CN112062805A - High-efficiency delta9,11Process for the preparation of (E) -canrenone - Google Patents
High-efficiency delta9,11Process for the preparation of (E) -canrenone Download PDFInfo
- Publication number
- CN112062805A CN112062805A CN202010793731.1A CN202010793731A CN112062805A CN 112062805 A CN112062805 A CN 112062805A CN 202010793731 A CN202010793731 A CN 202010793731A CN 112062805 A CN112062805 A CN 112062805A
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- China
- Prior art keywords
- beta
- solvent
- triene
- alpha
- pregna
- Prior art date
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Links
- 229960005057 canrenone Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 92
- 238000000034 method Methods 0.000 claims abstract description 24
- 230000001590 oxidative effect Effects 0.000 claims abstract description 14
- -1 diester malonate Chemical class 0.000 claims abstract description 9
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 5
- 238000001914 filtration Methods 0.000 claims description 80
- 239000002904 solvent Substances 0.000 claims description 68
- 239000000758 substrate Substances 0.000 claims description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 239000007787 solid Substances 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- 239000000047 product Substances 0.000 claims description 29
- 238000001035 drying Methods 0.000 claims description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 21
- MCNZISFQKMPWRJ-DOYHNPMNSA-N (8s,10r,13s,14s,17r)-10,13-dimethylspiro[2,8,12,14,15,16-hexahydro-1h-cyclopenta[a]phenanthrene-17,5'-oxolane]-2',3-dione Chemical compound C([C@H]1[C@H]2C([C@]3(CCC(=O)C=C3C=C2)C)=CC[C@@]11C)C[C@@]11CCC(=O)O1 MCNZISFQKMPWRJ-DOYHNPMNSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 238000005406 washing Methods 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 15
- 229960005471 androstenedione Drugs 0.000 claims description 14
- 239000012065 filter cake Substances 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 14
- 239000007800 oxidant agent Substances 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- SNMVJSSWZSJOGL-PLOWYNNNSA-N 9alpha-hydroxyandrost-4-en-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@@]3(O)CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 SNMVJSSWZSJOGL-PLOWYNNNSA-N 0.000 claims description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- 239000003223 protective agent Substances 0.000 claims description 12
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 12
- 235000011054 acetic acid Nutrition 0.000 claims description 10
- UJVLDDZCTMKXJK-WNHSNXHDSA-N canrenone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CCC(=O)C=C3C=C2)C)CC[C@@]11C)C[C@@]11CCC(=O)O1 UJVLDDZCTMKXJK-WNHSNXHDSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000001556 precipitation Methods 0.000 claims description 9
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 8
- AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 claims description 8
- 125000000457 gamma-lactone group Chemical group 0.000 claims description 8
- 238000006386 neutralization reaction Methods 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 7
- VRGCYEIGVVTZCC-UHFFFAOYSA-N 3,4,5,6-tetrachlorocyclohexa-3,5-diene-1,2-dione Chemical compound ClC1=C(Cl)C(=O)C(=O)C(Cl)=C1Cl VRGCYEIGVVTZCC-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000005690 diesters Chemical class 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 claims description 5
- LWIWFCDNJNZEKB-UHFFFAOYSA-N dipropyl propanedioate Chemical compound CCCOC(=O)CC(=O)OCCC LWIWFCDNJNZEKB-UHFFFAOYSA-N 0.000 claims description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 5
- VQKFNUFAXTZWDK-UHFFFAOYSA-N 2-Methylfuran Chemical compound CC1=CC=CO1 VQKFNUFAXTZWDK-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 238000005895 oxidative decarboxylation reaction Methods 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
- 125000006239 protecting group Chemical group 0.000 claims description 4
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- AEMFNILZOJDQLW-UHFFFAOYSA-N androstenedione Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-UHFFFAOYSA-N 0.000 claims description 3
- 125000005594 diketone group Chemical group 0.000 claims description 3
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- GOTIICCWNAPLMN-UHFFFAOYSA-M trimethylsulfanium;bromide Chemical compound [Br-].C[S+](C)C GOTIICCWNAPLMN-UHFFFAOYSA-M 0.000 claims description 3
- OWUGVJBQKGQQKJ-UHFFFAOYSA-M trimethylsulfanium;chloride Chemical compound [Cl-].C[S+](C)C OWUGVJBQKGQQKJ-UHFFFAOYSA-M 0.000 claims description 3
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 2
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 claims description 2
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000007795 chemical reaction product Substances 0.000 abstract description 2
- 238000006297 dehydration reaction Methods 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 150000002596 lactones Chemical group 0.000 abstract 1
- 239000007858 starting material Substances 0.000 description 9
- 125000000686 lactone group Chemical group 0.000 description 6
- 229960001701 chloroform Drugs 0.000 description 5
- 238000005869 desulfonation reaction Methods 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 3
- 230000006326 desulfonation Effects 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- PNXXUAJIUJFWPZ-USNOLKROSA-N (8s,10r,13s,14s)-3-ethoxy-10,13-dimethyl-1,2,7,8,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-one Chemical compound C1C=C2[C@](CCC(OCC)=C3)(C)C3=CC[C@H]2[C@@H]2CCC(=O)[C@]21C PNXXUAJIUJFWPZ-USNOLKROSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 description 2
- 229960001208 eplerenone Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 2
- 229960002256 spironolactone Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RJTDWMKVQUPGSY-GOAYFHFKSA-N (10r,11r,13s,17r)-11-hydroxy-10,13-dimethylspiro[2,8,9,11,12,14,15,16-octahydro-1h-cyclopenta[a]phenanthrene-17,5'-oxolane]-2',3-dione Chemical compound C([C@H](O)C[C@@]12C)([C@]3(CCC(=O)C=C3C=C3)C)C3C1CC[C@@]21CCC(=O)O1 RJTDWMKVQUPGSY-GOAYFHFKSA-N 0.000 description 1
- ZFQKEKFHIHHGSL-FVCZOJIISA-N (8s,10r,13s,14s)-3-methoxy-10,13-dimethyl-1,2,7,8,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-one Chemical compound C1C=C2[C@](CCC(OC)=C3)(C)C3=CC[C@H]2[C@@H]2CCC(=O)[C@]21C ZFQKEKFHIHHGSL-FVCZOJIISA-N 0.000 description 1
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 description 1
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 102000001307 androgen receptors Human genes 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 102000003998 progesterone receptors Human genes 0.000 description 1
- 108090000468 progesterone receptors Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/001—Lactones
- C07J21/003—Lactones at position 17
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a high-efficiency delta9,11A preparation method of-canrenone, belonging to the technical field of preparation of intermediates of medicaments. The method takes 9 alpha-hydroxy-4-androstenedione as a raw material, firstly, 9-hydroxy is eliminated to generate delta through dehydration reaction9,11Protecting the double bond, epoxidizing the carbonyl group at position 17, condensing with diester malonate to obtain lactone ring, and oxidizing decarboxylation or decarboxylation oxidizing reaction to obtain delta9,11The raw materials of the method are cheap and easy to obtain, the cost is low, the reaction products in the steps are easy to purify, the total mass yield of the final product is higher than 80 percent, the method has strong operability and extremely high commercial competitiveness, is suitable for industrial large-scale production, and has good economic benefit.
