CN107011402A - A kind of preparation method of melengestrol intermediate - Google Patents
A kind of preparation method of melengestrol intermediate Download PDFInfo
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- CN107011402A CN107011402A CN201710278199.8A CN201710278199A CN107011402A CN 107011402 A CN107011402 A CN 107011402A CN 201710278199 A CN201710278199 A CN 201710278199A CN 107011402 A CN107011402 A CN 107011402A
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- Prior art keywords
- reaction
- melengestrol
- added
- preparation
- compound
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 229960004805 melengestrol Drugs 0.000 title claims abstract description 42
- UDKABVSQKJNZBH-DWNQPYOZSA-N Melengestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC(=C)[C@](OC(=O)C)(C(C)=O)[C@@]1(C)CC2 UDKABVSQKJNZBH-DWNQPYOZSA-N 0.000 title claims abstract 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 149
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- -1 silane epoxide Chemical class 0.000 claims abstract description 22
- 229910000077 silane Inorganic materials 0.000 claims abstract description 18
- 238000006467 substitution reaction Methods 0.000 claims abstract description 18
- 238000006722 reduction reaction Methods 0.000 claims abstract description 14
- 238000005822 methylenation reaction Methods 0.000 claims abstract description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 11
- IATKKATWPOVYCC-VMXHOPILSA-N (8s,9s,10r,13s,14s)-10,13-dimethyl-2,3,6,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthrene Chemical compound C1CC2=CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 IATKKATWPOVYCC-VMXHOPILSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 125000005594 diketone group Chemical group 0.000 claims abstract description 4
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims abstract 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 76
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 34
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 25
- 239000003153 chemical reaction reagent Substances 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 12
- 229960000583 acetic acid Drugs 0.000 claims description 12
- 239000012362 glacial acetic acid Substances 0.000 claims description 11
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims description 10
- 238000006266 etherification reaction Methods 0.000 claims description 10
- 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 claims description 10
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 10
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 238000003379 elimination reaction Methods 0.000 claims description 9
- 230000008859 change Effects 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- 150000007530 organic bases Chemical class 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 150000002460 imidazoles Chemical class 0.000 claims description 6
- 229910052742 iron Inorganic materials 0.000 claims description 6
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical group COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 6
- 239000011701 zinc Substances 0.000 claims description 6
- 229910052725 zinc Inorganic materials 0.000 claims description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 5
- DOJXGHGHTWFZHK-UHFFFAOYSA-N Hexachloroacetone Chemical group ClC(Cl)(Cl)C(=O)C(Cl)(Cl)Cl DOJXGHGHTWFZHK-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 claims description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- APEKGSZABNZPEX-UHFFFAOYSA-N [SiH4].ClCI(C)C Chemical compound [SiH4].ClCI(C)C APEKGSZABNZPEX-UHFFFAOYSA-N 0.000 claims description 5
- HZHMMLIMOUNKCK-UHFFFAOYSA-N dipropyl oxalate Chemical compound CCCOC(=O)C(=O)OCCC HZHMMLIMOUNKCK-UHFFFAOYSA-N 0.000 claims description 5
- VBZWSGALLODQNC-UHFFFAOYSA-N hexafluoroacetone Chemical compound FC(F)(F)C(=O)C(F)(F)F VBZWSGALLODQNC-UHFFFAOYSA-N 0.000 claims description 5
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 5
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 5
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 4
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 4
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- 230000008030 elimination Effects 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 2
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- UHHKSVZZTYJVEG-UHFFFAOYSA-N oxepane Chemical compound C1CCCOCC1 UHHKSVZZTYJVEG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims 2
- 150000002118 epoxides Chemical class 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 1
- 239000005046 Chlorosilane Substances 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- GRWPXSTZEBUPPR-UHFFFAOYSA-N N#CC#N.CC(=O)C Chemical group N#CC#N.CC(=O)C GRWPXSTZEBUPPR-UHFFFAOYSA-N 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 claims 1
- 238000006073 displacement reaction Methods 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 43
- 230000008569 process Effects 0.000 abstract description 37
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 47
- 238000003756 stirring Methods 0.000 description 40
- 238000001035 drying Methods 0.000 description 32
- 239000003960 organic solvent Substances 0.000 description 30
- 238000000967 suction filtration Methods 0.000 description 30
- OKHAOBQKCCIRLO-IBVJIVQJSA-N melengestrol Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC(=C)[C@@](C(=O)C)(O)[C@@]1(C)CC2 OKHAOBQKCCIRLO-IBVJIVQJSA-N 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 239000000543 intermediate Substances 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- 230000007935 neutral effect Effects 0.000 description 12
- 238000009413 insulation Methods 0.000 description 11
- 235000011121 sodium hydroxide Nutrition 0.000 description 11
- 239000011259 mixed solution Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000010792 warming Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 238000005903 acid hydrolysis reaction Methods 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical group CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 description 4
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 4
- 150000001993 dienes Chemical class 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 235000011182 sodium carbonates Nutrition 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 150000003901 oxalic acid esters Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- ZPDIRKNRUWXYLJ-UHFFFAOYSA-N 2,2-dimethyloxolane Chemical class CC1(C)CCCO1 ZPDIRKNRUWXYLJ-UHFFFAOYSA-N 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 244000062245 Hedychium flavescens Species 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 239000003518 caustics Substances 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 150000002240 furans Chemical class 0.000 description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000000186 progesterone Substances 0.000 description 2
- 229960003387 progesterone Drugs 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000052 vinegar Substances 0.000 description 2
- 235000021419 vinegar Nutrition 0.000 description 2
- SEPPVOUBHWNCAW-FNORWQNLSA-N (E)-4-oxonon-2-enal Chemical group CCCCCC(=O)\C=C\C=O SEPPVOUBHWNCAW-FNORWQNLSA-N 0.000 description 1
- ZKFNOUUKULVDOB-UHFFFAOYSA-N 1-amino-1-phenylmethyl phosphonic acid Chemical compound OP(=O)(O)C(N)C1=CC=CC=C1 ZKFNOUUKULVDOB-UHFFFAOYSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- LLBZPESJRQGYMB-UHFFFAOYSA-N 4-one Natural products O1C(C(=O)CC)CC(C)C11C2(C)CCC(C3(C)C(C(C)(CO)C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)CO5)OC5C(C(OC6C(C(O)C(O)C(CO)O6)O)C(O)C(CO)O5)OC5C(C(O)C(O)C(C)O5)O)O4)O)CC3)CC3)=C3C2(C)CC1 LLBZPESJRQGYMB-UHFFFAOYSA-N 0.000 description 1
- DSEXNZAEROZMIF-BKHGZOHYSA-N CC(C1)C[C@@](C)(CC2)C1C(CC1)C2[C@@](C)(CC2)C1=CC2=O Chemical compound CC(C1)C[C@@](C)(CC2)C1C(CC1)C2[C@@](C)(CC2)C1=CC2=O DSEXNZAEROZMIF-BKHGZOHYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 235000002722 Dioscorea batatas Nutrition 0.000 description 1
- 235000006536 Dioscorea esculenta Nutrition 0.000 description 1
- 240000001811 Dioscorea oppositifolia Species 0.000 description 1
- 235000003416 Dioscorea oppositifolia Nutrition 0.000 description 1
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical compound OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 description 1
- DXRFZHILMCWCNG-UHFFFAOYSA-N N,N-dimethyl-1,8-naphthyridin-2-amine Chemical compound C1=CC=NC2=NC(N(C)C)=CC=C21 DXRFZHILMCWCNG-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960003846 melengestrol acetate Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000001072 progestational effect Effects 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0036—Nitrogen-containing hetero ring
- C07J71/0057—Nitrogen and oxygen
- C07J71/0068—Nitrogen and oxygen at position 16(17)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Toxicology (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a kind of preparation method of melengestrol intermediate; it is melengestrol intermediate that product Compound VII, which is made, by etherificate, methylenation, cyano group substitution, the protection of silane epoxide, Intramolecular and substitution, reduction reaction by the diketone of 4 androstene of compound 3,17 in the preparation method.Raw material 4 androstene, 3,17 diketone used are cheap and easily-available, the process route global design reasonably optimizing, and the product impurity of synthesis is few, quality is good, high income, simple to operate, reaction condition is gentle, cost is low, safer, is adapted to industrialization.
