CA1142916A - STEROIDAL [16.alpha., 17-B]NAPHTHALENO AND CYCLOHEXENE-21-CARBOXYLIC ACID ESTERS - Google Patents
STEROIDAL [16.alpha., 17-B]NAPHTHALENO AND CYCLOHEXENE-21-CARBOXYLIC ACID ESTERSInfo
- Publication number
- CA1142916A CA1142916A CA000328182A CA328182A CA1142916A CA 1142916 A CA1142916 A CA 1142916A CA 000328182 A CA000328182 A CA 000328182A CA 328182 A CA328182 A CA 328182A CA 1142916 A CA1142916 A CA 1142916A
- Authority
- CA
- Canada
- Prior art keywords
- hydrogen
- hydroxy
- fluoro
- dieno
- dioxopregna
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 230000003637 steroidlike Effects 0.000 title abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 59
- 239000001257 hydrogen Substances 0.000 claims abstract description 59
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 29
- 150000002148 esters Chemical class 0.000 claims abstract description 22
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- -1 ESTERS Steroids Chemical class 0.000 claims abstract description 17
- 229910052731 fluorine Chemical group 0.000 claims abstract description 16
- 239000011737 fluorine Chemical group 0.000 claims abstract description 16
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000003118 aryl group Chemical group 0.000 claims abstract description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 11
- 229910052736 halogen Chemical group 0.000 claims abstract description 10
- 150000002367 halogens Chemical group 0.000 claims abstract description 10
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 239000000460 chlorine Substances 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 14
- 239000002253 acid Substances 0.000 claims description 70
- 150000003431 steroids Chemical class 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 43
- 150000001875 compounds Chemical class 0.000 claims description 41
- 150000004702 methyl esters Chemical class 0.000 claims description 17
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims description 5
- 125000004494 ethyl ester group Chemical group 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- OPFTUNCRGUEPRZ-QLFBSQMISA-N Cyclohexane Natural products CC(=C)[C@@H]1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 OPFTUNCRGUEPRZ-QLFBSQMISA-N 0.000 claims description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical group C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 19
- PZQSQRCNMZGWFT-QXMHVHEDSA-N propan-2-yl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC(C)C PZQSQRCNMZGWFT-QXMHVHEDSA-N 0.000 claims 4
- 230000001590 oxidative effect Effects 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 abstract description 4
- 230000003110 anti-inflammatory effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 79
- 239000000243 solution Substances 0.000 description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 53
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 44
- 239000000203 mixture Substances 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 22
- 230000008018 melting Effects 0.000 description 22
- 238000002844 melting Methods 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 16
- 239000007787 solid Substances 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000000463 material Substances 0.000 description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 11
- 239000003054 catalyst Substances 0.000 description 11
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 description 9
- 150000001299 aldehydes Chemical class 0.000 description 9
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 8
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 6
- 150000001241 acetals Chemical class 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 238000005698 Diels-Alder reaction Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 5
- 238000002845 discoloration Methods 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical compound C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 4
- 239000005909 Kieselgur Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 4
- YADSGOSSYOOKMP-UHFFFAOYSA-N dioxolead Chemical compound O=[Pb]=O YADSGOSSYOOKMP-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- UMIVXZPTRXBADB-UHFFFAOYSA-N benzocyclobutene Chemical compound C1=CC=C2CCC2=C1 UMIVXZPTRXBADB-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 230000003595 spectral effect Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000005809 transesterification reaction Methods 0.000 description 3
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N 1,2-diethylbenzene Chemical compound CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 description 2
- SDJHPPZKZZWAKF-UHFFFAOYSA-N 2,3-dimethylbuta-1,3-diene Chemical compound CC(=C)C(C)=C SDJHPPZKZZWAKF-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000002026 chloroform extract Substances 0.000 description 2
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 2
- 229940090961 chromium dioxide Drugs 0.000 description 2
- IAQWMWUKBQPOIY-UHFFFAOYSA-N chromium(4+);oxygen(2-) Chemical compound [O-2].[O-2].[Cr+4] IAQWMWUKBQPOIY-UHFFFAOYSA-N 0.000 description 2
- AYTAKQFHWFYBMA-UHFFFAOYSA-N chromium(IV) oxide Inorganic materials O=[Cr]=O AYTAKQFHWFYBMA-UHFFFAOYSA-N 0.000 description 2
- 230000009850 completed effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 229910003439 heavy metal oxide Inorganic materials 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 125000000075 primary alcohol group Chemical group 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 150000003333 secondary alcohols Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- XJRIDJAGAYGJCK-UHFFFAOYSA-N (1-acetyl-5-bromoindol-3-yl) acetate Chemical compound C1=C(Br)C=C2C(OC(=O)C)=CN(C(C)=O)C2=C1 XJRIDJAGAYGJCK-UHFFFAOYSA-N 0.000 description 1
- PFJVIOBMBDFBCJ-UHFFFAOYSA-N (1z)-1-diazobutane Chemical compound CCCC=[N+]=[N-] PFJVIOBMBDFBCJ-UHFFFAOYSA-N 0.000 description 1
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical class C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101100439664 Arabidopsis thaliana CHR8 gene Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229910014033 C-OH Inorganic materials 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910014570 C—OH Inorganic materials 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 201000009053 Neurodermatitis Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940076286 cupric acetate Drugs 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- YXJYBPXSEKMEEJ-UHFFFAOYSA-N phosphoric acid;sulfuric acid Chemical compound OP(O)(O)=O.OS(O)(=O)=O YXJYBPXSEKMEEJ-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
- C07J53/002—Carbocyclic rings fused
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
- C07J13/005—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 16 (17)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
K570 ABSTRACT STEROIDAL[l6.alpha.,l7-b]CYCLOHEXENE AND NAPHTHALENO-21-CARBOXYLIC ACIDS AND ESTERS Steroids having the formula and esters thereof wherein X is hydrogen or halogen; Y is hydrogen, methyl or fluorine; R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or R4 and R5 together are =O; R2 and R3 are the same or different and are hydrogen, alkyl or aryl or taken together with the double bond to which they are attached form a benzene ring; R6 are R7 are the same or different and are hydrogen, alkyl, alkoxy, formyl, , phenyl or cyano and in addition hydroxy, halogen carboalkoxy and alkylcarbonyl when R2 and R3 are separate with the proviso that when R6 and R7 are different, one of R6 and R7 is hydrogen; R8 is hydrogen or wherein R9 and R10 are the same or different and are hydrogen or alkyl have useful antiinflammatory activity.
Description
3~6 STEROIDAL E16~l 17-b]CYCLOHEXENE AND NAPHTHAL~NO-21-CARBOXYLIC ACIDS AND ESTERS
. . _ . _ _ Steroids having the formula . . O
J~
and esters thereof are useful as topical anti-inflammatory agents. In formula I, and throughout the specification, the symbols are as defined below:
X is hydrogen or halogen;
Y is hydrogen, fluorine or methyl;
R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or R4 and R5 together are =O;
R2 and R3 are the same or difPeren-t and are hydrogen, alkyl or aryl or taken -together with the double bond -to which they are a-t-tached, form a benzene ring;
R6 and R7 are the same or different and are hydrogen,~ alkyl, alkoxy, formyl, alkyl-~-O-, phenyl or cyano and in addition, hydroxy, halogen, carbo-alkoxy and alkylcarbonyl when R2 and R3 are separate with the prov.iso that when R6 and R7 are di-Eferent, one of R6 and R7 is hydrogen; and R8 is hydrogen or CH-RgRlo wherein Rg and Rlo are the same or different and are hydrogen or alkyl.
' ~
~ X5~0 The dotted lines in the 1,2-position of khe steroids of this invention represent the optional presence of ethylenic unsaturation.
The terms "alkyl" and "alkoxy", as used throughout the specification (unless otherwise defined), refer to both straight and branched chain groups having 1 to 6 carbon atoms.
The term "aryl", as used throughout the sp~cification, refers to phenyl or phenyl substituted with one or more halogen, alkyl and alkoxy groups.
The term "halogen", as used throughout the specification, refers to fluorine, chlorine, bromine and iodine.
The esters contemplated are the Cl-C10 alkyl, aryl and aralkyl esters.
The steroids of formula I can be prepared from the corresponding 21-hydroxy-steroidal[16~, 17-b]-cyclic-enes having the structural formula fH2H R
II
wherein the symbols are as previously defined. The steroids of formula II are generally known in the art;
see, for example, United States patents 3,927,720 issued February 10, 1976; 3,994,935 issued November 30, 1976 and 3,944,584 issued March 16, 1976.
A steroid of formula II can be oxidized to the corresponding aldehyde having the formula ~ K570 _~_ HC=O
III ~ 2 using a catalyst such as copper acetate. The reaction can be run in an alcohol solvent.
If the above described oxidation reaction is carried out in the presence of oxygen (e.g., by bubbling air through the reaction mixture), the reaction will generally yield, in addition to a steroidal-21-aldehyde of formula III, the corresponding steroidal-21-acetal formed with the alcohol solvent (Rl-O~I); i.e., a steroid having the formula ~~~- ~ CH~OR ) IV C=O ,''< / R2 O ~ J 3 The oxidation reaction will generally be comple-ted within a relatively short period of time, i.e., about 1 hour.
If the above-described reaction is allowed to proceed for an extended period of time. e.g., more than about 24 hours, the major product will be the 2Q
hydroxy-21-carboxylic acid ester having the formula o V C-ORl R
HC~oH, ~ R2 ¦ L i ` ~ 3 If water is present as a co-solvent in the oxidation reaction, and the reaction is allowed to proceed for an extended period of time, in addition to the 20-hydroxy-21-carboxylic acid ester of formula V, the corresponding 20-hydroxy-21-carboxylic acid will be produced. i.e., a s-teroid havinq the -formula O ~
C-O~I R
HC~OH,''< / 2 VI ¦ ~ J ~ ~
, 8 ~he steroids of formulas V and VI exist as mixtures of the 20~- and 20~-hydroxysteroids. Reacting a steroid of formulas III or IV or a mixture thereof with an inorganic cyanide catalys~, an oxidizing agent, an inert solvent, an alcohol and an organic acid yields the product of formula I. More specificallyj a product of formula I can be obtained by reacting a steroidal-21-aldehyde of formula III or the corresponding steroidal-21-acetal of formula IV or a mixture thereof with a mixtuxe of (i) an inorganic ~, . . . . . .. . . . . ..
~5--cyanide catalyst (e.g., an ~lkali metal cyanide such as potassium cyanide); (ii) an oxidlzing agent, e.g., I a heavy metal oxide such as activated manganese dioxide or lead dioxide, (iii) an inert solvent, e.g., a halogenated hydrocarbon solvent such as dichloro-methane or chloroform; (iv) a primary or secondary alcohol, Ri-OH (throughout the speci~ication Ri is any primary or secondary Rl group); and (v) an acid, e.g., acetic acid, which serves to neutralize the alkali cyanide catalyst. The products of the above reaction have the formula o (~
VII R ~~~ ~ ~3 O ~ ~ R
Y
The 20 ~ and 20~-hydroxysteroids of Eormulas V
and VI can be oxidized to obtain the corresponding 20-ketosteroids, having the respective formulas O O
V II I a and ~42~1~ K570 6 __ ______ _ O O
~-COH R
VIIlb l ' ~ ,l~2 H
Y
Exemplary of suitable oxidizing agents are manganese dioxide and chromium dioxide. In the instance wherein the 20~- and 20~-hydroxysteroids being oxidized have an ll~-hydroxy substituent, the products of Eormulas I and VIII will be mixtures of ll~-hydroxy and ll-keto steroids.
