drained, indoor seasoning 1 hour, 2 hours dry under infrared lamp, obtains Icy.BF4 (74g), total recovery 57.8%.Color
Spectral purity 99.2%, 172~175 DEG C of fusing point1HNMR(400MHz,CDCl3): δ 8.96 (s, 1H), 7.43 (d, 2H), 4.30~
4.36 (m, 2H), 2.18~2.20 (m, 4H), 1.90~1.94 (m, 4H), 1.66 (m, 6H), 1.32~1.43 (m, 4H)),
1.25~1.30 (m, 2H).
(the R) -1-N-(of embodiment 2 terf-butylsulfinyl) -3- methyl butyl imines (b3) preparation
Equipped with reflux condenser 50L reactor in, sequentially add (R)-t-butyl sulfonamide (b2) (0.93Kg),
Methylene chloride (14.9Kg), isopentyl aldehyde (b1) (1.02Kg), anhydrous magnesium sulfate (5Kg), PPTS(0.094Kg), open stirring water-bath
It is warming up to reflux, at 47-50 DEG C, 6 hours HPLC monitoring b2 of back flow reaction disappear for bath temperature control, drop to room temperature filtering, use
Dichloromethane eluent aqua merges dichloromethane solution, and twice, saturated salt washing is primary for washing, and anhydrous sodium sulfate dry 3 is small
When, filtering, methylene chloride washes desiccant, merges dichloromethane solution, is spin-dried in 40 DEG C of water pump decompressions, then depressurized and taken out with diaphragm pump
3 hours.It obtains b3 (1.24Kg), yield 90%.The intermediate does not have to purifying and is directly used in the next step.
The preparation of the hydrochloride (I) of embodiment 3 (R) -1- amino -3- methyl butyl boric acid pinacol ester
Icy.BF4(0.062Kg), tetrahydrofuran (6.4Kg), potassium tert-butoxide (0.048Kg) are added to 30L reactor
In, CuCl(0.0192Kg is added under protection of argon gas), b4(1.176Kg) stirring 2 hours, be added b3(0.72Kg), methanol
(122g) reacts 3 hours TLC monitoring raw material b3 in 20-25 DEG C and disappears, reaction solution is drawn in 50L dispenser, acetic acid second is added
Ester (16.2Kg) dilution, is washed three times with pure water, is dried overnight with anhydrous sodium sulfate (7.5Kg), and next day filtering, filtrate subtracts in 34 DEG C
Pressure is concentrated to dryness, and obtains the grease b5(1.07Kg of yellow), the next step is directly used in without purifying.
With the b5 of dioxane (9.6Kg) and methanol (3.2Kg) dissolution previous step preparation, it is transferred in 30L reactor, temperature
Degree is adjusted to 20 DEG C, HCl dioxane solution (4M, 1.65Kg) is added dropwise, a large amount of solids are precipitated when being added dropwise to 2/3, accelerate to stir
Revolving speed is mixed, is added within about 40 minutes, PH=3-4,30 minutes TLC monitoring b5 is stirred and disappears, add n-hexane (7.9Kg), in 15-20 DEG C
It filters within stirring 3 hours within stirring 2 hours, 0-5 DEG C, is washed twice, drained with n-hexane (1Kg × 2), be placed at room temperature for 2 hours, 40 DEG C true
Sky is 4 hours dry, obtains the hydrochloride (I) (0.643Kg) of (R) 1- amino -3- methyl butyl boric acid pinacol ester, yield 67%, ee
Value 99.2%, boron removal by-product (3- methylbutylamine) content 0.8%, fusing point: 188-190 DEG C.1H-NMR(400MHz,CDCl3):δ0.90
(m,6H),1.24(s,12H),1.58(m,1H),1.74(m,1H),1.86(m,1H),2.88(br s,1H),8.18(br s,
2H).13C-NMR(100MHz,CDCl3):δ22.6,22.7,24.8,25.2,36.1(br),38.7,85.1.IR(neat):
2962,1350,1253,1137,854,674cm-1.Exact mass calcd for C11H25BNO2requires m/
z214.1978,found m/z214.1974(MH+,FAB).