Description
Technical field
Field, more particularly to a kind of preparation method of melengestrol intermediate are manufactured the present invention relates to pharmaceutical intermediate.
Background technology
Melengestrol, also known as 6-methyl-16-methylene-17.alpha.-hydroxy-.DELTA.6-progesterone, English name Melengestrol, chemical name：17 Alpha-hydroxy -16- methylenes
Pregnant steroid -3, the 20- diketone of base -4,6- diene, its structural formula is as follows：
Melengestrol is artificial synthesized progestogens medicine, with antitumor and progestational hormone sample activity, is also raised as herding
The additive of foster promotion growth, is widely used by the country beyond US and European, can effectively improve the efficiency of raising,
So as to accelerate increase of herding body weight etc..The today's society huge market demand, and it is reported that there is a variety of synthetic routes, but synthesis
Route is cumbersome, and cost is high, and yield is low.And the 17 pregnant steroid -3,20- diketone of Alpha-hydroxy -16- methylene -4- alkene are synthesis melengestrols
Important intermediate, it introduces methyl reaction by No. 5 positions and can obtain melengestrol.
The preparation of melengestrol, it is good to seek state, Liao Qingjiang：The new technique for synthesizing of melengestrol acetate, Chinese pharmaceutical chemistry
Magazine 2005 year volume 15 3 is interim to disclose a kind of preparation method of melengestrol, using diene alcohol ketone acetic ester as raw material, passes through
Multistep reaction is made, and its synthesis technique is as follows：
Diene alcohol ketone acetic ester is mainly synthesized with the Chinese yam saponin extracted in the raw material such as yellow ginger by multi-step chemical
Arrive.The cost increase of yellow ginger artificial growth in recent years, the price of diene also goes up therewith, and more in the synthesis technique of diene
The heavy metal oxidation agent such as use chromic anhydride, increased cost is also than larger in terms of environmental protection treatment.Introduce No. 16 methylene steps numerous
It is trivial.Also using progesterone as raw material, by the intermediate that obtains of methylenation, the method raw material progesterone is expensive.
Application publication number is in US4921638A, the side reaction on cyanalation reacted reaction is more, reaction condition
Very harsh, 17 pregnant steroid -3, the 20- diketone of beta-hydroxy -16- methylene -4- alkene of cyanalation rear reaction generation are different with target product
Structure, the selectivity of target product is very low, therefore is also unfavorable for industrial production, and its main synthesis technique is：
Application publication number discloses a kind of preparation method of melengestrol for US4443377A patent, with 4-AD
For raw material, by etherificate, carbonyl is introduced, elimination reaction etc. is made, and its synthesis route is as follows：
The method is 17 beta-hydroxies for the synthesis of the 3rd step, and target product is 17 Alpha-hydroxies, therefore it is empty to also need to conversion
Between isomery, and due to the presence of β acetyl group, be also easy to produce side reaction so that reaction is more difficult to carry out；The acetylene that 3rd step is used,
Acetylene is pole inflammable gas, and equipment requirement is very high, and cost is high, is unfavorable for industrial production.
The disclosure of background above technology contents is only used for inventive concept and the technical scheme that auxiliary understands the present invention, and it is not
The prior art of present patent application is necessarily belonged to, the applying date of the above in present patent application is being shown without tangible proof
In the case of disclosed, above-mentioned background technology should not be taken to evaluate the novelty and creativeness of the application.
The content of the invention
It is an object of the invention to propose that a kind of impurity is few, quality is good, high income, simple to operate, reaction condition it is gentle, into
A kind of preparation method of this low, safer melengestrol intermediate, to solve, the impurity that above-mentioned prior art is present is more, quality
Difference, the problem of low yield, complex operation, severe reaction conditions, cost are high, danger coefficient is high.
Therefore, the present invention proposes a kind of preparation method of melengestrol intermediate, concrete technical scheme is as follows：
A kind of preparation method of melengestrol intermediate, with compound I 4- androstenes -3,17 diketone for initiation material, including
Following steps：
S1：Etherification reaction：By compound I add etherificate solvent in, with the first catalyst action with etherifying reagent react,
Obtain compound ii；
S2：Methylenation：Compound ii is added in methylenation solvent, with the first organic base and oxalate to 16 α
Hydrogen is replaced, then carries out methylene elimination to 16 β hydrogen with reagent is eliminated, and finally hydrolyzes to obtain compound III；
S3：Cyano group substitution reaction：Compound III is added in cyaniding solvent, in alkaline environment under the second catalyst action
Reacted with cyanating reagent, obtain compounds Ⅳ；
S4：The protection reaction of silane epoxide：Compounds Ⅳ is added in protection solvent, with silane in the presence of the second organic base
Epoxide reagent reacting, obtains compound V；
S5：Intramolecular nucleophilic substitution reaction：Compound V is added in substitution solvent, and alkali amide reagent reacting,
Obtain compound VI；
S6：Reduction reaction：By in compound VI plus reduction solvent, with metal reaction, compound VII, i.e. melengestrol are obtained
Intermediate.