The esters of formula I can also be prepared byesterification of the corresponding steroidal-21-oic acid of formula ~III. (A steroid of formula VIII can be prepared as described above, or alternatively, by saponification of a corresponding steroidal-21-oic ! acid ester of formula I.) Still another route for the preparation of the products of ~ormula I wherein Rl is a non tertiary alkyl group of l -to 10 carbon atoms or aryl i9 the transesterification of another ester of formula I.
The starting steroid is reacted with the appropirate alcohol in the presence oE a basic alkoxide (e.g., sodium ethoxide or aluminum isopropoxide) or, preferabIy, a source of cyanide ion (e.g. r an alkali metal cyanide such as sod um cynaide or potassium cyanide to yield the transesterification product.
.... .
~57 The steroids oF formula I are llseful tol)ical antiinflammatory agents which can b~ uso(l ill lio~l ol~
known glucocorticoids in the treatment of conditions such as dermatitis, psoriasis, sunburn, neurodermatitis, eczema and anogenital pruritus. The steroids may be administered in a conventional cream, ointment, lotion, or spray in the range of 0.01 to 5.0~ by weight, preferably 0.025 to 2.0% by weight.
In an alternative process, steroids of the formula I can be prepared from the corresponding 21-hydroxy-~16 steroids having the formula 4 ~=o lS IX 8 Y
by first converting the 21-hydroxy group to a 21-carboxylic acid group and then fusing the cyclo-hexane and tetrahydronaphthalene groups in the 16,17-position.
The 21-hydroxy-~16-steroids of formula IX, which form the starting point for -the alternate process, or the corresponding 21-acyloxy steroids, are known in the art. The 21-acyloxy steroids are readily converted to the corresponding 21-hydroxy steroids using conventional techniques.
A steroid of formula IX can be oxidized to the corresponding aldehyde having the formula 4 ~ 9 ~ ~ K570 , . _ , HC=O
X R
5 0~
using oxygen (or air) and a catalyst such as copper acetate. The reaction can be run in an alcohol solvent.
If the above described oxidation reaction is carried out in the presencs of oxygen ~e.g., by bubbling air through the reaction mixture), the reaction will generally yield, in addition to a steroidal-21-aldehyde of formula X, the corresponding steroidal-21-acetal formed with the alcohol solvent (Rl-OH); i.e., a steroid having the forrnula . . .
CH(ORl~2 XI
0~;
Y
The oxidation reaction will generally be completed within a relatively short period of time, i.e.,about 1 hour.
If the above described reaction is allowed to proceed for an extended period of time, e.g., more than about 24 hours, the major product will be the 20-hydroxy-21-carboxylic acid ester ~aviny the formula , . .. .
~Z916 K570 _9_ XII l-ORl HCrVOH
X
'.:- O' ~
, . . I
-., y If water is present as a co-solvent in the oxidation reaction, and the reaction is allowed to proceed for .~ an extended period of time, in addition to the 2 O-.~,- : .
~-~ hydroxy-21-carboxylic acid ester of formula XI, the _ . corresponding 20-hydroxy-21-carboxylic acid will be .~--` producea, i.e., a steroid having the formula C-OH
XIIII -. R HCrVOH .
R5 ~
. ~ ` ;`
,~ ;,~
The stervids of formula~ XlI and XIII exi3~ as I ~ .D~
25 mixtures of the 20a- and ~0~-hydroxy-steroids.~ .3 Reacting a steroid of formu.las ~X. or XI or a mixture thereof with an inorganic cyanide catalyst, an oxidizing agent, an inert solvent, an alcohol and an organic acid yields the product of formula I. A
product of formula I can be.obtained by reacting a steroidal-21-aldehyde of formula X or the corresponding steroidal-21-acetal of formula XI or a mixture thereof with a mixture of (i)an inorganic cyanide catalyst (e.g., an alkali metal cyanide such as potassium cyanide); ~ii) an oxïdizing agent, e.g., a heavy metal oxide such as .,~' -' ~ Y~70 activated manganese dioxide or lead dioxide; ~iii) an inert solvent, e.g., a hal~genated hydrocarbon solvent such as dichloromethane or chloroform; (iv~
a primary or secondary alcohol, Rl-OH (throughout the specification Ri is any nontertiary Rl group);
and (v) an acid, e.g., acetic acid, which serves to neutralize the alkali cyanide catalyst. The products of the above reaction have the formula O p -- ,,. . ,_ R ~-~ORi XIV R ~
.' ~ ' '.
O ~
Y , ,.
The 20~- and 20~-hydroxysteroids of formulas XII
and XIIIcan be oxidized to obtain the corresponding 20-ketosteroids, having the respective formulas XVR --- ~ OR
' ~,~
~ ~ ~ ~
Y and _ _ XVI5 ~ ~
f~
O ~
. ~ ,. ,~b, S ~ ~ .
~ . . .
l6 Exemplary of suitable oxidizing agents are manganese dioxide and chromium dioxide. In the instance wherein the 20~ and 20~-hydroxysteroids being oxidized have an ll~-hydroxy substituent, the steroids of formulas XV and XVI will be mixtures of ll~-hydroxy and 11-~keto steroids.
The intermediates of formula XV can also be prepared by esterification of the corresponding steroidal-21-oic acid of formula XVI. (A steroid of formula XV can be prepared as described above, or alternatively, by saponification of a corresponding steroidal 21-oic acid ester of formula XV).
Still another route for the preparation of the intermediates of formula XV wherein Rl is a non-tertiary group is the transesterification of anotherester of formula XIV or XV. The starting steroid is reacted with the appropriate alcohol in the presence of a basic alkoxide (e.g., sodium ethoxide or aluminum isopropoxide), or preferably, a source of cyanide ion (e.g., an alkali me-tal cyanide such as sodium cyanicle or potassium cyanide) to yield the transesteri:Eication product.
A steroid of formulas XIV, XV or XVI can be converted to -the correspond.ing product of formula I
by reacting it with a benzocyclobutene having the formula XVII
~ R;
or with a butadiene having the formula R ~C- C - C- CHR8 using the Diels Alder reaction~
_ _ _ _ . _ .. . .. _ _, .. _ _ . .. _ _,, .. _, ., . . . , . _ . .. . , .,, . ,,, _, . ..
In the case of the XVII reactant, the reaction can be run neat or in an inert solvent, eOg., o-dichlorobenzene or diethylbenzene. Preferably the reaction will be run neat, in an inert atmosphere, at temperatures up to the boiling point of the solution.
A free radical inhibitor may be added to the mixture.
In the case of the XVIII reactant, the preferred catalysts for the reaction are anhydrous aluminum chloride and anhydrous aluminum bromide. The reaction can be run in an organic solvent, e.g., a halogenated hydrocarbon such as dichloromethane. The above described Diels-Alder reaction is highly selective and takes place exclusively at the double bond in the 16-position, even in the presence of the ~ ' -3-keto-function. In those instances wherein the butadiene isunstable in the presence of a Lewis acid catalyst, the Diels-Alder reaction is run in the presence of a free radical inhibltor at elevated temperatures.
If the steroid of formula XIV/ ~V or ~VI contalns an ll~-hydroxy group, it is desirable to first protect the group before running the Diels-Alder reaction.
While many means of protecting the ll-functional group will be apparent to a person skilled in the steroid - art, one particularly desirable method is the acylation of the group. The acylation reaction can be run using an acid anhydride, e.g., acetic anhydride in the presence of a Lewis catalyst, e.g., boron tri-fluoride etherate. After the Diels-Alder reaction has been run, the protective group can be removed using a conventional technique.
. . _ . _ _ Steroids having the formula . . O
J~
and esters thereof are useful as topical anti-inflammatory agents. In formula I, and throughout the specification, the symbols are as defined below:
X is hydrogen or halogen;
Y is hydrogen, fluorine or methyl;
R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or R4 and R5 together are =O;
R2 and R3 are the same or difPeren-t and are hydrogen, alkyl or aryl or taken -together with the double bond -to which they are a-t-tached, form a benzene ring;
R6 and R7 are the same or different and are hydrogen,~ alkyl, alkoxy, formyl, alkyl-~-O-, phenyl or cyano and in addition, hydroxy, halogen, carbo-alkoxy and alkylcarbonyl when R2 and R3 are separate with the prov.iso that when R6 and R7 are di-Eferent, one of R6 and R7 is hydrogen; and R8 is hydrogen or CH-RgRlo wherein Rg and Rlo are the same or different and are hydrogen or alkyl.
' ~
~ X5~0 The dotted lines in the 1,2-position of khe steroids of this invention represent the optional presence of ethylenic unsaturation.
The terms "alkyl" and "alkoxy", as used throughout the specification (unless otherwise defined), refer to both straight and branched chain groups having 1 to 6 carbon atoms.
The term "aryl", as used throughout the sp~cification, refers to phenyl or phenyl substituted with one or more halogen, alkyl and alkoxy groups.
The term "halogen", as used throughout the specification, refers to fluorine, chlorine, bromine and iodine.
The esters contemplated are the Cl-C10 alkyl, aryl and aralkyl esters.
The steroids of formula I can be prepared from the corresponding 21-hydroxy-steroidal[16~, 17-b]-cyclic-enes having the structural formula fH2H R
II
wherein the symbols are as previously defined. The steroids of formula II are generally known in the art;
see, for example, United States patents 3,927,720 issued February 10, 1976; 3,994,935 issued November 30, 1976 and 3,944,584 issued March 16, 1976.
A steroid of formula II can be oxidized to the corresponding aldehyde having the formula ~ K570 _~_ HC=O
III ~ 2 using a catalyst such as copper acetate. The reaction can be run in an alcohol solvent.
If the above described oxidation reaction is carried out in the presence of oxygen (e.g., by bubbling air through the reaction mixture), the reaction will generally yield, in addition to a steroidal-21-aldehyde of formula III, the corresponding steroidal-21-acetal formed with the alcohol solvent (Rl-O~I); i.e., a steroid having the formula ~~~- ~ CH~OR ) IV C=O ,''< / R2 O ~ J 3 The oxidation reaction will generally be comple-ted within a relatively short period of time, i.e., about 1 hour.