The preparation of the hydrochloride (I) of embodiment 4 (R) 1- amino -3- methyl butyl boric acid pinacol ester
Icy.BF4(0.26g is added in 100ml reaction flask), toluene (30ml), potassium tert-butoxide (0.2g), argon gas protect
In 20-25 DEG C of addition CuCl(0.08g under shield), b4(4.9g) stirring 2 hours, be added b3(3g), methanol (0.5g), in 20-25
DEG C reaction 3 hours TLC monitoring raw material b3 disappears, and reaction solution is drawn in dispenser, ethyl acetate (100ml) dilution is added, uses
Pure water is washed three times, is dried overnight with anhydrous sodium sulfate, and next day filtering, filtrate is concentrated to dryness in 34 DEG C, obtains the oily of yellow
Object b5(8.1g) it is directly used in the next step.
It is transferred in 100ml reaction flask after the b5 prepared with dioxane (40ml) and methanol (15ml) dissolution previous step,
Temperature is adjusted to 20 DEG C, is added dropwise HCl dioxane solution (4M, 8ml), is added within about 40 minutes, PH=3-4, and stirring passes through for 30 minutes
TLC monitors b5 and disappears, and adds n-hexane (5ml), stirs 2 hours, 0-5 DEG C and filters in 15-20 DEG C for stirring 3 hours, is washed with n-hexane
Twice, it drains, is placed at room temperature for 2 hours, 40 DEG C are dried in vacuo 4 hours, (R) -1- amino -3- methyl butyl boric acid pinacol ester
Hydrochloride (I) (2.4g), yield 60%, ee value 99.2%, boron removal by-product (3- methylbutylamine) content 0.5%.
The preparation of the hydrochloride (I) of embodiment 5 (R) 1- amino -3- methyl butyl boric acid pinacol ester
Icy.BF4(0.26g is added in 100ml reaction flask), benzene (30ml), potassium tert-butoxide (0.2g), argon gas protect
Under in 20-25 DEG C of addition CuCl(0.08g), b4(4.9g) stirring 2 hours, be added b3(3g), methanol (0.5g), in 20-25 DEG C
It reacts 3 hours TLC monitoring raw material b3 to disappear, reaction solution is drawn in dispenser, ethyl acetate (100ml) dilution is added, use is pure
Washing three times, is dried overnight with anhydrous sodium sulfate, and next day filtering, filtrate is concentrated to dryness in 34 DEG C, obtains the grease of yellow
B5(8.1g) it is directly used in the next step.
It is transferred in 100ml reaction flask after the b5 prepared with dioxane (40ml) and methanol (15ml) dissolution previous step,
Temperature is adjusted to 20 DEG C, is added dropwise HCl dioxane solution (4M, 8ml), is added within about 40 minutes, PH=3-4, and stirring passes through for 30 minutes
TLC monitors b5 and disappears, and adds n-hexane (5ml), stirs 2 hours, 0-5 DEG C and filters in 15-20 DEG C for stirring 3 hours, is washed with n-hexane
Twice, it drains, is placed at room temperature for 2 hours, 40 DEG C are dried in vacuo 4 hours, (R) -1- amino -3- methyl butyl boric acid pinacol ester
Hydrochloride (I) (2.4g), yield 61%, ee value 99%, boron removal by-product (3- methylbutylamine) content 0.6%.
The preparation of the hydrochloride (I) of embodiment 6 (R) 1- amino -3- methyl butyl boric acid pinacol ester
Icy.BF4(0.26g is added in 100ml reaction flask), dioxane (30ml), potassium tert-butoxide (0.2g), in argon
In 20-25 DEG C of addition CuCl(0.08g under gas shielded), b4(4.9g) stirring 2 hours, be added b3(3g), methanol (0.5g), in
3 hours TLC monitoring raw material b3 of 20-25 DEG C of reaction disappear, and reaction solution is drawn in dispenser, it is dilute that ethyl acetate (100ml) is added
It releases, is washed three times with pure water, be dried overnight with anhydrous sodium sulfate, next day filtering, filtrate is concentrated to dryness in 34 DEG C, obtains yellow
Grease b5(8.1g) it is directly used in the next step.