Further, it is four that solvent is etherified in the preparation method of described a kind of melengestrol intermediate, the step S1
One or more in hydrogen furans, dichloromethane, chloroform, dioxane；First catalyst be p-methyl benzenesulfonic acid or
Perchloric acid；Told etherifying reagent is trimethyl orthoformate or triethyl orthoformate；The reaction temperature of the etherification reaction be 30~
40℃。
Further, the preparation method of described a kind of melengestrol intermediate, the step S2 methylene reagents
For the one or more in dichloromethane, chloroform, acetone and dioxane；First organic base is sodium methoxide, methanol
One or more in potassium, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide；The elimination reagent is formaldehyde, acetaldehyde, one kind of propionic aldehyde
Or it is a variety of；The oxalate told is the one or more in diethy-aceto oxalate, dimethyl oxalate, dipropyl oxalate；The substitution
The reaction temperature of reaction is -10~0 DEG C, and the reaction temperature of elimination reaction is 10~40 DEG C.
Further, cyaniding solvent is first in the preparation method of described a kind of melengestrol intermediate, the step S3
One or more in alcohol, ethanol, normal propyl alcohol, isopropanol, acetone and water；The cyanating reagent is acetone cyanohydrin, potassium cyanide, cyanogen
Change the one or more in sodium；The alkaline environment is one kind or many in sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate
Kind；Second catalyst is hexachloroacetone or Hexafluoro acetone；The reaction temperature of the cyano group substitution reaction is 20~40 DEG C.
Further, it is two that solvent is protected in the preparation method of described a kind of melengestrol intermediate, the step S4
One or more in chloromethanes, chloroform, carbon tetrachloride, benzene, rudimentary aromatic hydrocarbon and acetone；Second organic base is 4-
One or more in dimethylamino naphthyridine, imidazoles, triethylamine, DBU；Described silane epoxide reagent is chloromethyl dimethyl chloride
One or more in silane, chloromethyl dimethyl bromo-silicane, chloromethyl dimethyl iodine silane；The silane epoxide protection reaction
Reaction temperature -10~30 DEG C；Described rudimentary aromatic hydrocarbon be benzene, toluene, ortho-xylene, paraxylene, one kind of ethylbenzene or
It is a variety of.
Further, it is four that solvent is replaced in the preparation method of described a kind of melengestrol intermediate, the step S5
One or more in hydrogen furans, dimethyl-tetrahydrofuran, hexamethylene, ether, benzene；The alkali amide reagent is diisopropyl
One or more in amido lithium, di-iso-butylmanice base lithium, n-BuLi；The reaction temperature of described intramolecular nucleophilic substitution reaction
For -80~-30 DEG C.
Further, it is ice that solvent is reduced in the preparation method of described a kind of melengestrol intermediate, the step S6
Acetic acid；The metal is the one or more in zinc, iron；The reaction temperature of the reduction reaction is 20~60 DEG C.
Further, a kind of preparation method of described melengestrol intermediate, the temperature of the step S2 elimination reactions
Spend for 25~30 DEG C.
Further, the preparation method of described a kind of melengestrol intermediate, the step S4 silane epoxide protection
The reaction temperature of reaction is -5~0 DEG C.
Further, a kind of preparation method of described melengestrol intermediate, the step S5 intramolecular nucleophilics take
The reaction temperature of generation reaction is -70~-65 DEG C.
Compared with prior art, advantage is as follows by the present invention：
(1) initiation material of the invention used is relatively inexpensive is easy to get, and each step reaction is easier to realize, yield is higher, makes
Production cost is low, is more suitable for industrial production.
(2) present invention avoids the operation of multistep protection and deprotection by the design optimization of synthetic line.
(3) present invention directly synthesizes 17 Alpha-hydroxies by the use of the second catalyst, and 17 β-acetyl group reduce space different
The conversion of structure.
(4) present invention uses new side chain preparation method, reduces the use of flammable explosive gas.
Embodiment
Embodiment 1
A kind of preparation method of melengestrol intermediate, specific preparation method is as follows：
S1：Etherification reaction：10g compounds I (4- androstenes -3,20- diketone) is added in reaction bulb, 40g tetrahydrochysene furans are added
Mutter, be passed through nitrogen, add 0.40g p-methyl benzenesulfonic acid, stir, be warming up to 30 DEG C, be slowly added to 24.06g orthoformic acid front threes
Ester, adds temperature control and reacts two hours, and TLC detection reactions are complete；
Last handling process：5~10 DEG C, plus 10g water are cooled to, reacts 6 minutes, rapidly joins the sodium carbonates of 20.05g 2%
Solution, stir half an hour, 160.04g frozen water elutriations, stirring, suction filtration, 20~32 DEG C drying obtain compound ii i.e. 3- methyl ethers-
4- androstene -17- ketone, molar yield 96.12%.
S2：Methylenation：10g compound iis are entered in reaction bulb, 90g dioxane is added and stirs, in nitrogen
Under gas shielded, and temperature setting will be replaced to -10 DEG C, 5.5g potassium methoxides are added into mixed solution, are stirred；It is molten to mixing
It is slowly added dropwise in liquid into 6g diethy-aceto oxalates are added, adds carry out insulation reaction, stirred 3~4 hours, TLC monitors complete to reaction；
0.45g glacial acetic acid, 3.05g triethylamines and 27g methanol are added, is stirred, 3.66g formaldehyde, elimination reaction temperature setting is added
To 10 DEG C, temperature control reacts 1~2 hour, and TLC monitors complete to reaction；
Last handling process：Plus 9g water is terminated, 45 DEG C of rotary evaporations fall organic solvent, and 10g water is recovered under reduced pressure, 1~7 DEG C of guarantor
Warm 2h, 90g elutriation, suction filtration, 40~42 DEG C of drying obtain compound III i.e. 16- methines -4- androstene -3,17- diketone, mole receipts
Rate 97.56%.
S3：Cyano group substitution reaction：10g compound IIIs are added in reaction bulb, 35g methanol is added, 5.52g acetone cyanohydrins are stirred
It is even, the sodium carbonates of 10g 5% are added, Hexafluoro acetone 0.3g is added, 20 DEG C of temperature controls react 22h, and TLC monitors complete to reaction；
Last handling process：70g elutriations, 1.5g hydrochloric acid is neutralized, and filtering, filter cake is washed with water to neutrality, and 25~30 DEG C dry
To compounds Ⅳ, molar yield 95.4%.
