CN103965280A - Preparation method of fulvestrant intermediate - Google Patents
Preparation method of fulvestrant intermediate Download PDFInfo
- Publication number
- CN103965280A CN103965280A CN201410215543.5A CN201410215543A CN103965280A CN 103965280 A CN103965280 A CN 103965280A CN 201410215543 A CN201410215543 A CN 201410215543A CN 103965280 A CN103965280 A CN 103965280A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- nonanediol
- fulvestrant
- product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 title claims abstract description 42
- 229960002258 fulvestrant Drugs 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 239000006227 byproduct Substances 0.000 claims abstract description 26
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 22
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 22
- ALVZNPYWJMLXKV-UHFFFAOYSA-N 1,9-Nonanediol Chemical compound OCCCCCCCCCO ALVZNPYWJMLXKV-UHFFFAOYSA-N 0.000 claims abstract description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 235000019439 ethyl acetate Nutrition 0.000 claims description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 22
- -1 dimethyl tertiary butyl Chemical group 0.000 claims description 22
- NPAGDVCDWIYMMC-IZPLOLCNSA-N nandrolone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 NPAGDVCDWIYMMC-IZPLOLCNSA-N 0.000 claims description 22
- 229960004719 nandrolone Drugs 0.000 claims description 22
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 18
- 239000012043 crude product Substances 0.000 claims description 15
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 14
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 12
- 229960005082 etohexadiol Drugs 0.000 claims description 11
- ZWRUINPWMLAQRD-UHFFFAOYSA-N n-Nonyl alcohol Natural products CCCCCCCCCO ZWRUINPWMLAQRD-UHFFFAOYSA-N 0.000 claims description 11
- 239000007818 Grignard reagent Substances 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- 150000004795 grignard reagents Chemical class 0.000 claims description 10
- 229940126214 compound 3 Drugs 0.000 claims description 9
- 150000004820 halides Chemical class 0.000 claims description 9
- 229940059936 lithium bromide Drugs 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 9
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 claims description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 6
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 6
- 229940045803 cuprous chloride Drugs 0.000 claims description 6
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- WGAXVZXBFBHLMC-UHFFFAOYSA-N 1,9-dibromononane Chemical class BrCCCCCCCCCBr WGAXVZXBFBHLMC-UHFFFAOYSA-N 0.000 claims description 4
- BGNXCDMCOKJUMV-UHFFFAOYSA-N Tert-Butylhydroquinone Chemical compound CC(C)(C)C1=CC(O)=CC=C1O BGNXCDMCOKJUMV-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 4
- 210000003746 feather Anatomy 0.000 claims description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 4
- 239000004250 tert-Butylhydroquinone Substances 0.000 claims description 4
- 235000019281 tert-butylhydroquinone Nutrition 0.000 claims description 4
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- 235000014493 Crataegus Nutrition 0.000 claims description 3
- 241001092040 Crataegus Species 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 3
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 229940093916 potassium phosphate Drugs 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 238000007259 addition reaction Methods 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 238000005906 dihydroxylation reaction Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- ZJKABZNFELLAQQ-UHFFFAOYSA-N octane Chemical compound CCCCCCCC.CCCCCCCC ZJKABZNFELLAQQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 23
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000006845 Michael addition reaction Methods 0.000 abstract 1
- 230000001276 controlling effect Effects 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- OEIJHBUUFURJLI-UHFFFAOYSA-N octane-1,8-diol Chemical compound OCCCCCCCCO OEIJHBUUFURJLI-UHFFFAOYSA-N 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 238000003809 water extraction Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000005406 washing Methods 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 229940125898 compound 5 Drugs 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 229910052749 magnesium Inorganic materials 0.000 description 5
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000006073 displacement reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- JCTGUJIBPLBUOA-UHFFFAOYSA-N 2,3,3,4,4-pentafluoro-1-phenylhexan-2-ol Chemical compound FC(C(C(O)(CC1=CC=CC=C1)F)(F)F)(CC)F JCTGUJIBPLBUOA-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- LWLSVNFEVKJDBZ-UHFFFAOYSA-N N-[4-(trifluoromethoxy)phenyl]-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC(=O)N1CCC(CC1)CC1=CC(=CC=C1)OC1=NC=C(C=C1)C(F)(F)F)(F)F LWLSVNFEVKJDBZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229960005309 estradiol Drugs 0.000 description 2
- 229930182833 estradiol Natural products 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZQFIAAFKCPCOQZ-UHFFFAOYSA-N 2-chloro-2,3-dimethylbutane silane Chemical compound [SiH4].CC(C(C)(C)Cl)C ZQFIAAFKCPCOQZ-UHFFFAOYSA-N 0.000 description 1
- NAFZWNVQWZIXCR-UHFFFAOYSA-N 5,5-dibromononane Chemical class CCCCC(Br)(Br)CCCC NAFZWNVQWZIXCR-UHFFFAOYSA-N 0.000 description 1
- IIXWCBMAAVQMEA-UHFFFAOYSA-N C(CCCC)S.[F] Chemical class C(CCCC)S.[F] IIXWCBMAAVQMEA-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- HXLVDKGPVGFXTH-UHFFFAOYSA-N butyl(dimethyl)silane Chemical group CCCC[SiH](C)C HXLVDKGPVGFXTH-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([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])[H] 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- GZQUFIUZBLOTMM-UHFFFAOYSA-N pentyl methanesulfonate Chemical class CCCCCOS(C)(=O)=O GZQUFIUZBLOTMM-UHFFFAOYSA-N 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of a fulvestrant intermediate. The preparation method of the fulvestrant intermediate is characterized in that a water extraction starting material 1,9-nonanediol is adopted for controlling the content of 1,8-octylene glycol, an antioxidant is added for reducing byproducts which are generated by Michael addition and difficult to purify and pH value is regulated for reducing production of aromatized impurities difficult to remove, so that a route for preparing fulvestrant by virtue of the fulvestrant intermediate has the advantages that a final product is difficult to purify, the cost is low and industrialization can be easily realized. The prepared fulvestrant intermediate lays a key foundation for obtaining a route for synthesizing fulvestrant which is easy to purify and easy for industrialization.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, relate to a kind of preparation method of fulvestrant intermediate.