Description
Technical Field
The invention relates to the technical field of preparation of intermediates of medicaments, in particular to a high-efficiency delta9,11-a method for the preparation of canrenone.
Background
Δ9,11-canrenone is an important intermediate of eplerenone, which is a novel selective aldosterone receptor antagonist, has stronger antagonistic aldosterone action than spironolactone, has extremely low affinity to androgen and progesterone receptors, has small adverse reaction, has exact curative effect on treating hypertension, heart failure and myocardial infarction, has less adverse reaction and good tolerance, and is a good substitute drug of spironolactone. Thus, studies on Δ 9, 11-canrenone have also driven the development of these areas.
Existing delta9,11The preparation process of-canrenone mainly uses diketone as raw material, firstly synthesizes canrenone, then ferments 11-position to form 11-hydroxy-canrenone, and then carries out sulfoacid esterification and desulfonation to obtain delta9,11-canrenone. The method has long process route and complicated process, and because the 17-position lactone ring is formed and then fermented, sulfonated and desulfonated, the 17-position lactone ring can generate adverse effects on the fermentation, the sulfonated and the desulfonation reactions, thereby causing the increase of the impurity content and the reduction of the yield. The specific route is as follows:
disclosure of Invention
To solve the prior art Δ9,11The preparation process of the-canrenone has the limitations of longer route, complicated process, large impurities and low yield, promotes the large-scale industrial production of the eplerenone, and provides a new method for preparing the delta 9, 11-canrenone.
The purpose of the invention is realized by the following modes: high-efficiency delta9,11-a process for the preparation of canrenone, the synthetic route of which is as follows:
wherein R1 represents a methoxy group, an ethoxy group or a pyrrolyl group, and represents a protecting group for protecting the carbonyl group at the 3-position; r2 represents methyl, ethyl or propyl; r3 represents methoxy, ethoxy or pyrrolyl, represents a protecting group for protecting the carbonyl group at position 3,
the method specifically comprises the following steps:
1) adding 9 alpha-hydroxy-4-androstene-3, 17-dione (1) into dilute sulfuric acid, reacting at 10-60 deg.C, eluting, extracting with solvent I, washing with water, concentrating, eluting with water, filtering, and drying to obtain delta9,11-4-androstene-3, 17-dione (2),
wherein the volume consumption of the dilute sulfuric acid is 2-20 times of the weight of the substrate 9 alpha-hydroxy-4-androstene-3, 17 dione (1), and the volume concentration is 20-80%; the volume consumption of the solvent I is 5-20 times of the weight of the substrate 9 alpha-hydroxy-4-androstene-3, 17 dione (1);
2) will be delta9,11Putting 4-androstene-3, 17-dione (2) into a solvent II, adding a protective agent and a catalyst, reacting at the temperature of 20-50 ℃, filtering after the reaction is finished, and drying to obtain 3-protecting group-androstane-3, 5,9(11) -triene-17-one (3),
wherein the volume dosage of the solvent II is substrate delta9,110.5-10 times of the weight of the-4-androstene-3, 17-dione (2); the protective agent is one of trimethyl orthoformate, triethyl orthoformate or pyrrolidine, and the molar amount of the protective agent is 1.01-5 times of that of a substrate delta 9, 11-4-androstene-3, 17 diketone (2); the weight consumption of the catalyst is 0.01-0.1 time of that of the substrate delta 9, 11-4-androstene-3, 17 dione (2);
3) adding alkali I and trimethyl sulfonium halide, 3-protecting group-androstane-3, 5,9(11) -triene-17-ketone (3) into a solvent III, preserving heat at 0-50 ℃ for reaction, adding water after the reaction is finished, concentrating, filtering, drying to obtain 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4),
the solvent III is one or more of dimethyl sulfoxide, tetrahydrofuran, acetonitrile, methyl furan and toluene, and the volume dosage of the solvent III is 2-10 times of the weight of a substrate 3-protecting group-androstane-3, 5,9(11) -triene-17-ketone (3); the alkali I is one or more of sodium hydride, potassium hydride, lithium hydride, sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, lithium ethoxide, potassium tert-butoxide, sodium tert-butoxide and lithium tert-butoxide, and the molar amount of the alkali I is 1.01-3 times of that of the substrate 3-protecting group-androstane-3, 5,9(11) -triene-17-ketone (3); the trimethyl sulfonium halide is one of trimethyl sulfonium iodide, trimethyl sulfonium bromide and trimethyl sulfonium chloride, and the molar amount of the trimethyl sulfonium halide is 1.01-2 times of that of the alkali;
4) adding a base I and a malonic diester into a solvent IV, reacting at the temperature of 30-80 ℃, adding 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4), reacting at the temperature of 30-80 ℃, adding an acid I for neutralization, carrying out water precipitation, filtering to obtain a solid (5), and carrying out oxidative decarboxylation or decarboxylative oxidation reaction on the solid (5) to obtain the delta 9, 11-canrenone (11); or after the heat preservation is finished at 30-80 ℃, adding an aqueous solution of alkali II, after the heat preservation is finished at 10-80 ℃, reacting, adding acid II, separating out, filtering to obtain a solid (8), performing decarboxylation oxidation reaction on the solid (8) to obtain the delta 9, 11-canrenone (11),
the solvent IV is one or more of methanol, ethanol and propanol, the volume dosage of the solvent IV is 2-10 times of the weight of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate, and the molar dosage of the base I is 1.01-5 times of the molar dosage of the 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as the substrate; the malonic diester is one of dimethyl malonate, diethyl malonate and dipropyl malonate, and the molar amount of the malonic diester is 1.01-5 times of that of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate; the acid I is one or more of formic acid, acetic acid and propionic acid, and the molar amount of the acid I is 1-3 times of that of the alkali; the alkali II is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate and lithium bicarbonate, and the molar amount of the alkali II is 1.01-5 times of that of the substrate 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4); wherein the acid II is one or more of hydrochloric acid, sulfuric acid and phosphoric acid, and the molar amount of the acid II is 1-5 times of the sum of the molar amounts of the alkali I and the alkali II.