S4：The protection reaction of silane epoxide：10g compounds Ⅳs are added in reaction bulb, 40.06g chloroforms, 3.5g is added
Imidazoles is stirred evenly, and under nitrogen protection, is cooled to -10 DEG C, is added dropwise to 5.3g CMDMCS chloromethyl dimethyl chlorosilanes, temperature control reaction 2h, TLC prison
Survey complete to reaction；
Last handling process：0.03% wet chemical terminating reaction, organic solvent 40g dichloromethane is extracted in three times,
Merge 40 DEG C of organic solvent and be concentrated under reduced pressure into small size, add suitable quantity of water, be concentrated under reduced pressure, addition 80g water elutriations, suction filtration, 45~
60 DEG C of drying obtain compound V, molar yield 83.48%.
S5：Intramolecular nucleophilic substitution reaction：10g compounds V are added in reaction bulb, 50g dimethyl-tetrahydrofurans are added
Stir evenly, under nitrogen protection, be cooled to -80 DEG C, add 4.03g trim,ethylchlorosilanes, 50.01g n-BuLis are added dropwise, temperature control is anti-
1~2h, TLC is answered to monitor complete to reaction；
Last handling process：0~10 DEG C of heating plus 50g hydrochloric acid hydrolysis, TLC are monitored to reaction completely, use 40% hydrogen-oxygen
Change sodium water solution and adjust neutral, organic solvent 40g chloroforms are extracted in three times, and 58 DEG C are concentrated under reduced pressure, plus suitable quantity of water, are depressurized dense
Contracting, adds 100g water elutriations, and crystallization, suction filtration, 45~60 DEG C of drying obtain compound VI, molar yield 97.83%.
S6：Reduction reaction：10.02g compounds VI are added in reaction bulb, 50.5g zinc powders are added, 40.06g ice vinegar is added
Acid, is warming up to 20 DEG C, temperature control reacts 5~6h, TLC monitors complete to reaction；
Last handling process：45 DEG C are cooled to, the stirring of 40.00g chloroforms is cooled to 40 DEG C, with 40% sodium hydroxide water
Solution adjusts neutral, and organic solvent 40.08g chloroforms are extracted in three times, and 45 DEG C are concentrated under reduced pressure into small size, plus appropriate water,
It is concentrated under reduced pressure, is recycled to organic solvent-free, adds 70g water elutriations, be down to normal temperature, suction filtration, 45~60 DEG C of drying obtain compound
VII, molar yield 95.45%.HPLC contents 98.46%.
Embodiment 2
A kind of preparation method of melengestrol intermediate, specific preparation method is as follows：
S1：50g compounds I (4- androstenes -3,20- diketone) is added in reaction bulb, 200g dichloromethane is added, is passed through nitrogen
Gas, adds 1g to perchloric acid, stirs, be warming up to 32 DEG C, be slowly added to 112g triethyl orthoformates, adds temperature control reaction two
Individual hour, TLC detection reactions are complete；
Last handling process：0 DEG C, plus 45g water are cooled to, reacts 6 minutes, rapidly joins the aqueous sodium carbonates of 100g 2%,
Stir half an hour, 700g frozen water elutriations, stirring, suction filtration, 20~32 DEG C drying obtain compound ii i.e. 3- methyl ethers -4- androstenes -
17- ketone, molar yield 96.53%.
S2：Methylenation：30g compound iis are entered in reaction bulb, 270g chloroforms is added and stirs, in nitrogen
Under gas shielded, and -8 DEG C are cooled to, 15g potassium methoxides are added into mixed solution, are stirred；It is slowly added dropwise into mixed solution
Enter plus 19.5g dimethyl oxalates, add carry out insulation reaction, stir 3~4 hours, TLC monitors complete to reaction；Add 1.5g
Glacial acetic acid, 10.5g triethylamines and 90g methanol, stir, and add 12.6g formaldehyde, and temperature is increased to 15 DEG C, and temperature control reaction 1~
2 hours, TLC monitored complete to reaction；
Last handling process：Plus 30g water is terminated, 45 DEG C of rotary evaporations fall organic solvent, add 60g water, are recovered under reduced pressure, 1~7
DEG C insulation 2h, 360g elutriations, suction filtration, 40~42 DEG C of drying obtain compound III i.e. 16- methines -4- androstene -3,17- diketone,
Molar yield 97.79%.
S3：Cyano group substitution reaction：30g compound IIIs are added in reaction bulb, 120g normal propyl alcohols are added, 18g potassium cyanide is stirred
It is even, the sodium hydrate aqueous solutions of 3.2g 5% are added, hexachloroacetone 1.1g is added, 25 DEG C of temperature controls react 22h, and TLC is monitored to reaction
Completely；
Last handling process：240g elutriations, 5g hydrochloric acid is neutralized, and filtering, filter cake is washed with water to neutrality, and 25~30 DEG C of drying are obtained
Compounds Ⅳ, molar yield 95.52%.
S4：The protection reaction of silane epoxide：20g compounds Ⅳs are added in reaction bulb, 80g DMAPs are added,
7g imidazoles is stirred evenly, and under nitrogen protection, is cooled to -8 DEG C, is added dropwise to 16g chloromethyl dimethyl bromo-silicanes, temperature control reaction 2h, TLC prison
Survey complete to reaction；
Last handling process：0.03% aqueous sodium carbonate terminating reaction, organic solvent 80g dichloromethane is extracted in three times,
Merge 40 DEG C of organic solvent and be concentrated under reduced pressure into small size, add suitable quantity of water, be concentrated under reduced pressure, addition 100g water elutriations, suction filtration, 45~
60 DEG C of drying obtain compound V, molar yield 87.63%.
S5：Intramolecular nucleophilic substitution reaction：20g compounds V are added in reaction bulb, 100g tetrahydrofurans is added and stirs evenly,
Under nitrogen protection, it is cooled to -70 DEG C, adds 8g trim,ethylchlorosilanes, is added dropwise 105g di-iso-butylmanice base lithiums, temperature control reaction 1~
2h, TLC monitor complete to reaction；
Last handling process：10 DEG C of heating plus 100g hydrochloric acid hydrolysis, TLC are monitored to reaction completely, use 40% hydroxide
Sodium water solution adjusts neutral, and organic solvent 80g chloroforms are extracted in three times, and 58 DEG C are concentrated under reduced pressure, plus suitable quantity of water, are concentrated under reduced pressure,
100g water elutriations are added, crystallization, suction filtration, 45~60 DEG C of drying obtain compound VI, molar yield 98.92%.
S6：Reduction reaction：15.0g compounds VI are added in reaction bulb, 7.5g iron powders are added, 60g glacial acetic acid is added, risen
Temperature is to 30 DEG C, and temperature control reacts 5~6h, and TLC monitors complete to reaction；
Last handling process：45 DEG C, plus the stirring of 60g chloroforms are cooled to, 40 DEG C are cooled to, it is water-soluble with 40% sodium hydroxide
Liquid adjusts neutral, and organic solvent 80g chloroforms are extracted in three times, and 45 DEG C are concentrated under reduced pressure into small size, plus appropriate water, depressurize dense
Contracting, adds 80g water elutriations, is down to normal temperature, suction filtration, 45~60 DEG C of drying obtain compound VII, molar yield 96.23%.HPLC
Content 98.75%.