If the above-described reaction is allowed to proceed for an extended period of time. e.g., more than about 24 hours, the major product will be the 2Q
hydroxy-21-carboxylic acid ester having the formula o V C-ORl R
HC~oH, ~ R2 ¦ L i ` ~ 3 If water is present as a co-solvent in the oxidation reaction, and the reaction is allowed to proceed for an extended period of time, in addition to the 20-hydroxy-21-carboxylic acid ester of formula V, the corresponding 20-hydroxy-21-carboxylic acid will be produced. i.e., a s-teroid havinq the -formula O ~
C-O~I R
HC~OH,''< / 2 VI ¦ ~ J ~ ~
, 8 ~he steroids of formulas V and VI exist as mixtures of the 20~- and 20~-hydroxysteroids. Reacting a steroid of formulas III or IV or a mixture thereof with an inorganic cyanide catalys~, an oxidizing agent, an inert solvent, an alcohol and an organic acid yields the product of formula I. More specificallyj a product of formula I can be obtained by reacting a steroidal-21-aldehyde of formula III or the corresponding steroidal-21-acetal of formula IV or a mixture thereof with a mixtuxe of (i) an inorganic ~, . . . . . .. . . . . ..
~5--cyanide catalyst (e.g., an ~lkali metal cyanide such as potassium cyanide); (ii) an oxidlzing agent, e.g., I a heavy metal oxide such as activated manganese dioxide or lead dioxide, (iii) an inert solvent, e.g., a halogenated hydrocarbon solvent such as dichloro-methane or chloroform; (iv) a primary or secondary alcohol, Ri-OH (throughout the speci~ication Ri is any primary or secondary Rl group); and (v) an acid, e.g., acetic acid, which serves to neutralize the alkali cyanide catalyst. The products of the above reaction have the formula o (~
VII R ~~~ ~ ~3 O ~ ~ R
Y
The 20 ~ and 20~-hydroxysteroids of Eormulas V
and VI can be oxidized to obtain the corresponding 20-ketosteroids, having the respective formulas O O
V II I a and ~42~1~ K570 6 __ ______ _ O O
~-COH R
VIIlb l ' ~ ,l~2 H
Y
Exemplary of suitable oxidizing agents are manganese dioxide and chromium dioxide. In the instance wherein the 20~- and 20~-hydroxysteroids being oxidized have an ll~-hydroxy substituent, the products of Eormulas I and VIII will be mixtures of ll~-hydroxy and ll-keto steroids.
The esters of formula I can also be prepared byesterification of the corresponding steroidal-21-oic acid of formula ~III. (A steroid of formula VIII can be prepared as described above, or alternatively, by saponification of a corresponding steroidal-21-oic ! acid ester of formula I.) Still another route for the preparation of the products of ~ormula I wherein Rl is a non tertiary alkyl group of l -to 10 carbon atoms or aryl i9 the transesterification of another ester of formula I.
The starting steroid is reacted with the appropirate alcohol in the presence oE a basic alkoxide (e.g., sodium ethoxide or aluminum isopropoxide) or, preferabIy, a source of cyanide ion (e.g. r an alkali metal cyanide such as sod um cynaide or potassium cyanide to yield the transesterification product.
.... .
~57 The steroids oF formula I are llseful tol)ical antiinflammatory agents which can b~ uso(l ill lio~l ol~
known glucocorticoids in the treatment of conditions such as dermatitis, psoriasis, sunburn, neurodermatitis, eczema and anogenital pruritus. The steroids may be administered in a conventional cream, ointment, lotion, or spray in the range of 0.01 to 5.0~ by weight, preferably 0.025 to 2.0% by weight.
In an alternative process, steroids of the formula I can be prepared from the corresponding 21-hydroxy-~16 steroids having the formula 4 ~=o lS IX 8 Y
by first converting the 21-hydroxy group to a 21-carboxylic acid group and then fusing the cyclo-hexane and tetrahydronaphthalene groups in the 16,17-position.
The 21-hydroxy-~16-steroids of formula IX, which form the starting point for -the alternate process, or the corresponding 21-acyloxy steroids, are known in the art. The 21-acyloxy steroids are readily converted to the corresponding 21-hydroxy steroids using conventional techniques.
A steroid of formula IX can be oxidized to the corresponding aldehyde having the formula 4 ~ 9 ~ ~ K570 , . _ , HC=O
X R
5 0~
using oxygen (or air) and a catalyst such as copper acetate. The reaction can be run in an alcohol solvent.
If the above described oxidation reaction is carried out in the presencs of oxygen ~e.g., by bubbling air through the reaction mixture), the reaction will generally yield, in addition to a steroidal-21-aldehyde of formula X, the corresponding steroidal-21-acetal formed with the alcohol solvent (Rl-OH); i.e., a steroid having the forrnula . . .
CH(ORl~2 XI
0~;
Y
The oxidation reaction will generally be completed within a relatively short period of time, i.e.,about 1 hour.
If the above described reaction is allowed to proceed for an extended period of time, e.g., more than about 24 hours, the major product will be the 20-hydroxy-21-carboxylic acid ester ~aviny the formula , . .. .
~Z916 K570 _9_ XII l-ORl HCrVOH
X
'.:- O' ~
, . . I
-., y If water is present as a co-solvent in the oxidation reaction, and the reaction is allowed to proceed for .~ an extended period of time, in addition to the 2 O-.~,- : .
~-~ hydroxy-21-carboxylic acid ester of formula XI, the _ . corresponding 20-hydroxy-21-carboxylic acid will be .~--` producea, i.e., a steroid having the formula C-OH
XIIII -. R HCrVOH .
R5 ~
. ~ ` ;`
,~ ;,~
The stervids of formula~ XlI and XIII exi3~ as I ~ .D~
25 mixtures of the 20a- and ~0~-hydroxy-steroids.~ .3 Reacting a steroid of formu.las ~X. or XI or a mixture thereof with an inorganic cyanide catalyst, an oxidizing agent, an inert solvent, an alcohol and an organic acid yields the product of formula I. A
product of formula I can be.obtained by reacting a steroidal-21-aldehyde of formula X or the corresponding steroidal-21-acetal of formula XI or a mixture thereof with a mixture of (i)an inorganic cyanide catalyst (e.g., an alkali metal cyanide such as potassium cyanide); ~ii) an oxïdizing agent, e.g., a heavy metal oxide such as .,~' -' ~ Y~70 activated manganese dioxide or lead dioxide; ~iii) an inert solvent, e.g., a hal~genated hydrocarbon solvent such as dichloromethane or chloroform; (iv~
a primary or secondary alcohol, Rl-OH (throughout the specification Ri is any nontertiary Rl group);
and (v) an acid, e.g., acetic acid, which serves to neutralize the alkali cyanide catalyst. The products of the above reaction have the formula O p -- ,,. . ,_ R ~-~ORi XIV R ~
.' ~ ' '.
O ~
Y , ,.
The 20~- and 20~-hydroxysteroids of formulas XII
and XIIIcan be oxidized to obtain the corresponding 20-ketosteroids, having the respective formulas XVR --- ~ OR
' ~,~
~ ~ ~ ~
Y and _ _ XVI5 ~ ~
f~
O ~
. ~ ,. ,~b, S ~ ~ .
~ . . .
l6 Exemplary of suitable oxidizing agents are manganese dioxide and chromium dioxide. In the instance wherein the 20~ and 20~-hydroxysteroids being oxidized have an ll~-hydroxy substituent, the steroids of formulas XV and XVI will be mixtures of ll~-hydroxy and 11-~keto steroids.
The intermediates of formula XV can also be prepared by esterification of the corresponding steroidal-21-oic acid of formula XVI. (A steroid of formula XV can be prepared as described above, or alternatively, by saponification of a corresponding steroidal 21-oic acid ester of formula XV).
Still another route for the preparation of the intermediates of formula XV wherein Rl is a non-tertiary group is the transesterification of anotherester of formula XIV or XV. The starting steroid is reacted with the appropriate alcohol in the presence of a basic alkoxide (e.g., sodium ethoxide or aluminum isopropoxide), or preferably, a source of cyanide ion (e.g., an alkali me-tal cyanide such as sodium cyanicle or potassium cyanide) to yield the transesteri:Eication product.
A steroid of formulas XIV, XV or XVI can be converted to -the correspond.ing product of formula I
by reacting it with a benzocyclobutene having the formula XVII
~ R;
or with a butadiene having the formula R ~C- C - C- CHR8 using the Diels Alder reaction~
_ _ _ _ . _ .. . .. _ _, .. _ _ . .. _ _,, .. _, ., . . . , . _ . .. . , .,, . ,,, _, . ..
In the case of the XVII reactant, the reaction can be run neat or in an inert solvent, eOg., o-dichlorobenzene or diethylbenzene. Preferably the reaction will be run neat, in an inert atmosphere, at temperatures up to the boiling point of the solution.
A free radical inhibitor may be added to the mixture.
In the case of the XVIII reactant, the preferred catalysts for the reaction are anhydrous aluminum chloride and anhydrous aluminum bromide. The reaction can be run in an organic solvent, e.g., a halogenated hydrocarbon such as dichloromethane. The above described Diels-Alder reaction is highly selective and takes place exclusively at the double bond in the 16-position, even in the presence of the ~ ' -3-keto-function. In those instances wherein the butadiene isunstable in the presence of a Lewis acid catalyst, the Diels-Alder reaction is run in the presence of a free radical inhibltor at elevated temperatures.
If the steroid of formula XIV/ ~V or ~VI contalns an ll~-hydroxy group, it is desirable to first protect the group before running the Diels-Alder reaction.
While many means of protecting the ll-functional group will be apparent to a person skilled in the steroid - art, one particularly desirable method is the acylation of the group. The acylation reaction can be run using an acid anhydride, e.g., acetic anhydride in the presence of a Lewis catalyst, e.g., boron tri-fluoride etherate. After the Diels-Alder reaction has been run, the protective group can be removed using a conventional technique.
2~
Example 1 9-Fluoro-1',2'3'4'-tetrah~o~ -hydrox~-3,20-dioxo regna-l 4-dieno~ ,17-hJna hthalene-21-oic P ~ P
acid, methyl ester 9-Fluoro-1',2',3',4'-tetrahydro-11~,21-dihydroxy pregna -1,4 dieno[l6a,17-b]naphthalene-
Example 1 9-Fluoro-1',2'3'4'-tetrah~o~ -hydrox~-3,20-dioxo regna-l 4-dieno~ ,17-hJna hthalene-21-oic P ~ P
acid, methyl ester 9-Fluoro-1',2',3',4'-tetrahydro-11~,21-dihydroxy pregna -1,4 dieno[l6a,17-b]naphthalene-
3,20-dione (1.0 g) is dissolved in anhydrous methanol (170 ml) by warming and the solution is cooled to room temperature. Cupric acetate hydrate (250 mg) is added and under stirring, a slow stream of air is passed into the solution.
Within 10 minutes, the starting steroid disappears to give essentially a single less polar material, as judged by thin-layer chrornatography (TLC).
The methanol is mostly evaporated in vacuo at room temperature; some steroid precipitates out. The concentrate is diluted with water and extracted with chloroEorm~ The chloroform solution is washed with a dilute ammonium chloride solution and water, dried over anhydrous magnesium sulfate and evaporated to leave 0.98 g of 9-fluoro-1',2',3',4'-te-trahydro~ -hydroxy pregna-1,4-dieno[16a,17-bl naphthalene-21-al-3,-20-dione. This material shows a single spot on TLC (chloroform-methanol, 93:7; silica gel) and an IR spectrum consistent with the structure.
However, the NMR spectrum shows that it is contaminated with a small amount of the corresponding 21~dimethyl acetal.