Background technology
Fulvestrant, molecular formula is C
32h
47f
5o
3s, chemical name is 7-α-[9-(4,4,5,5,5-, five fluorine penta sulfinyls) nonyl] female steroid-1,3,5-(10)-triolefin-3,17-beta-diol, structural formula is as follows:
A kind of novel anti-breast cancer medicines of fulvestrant Shi You Astrazeneca company exploitation, is mainly used in the treatment of the postmenopausal women with advanced mammary cancer that estrogen antagonist therapy for treating is invalid, estrogen receptor is positive.Since its 2002 Nian U.S. listing, and after being gone on the market by Europe approval in 2004, the curative effect that it is good and less side effect, make the postmenopausal women of mammary cancer see Gospel.In view of the relatively large demand of fulvestrant and expensive price, this causes, and people is unable greatly bears, and cannot well be treated.Therefore, searching at present can reduce the cost of fulvestrant, easy industrialized synthetic route has just become people to go the direction of making great efforts again.
The preparation method of fulvestrant can be summarized as two general orientation at present: the one, and the dehydrogenation nandrolone acetic ester (compd A 1) that the price of take is more expensive obtains fulvestrant as parent nucleus carries out a series of reaction; The 2nd, the estradiol of take is prepared fulvestrant as the derivative (compound B-11) of starting raw material as parent nucleus.This both direction all must use price higher 4,4,5,5,5-Pentafluorobenzyl pentanol
At patent US4659516(EP0138504) in introduced the general synthesis technique (Scheme 1) of preparing fulvestrant similar type compound, first this route introduces dehydrogenation nandrolone acetic ester (compd A 1) 7 side chain B by Mike's addition, and then by several steps, introduce five fluorine pentan-thiols by Compound C, final synthetic fulvestrant, but the chirality ratio that Mike's addition obtains is only 7 α: β=1.9:1;
Scheme 1：
Patent WO0232922 and WO03031399 and Chinese patent 01820270 have proposed the route (Scheme 2) that a total step has shortened a step, the long-chain connecing on first synthesizing 7, after addition, take fulvestrant crude product again by three steps, its chirality ratio is only also 7 α: β=2.5:1;
Scheme 2：
WO2006015081 has proposed the route of a similar Scheme 1, but simultaneously also many steps.Wherein the A1 of Mike's addition optimum can reach 7 α: β=12.1:1 with reacting of B, and A can reach 7 α: β=9.1:1 with reacting of G, but amount also just reaches 10 grams, does not reach industrialized degree far away;
Document Organic Process Research & Development 2010,14,544 – 552 have delivered the industrialized producing technology of route Scheme 2, and the isomerized products of Mike's addition is also 7 α: β=2.5:1; And Mike's addition isomerized products of feather weight in we Scheme 1 has reached 7 α: β=7.5:1.
CN200980147187 has described a longer synthetic route (Scheme 3), although he can take by crystallization the isomer J of 7 α: β=95:1-100:1, but the 7 αisomer J yields of taking are also 46%, and obtain fulvestrant and not only need preparation at least twice grignard reagent, and multistep needs column chromatography separated, and this suitability for industrialized production for fulvestrant is also disadvantageous.
Scheme 3：
Chinese patent CN102227441, CN201110163041, CN201110273964, CN201110278101 and US Patent No. 20100174101 are all to take compd B as parent nucleus, or spreading chain, or connect short chain, although the starting raw material estradiol of compound B-11 is cheap relatively a little, accomplish that compound B-11 also needs three steps (Scheme 4), not only the more expensive LDA of price has been used in the inside, and second step need to carry out under very harsh condition, pass through column purification and just can reach 50% left and right yield, so through calculating, not only price is cheap unlike dehydrogenation nandrolone acetic ester, and very difficult suitability for industrialized production, and the production of dehydrogenation nandrolone acetic ester has realized industrialization already, become an intermediate feed being easy to get.