Embodiment 3
A kind of preparation method of melengestrol intermediate, specific preparation method is as follows：
S1：Etherification reaction：Etherification reaction：100g compounds I (4- androstenes -3,20- diketone) is added in reaction bulb, added
400g chloroforms, are passed through nitrogen, add 4.02g p-methyl benzenesulfonic acid, stir, be warming up to 34 DEG C, be slowly added to 240.60g
Trimethyl orthoformate, adds temperature control and reacts two hours, and TLC detection reactions are complete；
Last handling process：0~5 DEG C, plus 100g water are cooled to, reacts 6 minutes, rapidly joins the sodium carbonate of 200.50g 2%
The aqueous solution, stir half an hour, 1600.40g frozen water elutriations, stirring, suction filtration, 34 DEG C drying obtain compound ii i.e. 3- methyl ethers-
4- androstene -17- ketone, molar yield 95.86%.
S2：Methylenation：100g compound iis are entered in reaction bulb, 900g acetone is added and stirs, in nitrogen
Under protection, and -6 DEG C are cooled to, 55g caustic alcohols are added into mixed solution, are stirred；Be slowly added dropwise into mixed solution into
Plus 60g dipropyl oxalates, carry out insulation reaction is added, is stirred 3~4 hours, TLC monitors, addition 4.5g ice vinegar complete to reaction
Acid, 30.5g triethylamines and 270g methanol, stir, and add 36.6g propionic aldehyde, and temperature is increased to 20 DEG C, and temperature control reaction 1~2 is small
When, TLC monitors complete to reaction；
Last handling process：Plus 90g water is terminated, 45 DEG C of rotary evaporations fall organic solvent, then add 100g water, are recovered under reduced pressure, 1~
7 DEG C of insulation 2h, 900g elutriations, suction filtration, 40~42 DEG C of drying obtain compound III i.e. 16- methines -4- androstene -3,17- diketone,
Molar yield 97.43%.
S3：Cyano group substitution reaction：100g compound IIIs are added in reaction bulb, 350g ethanol, 55.18g Cymags is added
Stir evenly, add the sodium hydroxide solutions of 100g 5%, add hexachloroacetone 3g, 30 DEG C of temperature controls react 22h, TLC is monitored to having reacted
Entirely；
Last handling process：700g elutriations, 15g hydrochloric acid is neutralized, and filtering, filter cake is washed with water to neutrality, and 25~30 DEG C dry
To compounds Ⅳ, molar yield 95.49%.
S4：The protection reaction of silane epoxide：100g compounds Ⅳs are added in reaction bulb, 400.80g carbon tetrachloride is added,
35g triethylamines are stirred evenly, and under nitrogen protection, are cooled to -5 DEG C, are added dropwise to 92.6g chloromethyl dimethyl iodine silane, and temperature control reacts 2h,
TLC monitors complete to reaction；
Last handling process：0.03% aqueous sodium carbonate terminating reaction, organic solvent 400g dichloromethane is extracted in three times,
Merge 40 DEG C of organic solvent and be concentrated under reduced pressure into small size, add suitable quantity of water, be concentrated under reduced pressure, addition 800g water elutriations, suction filtration, 45~
60 DEG C of drying obtain compound V, molar yield 88.15%.
S5：Intramolecular nucleophilic substitution reaction：100g compounds V are added in reaction bulb, 500g hexamethylenes is added and stirs evenly,
Under nitrogen protection, -65 DEG C are cooled to, 40.28g trim,ethylchlorosilanes are added, 500.10g diisopropylamine lithiums, temperature control is added dropwise
1~2h is reacted, TLC monitors complete to reaction；
Last handling process：0~10 DEG C of heating plus 500g hydrochloric acid hydrolysis, TLC are monitored to reaction completely, use 40% hydrogen-oxygen
Change sodium water solution and adjust neutral, organic solvent 400g chloroforms are extracted in three times, and 58 DEG C are concentrated under reduced pressure, plus suitable quantity of water, are depressurized dense
Contracting, plus 1200g water elutriations, crystallization, suction filtration, 45~60 DEG C of drying obtain compound VI, molar yield 98.56%.
S6：Reduction reaction：100.15g compounds VI are added in reaction bulb, 30.5g iron powders, 20g zinc powders is added, added
400.60g glacial acetic acid, is warming up to 40 DEG C, temperature control reacts 5~6h, TLC monitors complete to reaction；
Last handling process：45 DEG C are cooled to, the stirring of 400g chloroforms is cooled to 40 DEG C, water-soluble with 40% sodium hydroxide
Liquid adjusts neutral, and organic solvent 400.80g chloroforms are extracted in three times, and 45 DEG C are concentrated under reduced pressure into small size, plus appropriate water, subtract
Pressure concentration, adds 900g water elutriations, is down to normal temperature, suction filtration, 45~60 DEG C of drying obtain compound VII, molar yield 97.46%.
HPLC contents 99.16%.
Embodiment 4
A kind of preparation method of melengestrol intermediate, specific preparation method is as follows：
S1：Etherification reaction：10g compounds I (4- androstenes -3,20- diketone) is added in reaction bulb, 200g dioxies six are added
Ring, is passed through nitrogen, adds 1g perchloric acid, stirs, be warming up to 36 DEG C, be slowly added to 60g triethyl orthoformates, add temperature control
React two hours, TLC detection reactions are complete；
Last handling process：0~5 DEG C, plus 25g water are cooled to, reacts 6 minutes, rapidly joins the sodium carbonate of 50g 2% water-soluble
Liquid, is stirred half an hour, 400g frozen water elutriations, stirring, suction filtration, and it is male that 20~32 DEG C of drying obtain the i.e. 3- methyl ethers -4- of compound ii
Alkene -17- ketone, molar yield 95.32%.
S2：Methylenation：30g compound iis are entered in reaction bulb, 270g dichloromethane is added, stirs,
Under nitrogen protection, and -4 DEG C are cooled to, 15g sodium tert-butoxides are added into mixed solution, are stirred；It is slow into mixed solution
Be added dropwise to plus 10.5g diethy-aceto oxalates, 9g dimethyl oxalates, add carry out insulation reaction, stir 3~4 hours, TLC monitor to
Reaction is complete；
Last handling process：1.5g glacial acetic acid, 10.5g triethylamines and 90g methanol are added, is stirred, addition 9.6g formaldehyde,
3g acetaldehyde, temperature is increased to 25 DEG C, and temperature control reacts 1~2 hour, and TLC is monitored to reaction completely, plus 30g water is terminated, 45 DEG C of rotations
Organic solvent is evaporated, then adds 60g water, is recovered under reduced pressure, 1~7 DEG C of insulation 2h, 360g elutriations, suction filtration, 40~42 DEG C of drying are obtained
Compound III is 16- methine -4- androstene -3,17- diketone, molar yield 98.66%.