Further, the solid (5) is subjected to oxidative decarboxylation reaction in the step 4) to obtain the solid(5) Putting the mixture into a solvent V, adding an oxidant, keeping the temperature at 10-50 ℃ for reaction, concentrating, elutriating, filtering after the reaction is finished, dissolving a filter cake by using a solvent I, filtering again, washing the filtrate by using water to obtain a solution of (17 alpha) -17 beta-hydroxy-pregna-4, 6,9(11) -triene-3-ketone-21, 21-dicarboxylic acid alkyl ester gamma-lactone (6), concentrating, adding a solvent VI, keeping the temperature at 60-150 ℃, elutriating after the reaction is finished, filtering, and drying to obtain delta9,11-canrenone (11),
preferably, the solvent V is one or more of methanol, acetone, dichloromethane and acetonitrile, and the volume dosage of the solvent V is 2-10 times of the weight of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate; the molar amount of the oxidant is 1.01-2 times of that of the 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate; the volume dosage of the solvent I is 3-10 times of the weight of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate; the solvent VI is one or more of N, N-dimethylformamide, N-dimethylacetamide, toluene, acetic acid, pyridine, triethylamine and 1, 8-diazabicycloundecen-7-ene (DBU), and the volume consumption of the solvent VI is 2-10 times of the weight of a substrate 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4).
Further, the decarboxylation oxidation reaction of the solid (5) in the step 4) is to add the obtained wet solid (5) into a solvent VI, keep the temperature at 60-150 ℃, after the reaction is finished, perform elutriation and filtration to obtain 17 beta-hydroxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene-21-carboxylic acid-gamma-lactone (7), then put into a solvent V, add an oxidant, keep the temperature at 10-50 ℃ for reaction, after the reaction is finished, concentrate the elutriation and filtration, dissolve a filter cake with a solvent I, perform filtration, wash the filtrate with water, concentrate, elutriate, filter, and dry to obtain delta-alpha-pregnene-3, 5,9(11) -triene-21-carboxylic acid-gamma-lactone9,11-canrenone (11),
preferably, the volume usage amount of the solvent VI is 2-10 times of the weight of the 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) as the substrate; the volume dosage of the solvent V is 2-10 times of the weight of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate; the molar amount of the oxidant is 1.01-2 times of that of the 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate; the volume usage amount of the solvent I is 3-10 times of the weight of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate.
Further, the decarboxylation oxidation reaction of the solid (8) in the step 4) is to add the obtained wet solid (8) into a solvent VI, keep the temperature at 60-150 ℃, after the reaction is finished, separate out by water, filter, dry to obtain 17 beta-hydroxypregna-4, 9(11) -diene-3-ketone-21-carboxylic acid and gamma-lactone (9), then put into a solvent II, add a protective agent and a catalyst, keep the temperature at 20-50 ℃ for reaction, after the reaction is finished, filter to obtain 17 beta-hydroxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene-21-carboxylic acid-gamma-lactone (10), then put into a solvent V, add an oxidant, keep the temperature at 10-50 ℃ for reaction, concentrate the water separation after the reaction is finished, filtering, dissolving the filter cake with solvent I, filtering again, washing the filtrate with water, concentrating, elutriating, filtering, and drying to obtain delta9,11-canrenone (11),
preferably, the volume usage amount of the solvent VI is 2-10 times of the weight of the 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) as the substrate; the volume dosage of the solvent II is 0.5-10 times of the weight of the substrate 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4); the molar dosage of the protective agent is 1.01-5 times of the molar dosage of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) of the substrate; the weight consumption of the catalyst is 0.01-0.1 time of the weight of the substrate 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4); the volume dosage of the solvent V is 2-10 times of the weight of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate; the molar amount of the oxidant is 1.01-2 times of that of the 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate; the volume usage amount of the solvent I is 3-10 times of the weight of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate.
Preferably, the solvent I refers to one of dichloromethane, dichloroethane, chloroform and toluene.
Preferably, the solvent II refers to one of absolute methanol, absolute ethanol and THF; the protective agent is one of trimethyl orthoformate, triethyl orthoformate or pyrrolidine; the catalyst is at least one of pyridine hydrochloride, pyridine hydrobromide, p-toluenesulfonic acid or pyridine p-toluenesulfonic acid salt.
Preferably, the oxidizing agent is at least one of tetrachloroo-benzoquinone, tetrachloro-p-benzoquinone or dichlorodicyanobenzoquinone.
Compared with the prior art, the invention has the beneficial effects that:
1. delta described in the invention9,11The synthesis process route of the canrenone improves three steps of 11-position fermentation, 11-position hydroxyl sulfonic acid esterification and desulfonation into one-step dehydration in the existing process route, and reduces process steps.