Scheme 4：
According to prior art, we can draw, the dehydrogenation nandrolone acetic ester of take is parent nucleus, and after being placed on to Mike's addition, introduces again Pentafluorobenzyl pentanol, it is most economical method, route Scheme 1 has also just become our present first-selection, and wherein midbody compound X synthetic is one of key in whole route, the impurity that much has strict restriction in fulvestrant pharmacopeia is all also the derivative producing during synthetic this intermediate, although US4659516 and WO2006015081 synthesize and have certain description it, but to critical impurity wherein avoid and removal method not to appearing explanation, and these are to the whether easy industrialization of the route of the synthetic fulvestrant using this intermediate as starting raw material, lower the playing an important role whether cost can fall.
Summary of the invention
In order to address the above problem, the present invention relates to the improved preparation method of fulvestrant midbody compound X, remove and reduce the wherein impurity of crucial several steps, making take its route of preparing fulvestrant as intermediate to become an easy purifying of finished product, the lower easy industrialized route of cost.
For achieving the above object, the invention discloses following technology contents:
A preparation method of fulvestrant intermediate formula X, comprising: a, 1, the purifying of 9-nonanediol; B, 1, the bromo of 9-nonanediol; The silica-based protection of the dimethyl tertiary butyl of c, the bromo-1 nonyl alcohol of 9-; Mike's addition of d, dehydrogenation nandrolone acetic ester; E, dehydroxylation protection; The alkylsulfonyl protection of f, hydroxyl; G, aromizing; It is characterized in that:
A, 1, the purifying of 9-nonanediol: by starting raw material 1,9-nonanediol washes with water, obtains 1 of 1,8-ethohexadiol content < 0.1%, 9-nonanediol compound 1;
B, 1,9-nonanediol reacts with Hydrogen bromide and makes bromo-1 nonyl alcohol compound 2 crude products of 9-, with alkane, the bromo-1 nonyl alcohol crude product of 9-is carried out to recrystallization, removes by product 1,9-bis-bromononanes; Wherein said 1,9-nonanediol and hydrobromic mol ratio are 1:2.0-3.0;
Mike's addition of d, dehydrogenation nandrolone acetic ester: the grignard reagent that feather weight dehydrogenation nandrolone acetic ester and compound 3 are prepared is in tetrahydrofuran (THF), under the catalysis of cuprous halide, there is addition reaction and generate compound 4, gained isomer proportion reaches 7 α: β=7.5:1, in aftertreatment, by adding antioxidant that the generation of by product Z3 is dropped to below 0.1% by 0.3-0.5%, the generation of by product Z4 is dropped to below 0.1% by 0.3-0.4%;
Dehydrogenation nandrolone acetic ester wherein: cuprous halide: grignard reagent: the mol ratio of antioxidant is 1:0.5:1.5-2.5:0.2-0.3;
G, compound 6 react synthetic compound X with cupric bromide and lithiumbromide in solvent acetonitrile, and during aftertreatment, with thiocarbamide cancellation reaction, by adding adjusting PH with base value, the generation that reduces by product Z5, Z6, V7 drops to below 0.1% by approximately 0.3%; Wherein compound 6: cupric bromide: the mol ratio of lithiumbromide is 1:1.5-2.4:1.2-1.6;
Wherein R1 is methylsulfonyl, Methyl benzenesulfonyl base or p-toluenesulfonyl.
Wherein the alkane described in step b refers to sherwood oil, pentane, normal hexane, hexanaphthene, isohexane, normal heptane, octane or nonane.
Cuprous halide described in step c refers to cuprous chloride, cuprous bromide or cuprous iodide.Described antioxidant refers to tertiary butyl hydroxyl aubepine, di-t-butyl Pyrogentisinic Acid, Tenox PG or tertiarybutylhydroquinone.
The concentration of the antioxidant described in steps d is 0.2-0.5%.
Alkali described in step g refers to sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, potassiumphosphate, dipotassium hydrogen phosphate or sodium acetate etc.
Described pH value is 7.