S3：Cyano group substitution reaction：30g compound IIIs are added in reaction bulb, addition 120g isopropanols, 10g acetone cyanohydrins,
8g potassium cyanide is stirred evenly, and adds the wet chemicals of 32g 5%, adds Hexafluoro acetone 3.5g, and 32 DEG C of temperature controls react 22h, TLC monitorings
It is complete to reacting；
Last handling process：240g elutriations, 5g hydrochloric acid is neutralized, and filtering, filter cake is washed with water to neutrality, and 25~30 DEG C of drying are obtained
Compounds Ⅳ, molar yield 95.72%.
S4：The protection reaction of silane epoxide：20g compounds Ⅳs are added in reaction bulb, 80g benzene is added, 7g DBU are stirred evenly, nitrogen
Under gas shielded, -3 DEG C are cooled to, 10g CMDMCS chloromethyl dimethyl chlorosilanes, 4g chloromethyl dimethyl bromo-silicanes, temperature control reaction is added dropwise to
2h, TLC monitor complete to reaction；
Last handling process：0.03% aqueous sodium carbonate terminating reaction, organic solvent 80g dichloromethane is extracted in three times,
Merge 40 DEG C of organic solvent and be concentrated under reduced pressure into small size, add suitable quantity of water, be concentrated under reduced pressure, addition 160g water elutriations, suction filtration, 45~
60 DEG C of drying obtain compound V, molar yield 88.47%.
S5：Intramolecular nucleophilic substitution reaction：20g compounds V are added in reaction bulb, 100g ether is added and stirs evenly, in nitrogen
Under gas shielded, -60 DEG C are cooled to, 8g trim,ethylchlorosilanes are added, 70g diisopropylamine lithiums, 30g di-iso-butylmanice base lithiums is added dropwise,
Temperature control reacts 1~2h, and TLC monitors complete to reaction；
Last handling process：0~10 DEG C of heating plus 100g hydrochloric acid hydrolysis, TLC are monitored to reaction completely, use 40% hydrogen-oxygen
Change sodium water solution and adjust neutral, organic solvent 80g chloroforms are extracted in three times, and 58 DEG C are concentrated under reduced pressure, plus suitable quantity of water, are depressurized dense
Contracting, adds 90g water elutriations, and crystallization, suction filtration, 45~60 DEG C of drying obtain compound VI, molar yield 97.64%.
S6：Reduction reaction：15.0g compounds VI are added in reaction bulb, 7.5g zinc powders are added, 60g glacial acetic acid is added, risen
Temperature is to 50 DEG C, and temperature control reacts 5~6h, and TLC monitors complete to reaction；
Last handling process：45 DEG C, plus the stirring of 60g chloroforms are cooled to, 40 DEG C are cooled to, it is water-soluble with 40% sodium hydroxide
Liquid adjusts neutral, and organic solvent 80g chloroforms are extracted in three times, and 45 DEG C are concentrated under reduced pressure into small size, plus appropriate water, depressurize dense
Contracting, adds 150g water elutriations, is down to normal temperature, suction filtration, 45~60 DEG C of drying obtain compound VII, molar yield 97.55%.HPLC
Content 98.94%.
Embodiment 5
A kind of preparation method of melengestrol intermediate, specific preparation method is as follows：
S1：Etherification reaction：50g compounds I (4- androstenes -3,20- diketone) is added in reaction bulb, 100g tetrahydrochysene furans are added
Mutter, 100g chloroforms, be passed through nitrogen, add 1g p-methyl benzenesulfonic acid, stir, be warming up to 38 DEG C, be slowly added to 60g primitive nails
Sour trimethyl, adds temperature control and reacts two hours, and TLC detection reactions are complete；
Last handling process：0~5 DEG C, plus 25g water are cooled to, reacts 6 minutes, rapidly joins the sodium carbonate of 50g 2% water-soluble
Liquid, is stirred half an hour, 400g frozen water elutriations, stirring, suction filtration, and it is male that 20~32 DEG C of drying obtain the i.e. 3- methyl ethers -4- of compound ii
Alkene -17- ketone, molar yield 94.27%.
S2：Methylenation：30g compound iis are entered in reaction bulb, 200g dichloromethane, 70g dioxane is added
Stir, under nitrogen protection, and be cooled to -2 DEG C, 15g potassium tert-butoxides are added into mixed solution, are stirred；To mixed
Close and be slowly added dropwise in solution into 10.5g diethy-aceto oxalates, 9g dipropyl oxalates is added, add carry out insulation reaction, stirring 3~4 is small
When, TLC monitors complete to reaction；
Last handling process：1.5g glacial acetic acid, 10.5g triethylamines and 90g methanol are added, is stirred, addition 9.6g propionic aldehyde,
3g acetaldehyde, temperature is increased to 30 DEG C, and temperature control reacts 1~2 hour, and TLC is monitored to reaction completely, plus 30g water is terminated, 45 DEG C of rotations
Organic solvent is evaporated, then adds 60g water, is recovered under reduced pressure, 1~7 DEG C of insulation 2h, 360g elutriations, suction filtration, 40~42 DEG C of drying are obtained
Compound III is 16- methine -4- androstene -3,17- diketone, molar yield 98.59%.
S3：Cyano group substitution reaction：30g compound IIIs are added in reaction bulb, 120g acetone, 10g Cymags, 8g cyanogen is added
Change potassium to stir evenly, add the wet chemicals of 17g 5%, 15g5% sodium hydrate aqueous solutions, add hexachloroacetone 3.5g, 36 DEG C of controls
Temperature reaction 22h, TLC monitor complete to reaction；
Last handling process：240g elutriations, 5g hydrochloric acid is neutralized, and filtering, filter cake is washed with water to neutrality, and 25~30 DEG C of drying are obtained
Compounds Ⅳ, molar yield 96.05%.