~2~6 -14- K57~
A mixture of the impure aldehyde t950 mg), anhydrous methanol (50 ml), dry dichloromethane (50 ml), glacial acetic acid (Q.9 ml), potassium cyanide (200 mg) and active manganese dioxide (2.1 g) is stirred at room temperature for 10 hours. It is then fil-tered through a bed of diatomaceous earth. The cake is resuspended in chloroform which is refluxed and filtered again. The filtrates are comhined, washed with a dilute sodium hicarbonate solution and water, dried over anhydrous magnesium sulfate and evaporated ~o afford 0.86 g of a solid. This is dissolved in a mixture of dichloromethane and methanol. The dichloromethane is removed under reflux to precipi-tate 675 mg of a solid. This is again subjected to purification as abo~e to afford 630 mg of the title compound, melting point 319-321C (dec., discoloration starts from about 260C) with consistent spectral data.
Anal- Calc'd for C30H33F5 C, 73-15;
~1, 6.75;
F, 3.86 Found: C, 72.85;
H, 6.95;
F, 3.65 Example 2 9-Fluoro-1',2',3',4'-tetrahydro~ -hydroxy-3,20-dioxopregna-1,4-dieno[16~,17-b]naphthalen-21-oic acid, l-methylethyl ester A suspension of 9-fluoro-1',2',3',4'-tetrahydro-ll~-hydroxy-3,20-dioxopregna 1,4 dieno[l6a,17-b]naphthalen-21-oic acid, me-thyl ester (490 mg., see Example 1) in dry isopropanol (30 ml, freshly distilled from magnesium turnings) containing sodium cyanide (10 mg) is refluxed under an atmosphere of nitrogen for 20 minutes when a clear solution results. A TLC examination at this point shows complete conversion of the starting steroid into a less polar compound. The mixture is then evaporated ln vacuo, the residue is dissolved in chloroform, washed with dilute brine and water, dried over anhydrous magnesium sulfate and evaporated to afford 516 mg of the title compound. One crystallization from ethyl acetate affords the analytical specimen of the title compound as colorless needles (410 mg), melting point 269-271C (dec., discoloration starts from about 250 C) wi.th consistent spectral dataO
Anal. Calc'd for C32 H37FO5: C, 73.82;
H, 7.16;
F, 3.~5 Found: C, 73.45;
H, 7.11;
F, 3.47 xample 3 9-Fluoro-1',2',3',4'-tetrahydro~ -h~droxy, 3,20-dioxopregna-1,4-dieno~16a,17-b]naphthalen-21-oic acid, butyl ester 9-Fluoro-1',2',3',4'-tetrahydro~ ,21-39 dihydroxypregna-1,4-dieno[16a,17-blnaphthalene-3,20-dione (800 mg) is dissolved in n-butanol 'h916 ~150 ml) by warming. The solution ls cooled to room temperature, cooper acetate hydrate (250 mg) is added and air is buhbled into the solution with sitrring for 30 minutes. Mos-t o the n-butanol is then removed b~ evapora-tion _ vacuo at 40-42C. The concentrate is dlluted with water and extracted with chloroform. The chloroform extracts are combined, washed with a dilute ammonium chloride solution and water, dried over anhydrous magnesium sulfate and evaporated to afford 850 mg of 9-fluoro~
2',3',4'-tetrahydro-11~-hydroxypregna-1,4-dieno[16a,17-b]naphthalene-21-al-3,20-dione.
(This material is characterized spectroscopically.
A TLC examination shows the presence of one major compound, traces of starting material and traces of another impurity, less polar than the starting materlal, and believed to be 9-fluoro-1',2',3',4'-tetrah~dro~ hydroxy-21~21-di-n-butoxy-pregna-1,4-dienol16~,17-b~na~hthalene-3,20 dione).
The above crude mlxture (840 mg) is dissolved in a mixture of dry n-butanol (20 ml) and dichloromethane (50 ml). Acetic acid (0.8 ml), potassium cyanide (200 mg)and active manganese dioxide (2.0 g) are added and the mixture is stirred at room temperature for 60 hours. (A
shorter reaction time would he adequate). The mixture is then filtered through a bed of diatomaceous earth. The solids are washed with chloroform, the filtrate and the washings are ,.. , ~
-17~ K57n combined, washed with water, dried over anhydrous magnesium sulfate and evaporated to afford the crude product as a gum. From this the major component is isolated by preparative TLC (four, 5 2.Omm silica gel plates developed with chloro-form-ethyl acetate 1:1) and identified as the title compound (487 mg). One crystallization from ethyl acetate gives 381 mg of the analytical specimen of the title compound, meltiny point 245-246C with consistent spectral data.
Anal. Calc d for C33H3gFO5 C, 74-13;
~I, 7.35;
F, 3.55 Found: C, 74.37;
H, 7.41;
; F, 3.46 Example 4 9-Fluoro-1',2',3',4'-tetrahydro-11~-hydroxy~3 _ dioxopregna 1,4-dieno[16a,17-b]naphthalene-21-oic acid, l,l-dimethxleth~1 ester A) 9-Fluoro-1',2',3',4'-tetrahydro-ll~h~droxy-3,20-dioxo~regna-1,4-dieno~16a,17-blnaphthalene-21-oic acid ~ solu-tion o~ luoro-1',2',3',4'-tetrahydro-11~-hydroxypregna-1,4-dieno[16~, 17-b]naphthalene-21-al-3,20-dione (3.ny, see Example 1) in a mixture of dichloromethane (150 ml) and tetrahydrofuran (150 ml) containing acetic acid (3.0 ml) and water (4.0 ml) is stirred with activated manganese dioxide (6.0g) and potassium cyanide (700 mg) for 20 hours. The mixture is then filtered and the solids are washed with warm chloroform-methanol ~7:3~. The filtrate and the washings are combined and evaporated in v~cuo.
The residue is washed with wa-ter, dried, purified by chromatogra~hy, crvstalliz~d fr~m methanol~chIoroform to afford the title compound, melting point 280-281C (dec.).
B) 9-Fluoro-1',2',3',4'-tetrahydro~ hydroxy-3,20~dioxopregna-1,4-dieno[1_~,17-b]naphthalene 21-oic acid, l,l-dimet ylethyl -ester To a suspension of g-fluoro-1',2',3',4'-tetrahydro~ -hydroxy-3,20-dioxopregna-1,4-dieno 116a,17-b]naphthalene-21-oic acid(325 mg.) in dry dioxane (60 ml) containing sulfuric acid-phosphoric acid catalyst (0.4 ml.; prepared by the addition of the calculated amount of phosphorous pentoxide to 96~ sulfuric acid to react with all of the water) in a pressure reaction vessel is passed a stream of isobutylene (until about 6 ml is added). The reaction vessel is closed and maintained at ambient temperature for 30 hours with stirri.ng. The mixture is poured into a solution of sodium ace-tate hydrate (5.0g) in water (500 ml) and extracted successi.vely with chloroform and ethyl acetate. The extracts are washed with brine, combined, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel to afford 145 mg. of the -title compound, melting point 293-296C (dec., discoloration starts from about 275~C) after crystalliza-tion from acetone-hexane.
,. . .
Example 5 ~-Fluoro-1',2',3',4'-tetrahydro~ -hydroxy-3, 20-dioxopre~na-1,4-dienol16a,17-~]naphthalen-21-oic acid, 2,2-dimethylpropyl ester A solution of 9-fluoro-1',2',3',4'-tetrahydro-ll~-hydroxy-3,20-dioxopregna-1,4-dieno~l6a,17-b3naphthalene-21-oic acid, methyl ; ester in dry dioxane (20 ml, distilled over sodium) and dry pyridine (15 ml) is refluxed with neopentYl alcohol (2.2 g) and sodium cyanide (100 mg) under a nitrogen atmosphere for 18 hours. The resulting solution is evaporated ln vacuo and the residue is dissolved in chloroform. The chloroform solution is washed with dilute sodium chloride solution and water, dried over anhydrous sodium sulfate and evaporated ln vacuoO The residue is dissolved in chloroform-hexane (9:1) and ~ 20 chromatographed on a 35 g-silica gel column.
; Elution with chloroform-hexane (9:1) gives 540 mg of material. Crystallization :Erom acetone-hexane give~ 460 mg of an analytical specimen of the title compound, melting point 329-331C (dec.).
Anal. Calc d for C34 41 5 ; H, 7.53;
F, 3.46.
Found: C,- 74.39;
H, 7.73;
F, 3.37.
_20- K570 Example 6 9-Fluoro~ -hydroxy-3,20-dioxopregna-1,4-dieno-[16~!17-d]cyclohexen-21-oic acid meth 1 ester A solution of 1.2 g of 9-fluoro-11~,21-dihydroxypregna-1,4-dieno~16a,17-d]cyclohexene-3,20-dione and 3no mg of copper acetate in 150 ml of methanol is stirred at room temperature for 1 hour while a stream of air is hubbled through the solution. The solvent is evaporated in vacuo at 30C. The residue is diluted with water and extracted with chloroform, ana then, ethyl acetate. The chloroform solution and ethyl acetate solution are washed with aqueous ammonium chloride solution (ln~ and water, dried over anhydrous sodium sulfate, evaporated in vacuo and combined to give 1.3 g of a solid. The NMR
spectrum of the solid shows that it is an approxi-mately equimolar mixture of the 21-aldehyde and 21-dimethylacetal derivatives of the starting steroid.
The solid product of the above reaction (1.3 g) is stirred in a mixture of 50 ml dry me-thanol and 50 ml dry dichloromethane at room temperature for about 16 hours with activated manganese dioxide (2.0g), glacial acetic acid (1.0 ml) and potassium cyanide (2~0 mg) The suspension is filtered through a bed of Hyflo and washed with chloroform.
The filtrate and washings are comhined, washed with water and dried over anhydrous magnesium sulfate.
; 30 The solvent is evaporated in vacuo to give 1.1 g of a solid. Th~ is dissolved in chloroform and chromatographed on a 35 g-silica gel column.
Elution with chloroform gives 93~ mg of material.
* Trade Mark .
~2~
Crystallization from acetone-hexane gives 650 my of the title compound, melting point 256-258C, with consistent spectra data.
n ysis Calc d for C28H31FO5: C, 70.57;
H, 7.06;
F, 4.29 Found: C, 70O66;
H, 7.11;
F, 4.02 Example _ 9-Fluoro~ -hydroxv-3,20-dioxopregna-1,4-dieno-.... .. ..
[16a,17-d~cyclohexen-21-oic acid, l-meth~le-thyl ester A solution of 480 mg of 9-fluoro-11~-hydrox~-3,2~-dioxopregna-1,4-dieno[16a,17-d]
cyclohexen-21-oic acid, methyl ester (see Example 1) and 85 mg of sodium cyanide in 65 ml of dry isopropyl alcohol is stirred under a nitrogen atmosphere at 100C for about 16 hours.
The resulting solution is evaporated in vacuo and the residue is dissolved in chloroform ancl washed with 25 ml of water. The aqueous layer is saturated with sodium chloride and ex-tracted with chloroform. The chloroform solutions are z5 combined, dried over anhydrous sodium sulfate and evaporated ln acuo. The residue is dissolved in chloroform-hexane (7:3) and chromatographed on a 25 g-silica gel column.