2. Delta described in the invention9,11The synthesis process route of the-canrenone is to obtain 9,11 double bonds firstly and then construct 17-position lactone rings and 6,7 double bonds, so that the problems of impurities or yield loss caused by hydrolysis of the 17-position lactone rings in the processes of constructing the 17-position lactone rings firstly, then 11-position fermentation, 11-position hydroxyl sulfoacid esterification and desulfonation esterification in the existing process route due to the fact that the 17-position lactone rings encounter acid or alkali are avoided.
3. The method of the invention has the advantages that the purification of the reaction products in each step is easy, and the total mass yield of the final product is higher than 80%.
4. The method has the advantages of low overall production cost, strong operability, extremely high commercial competitiveness, suitability for industrial large-scale production and good economic benefit.
Detailed Description
The invention is further illustrated with reference to the following examples, which are not intended to limit the invention.
The specific experimental procedures or conditions are not shown in the examples, and the procedures can be performed according to the conventional experimental methods described in the publications in the field, and the reagents or equipment used are not indicated by manufacturers, and are all conventional products which can be obtained commercially.
Example 1. delta9,11The preparation method of the canrenone comprises the following specific steps:
1) three-mouth bottleAdding 100ml of 20 mass percent sulfuric acid solution, adding 10g of 9 alpha-hydroxy-4-androstene-3, 17-dione, reacting at the temperature of 60 ℃, after the reaction is finished, performing water separation, extracting with 50ml of dichloromethane, washing with water, concentrating, performing water separation, filtering, and drying to obtain delta9,119.1g of (E) -4-androstene-3, 17-dione.
2) Will be delta9,11Putting 4-androstene-3, 17-dione into 4.5ml methanol, adding 3.5ml trimethyl orthoformate and 0.09g pyridine hydrochloride, reacting at 20 ℃, filtering after the reaction is finished, and drying to obtain 9.2g 3-methoxy-androstane-3, 5,9(11) -triene-17-one.
3) Adding 1.2g of sodium methoxide, 12.9g of trimethyl sulfonium iodide and 9.2g of 3-methoxy-androstane-3, 5,9(11) -triene-17-ketone into a reaction bottle, adding 92ml of dimethyl sulfoxide, preserving heat at 0 ℃ for reaction, adding water after the reaction is finished, filtering, and drying to obtain 9.6g of 17 beta, 20 beta-epoxy-3-methoxy-17 alpha-pregna-3, 5,9(11) -triene.
4) Adding 19.2ml of methanol, 8.3g of sodium methoxide and 17.5ml of dimethyl malonate into a reaction bottle, reacting at the temperature of 30 ℃, adding 9.6g of 17 beta, 20 beta-epoxy-3-methoxy-17 alpha-pregna-3, 5,9(11) -triene, reacting at the temperature of 50 ℃, adding 8.7ml of acetic acid for neutralization after the reaction is finished, carrying out elutriation, filtering to obtain a solid wet product, adding 96ml of acetone into the solid wet product, adding 5.8g of tetrachloro-o-benzoquinone, reacting at the temperature of 10 ℃, concentrating, carrying out elutriation, filtering after the reaction is finished, dissolving a filter cake with 28.8ml of dichloromethane, filtering, washing with water to obtain a dichloromethane solution of (17 alpha) -17 beta-hydroxy-pregna-4, 6,9(11) -triene-3-one-21, 21-dicarboxylic acid methyl ester gamma-lactone, concentrating, adding 19.2ml of N, N-dimethylformamide, keeping the temperature at 60 ℃, after the reaction is finished, performing elutriation, filtering and drying to obtain delta9,11-canrenone 8.35g, yield 83.5% relative to starting material, purity 95.6%.
5) 30ml of propanol, 10.3g of potassium tert-butoxide and 13.9ml of dipropyl malonate are put into a reaction bottle, the mixture is reacted at the temperature of 80 ℃, 10g of 17 beta, 20 beta-epoxy-3-ethoxy-17 alpha-pregna-3, 5,9(11) -triene is put into the reaction bottle, the reaction is carried out at the temperature of 30 ℃, 16.4ml of acetic acid is added for neutralization after the reaction is finished, water is separated out, a solid wet product is obtained by filtration, 50ml of N, N-dimethylformamide and 50ml of N, N-dimethylacetamide are added into the solid wet product, the temperature is kept for 150 ℃, after the reaction is finished,elutriating and filtering to obtain 17 beta-hydroxy-3-ethoxy-17 alpha-pregna-3, 5,9(11) -triene-21-carboxylic acid-gamma-lactone, putting the 17 beta-hydroxy-3-ethoxy-17 alpha-pregna-3, 5,9(11) -triene-21-carboxylic acid-gamma-lactone into 20ml of acetone, adding 8.9g of tetrachloro-p-benzoquinone, reacting at the temperature of 30 ℃, concentrating and elutriating after the reaction is finished, filtering, dissolving a filter cake by 50ml of trichloromethane, filtering again, washing a filtrate by water, concentrating, elutriating, filtering and drying to obtain delta-beta-hydroxy-3-ethoxy-17 alpha-pregna-3, 5,9(11) -triene-21-9,11-canrenone 8.6g, relative to starting material yield 82.6%, purity 95.9%.