S4：The protection reaction of silane epoxide：20g compounds Ⅳs are added in reaction bulb, 80g toluene, 4g4- diformazan ammonia is added
Yl pyridines, 3g imidazoles are stirred evenly, and under nitrogen protection, are cooled to 0 DEG C, are added dropwise to 15g chloromethyl dimethyl iodine silane, 6g chloromethyls two
Methyl bromo-silicane, temperature control reaction 2h, TLC monitor complete to reaction；
Last handling process：0.03% aqueous sodium carbonate terminating reaction, organic solvent 80g dichloromethane is extracted in three times,
Merge 40 DEG C of organic solvent and be concentrated under reduced pressure into small size, add suitable quantity of water, be concentrated under reduced pressure, addition 180g water elutriations, suction filtration, 45~
60 DEG C of drying obtain compound V, molar yield 87.24%.
S5：Intramolecular nucleophilic substitution reaction：20g compounds V are added in reaction bulb, 100g benzene is added and stirs evenly, in nitrogen
Under protection, -50 DEG C are cooled to, 8g trim,ethylchlorosilanes are added, 70g di-iso-butylmanice bases lithium, 30g n-BuLis is added dropwise, temperature control is anti-
1~2h, TLC is answered to monitor complete to reaction；
Last handling process：0~10 DEG C of heating plus 100g hydrochloric acid hydrolysis, TLC are monitored to reaction completely, use 40% hydrogen-oxygen
Change sodium water solution and adjust neutral, organic solvent 80g chloroforms are extracted in three times, and 58 DEG C are concentrated under reduced pressure, plus suitable quantity of water, are depressurized dense
Contracting, adds 140g water elutriations, and crystallization, suction filtration, 45~60 DEG C of drying obtain compound VI, molar yield 96.35%.
S6：Reduction reaction：15.0g compounds VI are added in reaction bulb, 7.5g iron powders are added, 60g glacial acetic acid is added, risen
Temperature is to 55 DEG C, and temperature control reacts 5~6h, and TLC monitors complete to reaction；
Last handling process：45 DEG C, plus the stirring of 60g chloroforms are cooled to, 40 DEG C are cooled to, it is water-soluble with 40% sodium hydroxide
Liquid adjusts neutral, and organic solvent 80g chloroforms are extracted in three times, and 45 DEG C are concentrated under reduced pressure into small size, plus appropriate water, depressurize dense
Contracting, adds 90g water elutriations, is down to normal temperature, suction filtration, 45~60 DEG C of drying obtain compound VII, molar yield 98.62%.HPLC
Content 99.07%.
Embodiment 6
A kind of preparation method of melengestrol intermediate, specific preparation method is as follows：
S1：Etherification reaction：100g compounds I (4- androstenes -3,20- diketone) is added in reaction bulb, 200g dichloros are added
Methane, 200g dioxane, are passed through nitrogen, add 4.02g perchloric acid, stir, be warming up to 40 DEG C, be slowly added to
240.60g triethyl orthoformates, add temperature control and react two hours, and TLC detection reactions are complete；
Last handling process：5~10 DEG C, plus 100g water are cooled to, reacts 6 minutes, rapidly joins the sodium carbonate of 200.50g 2%
The aqueous solution, is stirred half an hour, 1600.40g frozen water elutriations, and stirring, suction filtration, 20~32 DEG C of drying obtain compound ii i.e. 3- first
Ether -4- androstene -17- ketone, molar yield 94.33%.
S2：Methylenation：100g compound iis are entered in reaction bulb, 500g acetone, 400g chloroforms is added and stirs
Mix uniform, under nitrogen protection, and be cooled to 0 DEG C, 40g sodium methoxides, 15g caustic alcohols are added into mixed solution, is stirred；
It is slowly added dropwise into mixed solution into 40g dimethyl oxalates, 20g dipropyl oxalates is added, adds carry out insulation reaction, stirring 3~4
Hour, TLC monitors complete to reaction；
Last handling process：4.5g glacial acetic acid, 30.5g triethylamines and 270g methanol are added, is stirred, 16.6g first is added
Aldehyde, 20g propionic aldehyde, temperature are increased to 40 DEG C, and temperature control reacts 1~2 hour, and TLC is monitored to reaction completely, plus 90g water is terminated, 45 DEG C
Rotary evaporation falls organic solvent, then adds 100g water, is recovered under reduced pressure, 1~7 DEG C of insulation 2h, 900g elutriations, suction filtration, 40~42 DEG C of bakings
It is dry to obtain compound III i.e. 16- methines -4- androstene -3,17- diketone, molar yield 97.43%.
S3：Cyano group substitution reaction：100g compound IIIs are added in reaction bulb, 340g ethanol, 10g water, 45.18g is added
Acetone cyanohydrin, 10g Cymags are stirred evenly, and add the sodium carbonates of 90g 5%, 10g5% sodium hydrate aqueous solutions, add Hexafluoro acetone
3g, 40 DEG C of temperature controls react 22h, and TLC monitors complete to reaction；
Last handling process：700g elutriations, 15g hydrochloric acid is neutralized, and filtering, filter cake is washed with water to neutrality, and 25~30 DEG C dry
To compounds Ⅳ, molar yield 95.77%.
S4：The protection reaction of silane epoxide：100g compounds Ⅳs are added in reaction bulb, addition 300.60g dichloromethane,
100g benzene, 30g imidazoles, 5g triethylamines are stirred evenly, and under nitrogen protection, 30 DEG C of temperature setting is added dropwise to 51g chloromethyl dimethyl chloride silicon
Alkane, 10g chloromethyl dimethyl iodine silane, temperature control reaction 2h, TLC monitor complete to reaction；
Last handling process：0.03% wet chemical terminating reaction, organic solvent 400g dichloromethane is extracted in three times,
Merge 40 DEG C of organic solvent and be concentrated under reduced pressure into small size, add suitable quantity of water, be concentrated under reduced pressure, add 1200g water elutriations, suction filtration, 45
~60 DEG C of drying obtain compound V, molar yield 82.56%.
S5：Intramolecular nucleophilic substitution reaction：100g compounds V are added in reaction bulb, 400g dimethyl tetrahydro furans are added
Mutter, 100g hexamethylenes are stirred evenly, under nitrogen protection, be cooled to -30 DEG C, add 40.28g trim,ethylchlorosilanes, 450.10g is added dropwise
Diisopropylamine lithium, 50g n-BuLis, temperature control react 1~2h, and TLC monitors complete to reaction；
Last handling process：0~10 DEG C of heating plus 500g hydrochloric acid hydrolysis, TLC are monitored to reaction completely, use 40% hydrogen-oxygen
Change sodium water solution and adjust neutral, organic solvent 400g chloroforms are extracted in three times, and 58 DEG C are concentrated under reduced pressure, plus suitable quantity of water, are depressurized dense
Contracting, adds 1400g water elutriations, and crystallization, suction filtration, 45~60 DEG C of drying obtain compound VI, molar yield 93.59%.