The more detailed preparation method of the present invention is as follows:
A, 1, the purifying of 9-nonanediol: on market, sell now 1,9-nonanediol all contain 0.2%～0.5% 1,8-ethohexadiol, if this impurity takes in the step of back, due to its derivative character and product and similar, be difficult to remove, even and will remove, also to lose a large amount of products.The difference of solubleness in water according to 1,9-nonanediol and 1,8-ethohexadiol, water washs 1,9-nonanediol, obtains containing 1 of < 0.1%, 1 of 8-ethohexadiol, 9-nonanediol.Reduce industrialization product 1,1 in 9-nonanediol, below the content to 0.1% of 8-ethohexadiol, in case generate the more derivative impurity Z1 that is difficult to remove, causes to such an extent that impurity content restriction in fulvestrant pharmacopeia is to be less than 0.1% by Z1;
The preparation of b, (compound 2) bromo-1 nonyl alcohol of 9-: in the high boiling point non-protonic solvents such as toluene or dimethylbenzene, 1,9 nonanediols and Hydrogen bromide back flow reaction, make the bromo-1 nonyl alcohol crude product of 9-, then with a kind of alkane solvent, crude product is carried out to recrystallization, remove the by product 1 of generation, 9-bis-bromononanes, in case back generates the by product Z that is difficult to remove
2, and reduce the loss of dehydrogenation nandrolone acetic ester.
Described alkane solvent refers to but is not limited to sherwood oil, pentane, normal hexane, hexanaphthene, isohexane, normal heptane, octane, nonane, preferred normal hexane, sherwood oil; Wherein said 1,9-nonanediol and hydrobromic mol ratio are 1:2.0-3.0; Reaction times is 18～24 hours;
The preparation of c, (compound 3): referenced patent WO2006015081.
The preparation of d, (compound 4): under causing with iodine, (9-oxygen base in the bromo-ninth of the ten Heavenly Stems)-tertiary butyl dimethylsilane is reacted with magnesium chips, with anhydrous tetrahydro furan, make solvent, temperature of reaction is 30-67 ℃, preparing gained grignard reagent, be added drop-wise in the tetrahydrofuran solution of dehydrogenation nandrolone acetic ester (compd A 1) and cuprous halide afterwards, during dropping, temperature of reaction is-30--10 ℃, reacting generating compound 4.Products therefrom isomer proportion is 7 α: β=5:1-7.5:1, when cancellation is processed, adds antioxidant, reduces the generation of by product Z3 and by product Z4.Cross column purification to by product 7 β≤2%; On the one hand due to after the derivative character of 7 α and 7 β and similar, be difficult to separatedly, until the finished product could remove it, if amount is large, also to just can remove through recrystallization repeatedly; On the other hand, after the derivative of 7 β also will with more expensive Pentafluorobenzyl pentanol derivatives reaction, Pentafluorobenzyl pentanol has been caused to unnecessary waste.In aftertreatment, by adding antioxidant that the generation of by product Z3 is dropped to below 0.1% by 0.3-0.5%, the generation of by product Z4 is dropped to below 0.1% by 0.3-0.4%; By by product Z3, cause to such an extent that impurity content restriction in fulvestrant pharmacopeia is to be less than 0.15%, by by product Z4, cause to such an extent that impurity content restriction in fulvestrant pharmacopeia is to be less than 0.1%.
Described cuprous halide is: cuprous chloride, cuprous bromide or cuprous iodide;
Described antioxidant refers to but is not limited to tertiary butyl hydroxyl aubepine (BHA), di-t-butyl Pyrogentisinic Acid (BHT), Tenox PG (PG) or tertiarybutylhydroquinone (TBHQ);
Dehydrogenation nandrolone acetic ester wherein: cuprous halide: grignard reagent: the mol ratio of antioxidant is 1:0.5:1.5-2.5:0.2-0.3; The amount of antioxidant lower than 0.2 molar equivalent time, does not reach for the inhibition that produces by product Z3 and Z4 the effect that we require, all higher than 0.1%.
The preparation of e, (compound 5): compound 4 is sloughed the silica-based protection of the dimethyl tertiary butyl with dilute hydrochloric acid in methyl alcohol, obtains compound 5;
The preparation of f, (compound 6): compound 5 in methylene dichloride with SULPHURYL CHLORIDE, reaction under triethylamine exists, generates compound 6;
The preparation of g, (compounds X): the solution of lithiumbromide and cupric bromide is added drop-wise in the acetonitrile solution of compound 6, temperature of reaction is 20-30 ℃.With thiocarbamide cancellation reaction, with alkali, adjust cancellation pH to be about 7, carry out the generation of inhibition of impurities Z5, Z6, Z7.The generation of by product Z5, Z6, Z7 drops to below 0.1% by approximately 0.3%, and the impurity that these by products can cause content restriction in fulvestrant pharmacopeia is to be less than 0.1%, and these impurity are due to closely similar with product polarity, are difficult to remove.
Described alkali refers to sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, potassiumphosphate, dipotassium hydrogen phosphate, sodium acetate etc., preferably sodium bicarbonate;
Wherein compound 6: cupric bromide: the mol ratio of lithiumbromide is 1:1.5-2.4:1.2-1.6, preferably 1:2.35:1.6.