Elution with chloro~orm-hexane (7:3)gives 370 mg of material. Cr~stallization from acetone~
hexane gives 3no mg of the title compound, melting ~z~
point 226-228C, with consistent spec~ral data.
~nalysis calc'd. for C28ll35FO5 H, 7.50;
F, 4.04 Found: C, 71.47;
H, 7.44;
F, 3.82 Example 8 . 9-Fluoro-ll~-h~droxy-3,20-dioxopregna-1,4-dieno-~.6a,17-d]cyclohexen-21- ic aci_, b~tyl ester A mixture of 1.0 g of 9-fluoro-11~,21-dihydroxypregna-1,4-dieno[16~,17-d]cyclohexene-3,20-dione.and 250 mg of copper acetate in 50 ml of dichloromethane and 30 ml of n-butanol is ; 15 stirred at room temperature for 1 hour while a slow stream of air is bubbled through the solution.
Since the rate of oxidation is extremely 510w, the dichloromethane is evaporated and replaced with 50 ml of n-butanol. Another 200 mg of copper acetate is added and the reac-tion is continued for 1.5 hour when the starting material disappears. The sol~ent is then evaporated .ln vacuo at 35-40C and the residue is diluted with 200 ml of water and extracted with dichloromethane, and then ethyl acetate. The dichloromethane solution and ethyl acetate solution are washed with ammonium chloride solution (10%) and water, combined, dried over anhydrous sodium sulfate and evaporated 1n vacuo to.give 1.2 g of solid. The NMR spectrum of the ,, _ solid shows that it is an approximately equimolar mixture of the 21-aldehyde and 21-di-n-butylacetal derivatives of the starting steroid.
The solid product of the above reaction (1.2 g) is dissolved in 50 ml of dry dichloro-methane and 30 ml of dry n-hutanol and stirred at room temperature for ahout 16 hours with 2.0 g of activated manganese dioxide, 1.0 ml of glacial acetic acid and 200 mg of potassium cyanide. A dry calcium chloride tube is attached to the flask to avoid contact with moisture.
After 20 hours another 2.0 g of activated manganese dioxide and 200 mg of potassi~n cyanide are added. The suspension is stirred at room 1~ temperature for 7 hours, filtered through a bed of Hyflo, and washed thoroughly with dichloro-methane. The filtrate and washings are combined and washed with a saturated sodium ~icarbonate solution and water, dried over anh~drous sodiwn ~o sulfate ana evaporated ln vacuo. The title compound in the residue cannot be success~ully separated from impurities on precoated silica gel TLC plate. It can, however, be successully purified on E. Merck precoated silica gel TLC
plate (2 mm, 2.5:97.5 methanol~chloroform) to yive 400 mg of a foam Crystallization from ethyl acetate-hexane gives 330 mg of the title compound, melting point 203-209C, with consistent spectra data Analysis calcld for C29H37FO5: C, 71.87;
H, 7.70;
F, 3.92 Found: C, 71.98 H, 7.73 F, 3.62 Example 9 9-Fluoro~llo~Ao~ L~ thYl-3~2o-diox~E~regna~1,4-dieno~16a,17-d]cyclohexen-21-oic acid, met~l ester A solution of 4.9 g of q-fluoro-11~,21-dihydroxy-1',2'-dimethyl-3 r 20~dioxopregna-1,4-dieno[16a,17-d~ c~clohexene and 1.1 g of copper acetate in 800 ml of methanol is reacted with air following the procedure described in Example 1 (first paragraph) to yield 5.0 g of an approximately equimolar mixture of the 21-; aldehyde and 21-dimethylacetal derlvatives of the starting s-teroid~
~ The solid product of the above reaction (4.5 g) is stlrred in a mlxture o~ 250 ml dry methanol and 250 ml dry dichloromethane at room temperature for abouk 16 hours under a nitrogen atmosphere with activated manganese dioxide (7.0 g), glacial acetlc acid (4.0 ml) and potassium cyanide (700 mg). The resulting suspenslon is filtered through a bed of diatomaceous earth and washed with chloroform-methanol (~
The flltrate and washlngs are comblned and evaporated ln vacuo to give 5O6 g of a solld.
This is dissolved in chloroform-hexane (9:1) and chromatographed on a 100 g silica gel column.
Elution with chloroform-hexane (9:1) yields
Within 10 minutes, the starting steroid disappears to give essentially a single less polar material, as judged by thin-layer chrornatography (TLC).
The methanol is mostly evaporated in vacuo at room temperature; some steroid precipitates out. The concentrate is diluted with water and extracted with chloroEorm~ The chloroform solution is washed with a dilute ammonium chloride solution and water, dried over anhydrous magnesium sulfate and evaporated to leave 0.98 g of 9-fluoro-1',2',3',4'-te-trahydro~ -hydroxy pregna-1,4-dieno[16a,17-bl naphthalene-21-al-3,-20-dione. This material shows a single spot on TLC (chloroform-methanol, 93:7; silica gel) and an IR spectrum consistent with the structure.
However, the NMR spectrum shows that it is contaminated with a small amount of the corresponding 21~dimethyl acetal.
~2~6 -14- K57~
A mixture of the impure aldehyde t950 mg), anhydrous methanol (50 ml), dry dichloromethane (50 ml), glacial acetic acid (Q.9 ml), potassium cyanide (200 mg) and active manganese dioxide (2.1 g) is stirred at room temperature for 10 hours. It is then fil-tered through a bed of diatomaceous earth. The cake is resuspended in chloroform which is refluxed and filtered again. The filtrates are comhined, washed with a dilute sodium hicarbonate solution and water, dried over anhydrous magnesium sulfate and evaporated ~o afford 0.86 g of a solid. This is dissolved in a mixture of dichloromethane and methanol. The dichloromethane is removed under reflux to precipi-tate 675 mg of a solid. This is again subjected to purification as abo~e to afford 630 mg of the title compound, melting point 319-321C (dec., discoloration starts from about 260C) with consistent spectral data.
Anal- Calc'd for C30H33F5 C, 73-15;
~1, 6.75;
F, 3.86 Found: C, 72.85;
H, 6.95;
F, 3.65 Example 2 9-Fluoro-1',2',3',4'-tetrahydro~ -hydroxy-3,20-dioxopregna-1,4-dieno[16~,17-b]naphthalen-21-oic acid, l-methylethyl ester A suspension of 9-fluoro-1',2',3',4'-tetrahydro-ll~-hydroxy-3,20-dioxopregna 1,4 dieno[l6a,17-b]naphthalen-21-oic acid, me-thyl ester (490 mg., see Example 1) in dry isopropanol (30 ml, freshly distilled from magnesium turnings) containing sodium cyanide (10 mg) is refluxed under an atmosphere of nitrogen for 20 minutes when a clear solution results. A TLC examination at this point shows complete conversion of the starting steroid into a less polar compound. The mixture is then evaporated ln vacuo, the residue is dissolved in chloroform, washed with dilute brine and water, dried over anhydrous magnesium sulfate and evaporated to afford 516 mg of the title compound. One crystallization from ethyl acetate affords the analytical specimen of the title compound as colorless needles (410 mg), melting point 269-271C (dec., discoloration starts from about 250 C) wi.th consistent spectral dataO
Anal. Calc'd for C32 H37FO5: C, 73.82;
H, 7.16;
F, 3.~5 Found: C, 73.45;
H, 7.11;
F, 3.47 xample 3 9-Fluoro-1',2',3',4'-tetrahydro~ -h~droxy, 3,20-dioxopregna-1,4-dieno~16a,17-b]naphthalen-21-oic acid, butyl ester 9-Fluoro-1',2',3',4'-tetrahydro~ ,21-39 dihydroxypregna-1,4-dieno[16a,17-blnaphthalene-3,20-dione (800 mg) is dissolved in n-butanol 'h916 ~150 ml) by warming. The solution ls cooled to room temperature, cooper acetate hydrate (250 mg) is added and air is buhbled into the solution with sitrring for 30 minutes. Mos-t o the n-butanol is then removed b~ evapora-tion _ vacuo at 40-42C. The concentrate is dlluted with water and extracted with chloroform. The chloroform extracts are combined, washed with a dilute ammonium chloride solution and water, dried over anhydrous magnesium sulfate and evaporated to afford 850 mg of 9-fluoro~
2',3',4'-tetrahydro-11~-hydroxypregna-1,4-dieno[16a,17-b]naphthalene-21-al-3,20-dione.
(This material is characterized spectroscopically.
A TLC examination shows the presence of one major compound, traces of starting material and traces of another impurity, less polar than the starting materlal, and believed to be 9-fluoro-1',2',3',4'-tetrah~dro~ hydroxy-21~21-di-n-butoxy-pregna-1,4-dienol16~,17-b~na~hthalene-3,20 dione).
The above crude mlxture (840 mg) is dissolved in a mixture of dry n-butanol (20 ml) and dichloromethane (50 ml). Acetic acid (0.8 ml), potassium cyanide (200 mg)and active manganese dioxide (2.0 g) are added and the mixture is stirred at room temperature for 60 hours. (A
shorter reaction time would he adequate). The mixture is then filtered through a bed of diatomaceous earth. The solids are washed with chloroform, the filtrate and the washings are ,.. , ~
-17~ K57n combined, washed with water, dried over anhydrous magnesium sulfate and evaporated to afford the crude product as a gum. From this the major component is isolated by preparative TLC (four, 5 2.Omm silica gel plates developed with chloro-form-ethyl acetate 1:1) and identified as the title compound (487 mg). One crystallization from ethyl acetate gives 381 mg of the analytical specimen of the title compound, meltiny point 245-246C with consistent spectral data.
Anal. Calc d for C33H3gFO5 C, 74-13;
~I, 7.35;
F, 3.55 Found: C, 74.37;
H, 7.41;
; F, 3.46 Example 4 9-Fluoro-1',2',3',4'-tetrahydro-11~-hydroxy~3 _ dioxopregna 1,4-dieno[16a,17-b]naphthalene-21-oic acid, l,l-dimethxleth~1 ester A) 9-Fluoro-1',2',3',4'-tetrahydro-ll~h~droxy-3,20-dioxo~regna-1,4-dieno~16a,17-blnaphthalene-21-oic acid ~ solu-tion o~ luoro-1',2',3',4'-tetrahydro-11~-hydroxypregna-1,4-dieno[16~, 17-b]naphthalene-21-al-3,20-dione (3.ny, see Example 1) in a mixture of dichloromethane (150 ml) and tetrahydrofuran (150 ml) containing acetic acid (3.0 ml) and water (4.0 ml) is stirred with activated manganese dioxide (6.0g) and potassium cyanide (700 mg) for 20 hours. The mixture is then filtered and the solids are washed with warm chloroform-methanol ~7:3~. The filtrate and the washings are combined and evaporated in v~cuo.
The residue is washed with wa-ter, dried, purified by chromatogra~hy, crvstalliz~d fr~m methanol~chIoroform to afford the title compound, melting point 280-281C (dec.).