It is transferred in 100ml reaction flask after the b5 prepared with dioxane (40ml) and methanol (15ml) dissolution previous step,
Temperature is adjusted to 20 DEG C, is added dropwise HCl dioxane solution (4M, 8ml), is added within about 40 minutes, PH=3-4, and stirring passes through for 30 minutes
TLC monitors b5 and disappears, and adds n-hexane (5ml), stirs 2 hours, 0-5 DEG C and filters in 15-20 DEG C for stirring 3 hours, is washed with n-hexane
Twice, it drains, is placed at room temperature for 2 hours, 40 DEG C are dried in vacuo 4 hours, (R) -1- amino -3- methyl butyl boric acid pinacol ester
Hydrochloride (I) (2.4g), yield 62%, ee value 99%, boron removal by-product (3- methylbutylamine) content 1.2%.
The preparation of the hydrochloride (I) of embodiment 7 (R) 1- amino -3- methyl butyl boric acid pinacol ester
Icy.BF4(0.26g is added in 100ml reaction flask), isopropyl ether (30ml), potassium tert-butoxide (0.2g), in argon gas
In 20-25 DEG C of addition CuCl(0.08g under protection), b4(4.9g) stirring 2 hours, be added b3(3g), methanol (0.5g), in 20-
25 DEG C of reactions, 3 hours TLC monitoring raw material b3 disappear, and reaction solution is drawn in dispenser, ethyl acetate (100ml) dilution is added,
It is washed three times with pure water, is dried overnight with anhydrous sodium sulfate, next day filtering, filtrate is concentrated to dryness in 34 DEG C, obtains the oil of yellow
Shape object b5(8.1g) it is directly used in the next step.
It is transferred in 100ml reaction flask after the b5 prepared with dioxane (40ml) and methanol (15ml) dissolution previous step,
Temperature is adjusted to 20 DEG C, is added dropwise HCl dioxane solution (4M, 8ml), is added within about 40 minutes, PH=3-4, and stirring passes through for 30 minutes
TLC monitors b5 and disappears, and adds n-hexane (5ml), stirs 2 hours, 0-5 DEG C and filters in 15-20 DEG C for stirring 3 hours, is washed with n-hexane
Twice, it drains, is placed at room temperature for 2 hours, 40 DEG C are dried in vacuo 4 hours, (R) -1- amino -3- methyl butyl boric acid pinacol ester
Hydrochloride (I) (2.4g), yield 59%, ee value 99%, boron removal by-product (3- methylbutylamine) content 1.2%.
Embodiment 8(R) 1- amino -3- methyl butyl boric acid pinacol ester hydrochloride (I) preparation
Ipp.BF4(0.19g is added in 100ml reaction flask), tetrahydrofuran (30ml), potassium tert-butoxide (0.2g), in argon
In 20-25 DEG C of addition CuCl(0.08g under gas shielded), b4(4.9g) stirring 2 hours, be added b3(3g), methanol (0.5g), in
3 hours TLC monitoring raw material b3 of 20-25 DEG C of reaction disappear, and reaction solution is drawn in dispenser, it is dilute that ethyl acetate (100ml) is added
It releases, is washed three times with pure water, be dried overnight with anhydrous sodium sulfate, next day filtering, filtrate is concentrated to dryness in 34 DEG C, obtains yellow
Grease b5(8.5g) it is directly used in the next step.
It is transferred in 100ml reaction flask after the b5 prepared with dioxane (40ml) and methanol (15ml) dissolution previous step,
Temperature is adjusted to 20 DEG C, is added dropwise HCl dioxane solution (4M, 8ml), is added within about 40 minutes, PH=3-4, and stirring passes through for 30 minutes
TLC monitors b5 and disappears, and adds n-hexane (5ml), stirs 2 hours, 0-5 DEG C and filters in 15-20 DEG C for stirring 3 hours, is washed with n-hexane
Twice, it drains, is placed at room temperature for 2 hours, 40 DEG C are dried in vacuo 4 hours, obtain (R) -1- amino -3- methyl butyl boric acid pinacol ester
Hydrochloride (I) (2.7g), yield 67.5%, ee value 96%, boron removal by-product (3- methylbutylamine) content 0.5%.