Synthetic route of the present invention is as follows:
Fulvestrant intermediate formula X preparation method disclosed by the invention compared with prior art has the positively effect cuing open and is:
(1) pass through commercially available starting raw material 1,9-nonanediol reduces impurity 1 with simple washing, the content of 8-ethohexadiol is to acceptable scope, by recrystallization, remove bromination reaction by product 1,9-bis-bromononanes, not only reduce the raw materials cost reacting with impurity, after also having avoided, removed the loss that this impurity causes;
(2) by reducing and can be derivatized to the intermediate impurity that is difficult to remove impurity in finished product, can largely reduce the purifying difficulty of fulvestrant finished product, the suitability for industrialized production of more convenient fulvestrant in reaction;
(3) dehydrogenation nandrolone acetic ester has reached 7 α: β=7.5:1 with Mike's addition chirality ratio in feather weight is reacted of branched compound 3, and Organic Process Research & Development 2010,14, the industrialization Mike addition chirality ratio of 544 – 552 inventions is only 7 α: β=2.5:1, isomer 7 α need product, 7 β are the by products that need to remove, improved the ratio of 7 α and 7 β, fulvestrant for suitability for industrialized production has not only reduced cost, has also reduced the purifying difficulty of removing by product 7 β simultaneously.
The intermediate X that synthetic method after improving obtains is prepared the fulvestrant that obtains standards of pharmacopoeia that synthetic fulvestrant crude product just can high yield by recrystallization, can well solve the problem of fulvestrant cost height and industrialization difficulty.
Embodiment:
Following embodiment is convenient to understand better the present invention, but does not limit the present invention.Starting raw material 1 wherein, the chemical reagents such as 9-nonanediol, dehydrogenation nandrolone acetic ester all have commercially available.
Embodiment 1:
The purifying of 1,9-nonanediol:
By 1 of technical grade, 9-nonanediol 1 kg heating and melting, washes with water four times, can take 673 g satisfactory 1, and 9-nonanediol reclaims 297 g defective 1,9-nonanediol, loss material 30 g in water, raw material overall utilization 97%.
GC: before washing: 1,8-ethohexadiol content: 0.2143%;
After washing: 1,8-ethohexadiol content: 0.0573%;
Recovery sample: 1,8-ethohexadiol content: 0.2971%;
Loss material in water: 1,8-ethohexadiol content: 0.4182%;
Embodiment 2:
The preparation of the bromo-1 nonyl alcohol of 9-(compound 2):
1,9-nonanediol (1 kg) is added to toluene (20 L), under stirring, adds Hydrogen bromide (40%, 2.5 L), reflux (interior temperature 90-100 ℃) 24 hrs.Stop heating, be cooled to 40 ℃, add ethyl acetate (4L) and cold water (4L), stir layering, organic phase is used saturated sodium bicarbonate aqueous solution and solution washing successively, with anhydrous sodium sulfate drying, be spin-dried for to obtain 1.6 kg crude products, add normal hexane 4.8 L, stirring heating is dissolved, cooling crystallization, obtains the bromo-1 nonyl alcohol of 1.1 kg 9-.
GC: before crystallization: product: 95.2033%, 1,9-bis-bromononanes: 1.9985%;
After crystallization: product: 98.8413%, 1,9-, bis-bromononanes: nothing.
Embodiment 3:
The preparation of compound 3:
By the bromo-1 nonyl alcohol of 9-(1.1 kg), N, dinethylformamide (2.86 L), imidazoles (363 g) are added in the reaction flask of 10 L, under ice bath, add dimethyl tertiary butyl chloride silane (772 g), temperature is lower than 20 ℃, react 1 hour, add successively water (5 L), toluene (1 L), stir separatory, toluene for water (1 L) extraction, mix organic phase, organic phase water (1L) washing with anhydrous sodium sulfate drying, is reduced pressure and is spin-dried at 80 ℃, obtain 1.56 kg products, be directly used in the next step.
Embodiment 4:
Comparison example, goes out 2010,14,544 – 552 to Organic Process Research & Development
Magnesium chips (9.76 kg) and tetrahydrofuran (THF) (738 L) are added in reactor, be heated to 45 ℃, bromo-derivative G(160.4 kg) be divided into four batches and be added in reactor, every batch adds and can cause temperature rising 4-10 ℃, add tetrahydrofuran (THF) (34 L) to rinse bromo-derivative, react completely, be cooled to 10 ℃, filter excessive magnesium chips.The grignard reagent preparing is added in reactor, with tetrahydrofuran (THF) (170 L), dilute, be cooled to-34 ℃, add cuprous chloride (2.0 kg), drip tetrahydrofuran (THF) (350 L) solution of dehydrogenation nandrolone acetic ester (82 kg), in 3.5 hours whens flower, temperature remains on-34 ℃, adds tetrahydrofuran (THF) (35 L) wash residual dehydrogenation nandrolone acetic ester.Tetrahydrofuran (THF) (79 L) the solution cancellation reaction that adds acetic acid (70 kg), the product H isomer proportion obtaining is 7 α: β=2.5:1.