6) Adding 20ml of methanol, 8.6g of sodium methoxide and 18.2ml of dimethyl malonate into a reaction bottle, reacting at the temperature of 30 ℃, adding 10g of 17 beta, 20 beta-epoxy-3-methoxy-17 alpha-pregna-3, 5,9(11) -triene, reacting at the temperature of 50 ℃, adding 1.28g of aqueous solution of sodium hydroxide after the reaction is finished, reacting at the temperature of 10 ℃, adding 16ml of hydrochloric acid after the reaction is finished, acidifying, elutriating, filtering to obtain a solid wet product, adding 20ml of N, N-dimethylformamide into the solid wet product, standing at the temperature of 60 ℃, elutriating and filtering to obtain 17 beta-hydroxypregna-4, 9(11) -diene-3-ketone-21-carboxylic acid and gamma-lactone, adding 17 beta-hydroxypregna-4, 9(11) -diene-3-ketone-21-carboxylic acid, adding gamma-lactone into 5ml of methanol, adding 3.85ml of trimethyl orthoformate and 0.1g of pyridine hydrochloride, reacting at the temperature of 20 ℃, filtering after the reaction is finished to obtain a wet product, adding the wet product into 100ml of acetonitrile, adding 11g of dichlorodicyanobenzoquinone, reacting at the temperature of 50 ℃, concentrating and elutriating after the reaction is finished, filtering, dissolving a filter cake by 100ml of toluene, filtering again, washing the filtrate by water, concentrating, elutriating, filtering, and drying to obtain delta-beta-butyrolactone hydrochloride9,11-canrenone 8.5g, yield 81.6% relative to starting material, purity 95.7%.
Example 2. delta9,11The preparation method of the canrenone comprises the following specific steps:
1) adding 80% sulfuric acid solution 20ml into a three-neck bottle, cooling to 10 deg.C, adding 10g 9 alpha-hydroxy-4-androstene-3, 17 dione, reacting at 10 deg.C, eluting, extracting with 200ml dichloromethane, washing with water, concentrating, eluting, filtering, and drying to obtain delta9,119.2g of (E) -4-androstene-3, 17-dione.
2) 9.2g of. delta9,11-4-androstene-3, 17-dione inputAdding 16.2ml of pyrrolidine and 0.46g of pyridine hydrobromide into 92ml of tetrahydrofuran, reacting at the temperature of 50 ℃, filtering after the reaction is finished, and drying to obtain 9.48g of 3-pyrrolyl-androstane-3, 5,9(11) -triene-17-ketone.
3) 5.36g of potassium ethoxide, 10.05g of trimethylsulfonium bromide, 9.48g of 3-pyrrolyl-androstane-3, 5,9(11) -triene-17-ketone and 19ml of acetonitrile are added into a reaction bottle, the reaction is carried out at the temperature of 30 ℃, after the reaction is finished, water is added, the mixture is concentrated, filtered and dried to obtain 9.76g of 17 beta, 20 beta-epoxy-3-pyrrolyl-17 alpha-pregna-3, 5,9(11) -triene.
4) Adding 98ml of ethanol, 2.15g of sodium ethoxide and 4.7ml of diethyl malonate into a reaction bottle, reacting at the temperature of 50 ℃, adding 9.76g of 17 beta, 20 beta-epoxy-3-pyrrolyl-17 alpha-pregna-3, 5,9(11) -triene, reacting at the temperature of 80 ℃, adding 3.5ml of acetic acid for neutralization after the reaction is finished, elutriating, filtering to obtain a solid wet product, adding 19.5ml of dichloromethane into the solid wet product, adding 48.8ml of methanol, adding 8.7g of tetrachloro p-benzoquinone, reacting at the temperature of 30 ℃, concentrating, elutriating, filtering, dissolving a filter cake by 58.6ml of trichloromethane, filtering, washing the filtrate to obtain a trichloromethane solution of (17 alpha) -17 beta-hydroxy-pregna-4, 6,9(11) -triene-3-one-21, 21-dicarboxylic acid methyl ester gamma-lactone, concentrating, adding 48.8ml N, N-dimethylacetamide, keeping the temperature at 100 ℃, after the reaction is finished, elutriating, filtering and drying to obtain delta9,11-canrenone 8.39g, yield 83.9% relative to starting material, purity 95.5%.
5) Adding 100ml ethanol, 2.2g sodium ethoxide and 4.83ml diethyl malonate into a reaction bottle, keeping the temperature at 50 ℃ for reaction, adding 10g 17 beta, 20 beta-epoxy-3-methoxy-17 alpha-pregna-3, 5,9(11) -triene, keeping the temperature at 80 ℃ for reaction, adding 3.6ml acetic acid for neutralization after the reaction is finished, carrying out water precipitation, filtering to obtain a solid wet product, adding 50ml N, N-dimethylacetamide into the solid wet product, keeping the temperature at 100 ℃, carrying out water precipitation after the reaction is finished, filtering to obtain 17 beta-hydroxy-3-methoxy-17 alpha-pregna-3, 5,9(11) -triene-21-carboxylic acid-gamma-lactone, adding 17 beta-hydroxy-3-methoxy-17 alpha-pregna-3, adding 5,9(11) -triene-21-carboxylic acid-gamma-lactone into 30ml dichloromethane and 30ml methanol, adding 6g tetrachloro-o-benzoquinone, reacting at 10 deg.C, concentrating, precipitating, filtering, and dissolving filter cake with 30ml dichloromethaneThen filtered again, the filtrate is washed by water, concentrated, elutriated, filtered and dried to obtain delta9,11-canrenone 8.6g, yield 83.9% relative to starting material, purity 95.4%.
6) Adding 100ml ethanol, 2.2g sodium ethoxide and 4.83ml diethyl malonate into a reaction bottle, reacting at the temperature of 50 ℃, adding 10g 17 beta, 20 beta-epoxy-3-methoxy-17 alpha-pregna-3, 5,9(11) -triene, reacting at the temperature of 80 ℃, adding 3.6g potassium hydroxide aqueous solution after the reaction is finished, reacting at the temperature of 50 ℃, adding 31.3ml sulfuric acid for acidification, elutriating, filtering to obtain a solid wet product, adding 50ml N, N-dimethylacetamide into the solid wet product, reacting at the temperature of 100 ℃, elutriating, filtering to obtain 17 beta-hydroxypregna-4, 9(11) -diene-3-ketone-21-carboxylic acid and gamma-lactone, adding 17 beta-hydroxypregna-4, 9(11) -diene-3-ketone-21-carboxylic acid, adding gamma-lactone into 100ml of absolute ethyl alcohol, adding 17.6ml of triethyl orthoformate and 0.5g of pyridine hydrobromide, preserving heat for reacting at 80 ℃, filtering after the reaction is finished to obtain a wet product, adding the wet product into 30ml of dichloromethane and 30ml of methanol, adding 6g of tetrachloro-o-benzoquinone, preserving heat for reacting at 10 ℃, concentrating and elutriating after the reaction is finished, filtering, dissolving a filter cake with 30ml of dichloromethane, filtering again, washing the filtrate with water, concentrating, elutriating, filtering and drying to obtain delta-delta9,11-canrenone 8.5g, yield 83.0% relative to starting material, purity 95.7%.