B) 9-Fluoro-1',2',3',4'-tetrahydro~ hydroxy-3,20~dioxopregna-1,4-dieno[1_~,17-b]naphthalene 21-oic acid, l,l-dimet ylethyl -ester To a suspension of g-fluoro-1',2',3',4'-tetrahydro~ -hydroxy-3,20-dioxopregna-1,4-dieno 116a,17-b]naphthalene-21-oic acid(325 mg.) in dry dioxane (60 ml) containing sulfuric acid-phosphoric acid catalyst (0.4 ml.; prepared by the addition of the calculated amount of phosphorous pentoxide to 96~ sulfuric acid to react with all of the water) in a pressure reaction vessel is passed a stream of isobutylene (until about 6 ml is added). The reaction vessel is closed and maintained at ambient temperature for 30 hours with stirri.ng. The mixture is poured into a solution of sodium ace-tate hydrate (5.0g) in water (500 ml) and extracted successi.vely with chloroform and ethyl acetate. The extracts are washed with brine, combined, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel to afford 145 mg. of the -title compound, melting point 293-296C (dec., discoloration starts from about 275~C) after crystalliza-tion from acetone-hexane.
,. . .
Example 5 ~-Fluoro-1',2',3',4'-tetrahydro~ -hydroxy-3, 20-dioxopre~na-1,4-dienol16a,17-~]naphthalen-21-oic acid, 2,2-dimethylpropyl ester A solution of 9-fluoro-1',2',3',4'-tetrahydro-ll~-hydroxy-3,20-dioxopregna-1,4-dieno~l6a,17-b3naphthalene-21-oic acid, methyl ; ester in dry dioxane (20 ml, distilled over sodium) and dry pyridine (15 ml) is refluxed with neopentYl alcohol (2.2 g) and sodium cyanide (100 mg) under a nitrogen atmosphere for 18 hours. The resulting solution is evaporated ln vacuo and the residue is dissolved in chloroform. The chloroform solution is washed with dilute sodium chloride solution and water, dried over anhydrous sodium sulfate and evaporated ln vacuoO The residue is dissolved in chloroform-hexane (9:1) and ~ 20 chromatographed on a 35 g-silica gel column.
; Elution with chloroform-hexane (9:1) gives 540 mg of material. Crystallization :Erom acetone-hexane give~ 460 mg of an analytical specimen of the title compound, melting point 329-331C (dec.).
Anal. Calc d for C34 41 5 ; H, 7.53;
F, 3.46.
Found: C,- 74.39;
H, 7.73;
F, 3.37.
_20- K570 Example 6 9-Fluoro~ -hydroxy-3,20-dioxopregna-1,4-dieno-[16~!17-d]cyclohexen-21-oic acid meth 1 ester A solution of 1.2 g of 9-fluoro-11~,21-dihydroxypregna-1,4-dieno~16a,17-d]cyclohexene-3,20-dione and 3no mg of copper acetate in 150 ml of methanol is stirred at room temperature for 1 hour while a stream of air is hubbled through the solution. The solvent is evaporated in vacuo at 30C. The residue is diluted with water and extracted with chloroform, ana then, ethyl acetate. The chloroform solution and ethyl acetate solution are washed with aqueous ammonium chloride solution (ln~ and water, dried over anhydrous sodium sulfate, evaporated in vacuo and combined to give 1.3 g of a solid. The NMR
spectrum of the solid shows that it is an approxi-mately equimolar mixture of the 21-aldehyde and 21-dimethylacetal derivatives of the starting steroid.
The solid product of the above reaction (1.3 g) is stirred in a mixture of 50 ml dry me-thanol and 50 ml dry dichloromethane at room temperature for about 16 hours with activated manganese dioxide (2.0g), glacial acetic acid (1.0 ml) and potassium cyanide (2~0 mg) The suspension is filtered through a bed of Hyflo and washed with chloroform.
The filtrate and washings are comhined, washed with water and dried over anhydrous magnesium sulfate.
; 30 The solvent is evaporated in vacuo to give 1.1 g of a solid. Th~ is dissolved in chloroform and chromatographed on a 35 g-silica gel column.
Elution with chloroform gives 93~ mg of material.
* Trade Mark .
~2~
Crystallization from acetone-hexane gives 650 my of the title compound, melting point 256-258C, with consistent spectra data.
n ysis Calc d for C28H31FO5: C, 70.57;
H, 7.06;
F, 4.29 Found: C, 70O66;
H, 7.11;
F, 4.02 Example _ 9-Fluoro~ -hydroxv-3,20-dioxopregna-1,4-dieno-.... .. ..
[16a,17-d~cyclohexen-21-oic acid, l-meth~le-thyl ester A solution of 480 mg of 9-fluoro-11~-hydrox~-3,2~-dioxopregna-1,4-dieno[16a,17-d]
cyclohexen-21-oic acid, methyl ester (see Example 1) and 85 mg of sodium cyanide in 65 ml of dry isopropyl alcohol is stirred under a nitrogen atmosphere at 100C for about 16 hours.
The resulting solution is evaporated in vacuo and the residue is dissolved in chloroform ancl washed with 25 ml of water. The aqueous layer is saturated with sodium chloride and ex-tracted with chloroform. The chloroform solutions are z5 combined, dried over anhydrous sodium sulfate and evaporated ln acuo. The residue is dissolved in chloroform-hexane (7:3) and chromatographed on a 25 g-silica gel column.
Elution with chloro~orm-hexane (7:3)gives 370 mg of material. Cr~stallization from acetone~
hexane gives 3no mg of the title compound, melting ~z~
point 226-228C, with consistent spec~ral data.
~nalysis calc'd. for C28ll35FO5 H, 7.50;
F, 4.04 Found: C, 71.47;
H, 7.44;
F, 3.82 Example 8 . 9-Fluoro-ll~-h~droxy-3,20-dioxopregna-1,4-dieno-~.6a,17-d]cyclohexen-21- ic aci_, b~tyl ester A mixture of 1.0 g of 9-fluoro-11~,21-dihydroxypregna-1,4-dieno[16~,17-d]cyclohexene-3,20-dione.and 250 mg of copper acetate in 50 ml of dichloromethane and 30 ml of n-butanol is ; 15 stirred at room temperature for 1 hour while a slow stream of air is bubbled through the solution.
Since the rate of oxidation is extremely 510w, the dichloromethane is evaporated and replaced with 50 ml of n-butanol. Another 200 mg of copper acetate is added and the reac-tion is continued for 1.5 hour when the starting material disappears. The sol~ent is then evaporated .ln vacuo at 35-40C and the residue is diluted with 200 ml of water and extracted with dichloromethane, and then ethyl acetate. The dichloromethane solution and ethyl acetate solution are washed with ammonium chloride solution (10%) and water, combined, dried over anhydrous sodium sulfate and evaporated 1n vacuo to.give 1.2 g of solid. The NMR spectrum of the ,, _ solid shows that it is an approximately equimolar mixture of the 21-aldehyde and 21-di-n-butylacetal derivatives of the starting steroid.
The solid product of the above reaction (1.2 g) is dissolved in 50 ml of dry dichloro-methane and 30 ml of dry n-hutanol and stirred at room temperature for ahout 16 hours with 2.0 g of activated manganese dioxide, 1.0 ml of glacial acetic acid and 200 mg of potassium cyanide. A dry calcium chloride tube is attached to the flask to avoid contact with moisture.
After 20 hours another 2.0 g of activated manganese dioxide and 200 mg of potassi~n cyanide are added. The suspension is stirred at room 1~ temperature for 7 hours, filtered through a bed of Hyflo, and washed thoroughly with dichloro-methane. The filtrate and washings are combined and washed with a saturated sodium ~icarbonate solution and water, dried over anh~drous sodiwn ~o sulfate ana evaporated ln vacuo. The title compound in the residue cannot be success~ully separated from impurities on precoated silica gel TLC plate. It can, however, be successully purified on E. Merck precoated silica gel TLC
plate (2 mm, 2.5:97.5 methanol~chloroform) to yive 400 mg of a foam Crystallization from ethyl acetate-hexane gives 330 mg of the title compound, melting point 203-209C, with consistent spectra data Analysis calcld for C29H37FO5: C, 71.87;
H, 7.70;
F, 3.92 Found: C, 71.98 H, 7.73 F, 3.62 Example 9 9-Fluoro~llo~Ao~ L~ thYl-3~2o-diox~E~regna~1,4-dieno~16a,17-d]cyclohexen-21-oic acid, met~l ester A solution of 4.9 g of q-fluoro-11~,21-dihydroxy-1',2'-dimethyl-3 r 20~dioxopregna-1,4-dieno[16a,17-d~ c~clohexene and 1.1 g of copper acetate in 800 ml of methanol is reacted with air following the procedure described in Example 1 (first paragraph) to yield 5.0 g of an approximately equimolar mixture of the 21-; aldehyde and 21-dimethylacetal derlvatives of the starting s-teroid~
~ The solid product of the above reaction (4.5 g) is stlrred in a mlxture o~ 250 ml dry methanol and 250 ml dry dichloromethane at room temperature for abouk 16 hours under a nitrogen atmosphere with activated manganese dioxide (7.0 g), glacial acetlc acid (4.0 ml) and potassium cyanide (700 mg). The resulting suspenslon is filtered through a bed of diatomaceous earth and washed with chloroform-methanol (~
The flltrate and washlngs are comblned and evaporated ln vacuo to give 5O6 g of a solld.
This is dissolved in chloroform-hexane (9:1) and chromatographed on a 100 g silica gel column.
Elution with chloroform-hexane (9:1) yields
4.2 g of material, 1.5 g of whlch ls crystallized from acetone-hexane to give 900 mg of an analytical specimen of the title compound, melting point 256-258C.
Analysis Calc'd for C28H35FO5: C, 71.46;
H, 7.50;
F, 4~04 Found: C, 71.38;
H, 7.50;
F, 3.95 Example 10 9-Fluoro-~ hydroxy-ll~2l-dimethyl-3~2o-d-loxo-pregna-1,4-dieno[16a,17-d]cyclohexen~21-oic acid, ethyl ester A? 9-Fluoro-ll~-hydrox~-1' ! 2'-dimethy~-3,20-dioxop_e~na,l,4-dieno[16 _17-d]cyclohexen-21-oic acid ~ solution of 9-fluoro~ -hydroxy-1',2', dimethyl--3,20-dioxopreyna-1,4-dieno[16a,17-d]
cyclohexen-21-oic acid, methyl ester (2.5 g) in a mixture of methanol (110 ml) and tetrahydro:Euran (200 ~1) is stirred with a solution of potassium hydroxide (640 mg) in water (10 ml) for 1.0 hour under a nitrogen atmosphereO The reaction mixture is then acidified with 5% hydrochloric acid and is evaporated in vacuo. The resulting slurry is mixed with water and filtered to afford 700 mg of the title 3~ compound, melting point 234-238C.
The filtrate is evaporated in vacuo and washed with chloroform-methanol (4:1). The solvents are evaporated to afford 1.4 g of the hydrated form of the title compound, melting point 215-240oc.