The preparation of the compounds of this invention 4:
(1) do not add antioxidant
Magnesium chips (1.38 g), iodine (0.07 g) are put into reactor, put into anhydrous tetrahydro furan (32 mL), compound 3(3.2 g), vacuumize displacement nitrogen, reaction is heated to 40 ℃ of initiations, then add anhydrous tetrahydro furan (48 mL), drip compound 3(12.9 g), dropwise, continue 1 h that refluxes, be cooled to room temperature and be directly used in following reaction.
By dehydrogenation nandrolone acetic ester (10 g), tetrahydrofuran (THF) (60 mL), cuprous chloride (1.58 g) is put in reactor, vacuumize displacement nitrogen, be cooled to-30 ℃, slowly drip grignard reagent prepared by top, dropwise, under nitrogen protection, add acetic acid, stirring at room 30 minutes, add ammonium chloride (10 g) and ammoniacal liquor (25%, 15 g) the aqueous solution (73 mL), continue to stir 2 hours, standing separatory, the aqueous solution (37 mL) washing of ammonium chloride for organic phase (5 g), with anhydrous sodium sulfate drying, be spin-dried for, obtain crude product (20 g, 7 α: β=7.0:1) cross post, obtain 11.5 g containing the compound 4 of 1.1% by product 7 β.
(2) add antioxidant
Magnesium chips (138 g), iodine (7 g) are put into reactor, put into anhydrous tetrahydro furan (3.2 L), compound 3(320 g), vacuumize displacement nitrogen, reaction is heated to 40 ℃ of initiations, then add anhydrous tetrahydro furan (4.8 L), drip compound 3(1.29 kg), dropwise, continue 1 h that refluxes, cooling is directly used in following reaction.
By dehydrogenation nandrolone acetic ester (1 kg), tetrahydrofuran (THF) (6 L), cuprous chloride (158.4 g) is put in reactor, vacuumize displacement nitrogen, be cooled to-30 ℃, slowly drip grignard reagent prepared by top, dropwise, under nitrogen protection, add acetic acid and antioxidant 2, 6-di-tert-butyl-4-methy phenol (150 g), stirring at room 30 minutes, add ammonium chloride (1 kg) and ammoniacal liquor (25%, 1.5 kg) the aqueous solution (7.3 L), continue to stir 2 hours, standing separatory, the aqueous solution (3.7 L) washing of ammonium chloride for organic phase (500 g), with anhydrous sodium sulfate drying, be spin-dried for, obtain crude product (2.1 kg, 7 α: β=7.5:1) cross post, obtain 1.28 kg containing the compound 4 of 1.6% by product 7 β.
Embodiment 5:
The preparation of compound 5:
By compound 4(1 kg) molten in methyl alcohol (10 L), under ice bath, drip 2N aqueous hydrochloric acid (1.74 L), drip reaction 1 hour, slowly add ammoniacal liquor (25%, 160 mL) the aqueous solution (480 mL), concentrating under reduced pressure falls methyl alcohol, adds methylene dichloride (10 L), separatory, methylene dichloride washes with water mutually, with anhydrous sodium sulfate drying, be spin-dried for to obtain 1 kg compound 5 crude products, be directly used in the next step.
Embodiment 6:
The preparation of compound 6:
By upper step compound 5(1 kg) crude product is molten in methylene dichloride (10 L), under ice bath, add triethylamine (535 g), drip afterwards Methanesulfonyl chloride (300 g), drip completely, react 1 hour, wash with water, wash excess of triethylamine off, with anhydrous sodium sulfate drying, be spin-dried for to obtain 909 g compound 6 crude products, be directly used in the next step.
Embodiment 7:
The preparation of compounds X:
(1) while preparing compound 4, do not add antioxidant
A: by compound 6(5 g) molten in acetonitrile (25 mL), under room temperature, drip acetonitrile (25 mL) solution of Xiuization Copper (4.82 g) and lithiumbromide (1.29 g), temperature is no more than 30 ℃, drip completely, react again 6 hours, reaction solution is slowly poured in the water (29.6 mL) and toluene (18.4 mL) solution of the thiocarbamide (2.7 g) at 10 ℃, be cooled to 0 ℃, add dipotassium hydrogen phosphate (3.54 g), adjust pH is about 5, stir 1 hour, filter, filtrate water washing, with anhydrous sodium sulfate drying, be spin-dried for and send HPLC, cross post and obtain 1.5 g compounds Xs.
HPLC: product: 91.754%, Z1:0.040%, Z2: nothing, Z3:0.469%, Z4:0.349%, Z5:0.341%, Z6:0.226%, Z7:0.165%.
B: by compound 6(5 g) molten in acetonitrile (25 mL), under room temperature, drip acetonitrile (25 mL) solution of Xiuization Copper (4.82 g) and lithiumbromide (1.29 g), temperature is no more than 30 ℃, drip completely, react again 6 hours, reaction solution is slowly poured in the water (29.6 mL) and toluene (18.4 mL) solution of the thiocarbamide (2.7 g) at 10 ℃, be cooled to 0 ℃, add sodium bicarbonate (4.96 g), adjust pH is about 7, stir 1 hour, filter, filtrate water washing, with anhydrous sodium sulfate drying, be spin-dried for and send HPLC, cross post and obtain 2.3 g compounds Xs.