S6：Reduction reaction：100.15g compounds VI are added in reaction bulb, 40.5g iron powders, 10g zinc powders is added, added
400.60g glacial acetic acid, is warming up to 60 DEG C, temperature control reacts 5~6h, TLC monitors complete to reaction；
Last handling process：45 DEG C are cooled to, the stirring of 400g chloroforms is cooled to 40 DEG C, water-soluble with 40% sodium hydroxide
Liquid adjusts neutral, and organic solvent 400.80g chloroforms are extracted in three times, and 45 DEG C are concentrated under reduced pressure into small size, plus appropriate water, subtract
Pressure concentration, adds 1400g water elutriations, is down to normal temperature, suction filtration, 45~60 DEG C of drying obtain compound VII, molar yield
97.87%.HPLC contents 98.62%.
Above content is to combine specific/preferred embodiment made for the present invention be further described, it is impossible to
Assert that the specific implementation of the present invention is confined to these explanations.Come for general technical staff of the technical field of the invention
Say, without departing from the inventive concept of the premise, it can also make some replacements or modification to the embodiment that these have been described,
And these are substituted or variant should all be considered as belonging to protection scope of the present invention.
Claims (10)
1. a kind of preparation method of melengestrol intermediate, it is characterised in that：Using the diketone of compound I 4- androstenes -3,17 as starting
Raw material, comprises the following steps：
S1：Etherification reaction：Compound I is added in etherificate solvent, with being reacted under the first catalyst action with etherifying reagent, must be changed
Compound II；
S2：Methylenation：Compound ii is added in methylenation solvent, 16 α hydrogen entered with the first organic base and oxalate
Row substitution, then methylene elimination is carried out to 16 β hydrogen with reagent is eliminated, finally hydrolyze to obtain compound III；
S3：Cyano group substitution reaction：By compound III add cyaniding solvent in, in alkaline environment under the second catalyst action with cyanogen
Change reagent reacting, obtain compounds Ⅳ；
S4：The protection reaction of silane epoxide：Compounds Ⅳ is added in protection solvent, with silane epoxide in the presence of the second organic base
Reagent reacting, obtains compound V；
S5：Intramolecular nucleophilic substitution reaction：Compound V is added in substitution solvent, with alkali amide reagent reacting, must be changed
Compound VI；
S6：Reduction reaction：By in compound VI plus reduction solvent, with metal reaction, the centre of compound VII, i.e. melengestrol is obtained
Body.
2. a kind of preparation method of melengestrol intermediate according to claim 1, it is characterised in that：In the step S1
Etherificate solvent is the one or more in tetrahydrofuran, dichloromethane, chloroform, dioxane；First catalyst is
P-methyl benzenesulfonic acid or perchloric acid；Told etherifying reagent is trimethyl orthoformate or triethyl orthoformate；The etherification reaction it is anti-
It is 30~40 DEG C to answer temperature.
3. a kind of preparation method of melengestrol intermediate according to claim 1, it is characterised in that：In the step S2
Methylenation reagents are the one or more in dichloromethane, chloroform, acetone and dioxane；First organic base is
One or more in sodium methoxide, potassium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide；It is described elimination reagent be formaldehyde, acetaldehyde,
The one or more of propionic aldehyde；The oxalate told is one kind or many in diethy-aceto oxalate, dimethyl oxalate, dipropyl oxalate
Kind；The reaction temperature of the substitution reaction is -10~0 DEG C, and the reaction temperature of elimination reaction is 10~40 DEG C.
4. a kind of preparation method of melengestrol intermediate according to claim 1, it is characterised in that：In the step S3
Cyaniding solvent is the one or more in methanol, ethanol, normal propyl alcohol, isopropanol, acetone and water；The cyanating reagent is acetone cyanogen
One or more in alcohol, potassium cyanide, Cymag；The alkaline environment is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate
In one or more；Second catalyst is hexachloroacetone or Hexafluoro acetone；The reaction temperature of the cyano group substitution reaction
For 20~40 DEG C.
5. a kind of preparation method of melengestrol intermediate according to claim 1, it is characterised in that：In the step S4
Protection solvent is the one or more in dichloromethane, chloroform, carbon tetrachloride, benzene, rudimentary aromatic hydrocarbon and acetone；Described
Two organic bases are the one or more in DMAP, imidazoles, triethylamine, DBU；Described silane epoxide reagent is chlorine
One or more in methyl dimethoxy base chlorosilane, chloromethyl dimethyl bromo-silicane, chloromethyl dimethyl iodine silane；The silane
Reaction temperature -10~30 DEG C of epoxide protection reaction；Described rudimentary aromatic hydrocarbon be benzene, toluene, ortho-xylene, paraxylene,
The one or more of ethylbenzene.
6. a kind of preparation method of melengestrol intermediate according to claim 1, it is characterised in that：In the step S5
Substitution solvent is the one or more in tetrahydrofuran, dimethyl-tetrahydrofuran, hexamethylene, ether, benzene；The alkali amide
Reagent is the one or more in diisopropylamine lithium, di-iso-butylmanice base lithium, n-BuLi；Described intramolecular nucleophilic displacement of fluorine is anti-
The reaction temperature answered is -80~-30 DEG C.
7. a kind of preparation method of melengestrol intermediate according to claim 1, it is characterised in that：In the step S6
Reduction solvent is glacial acetic acid；The metal is the one or more in zinc, iron；The reaction temperature of the reduction reaction is 20~60
℃。
8. a kind of preparation method of melengestrol intermediate as claimed in claim 3, it is characterised in that：The step S2 is eliminated
The temperature of reaction is 25~30 DEG C.
9. a kind of preparation method of melengestrol intermediate as claimed in claim 5, it is characterised in that：The step S4 silane
The reaction temperature of epoxide protection reaction is -5~0 DEG C.
10. a kind of preparation method of melengestrol intermediate as claimed in claim 6, it is characterised in that：The step S5 points
The reaction temperature of nucleophilic substitution is -70~-65 DEG C in sub.
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| CN115260276A (en) * | 2022-08-09 | 2022-11-01 | 湖南科益新生物医药有限公司 | Process for the preparation of steroids 16,17-epoxides |
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| US4921638A (en) * | 1986-11-05 | 1990-05-01 | The Upjohn Company | 17β-cyano-9α,17α-dihydroxyandrost-4-en-3-one |
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| CN108084238A (en) * | 2017-12-28 | 2018-05-29 | 广西万德药业有限公司 | A kind of preparation method of canrenone intermediate |
| CN115260276A (en) * | 2022-08-09 | 2022-11-01 | 湖南科益新生物医药有限公司 | Process for the preparation of steroids 16,17-epoxides |
| CN115260276B (en) * | 2022-08-09 | 2024-06-07 | 湖南科益新生物医药有限公司 | Process for preparing steroid 16, 17-epoxy compound |
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