~26_ K570 B) 9-Fluoro~ hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[16a,17-d] cyclohexen-21-oic acid, ethyl ester To a suspension of 235 mg of 9-fluoro-11~-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno [16a,17-d]cyclohexen-21-oic acid in 5.0 ml of dry dichloromethane is added successively, 0.5 ml of triethylamine and 0.068 ml of pivaloyl chloride. After the resulting solution is stirred at room temperature for 15 minutes, 0.116 ml of absolute ethanol is added. After 3.0 hours, the mixt~re is acidified with 50%
hydrochloric acidj poured into water and extracted with çhloroform. The chloroform extracts are combined, washed with water, dried over anhydrous magnesium sulfate, and evaporated.
The residue is subjected to preparative thin-layer chromatography to isolate 97 mg of the title compound, melting point 198-200C.
Exam~le 11 9-Fluoro-ll~-hydroxy-1',2'-dimethyl-3L~ o-pregna-1,4-dieno [16a,17-dlcyclohexen-21-oic acid, l,l-dim ~ ester A solution of 700 mg of 9-fluoro-11~-hydroxy-1',2'-dimethyl-3,20~dioxopregna-1,4-dieno ~16a,I7-d]cyclohexen-21-oic-acid (see Example lOA) in 60 ml of dry dioxane containing 12 ml of isobutylene and 0.7 ml of a sulfuric acid/
phosphoric acid catalyst (prepared hy adding phosphorous pentoxide to 96% sulfuric acid) is maintained in a pressure reaction vessel at room temperature for 24 hours. A stream of dry nitrogen is then passed through the solution to remove the excess isokutylene and the mixture is poured into a saturated sodium bicarbonate solution. The steroid is isolated by ex-traction with chloroform and the chloroform solution is washed with water, dried over anhydrous magnesium sulfate and the solvents are evaporated. The residue (7~0 mg) is subjected to chromatography on a column of silica yel to isolate 500 mg of the title compound, melting pount 2~9-21~C after crystal-lization from acetone hexane.
Example 12 9-Fluoro-~ hydroxy-3t2o-dioxopregna-lt4-dien [16a,17-d]cyclohexen-?1-oic acid, 2,2-dimeth~lJ~o~
_ . .
ester A solution of 9-fluoro~ hydroxy-3,2n-dioxopregna-1,4-dieno-[16a,17-d]cyclohexen-21-oic acid, methyl ester (25 mg) in dry dioxane (2,0 ml) containing dry neopentyl alcohol (400 mg) and sodium cyanide (5.0 my) is refluxed under anhydrous conditions for 2. n hours. The mixture is then cooled, aclded to water, and extracted with chloroform. The ch].oroform extract is washed with water, dried over anhydrous maynesium sulfate, evaporated and the residue is crystallized from ethyl acetate-chloroform to afford 23 mg. of the title compound, melting point 288C (dec., discoloration starts ~efore melting point)~
9 ~ ~ K570 ~xample ~3 9-Fluoro-1',2i,3',4'-tetrahydro-llB-hydrox~ 3,20-dioxopregna-1,4-dieno[16a~,17-b]naphthalene-21-oic acid,methyl ester ~ ... . .
A) 9-Fluoro-ll~-hydroxy-3,20-dioxopregna-1,4,16-triene-21-carboxaldehyde and 9-fluoro-11~-hydroxy-21-dimethoxypregna-1,4,16-triene-3, 20~dione , A solution of 9-fluoro~ ,21-dihydroxypregna-- 1,4,16-triene-3,20-dione (1.7gj is dissolved in methanol (30Oml) by warming and the solution is cooled to room temperature. Copper ace-tate (lOOmg) is added and a stream of air is passed into the solution under stirr1ng. In about 20 minutes the starting material disappears to give less polar compounds as indicated by thin layer chromatography. The solution is then evaporated ln vacuo, -the residual solid is washed successively with a dilute ammonium chloride solution and water and is dried to a~ford an essentially equimolar mixture (1.9g) of the title aldehyde (as iks hydrate) and the title acetal as indica-ted by the NMR spectrum. When dried in vacuo (125-130C, 005mm of Hg) for 2.0 hours, this material is converted into an essentailly equimolar mixture (1.77g~ of the title aldehyde and acetal as shown by NMR and IR spectra.
,.~ ,~
11 4Z ~ 1 ~ K570 s) 9-Fluoro-llB-hydroxy-3,20-dio o~re~na-1,4, 16~trieno-21-olc acld, met~yl ester To a stirred solution oE the mixture of aldehyde and acetal prepared in part A (1.75g), in a mixture of anhydrous dichloromethane (lOOml) and anhydrous methanol (20ml) is added successively activated manganese dioxide (4.0g), potassium cyanide (500mg) and glacial acetic acid (0.5ml). In less than 1.0 hour, the starting mat~rials disappear to give essentially a single less polar compound as indicated by thin layer chromatography. The reaction mixture is filtered through a ~ed of 1~ diatornaceous earth and the fi.lter cake is washed with several small portions of a warm mixture of dichloromethane~methanol. The iltrate and the washings are combined and evaporated to a solid residue which is washed with water and dried. Crystallization of the resulting material from methanol-dichloromethane (with evaporative removal of dichloromethane) yields 1.4g oE khe title compound, melting point 28~-286C.
C) 9-Fluoro-1',2',3',4'-tetrahydro~ h~ydroxy-3~
20-dioxopregna-1,4-dieno[16a,17-b]naph-thalene-. . _ . _ . . .
21-oic acid, methyl:ester A solution of 9-fluoro~ -hydroxy-3, 20-dioxopregna-1,4,16-trieno-21-oic acid, ~42916 K570 methyl ester (lOOmg) in benzocyclobutene (5.Oml) containing 4,4'-thiobis-6-t-butyl-m-cresol (6.Omg) is reEluxed under an atmos-phere o~ nitrogen for 10 hours; a solid separates from the solution. The unreacted ben~ocyclobutene is recovered by vacuum distillation and the pot residue is crystallized from methanol-dichlorome-thane (by evaporative removal of the dichloromethane) to yield the title compound, melting point 325-326C
(discoloration starts from about 295 C).
Exam~le 14 15 9-Fluoro~ hydroxy-3,20-dioxopre~na-1,4,16-trieno 21-oic acid .
A solution of 9-Eluoro-ll~-hydroxy-3,20-dioxopregna-1,4,16-trieno-21-oic acid, methyl ester (lOOmg; see Example lB) in a mixture of methanol (15ml) and tetrahydrofuran tl5ml) is stirred with 3~ sodium hydroxide (l.Oml) under a nitroyen atmosphere for 2.0 hours. The mixture i.s then acidified with 5% hydrochloric acid and evaporated to a residue. The residue is washed with water and crystallized from chloroform-methanol to yield the title compound. This material turns black when heated to 400C, but does not melt.
The steroid of this Example can be esterified using conventional techniques and then reacted with a benzocyclobutene as described in Example 13C
to yield a product of formula I.
~31-~ 5 9-Fluoro~ -hydroxy-1 , 2'-dimethyl-3,20-dioxopr--egna-1,4-dieno[16~,_17-d]cyclohexene-21-oic acid, n-butyl ester A) 9-Fluoro-113-hydroxy-3L20~ opre~na-1,4,16-triene-21-carboxaldeh~e and 9-fluoro-11~-hydroxy-2l-dimethoxy~vreqn~a-l~ 4 L 16-triene-3 20-dione A solution of 9-fluoro-ll~J21-dihydroxypregna-1-,4,16-triene-3,20-dione (1.7g) is dissolved in - methanol (300ml) by warming and the solution is cooled to room temperature. Copper acetate (lOOmg) is added and a stream of air is passed into the solution under stirring. In about 20 minutes the startiny material disappears to give less polar compounds as indicated by thin layax chromatography. The solution is then evaporated ln vacuo, the residual solid is washed successively with a dilute ammonium chloride solution and water and i5 dried to afford an essentially equimolar mixkure (1.9g) oE the title aldehyde (as its hydrate) and the title acetal as indicated by the ~R spectrum. When dried ln vacuo (125-130C, 0.5mm of H~) for 2.0 hours, this material is converted into an essentially equimolar mixture (1.77g) of the title aldehyde and acetal as shown by NMR and IR spectra.
~1.4 Z9 ~ ~ K570 B) 9-Fluoro~ -hydroxy-3,20-dioxopregna-1,4 16-trieno-21-oic acid, me-thyl ester , To a stirred solution of the mix-ture of ~d~hyde and acetal prepared in part A, in a mix-ture of anhydrous dichloromethane (lOOml) and anhydrous methanol (20ml) ls added successively activated manganese dioxide (4.0g), potassium c~anide (500mg) and glacial acetic acid (0.5ml). In less than 1.0 hour, the starting materials disappear to give essentially a single less polar compound as indicated by thin layer chromatography. The reaction mixture is filtered through a bed of diatomaceous earth and the filter cake is washed with several small portions of a warm mixture of dichloromethane-methanol. The filtrate and the washings are combined and evaporated to a solid residue which is washed with water and dried.
Crystallization of the resulting material from methanol-dichloromethane (with evaporative removal of dichlorornethane) yields 1.4g of the title compound, melting point 284-286C.
C) ll~-~Acetyloxy)-9~f _ oro-3,20-dioxo~re~na-~5 1,4,16-trieno-21-oic acid! methyl f~ster A solution of 9-fluoro-11~-hydroxy-3,20-dioxopregna-1,4,16-trieno-21-oic acid, methyl ester (400mg) in a mixture of glac~ial acetic acid ~9.Oml) and acetic anhydride ~9 n Oml) containing p-toluenesulfonic acid (200mg) is stirred at room temperature for 24 hours. Sodium acetate (300mg) is added and the mixture is pour2d into ice water ~200ml) with stirring.
The solid that separates is isolated by filtration, washed with water and dried to yield 400mg of the title compound that is contaminated with only trace amount impurities as judged by thin layer chromatography. Crystallization of this material from ethyl acetate-hexane yields 350mg of the title compound, melting point 235-236C.
D) ll~-(Acetyloxy)-9-fluoro-1'~ 2'-dimethyl-3,20-dioxopregna-1,4-dieno-[16~, 17 d]cyclohexen-21-oic acid, methyl ester To a stirred solution of ll~-(acetyloxy)-9-fluoro-3 t 20-dioxopregna 1,4,16-trieno-21-oic acid, methyl ester (320mg) in anhydrous dichloromethane (25ml) containing aluminum chloride (lOOmg) is added 2,3-dimethyl-1,3-butadiene (0.25~1).
The mixture is stirred at room -temperature for 1.5 hour, poured into water and extractéd wl-th dichloromethane. The dichloromethane extract is washed with ~later, dried over anhydrous magnesium sulfate and evaporated to a residue (300mg). This is subjected to chromatography on a column of silica gel (lOg) to isolate the title compound (265mg). Crystallization from ethyl acetate-hexane gives need]es (160mg), melting point 172-173C.
~34-E) 9-Fluoro-ll~-hydroxy-1',2'-d1methyl-3,20-dioxopre~na-1,4-dieno~16~,17-d]cyclohexen-21-oic acid A solution o~ -(acetyloxy)-9-fluoro-1', 2'-dimethyl-3,20-dioxopregna-1,4-dieno[16~,17-d]
cyclohexen-21-oic acid, methyl ester (235mg) in a mixture of 90% methanol (lOOml) and tetrahydrofuran (lOml) containing 3M sodium hydroxide (2.Oml) is stirred under an atmosphere of nitrogen in a bath at 60-70C for 2-3 hours. The mixture is acidified with the minimum amount of 5~ hydrochloric acid and evaporated in vacuo. The residue is worked up with water and dried to yield 195mg of the title compound. Crystalliaation from a mixture of chloroform-methanol gives the analytical s~ecimen of the title compound, melting point 236-239C.