The preparation of the hydrochloride (I) of embodiment 9 (R) 1- amino -3- methyl butyl boric acid pinacol ester
Ipr.BF4(0.38g is added in 100ml reaction flask), tetrahydrofuran (30ml), potassium tert-butoxide (0.2g), in argon
In 20-25 DEG C of addition CuCl(0.08g under gas shielded), b4(4.9g) stirring 2 hours, be added b3(3g), methanol (0.5g), in
8 hours TLC monitoring raw material b3 of 20-25 DEG C of reaction disappear, and reaction solution is drawn in dispenser, it is dilute that ethyl acetate (100ml) is added
It releases, is washed three times with pure water, be dried overnight with anhydrous sodium sulfate, next day filtering, filtrate is concentrated to dryness in 34 DEG C, obtains yellow
Grease b5(7.5g) it is directly used in the next step.
It is transferred in 100ml reaction flask after the b5 prepared with dioxane (40ml) and methanol (15ml) dissolution previous step,
Temperature is adjusted to 20 DEG C, is added dropwise HCl dioxane solution (4M, 8ml), is added within about 40 minutes, PH=3-4, and stirring passes through for 30 minutes
TLC monitors b5 and disappears, and adds n-hexane (5ml), stirs 2 hours, 0-5 DEG C and filters in 15-20 DEG C for stirring 3 hours, is washed with n-hexane
Twice, it drains, is placed at room temperature for 2 hours, 40 DEG C are dried in vacuo 4 hours, obtain (R) -1- amino -3- methyl butyl boric acid pinacol ester
Hydrochloride (I) (1.7g), yield 42.5%, ee value 99%, boron removal by-product (3- methylbutylamine) content 0.5%.
The preparation of the hydrochloride (I) of embodiment 10 (R) 1- amino -3- methyl butyl boric acid pinacol ester
IAd.BF4(0.34g is added in 100ml reaction flask), tetrahydrofuran (30ml), potassium tert-butoxide (0.2g), in argon
In 20-25 DEG C of addition CuCl(0.08g under gas shielded), b4(4.9g) stirring 2 hours, be added b3(3g), methanol (0.5g), in
10 hours TLC monitoring raw material b3 of 20-25 DEG C of reaction disappear, and reaction solution is drawn in dispenser, it is dilute that ethyl acetate (100ml) is added
It releases, is washed three times with pure water, be dried overnight with anhydrous sodium sulfate, next day filtering, filtrate is concentrated to dryness in 34 DEG C, obtains yellow
Grease b5(6.7g) it is directly used in the next step.
It is transferred in 100ml reaction flask after the b5 prepared with dioxane (40ml) and methanol (15ml) dissolution previous step,
Temperature is adjusted to 20 DEG C, is added dropwise HCl dioxane solution (4M, 8ml), is added within about 40 minutes, PH=3-4, is stirred 30 minutes and is led to
It crosses TLC monitoring b5 to disappear, adds n-hexane (5ml), stir 2 hours, 0-5 DEG C and filter in 15-20 DEG C for stirring 3 hours, use n-hexane
It washes twice, drains, be placed at room temperature for 2 hours, 40 DEG C are dried in vacuo 4 hours, obtain (R) -1- amino -3- methyl butyl boric acid pinacol
The hydrochloride (I) (1.5g) of ester, yield 37.5%, ee value 99.2%.Boron removal by-product (3- methylbutylamine) content 0.5%.
The preparation of the hydrochloride (I) of embodiment 11 (R) 1- amino -3- methyl butyl boric acid pinacol ester
Icy.BF4(0.26g is added in 100ml reaction flask), tetrahydrofuran (30ml), potassium tert-butoxide (0.2g), in argon
In 20-25 DEG C of addition CuCl(0.08g under gas shielded), b4 stir 2 hours, be added b3, ethyl alcohol, wherein b3:b4:Icy.BF4:
The molar ratio of ethyl alcohol is 1:1.2:0.05:1.