Example 3. delta9,11The preparation method of the canrenone comprises the following specific steps:
1) 50ml of 50 percent sulfuric acid solution is put into a three-mouth bottle, 10g of 9 alpha-hydroxy-4-androstene-3, 17-dione is put into the bottle, the temperature is kept at 40 ℃ for reaction, water is separated out after the reaction is finished, 100ml of toluene is used for extraction, water washing, concentration, water separation, filtration and drying are carried out to obtain delta9,119.0g of (E) -4-androstene-3, 17-dione.
2) 9.0 g.DELTA.9,11Putting the-4-androstene-3, 17-dione into 27ml tetrahydrofuran, adding 26.4ml triethyl orthoformate and 0.9g p-toluenesulfonic acid, keeping the temperature at 40 ℃ for reaction, filtering after the reaction is finished, and drying to obtain 9.0g of 3-ethoxy-androstane-3, 5,9(11) -triene-17-one.
3) 10.2g of potassium tert-butoxide, 15.3g of trimethylsulfonium chloride, 9g of 3-ethoxy-androstane-3, 5,9(11) -triene-17-one, 27ml of tetrahydrofuran and 27ml of dimethyl sulfoxide are added into a reaction bottle, the temperature is kept at 50 ℃ for reaction, after the reaction is finished, water is added, concentration, filtration and drying are carried out, and 9.45g of 17 beta, 20 beta-epoxy-3-ethoxy-17 alpha-pregna-3, 5,9(11) -triene is obtained.
4) Adding 28.4ml of propanol, 9.7g of potassium tert-butoxide and 13.1ml of dipropyl malonate into a reaction bottle, reacting at the temperature of 80 ℃, adding 9.45g of 17 beta, 20 beta-epoxy-3-ethoxy-17 alpha-pregna-3, 5,9(11) -triene, reacting at the temperature of 30 ℃, adding 15.5ml of acetic acid for neutralization after the reaction is finished, elutriating, filtering to obtain a solid wet product, adding 18.9ml of acetonitrile into the solid wet product, adding 5.6g of tetrachloroo-benzoquinone and 5.6g of tetrachlorop-benzoquinone, reacting at the temperature of 50 ℃, concentrating, elutriating, filtering, dissolving a filter cake with 95ml of toluene, filtering again, washing the filtrate to obtain a toluene solution of (17 alpha) -17 beta-hydroxy-pregna-4, 6,9(11) -trien-3-one-21, 21-dicarboxylic acid methyl ester gamma-lactone, concentrating, adding 47.3ml N, N-dimethylformamide and 47.3ml dimethylacetamide, keeping the temperature at 150 ℃, after the reaction is finished, performing water precipitation, filtering and drying to obtain delta9,11-canrenone 8.22g, relative to starting material yield 82.2%, purity 95.6%.
5) Adding 20ml of methanol, 8.6g of sodium methoxide and 18.2ml of dimethyl malonate into a reaction bottle, preserving heat at 30 ℃ for reaction, adding 10g of 17 beta, 20 beta-epoxy-3-ethoxy-17 alpha-pregna-3, 5,9(11) -triene, preserving heat at 50 ℃ for reaction, adding 9.1ml of acetic acid for neutralization after the reaction is finished, carrying out water precipitation and filtration to obtain a solid wet product, adding 20ml of N, N-dimethylformamide into the solid wet product, preserving heat at 60 ℃, carrying out water precipitation and filtration after the reaction is finished to obtain 17 beta-hydroxy-3-methoxy-17 alpha-pregna-3, 5,9(11) -triene-21-carboxylic acid-gamma-lactone, adding 17 beta-hydroxy-3-methoxy-17 alpha-pregna-3, adding 5,9(11) -triene-21-carboxylic acid-gamma-lactone into 100ml acetonitrile, adding 11g dichlorodicyanobenzoquinone, reacting at 50 ℃, concentrating and elutriating after the reaction is finished, filtering, dissolving a filter cake with 100ml toluene, filtering again, washing the filtrate with water, concentrating, elutriating, filtering, and drying to obtain delta9,11-canrenone 8.6g, yield 81.3% relative to starting material, purity 95.7%.
6) 30ml of propanol, 10.3g of potassium tert-butoxide and 13.9ml of dipropyl malonate are put into a reaction bottle and reacted at the temperature of 80 DEG CAdding 10g of 17 beta, 20 beta-epoxy-3-ethoxy-17 alpha-pregna-3, 5,9(11) -triene, preserving heat at 30 ℃ for reaction, adding 17g of sodium carbonate aqueous solution after the reaction is finished, preserving heat at 80 ℃ for reaction, adding 40ml of phosphoric acid for acidification after the reaction is finished, carrying out water precipitation, filtering to obtain a solid wet product, adding 50ml of N, N-dimethylformamide and 50ml of N, N-dimethylacetamide into the solid wet product, preserving heat at 150 ℃, carrying out water precipitation and filtering after the reaction is finished to obtain 17 beta-hydroxypregna-4, 9(11) -diene-3-ketone-21-carboxylic acid and gamma-lactone, adding 17 beta-hydroxypregna-4, 9(11) -diene-3-ketone-21-carboxylic acid, adding gamma-lactone into 30ml tetrahydrofuran, adding 29.3ml triethyl orthoformate and 1g p-toluenesulfonic acid, reacting at 40 ℃ under heat preservation, filtering after the reaction is finished, obtaining a wet product, adding the wet product into 20ml acetone, adding 8.9g tetrachloro-p-benzoquinone, reacting at 30 ℃ under heat preservation, concentrating and elutriating after the reaction is finished, filtering, dissolving a filter cake with 50ml trichloromethane, filtering again, washing the filtrate with water, concentrating, elutriating, filtering, and drying to obtain delta-beta-methyl-ethyl-benzoate9,11-canrenone 8.5g, yield 80.3% relative to starting material, purity 95.8%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention.