HPLC: product: 92.034%, Z1:0.043%, Z2: nothing, Z3:0.476%, Z4:0.365%, Z5:0.067%, Z6:0.035%, Z7:0.020%
(2) while preparing compound 4, add antioxidant
By compound 6(500 g) molten in acetonitrile (2.5 L), under room temperature, drip acetonitrile (2.5 L) solution of Xiuization Copper (482 g) and lithiumbromide (129 g), temperature is no more than 30 ℃, drip completely, react again 1 hour, reaction solution is slowly poured in the water (2.96 L) and toluene (1.84 L) solution of the thiocarbamide (270 g) at 10 ℃, be cooled to 0 ℃, add sodium bicarbonate (496 g), adjust pH is about 7, stir 1 hour, filter, filtrate water washing, with anhydrous sodium sulfate drying, be spin-dried for and send HPLC, cross post and obtain 376 g compounds Xs.
HPLC: product: 92.834%, Z1:0.041%, Z2: nothing, Z3:0.087%, Z4:0.050%, Z5:0.066%, Z6:0.038%, Z7:0.011%
The purity of crossing the complete compounds X of post is 98.7%, impurity Z1:0.040%, Z2: nothing, Z3:0.076%, Z4:0.024%, Z5:0.035%, Z6:0.013%, Z7: nothing.
Presentation of results relatively:
When Mike's addition aftertreatment, do not add antioxidant, preparing compounds X aftertreatment adjusts pH value lower than 7 o'clock, impurity Z3, Z4, Z5, Z6, Z7 are all greater than 0.1%, during compounds X purifying, need the repeated multiple times post of crossing, could these impurity all be dropped to below 0.1%, lose greatlyr, yield only reaches 29.9%; When Mike's addition aftertreatment, do not add antioxidant, prepare compounds X aftertreatment pH value is transferred to at 7 o'clock, Z3, Z4 are greater than 1%, Z5, Z6, Z7 and are less than 0.1%, and yield is 45.8%; When Mike's addition aftertreatment, add antioxidant, prepare compounds X aftertreatment pH value is transferred to at 7 o'clock, compounds X purifying only needs the simple post of crossing, and yield can reach 74.9%.
This route is limited in the impurity that is difficult to remove below 0.1% in advance by improving, and has greatly simplified the purifying difficulty of product, and the corresponding product yield that largely improved.Make this route be more suitable for suitability for industrialized production.
Embodiment 8
Adopt compounds X of the present invention to prepare method and the result of fulvestrant
4,4,5,5,5-Pentafluorobenzyl pentanol (10 g) and methylene dichloride (100 mL) are added in reaction flask, add triethylamine (11.3 g), under ice bath, drip Methanesulfonyl chloride (6.72 g), dropwise, recover room temperature reaction 2 hours.Water washes away excess of triethylamine and Methanesulfonyl chloride, with anhydrous sodium sulfate drying, is spin-dried for, and obtains 14.14 g4,4,5,5,5-Pentafluorobenzyl pentanol methanesulfonates.
By Compound I I(20g) be dissolved in DMF (200 mL), add thiocarbamide (6.6g), reflux is spent the night, and is cooled to room temperature and directly drops into the next step.
By the N of compounds X (10.7 g), dinethylformamide solution (50 mL) is added to the N of compound III, dinethylformamide solution (0.4 mol/L, 50 mL) in, the aqueous solution (5 mL) that adds 50% sodium hydroxide, be heated to react at 50 ℃ 48 h, with isohexane (50 mL) washing, with Glacial acetic acid, adjust pH value to 7, add 100 mL water, by ethyl acetate (60 mL * 3), extract, organic phase saturated common salt water washing, dry, be evaporated to dry, obtain 11.7 g compound IV, directly drop into the next step.
Compound IV (10 g) and methyl alcohol (100 mL) are joined in reaction flask successively, under ice bath, slowly drip the aqueous solution (15 ml) of sodium periodate (7.98 g), recover afterwards room temperature reaction 24 hours, the excessive sodium periodate of the aqueous solution (40 mL) cancellation that adds five water Sulfothiorine (9.2 g), concentrating under reduced pressure is removed methyl alcohol, add ethyl acetate (100 mL) and water (50 mL) to dissolve, separatory, organic phase saturated common salt water washing, dry, be evaporated to dry, obtain 9.5 g crude product compounds 6, compound 6 by with ethyl acetate repeatedly recrystallization take fulvestrant 6.7 g.From intermediate X, to taking qualified fulvestrant productive rate, be about 60%.
HPLC:99.85%, other impurity is all less than 0.1%.