Above-mentioned reactant reacts 2 hours TLC monitoring raw material b3 at 20-25 DEG C and disappears, and reaction solution is drawn in dispenser, is added
Enter ethyl acetate (100ml) dilution, washed three times with pure water, be dried overnight with anhydrous sodium sulfate, next day filtering, filtrate subtracts in 34 DEG C
Pressure is concentrated to dryness, and obtains the grease b5(7.5g of yellow) it is directly used in the next step.
It is transferred in 100ml reaction flask after the b5 prepared with dioxane (40ml) and methanol (15ml) dissolution previous step,
Temperature is adjusted to 20 DEG C, is added dropwise HCl dioxane solution (4M, 8ml), is added within about 40 minutes, PH=3-4, and stirring passes through for 30 minutes
TLC monitors b5 and disappears, and adds n-hexane (50ml), stirs 2 hours, 0-5 DEG C and filters in 15-20 DEG C for stirring 3 hours, is washed with n-hexane
Twice, it drains, is placed at room temperature for 2 hours, 40 DEG C are dried in vacuo 4 hours, obtain (R) -1- amino -3- methyl butyl boric acid pinacol ester
Hydrochloride (I) (1.8g), yield 45%, ee value 99%, boron removal by-product (3- methylbutylamine) 0.3%.
The preparation of the hydrochloride (I) of embodiment 12 (R) 1- amino -3- methyl butyl boric acid pinacol ester
Icy.BF4(0.26g is added in 100ml reaction flask), tetrahydrofuran (30ml), potassium tert-butoxide (0.2g), in argon
In 20-25 DEG C of addition CuCl(0.08g under gas shielded), b4 stir 2 hours, be added b3, isopropanol.Wherein, b3:b4:
Icy.BF4: the molar ratio of isopropanol are as follows: 1:1.2:0.05:1.
10 hours TLC monitoring raw material b3 are reacted in 20-25 DEG C to disappear, and reaction solution is drawn in dispenser, acetic acid second is added
Ester (100ml) dilution, is washed three times with pure water, is dried overnight with anhydrous sodium sulfate, and next day filtering, filtrate is concentrated under reduced pressure into 34 DEG C
It is dry, obtain the grease b5(7.5g of yellow) it is directly used in the next step.
It is transferred in 100ml reaction flask after the b5 prepared with dioxane (40ml) and methanol (15ml) dissolution previous step,
Temperature is adjusted to 20 DEG C, is added dropwise HCl dioxane solution (4M, 8ml), is added within about 40 minutes, PH=3-4, is stirred 30 minutes and is led to
It crosses TLC monitoring b5 to disappear, adds n-hexane (50ml), stir 2 hours, 0-5 DEG C and filter in 15-20 DEG C for stirring 3 hours, use n-hexane
It washes twice, drains, be placed at room temperature for 2 hours, 40 DEG C are dried in vacuo 4 hours, obtain (R) -1- amino -3- methyl butyl boric acid pinacol
The hydrochloride (I) (1.6g) of ester, yield 42%, ee value 99%, boron removal by-product (3- methylbutylamine) content 0.1%.
The preparation of 13 bortezomib of embodiment (bortezomib)
By the hydrochloride (I) (0.45Kg) of (the R) -1- amino -3- methyl butyl boric acid pinacol ester prepared in embodiment 3
With N- (2- pyrazinecarbonyl)-L-phenylalanine (b7) (0.408Kg), O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro
Borate (TBTU) (0.96Kg) and methylene chloride (7.96Kg) are added in 30L reactor, and stirring is cooled to 0 DEG C, and N is added dropwise,
N- diisopropylethylamine (DIPEA) (0.25Kg) finishes for about 1 hour, and 0-5 DEG C is reacted 1.5 hours, and HPLC monitoring b7 content is less than
1.5%, reaction solution is drawn onto 50L liquid separation tank, ethyl acetate (27.6Kg) dilution is added, washing is primary, and 1%H3PO4 is washed twice；
5%NaHCO3 is washed once；Washing is primary, and PH=7 after washing are spin-dried for obtaining intermediate b8 in 35 DEG C, is directly used in lower step without purifying
Reaction.