Claims (7)
1. Efficient delta9,11-canrenone preparation method, characterized in that the synthetic route of the method is as follows:
wherein R1 represents a methoxy group, an ethoxy group or a pyrrolyl group, and represents a protecting group for protecting the carbonyl group at the 3-position; r2 represents methyl, ethyl or propyl; r3 represents methoxy, ethoxy or pyrrolyl, represents a protecting group for protecting the carbonyl group at position 3,
the method specifically comprises the following steps:
1) reacting 9 alpha-hydroxy-4-Adding androstene-3, 17-dione (1) into dilute sulfuric acid, reacting at 10-60 deg.C, eluting after reaction, extracting with solvent I, washing with water, concentrating, eluting with water, filtering, and drying to obtain delta9,11-4-androstene-3, 17-dione (2),
wherein the volume consumption of the dilute sulfuric acid is 2-20 times of the weight of the substrate 9 alpha-hydroxy-4-androstene-3, 17 dione (1), and the volume concentration is 20-80%; the volume consumption of the solvent I is 5-20 times of the weight of the substrate 9 alpha-hydroxy-4-androstene-3, 17 dione (1);
2) will be delta9,11Putting 4-androstene-3, 17-dione (2) into a solvent II, adding a protective agent and a catalyst, reacting at the temperature of 20-50 ℃, filtering after the reaction is finished, and drying to obtain 3-protecting group-androstane-3, 5,9(11) -triene-17-one (3),
wherein the volume dosage of the solvent II is substrate delta9,110.5-10 times of the weight of the-4-androstene-3, 17-dione (2); the protective agent is one of trimethyl orthoformate, triethyl orthoformate or pyrrolidine, and the molar amount of the protective agent is 1.01-5 times of that of a substrate delta 9, 11-4-androstene-3, 17 diketone (2); the weight consumption of the catalyst is 0.01-0.1 time of that of the substrate delta 9, 11-4-androstene-3, 17 dione (2);
3) adding alkali I and trimethyl sulfonium halide, 3-protecting group-androstane-3, 5,9(11) -triene-17-ketone (3) into a solvent III, preserving heat at 0-50 ℃ for reaction, adding water after the reaction is finished, concentrating, filtering, drying to obtain 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4),
the solvent III is one or more of dimethyl sulfoxide, tetrahydrofuran, acetonitrile, methyl furan and toluene, and the volume dosage of the solvent III is 2-10 times of the weight of a substrate 3-protecting group-androstane-3, 5,9(11) -triene-17-ketone (3); the alkali I is one or more of sodium hydride, potassium hydride, lithium hydride, sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, lithium ethoxide, potassium tert-butoxide, sodium tert-butoxide and lithium tert-butoxide, and the molar amount of the alkali I is 1.01-3 times of that of the substrate 3-protecting group-androstane-3, 5,9(11) -triene-17-ketone (3); the trimethyl sulfonium halide is one of trimethyl sulfonium iodide, trimethyl sulfonium bromide and trimethyl sulfonium chloride, and the molar amount of the trimethyl sulfonium halide is 1.01-2 times of that of the alkali;
4) adding a base I and a malonic diester into a solvent IV, reacting at the temperature of 30-80 ℃, adding 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4), reacting at the temperature of 30-80 ℃, adding an acid I for neutralization, carrying out water precipitation, filtering to obtain a solid (5), and carrying out oxidative decarboxylation or decarboxylative oxidation reaction on the solid (5) to obtain the delta 9, 11-canrenone (11); or after the reaction is finished by keeping the temperature at 30-80 ℃, adding an aqueous solution of alkali II, after the reaction is finished by keeping the temperature at 10-80 ℃, adding acid II, separating out, filtering to obtain a solid (8), and performing decarboxylation oxidation reaction on the solid (8) to obtain the delta 9, 11-canrenone (11),
the solvent IV is one or more of methanol, ethanol and propanol, the volume dosage of the solvent IV is 2-10 times of the weight of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate, and the molar dosage of the base I is 1.01-5 times of the molar dosage of the 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as the substrate; the malonic diester is one of dimethyl malonate, diethyl malonate and dipropyl malonate, and the molar amount of the malonic diester is 1.01-5 times of that of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate; the acid I is one or more of formic acid, acetic acid and propionic acid, and the molar amount of the acid I is 1-3 times of that of the alkali; the alkali II is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate and lithium bicarbonate, and the molar amount of the alkali II is 1.01-5 times of that of the substrate 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4); wherein the acid II is one or more of hydrochloric acid, sulfuric acid and phosphoric acid, and the molar amount of the acid II is 1-5 times of the sum of the molar amounts of the alkali I and the alkali II.
2.Δ according to claim 19,11The preparation method of the-canrenone is characterized in that the solid (5) is subjected to oxidative decarboxylation in the step 4, the obtained solid (5) is put into a solvent V, an oxidant is added, the temperature is kept at 10-50 ℃ for reaction, after the reaction is finished, water is concentrated and separated out, the filtration and the filtration are carried outDissolving the cake with a solvent I, filtering, washing the filtrate with water to obtain a solution of (17 alpha) -17 beta-hydroxy-pregna-4, 6,9(11) -triene-3-one-21, 21-dicarboxylic acid alkyl ester gamma-lactone (6), concentrating, adding a solvent VI, preserving the temperature at 60-150 ℃, after the reaction is finished, elutriating, filtering, and drying to obtain delta-beta-hydroxy-pregna-4, 6,9(11) -triene-3-one9,11-canrenone (11),
the solvent V is one or more of methanol, acetone, dichloromethane and acetonitrile, and the volume consumption of the solvent V is 2-10 times of the weight of a substrate 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4); the molar amount of the oxidant is 1.01-2 times of that of the 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate; the volume dosage of the solvent I is 3-10 times of the weight of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate; the solvent VI is one or more of N, N-dimethylformamide, N-dimethylacetamide, toluene, acetic acid, pyridine, triethylamine and 1, 8-diazabicycloundecen-7-ene (DBU), and the volume consumption of the solvent VI is 2-10 times of the weight of a substrate 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4).