Isomer A：isomer B=46.4：53.5
Molecular formula: C
32h
47f
5o
3s
Nucleus magnetic resonance and mass spectrum are as follows:
1HNMR（CDCl
3，400 M）：δ=0.782（s,3H）, 1.009-1.069(m,1H), 1.231-1.517(m,19H), 1.573-1.663(m, 2H), 1.717-1.794(m, 3H), 1.883-1.922(m, 1H), 2.078-2.355(m, 7H), 2.595-2.882(m, 6H), 3.716-3.770(dd, J1=8.0 Hz, J2=5.6 Hz, 1H)), 6.559-6.564(d, J=2.0Hz, 1H), 6.617-6.651(dt, J1=8.4Hz, J2=2.4 Hz, 1H), 7.121-7.142(d, J=8.4 Hz, 1H).
MS：607.3 [M+H
+]；629.3 [M+Na
+]；645.1 [M+K
+].
Conclusion:
Utilize the synthetic intermediate X of this synthetic route to prepare fulvestrant, fairly simple when removal of impurities, do not need other special separation means, only need to be by recrystallization, and reach pharmacopeia requirement with higher yields.
Claims (7)
1. a preparation method for fulvestrant intermediate, comprising: a, 1, the purifying of 9-nonanediol; B, 1, the bromo of 9-nonanediol; The silica-based protection of the dimethyl tertiary butyl of c, the bromo-1 nonyl alcohol of 9-; Mike's addition of d, dehydrogenation nandrolone acetic ester; E, dehydroxylation protection; The alkylsulfonyl protection of f, hydroxyl; G, aromizing; It is characterized in that:
A, 1, the purifying of 9-nonanediol: by starting raw material 1,9-nonanediol washes with water, obtains 1 of 1,8-ethohexadiol content < 0.1%, 9-nonanediol compound 1;
B, 1,9-nonanediol reacts with Hydrogen bromide and makes bromo-1 nonyl alcohol compound 2 crude products of 9-, with alkane, the bromo-1 nonyl alcohol crude product of 9-is carried out to recrystallization, removes by product 1,9-bis-bromononanes; Wherein said 1,9-nonanediol and hydrobromic mol ratio are 1:2.0-3.0;
Mike's addition of d, dehydrogenation nandrolone acetic ester: the grignard reagent that feather weight dehydrogenation nandrolone acetic ester and compound 3 are prepared is in tetrahydrofuran (THF), under the catalysis of cuprous halide, there is addition reaction and generate compound 4, gained isomer proportion reaches 7 α: β=7.5:1, in aftertreatment, by adding antioxidant that the generation of by product Z3 is dropped to below 0.1% by 0.3-0.5%, the generation of by product Z4 is dropped to below 0.1% by 0.3-0.4%;
Dehydrogenation nandrolone acetic ester wherein: cuprous halide: grignard reagent: the mol ratio of antioxidant is 1:0.5:1.5-2.5:0.2-0.3;
G, compound 6 react synthetic compound X with cupric bromide and lithiumbromide in solvent acetonitrile, and during aftertreatment, with thiocarbamide cancellation reaction, by adding adjusting PH with base value, the generation that reduces by product Z5, Z6, V7 drops to below 0.1% by approximately 0.3%; Wherein compound 6: cupric bromide: the mol ratio of lithiumbromide is 1:1.5-2.4:1.2-1.6;
Wherein R1 is methylsulfonyl, Methyl benzenesulfonyl base or p-toluenesulfonyl.
2. preparation method claimed in claim 1, wherein the alkane described in step b refers to sherwood oil, pentane, normal hexane, hexanaphthene, isohexane, normal heptane, octane or nonane.
3. preparation method claimed in claim 1, wherein the cuprous halide described in step c refers to cuprous chloride, cuprous bromide or cuprous iodide.
4. preparation method claimed in claim 1, wherein the antioxidant described in step c refers to tertiary butyl hydroxyl aubepine, di-t-butyl Pyrogentisinic Acid, Tenox PG or tertiarybutylhydroquinone.
5. preparation method claimed in claim 1, wherein the concentration of the antioxidant described in steps d is 0.2-0.5%.
6. preparation method claimed in claim 1, the alkali described in wherein said step g refers to sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, potassiumphosphate, dipotassium hydrogen phosphate or sodium acetate etc.
7. preparation method claimed in claim 1, the pH value described in wherein said step g is 7.
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| CN107286213A (en) * | 2016-03-31 | 2017-10-24 | 杭州共泽医药科技有限公司 | A kind of preparation method of fulvestrant intermediate |
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| CN111377990A (en) * | 2018-12-29 | 2020-07-07 | 江苏豪森药业集团有限公司 | Preparation method of fulvestrant related substance |
| CN111662356A (en) * | 2019-03-06 | 2020-09-15 | 正大天晴药业集团股份有限公司 | Impurity control method of fulvestrant |
| CN112079894A (en) * | 2020-09-28 | 2020-12-15 | 湖南新合新生物医药有限公司 | Preparation method of levonorgestrel pharmacopoeia impurity V |
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