The b8 being spin-dried for is dissolved with methanol (4.75Kg), is added in 30L reactor, adds n-hexane (3.95Kg) and different
Butyl boron dihydroxide (0.3Kg), reactor temperature are adjusted to 15-20 DEG C, are added dropwise 1N hydrochloric acid (3Kg), are added within about 20-30 minutes, instead
It answers 1 hour HPLC monitoring b8 content less than 1%, terminates reaction, reaction solution is drawn in 50L dispenser, hexane solution is separated,
The n-hexane extraction for adding equivalent is primary.Then pure water (12Kg) is added, methylene chloride (10Kg) extracts product, separates dichloro
Dichloromethane adds methylene chloride (5Kg) extraction, and combining extraction liquid, washing is twice.It is spin-dried in 33 DEG C, adds ethyl acetate
(5.52Kg) dissolution, is placed at room temperature for 2 hours, stands overnight in refrigerator-freezer, and next day filtering, ethyl acetate is washed once, drained, and room temperature is put
It sets 2 hours, 30 DEG C are dried in vacuo 10 hours, obtain bortezomib crude product (390g), and two step yields are 67.66%, chromatographic purity
99.4%, 169-173 DEG C of fusing point, [α]=- 50~-51 ° (C=1, MeOH).1H-NMR(400MHz,d6- DMSO, ppm): δ 9.09
(d, 1H), 8.84 (d, 2H), 8.72 (d, 2H), 7.13~7.24 (m, 5H), 4.94 (m, 1H), 3.13 (m, 2H), 2.64 (m,
1H),1.54(m,1H),1.30(m,1H),1.18(m,1H),0.76(d,6H)；13C-NMR(400MHz,d6- DMSO, ppm): δ
173.17,162.97,148.18,144.55,143.96,143.78,137.32,129.75,52.17,40.68,40.45,
37.79,25.51,23.43,22.94；IR(neat):3338,1633,1525,1378,1245,1020cm-1.Anal.Calcd
for C19H25BN4O4:C,59.39;H,6.56;N,14.58.Found:C,59.49;H,6.27;N,14.30。
Claims (9)
1. a kind of preparation method of bortezomib key intermediate (I),
It is characterized in that, the preparation method includes the following steps:
Step (1), in chloro alkanes and/or ether solvent, excessive isopentyl aldehyde (b1) and (R)-t-butyl sulfonamide
(b2) in the presence of a dehydrating agent, (R) -1-N- (terf-butylsulfinyl) -3- methyl butyl imines is condensed to yield in 40-50 DEG C
(b3)；
Step (2), in ethers and/or benzene kind solvent, (R) -1-N- (terf-butylsulfinyl) -3- methyl butyl imines (b3)
With connection boric acid pinacol ester (b4) at catalyst (NHC) CuOt-Bu and proton donor co-catalysis, it is being full of argon gas or nitrogen
Reactor in, in 0-30 DEG C of nucleophilic addition obtain (R) -1-N- (terf-butylsulfinyl) -3- methylbutylamine -1- boric acid frequency that
Alcohol ester (b5)；
Step (3), in alcohols and/or ether solvent, (R) -1-N- (terf-butylsulfinyl) -3- methylbutylamine -1- boric acid
Pinacol ester (b5) in 0-30 DEG C after sour water solution, then through solvent dilution, washing, concentration, crystallization, obtain (R) -1- of high-purity
The hydrochloride (I) of amino -3- methyl butyl boric acid pinacol ester；
Wherein, in step (2), the molar ratio of b3 and b4, (NHC) CuOt-Bu and proton donor are 1:(1~1.2):
(0.03~0.06): (0.5~5)；Proton donor is selected from methanol；The addition reaction time is 2-6 hours.
2. the method according to claim 1, wherein wherein, in the step (2):
Ethers and/or benzene kind solvent are selected from: tetrahydrofuran, dioxane, ether, isopropyl ether, methyl tertiary butyl ether(MTBE), benzene, toluene
One or more of；
NHC is selected from catalyst (NHC) CuOt-Bu: 1,3- dicyclohexyl imidazoles, 1,3- be bis--(2,6- diisopropyl phenyl) miaow
Azoles, 1,3- diisopropyl imidazoles or 1, bis- adamantyl imidazoles of 3-.