3.Δ according to claim 19,11The preparation method of the-canrenone is characterized in that the solid (5) is subjected to decarboxylation oxidation reaction in the step 4, the obtained wet solid (5) is added into a solvent VI, the temperature is kept at 60-150 ℃, after the reaction is finished, elutriation and filtration are carried out to obtain 17 beta-hydroxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene-21-carboxylic acid-gamma-lactone (7), then the mixture is put into a solvent V, an oxidant is added, the temperature is kept at 10-50 ℃ for reaction, after the reaction is finished, the elutriation and filtration are carried out, a filter cake is dissolved by a solvent I and then filtration is carried out, the filtrate is washed by water, concentrated, elutriated, filtered and dried to obtain delta-ion9,11-canrenone (11),
wherein the volume consumption of the solvent VI is 2-10 times of the weight of the 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) as a substrate; the volume dosage of the solvent V is 2-10 times of the weight of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate; the molar amount of the oxidant is 1.01-2 times of that of the 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate; the volume usage amount of the solvent I is 3-10 times of the weight of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate.
4.Δ according to claim 19,11The preparation method of the-canrenone is characterized in that the solid (8) is subjected to decarboxylation oxidation reaction in the step 4, the obtained wet solid (8) is added into a solvent VI, the temperature is kept at 60-150 ℃, after the reaction is completed, water is separated out, the obtained product is filtered and dried to obtain 17 beta-hydroxypregna-4, 9(11) -diene-3-one-21-carboxylic acid and gamma-lactone (9), then the obtained product is put into a solvent II, a protective agent and a catalyst are added, the temperature is kept at 20-50 ℃ for reaction, after the reaction is completed, the obtained product is filtered to obtain 17 beta-hydroxy-3-protective group-17 alpha-pregna-3, 5,9(11) -triene-21-carboxylic acid-gamma-lactone (10), then the obtained product is put into a solvent V, an oxidizing agent is added, the temperature is kept at 10-50 ℃ for reaction, after the reaction is finished, concentrating, elutriating, filtering, dissolving filter cake with solvent I, filtering again, washing filtrate with water, concentrating, elutriating, filtering, drying to obtain delta9,11-canrenone (11),
wherein the volume consumption of the solvent VI is 2-10 times of the weight of the 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) as a substrate; the volume dosage of the solvent II is 0.5-10 times of the weight of the substrate 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4); the molar dosage of the protective agent is 1.01-5 times of the molar dosage of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) of the substrate; the weight consumption of the catalyst is 0.01-0.1 time of the weight of the substrate 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4); the volume dosage of the solvent V is 2-10 times of the weight of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate; the molar amount of the oxidant is 1.01-2 times of that of the 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate; the volume usage amount of the solvent I is 3-10 times of the weight of 17 beta, 20 beta-epoxy-3-protecting group-17 alpha-pregna-3, 5,9(11) -triene (4) serving as a substrate.
5. Delta according to any of claims 1-49,11The preparation method of the canrenone is characterized in that the solvent I is one of dichloromethane, dichloroethane, chloroform or toluene.
6. A.DELTA.as claimed in claim 1 or 49,11-a method for preparing canrenone, characterized in that the solvent II is one of absolute methanol, absolute ethanol or THF; the protective agent is one of trimethyl orthoformate, triethyl orthoformate or pyrrolidine; the catalyst is at least one of pyridine hydrochloride, pyridine hydrobromide, p-toluenesulfonic acid or pyridine p-toluenesulfonic acid salt.
7. Delta according to any of claims 2-49,11The method for preparing canrenone is characterized in that the oxidant is at least one of tetrachloroo-benzoquinone, tetrachlorop-benzoquinone or dichlorodicyanobenzoquinone.
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| CN115433252A (en) * | 2022-08-24 | 2022-12-06 | 浙江亚瑟医药有限公司 | Preparation method of delta 9 (11) -canrenone |
| CN115594728A (en) * | 2022-10-28 | 2023-01-13 | 湖南科瑞生物制药股份有限公司（Cn） | 3-ketone-4,22-dienestolic acid ester and preparation method thereof |
| CN117624274A (en) * | 2023-10-19 | 2024-03-01 | 浙江晟创制药有限公司 | Preparation method of eplerenone intermediate delta 9,11-canrenone |
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| CN102617697A (en) * | 2011-01-26 | 2012-08-01 | 上海博悦生物科技有限公司 | New method for preparing eplerenone |
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| CN102617697A (en) * | 2011-01-26 | 2012-08-01 | 上海博悦生物科技有限公司 | New method for preparing eplerenone |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115433252A (en) * | 2022-08-24 | 2022-12-06 | 浙江亚瑟医药有限公司 | Preparation method of delta 9 (11) -canrenone |
| CN115594728A (en) * | 2022-10-28 | 2023-01-13 | 湖南科瑞生物制药股份有限公司（Cn） | 3-ketone-4,22-dienestolic acid ester and preparation method thereof |
| CN115594728B (en) * | 2022-10-28 | 2024-01-26 | 湖南科瑞生物制药股份有限公司 | 3-ketone-4, 22-dienoic cholate and preparation method thereof |
| CN117624274A (en) * | 2023-10-19 | 2024-03-01 | 浙江晟创制药有限公司 | Preparation method of eplerenone intermediate delta 9,11-canrenone |
| CN117624274B (en) * | 2023-10-19 | 2024-08-27 | 浙江晟创制药有限公司 | Preparation method of eplerenone intermediate delta 9, 11-canrenone |
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