3. according to the method described in claim 2, it is characterized in that, wherein in the step (2):
NHC preferably is selected from catalyst (NHC) CuOt-Bu: 1,3- dicyclohexyl imidazoles；
The addition reaction time is 3 hours；
Catalyst (NHC) CuOt-Bu's the preparation method is as follows: NHC.BF4 is reacted with stannous chloride, highly basic, their molar ratio
For 1:1:(2~8), reaction temperature is 0-40 DEG C；
Wherein NHC.BF4's the preparation method is as follows: in organic solvent, it is the primary amine of 2:1:1:1, poly first that molar ratio, which is added,
Aldehyde, glyoxal, tetrafluoro boric acid treat different things alike for 0-60 DEG C and generate NHC.BF4 crude product；It is tied again through methylene chloride and/or ethyl acetate again
Crystalline substance obtains NHC.BF4.
4. according to the method described in claim 3, it is characterized in that, wherein, in the step (2):
In the preparation method of catalyst (NHC) CuOt-Bu: highly basic is selected from potassium tert-butoxide or sodium tert-butoxide；
In the preparation method of NHC.BF4: organic solvent is selected from: one of methylene chloride, tetrahydrofuran, dioxane or toluene
Or several, primary amine R-NH2, wherein R substituent is selected from: cyclohexyl, 2,6- diisopropyl phenyls, adamantyl, diisopropyl
Base.
5. the method according to claim 1, wherein wherein, in step (1):
Chloro alkanes and/or ether solvent are one or more of methylene chloride, dichloroethanes, tetrahydrofuran, dioxane；
Dehydrating agent is one of mixture, tetraethyl titanate, cesium carbonate of p-methyl benzenesulfonic acid pyridiniujm and anhydrous magnesium sulfate；
The molar ratio of b1, b2 and dehydrating agent is (1~1.5): 1:(0.01~5.1).
6. according to the method described in claim 5, it is characterized in that, wherein, in step (1):
When dehydrating agent is the mixture of p-methyl benzenesulfonic acid pyridiniujm and anhydrous magnesium sulfate, b1, b2 and feeding intake for dehydrating agent are rubbed
You are than being (1~1.5): 1:(5.01~5.1), wherein the ratio of p-methyl benzenesulfonic acid pyridiniujm and anhydrous magnesium sulfate is (0.01
~0.1): 5；
When dehydrating agent is tetraethyl titanate, the molar ratio of b1, b2 and dehydrating agent is (1~1.5): 1:(0.9~1.1)；
When dehydrating agent is cesium carbonate, the molar ratio of b1, b2 and dehydrating agent is (1~1.5): 1:(0.01~0.1).
7. according to the method described in claim 5, it is characterized in that, wherein, in step (1):
Chloro alkanes/or ether solvent are preferably methylene chloride, and dehydrating agent is preferably p-methyl benzenesulfonic acid pyridiniujm and anhydrous sulphur
The ratio of the mixture of sour magnesium, p-methyl benzenesulfonic acid pyridiniujm and anhydrous magnesium sulfate is (0.01~0.1): 5.
8. the method according to claim 1, wherein wherein in the step (3):
Alcohols and/or ether solvent be methanol, ethyl alcohol, tetrahydrofuran, dioxane, ether, isopropyl ether, in methyl tertiary butyl ether(MTBE)
One or more；
Acid used in hydrolysis is the organic solution containing HCl；
Retarder thinner is methylene chloride or ethyl acetate, and recrystallisation solvent is ether, isopropyl ether, methyl tertiary butyl ether(MTBE), n-hexane, just
One or more of heptane.
9. according to the method described in claim 8, it is characterized in that, wherein, in the step (3):
Containing the organic solution of HCl used in hydrolysis, ether, isopropyl ether, methyl tertiary butyl ether(MTBE) or dioxane selected from HCl
Solution.
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