F) 9-Fluoro-11~-hydroxy-1',2'-dimethyl-3,20-dioxopre~na-1,4-dieno[16~tl7_d]c~clohexen-21-oic acld, n-butyl ester.
To a solution of 9-fluoro~ -hydroxy-1', 2'-dimethyl-3,20-dioxopregna-1,4~dieno[16~tl7-d]
cyclohexen-21-oic acid (175mg) in dichloromethane (40ml) containing a few drops of methanol is added an excess of an ethereal solution of diazobutane.
After 5 minutes, the excess diaxobutane is destroyed by the addition of a few drops of acetic acid.
The solution is evaporated to dryness and the residue is crystallized from acetone-hexane to yield 127mg of the title compound melting point 209-~11C.
~z~
Example 16 16~)-9-Fluoro-1~2',3'~4'-tetrahydro-ll-hydroxy ... . _ _ .
3,20-dioxopregna-1,4-dienol16,17-b]naphthalen-21-oic _ _ . . .. .. _ acid, octyl ester A solution of 500 mg (0.96 mmole) of 11~,16~-9-fluoro-1',2',3',4'-tetra-11-hydroxy-3,20-dioxopregna-1,4-dieno[16,17-b]naphthalen-21-oic acid, l-methylethyl ester and 40 mg of sodium cyanide in 40 ml of dry octanol-l (distilled over calcium hydride) was stirred at 130 under nitrogen atmosphere for 1.5 hour. The resulting solution was evaporated in vacuo. The residue was dissolved in dichloromethane, washed wi-th water, dried over anhydrous Na2SO4 and evaporated in vacuo to give a residue which was dissolved in chloroform-hexane (7:3) and chromatographed on a 20g silica gel column. Elution with chloroform-hexane (7:3) gave 485 mg (97%) of product. Crystallization from acetone-hexane gave 370 my (74%) of product, m.p.
215-216.
Anal~ Calcd- ~or c37H47FO5: C~ 75-22; El~8-02 F, 3,22 Found: C,75.34; H,8.23;
F,3.21
Analysis Calc'd for C28H35FO5: C, 71.46;
H, 7.50;
F, 4~04 Found: C, 71.38;
H, 7.50;
F, 3.95 Example 10 9-Fluoro-~ hydroxy-ll~2l-dimethyl-3~2o-d-loxo-pregna-1,4-dieno[16a,17-d]cyclohexen~21-oic acid, ethyl ester A? 9-Fluoro-ll~-hydrox~-1' ! 2'-dimethy~-3,20-dioxop_e~na,l,4-dieno[16 _17-d]cyclohexen-21-oic acid ~ solution of 9-fluoro~ -hydroxy-1',2', dimethyl--3,20-dioxopreyna-1,4-dieno[16a,17-d]
cyclohexen-21-oic acid, methyl ester (2.5 g) in a mixture of methanol (110 ml) and tetrahydro:Euran (200 ~1) is stirred with a solution of potassium hydroxide (640 mg) in water (10 ml) for 1.0 hour under a nitrogen atmosphereO The reaction mixture is then acidified with 5% hydrochloric acid and is evaporated in vacuo. The resulting slurry is mixed with water and filtered to afford 700 mg of the title 3~ compound, melting point 234-238C.
The filtrate is evaporated in vacuo and washed with chloroform-methanol (4:1). The solvents are evaporated to afford 1.4 g of the hydrated form of the title compound, melting point 215-240oc.
~26_ K570 B) 9-Fluoro~ hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[16a,17-d] cyclohexen-21-oic acid, ethyl ester To a suspension of 235 mg of 9-fluoro-11~-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno [16a,17-d]cyclohexen-21-oic acid in 5.0 ml of dry dichloromethane is added successively, 0.5 ml of triethylamine and 0.068 ml of pivaloyl chloride. After the resulting solution is stirred at room temperature for 15 minutes, 0.116 ml of absolute ethanol is added. After 3.0 hours, the mixt~re is acidified with 50%
hydrochloric acidj poured into water and extracted with çhloroform. The chloroform extracts are combined, washed with water, dried over anhydrous magnesium sulfate, and evaporated.
The residue is subjected to preparative thin-layer chromatography to isolate 97 mg of the title compound, melting point 198-200C.
Exam~le 11 9-Fluoro-ll~-hydroxy-1',2'-dimethyl-3L~ o-pregna-1,4-dieno [16a,17-dlcyclohexen-21-oic acid, l,l-dim ~ ester A solution of 700 mg of 9-fluoro-11~-hydroxy-1',2'-dimethyl-3,20~dioxopregna-1,4-dieno ~16a,I7-d]cyclohexen-21-oic-acid (see Example lOA) in 60 ml of dry dioxane containing 12 ml of isobutylene and 0.7 ml of a sulfuric acid/
phosphoric acid catalyst (prepared hy adding phosphorous pentoxide to 96% sulfuric acid) is maintained in a pressure reaction vessel at room temperature for 24 hours. A stream of dry nitrogen is then passed through the solution to remove the excess isokutylene and the mixture is poured into a saturated sodium bicarbonate solution. The steroid is isolated by ex-traction with chloroform and the chloroform solution is washed with water, dried over anhydrous magnesium sulfate and the solvents are evaporated. The residue (7~0 mg) is subjected to chromatography on a column of silica yel to isolate 500 mg of the title compound, melting pount 2~9-21~C after crystal-lization from acetone hexane.
Example 12 9-Fluoro-~ hydroxy-3t2o-dioxopregna-lt4-dien [16a,17-d]cyclohexen-?1-oic acid, 2,2-dimeth~lJ~o~
_ . .
ester A solution of 9-fluoro~ hydroxy-3,2n-dioxopregna-1,4-dieno-[16a,17-d]cyclohexen-21-oic acid, methyl ester (25 mg) in dry dioxane (2,0 ml) containing dry neopentyl alcohol (400 mg) and sodium cyanide (5.0 my) is refluxed under anhydrous conditions for 2. n hours. The mixture is then cooled, aclded to water, and extracted with chloroform. The ch].oroform extract is washed with water, dried over anhydrous maynesium sulfate, evaporated and the residue is crystallized from ethyl acetate-chloroform to afford 23 mg. of the title compound, melting point 288C (dec., discoloration starts ~efore melting point)~
9 ~ ~ K570 ~xample ~3 9-Fluoro-1',2i,3',4'-tetrahydro-llB-hydrox~ 3,20-dioxopregna-1,4-dieno[16a~,17-b]naphthalene-21-oic acid,methyl ester ~ ... . .
A) 9-Fluoro-ll~-hydroxy-3,20-dioxopregna-1,4,16-triene-21-carboxaldehyde and 9-fluoro-11~-hydroxy-21-dimethoxypregna-1,4,16-triene-3, 20~dione , A solution of 9-fluoro~ ,21-dihydroxypregna-- 1,4,16-triene-3,20-dione (1.7gj is dissolved in methanol (30Oml) by warming and the solution is cooled to room temperature. Copper ace-tate (lOOmg) is added and a stream of air is passed into the solution under stirr1ng. In about 20 minutes the starting material disappears to give less polar compounds as indicated by thin layer chromatography. The solution is then evaporated ln vacuo, -the residual solid is washed successively with a dilute ammonium chloride solution and water and is dried to a~ford an essentially equimolar mixture (1.9g) of the title aldehyde (as iks hydrate) and the title acetal as indica-ted by the NMR spectrum. When dried in vacuo (125-130C, 005mm of Hg) for 2.0 hours, this material is converted into an essentailly equimolar mixture (1.77g~ of the title aldehyde and acetal as shown by NMR and IR spectra.
,.~ ,~
11 4Z ~ 1 ~ K570 s) 9-Fluoro-llB-hydroxy-3,20-dio o~re~na-1,4, 16~trieno-21-olc acld, met~yl ester To a stirred solution oE the mixture of aldehyde and acetal prepared in part A (1.75g), in a mixture of anhydrous dichloromethane (lOOml) and anhydrous methanol (20ml) is added successively activated manganese dioxide (4.0g), potassium cyanide (500mg) and glacial acetic acid (0.5ml). In less than 1.0 hour, the starting mat~rials disappear to give essentially a single less polar compound as indicated by thin layer chromatography. The reaction mixture is filtered through a ~ed of 1~ diatornaceous earth and the fi.lter cake is washed with several small portions of a warm mixture of dichloromethane~methanol. The iltrate and the washings are combined and evaporated to a solid residue which is washed with water and dried. Crystallization of the resulting material from methanol-dichloromethane (with evaporative removal of dichloromethane) yields 1.4g oE khe title compound, melting point 28~-286C.
C) 9-Fluoro-1',2',3',4'-tetrahydro~ h~ydroxy-3~
20-dioxopregna-1,4-dieno[16a,17-b]naph-thalene-. . _ . _ . . .
21-oic acid, methyl:ester A solution of 9-fluoro~ -hydroxy-3, 20-dioxopregna-1,4,16-trieno-21-oic acid, ~42916 K570 methyl ester (lOOmg) in benzocyclobutene (5.Oml) containing 4,4'-thiobis-6-t-butyl-m-cresol (6.Omg) is reEluxed under an atmos-phere o~ nitrogen for 10 hours; a solid separates from the solution. The unreacted ben~ocyclobutene is recovered by vacuum distillation and the pot residue is crystallized from methanol-dichlorome-thane (by evaporative removal of the dichloromethane) to yield the title compound, melting point 325-326C
(discoloration starts from about 295 C).
Exam~le 14 15 9-Fluoro~ hydroxy-3,20-dioxopre~na-1,4,16-trieno 21-oic acid .
A solution of 9-Eluoro-ll~-hydroxy-3,20-dioxopregna-1,4,16-trieno-21-oic acid, methyl ester (lOOmg; see Example lB) in a mixture of methanol (15ml) and tetrahydrofuran tl5ml) is stirred with 3~ sodium hydroxide (l.Oml) under a nitroyen atmosphere for 2.0 hours. The mixture i.s then acidified with 5% hydrochloric acid and evaporated to a residue. The residue is washed with water and crystallized from chloroform-methanol to yield the title compound. This material turns black when heated to 400C, but does not melt.
The steroid of this Example can be esterified using conventional techniques and then reacted with a benzocyclobutene as described in Example 13C
to yield a product of formula I.
~31-~ 5 9-Fluoro~ -hydroxy-1 , 2'-dimethyl-3,20-dioxopr--egna-1,4-dieno[16~,_17-d]cyclohexene-21-oic acid, n-butyl ester A) 9-Fluoro-113-hydroxy-3L20~ opre~na-1,4,16-triene-21-carboxaldeh~e and 9-fluoro-11~-hydroxy-2l-dimethoxy~vreqn~a-l~ 4 L 16-triene-3 20-dione A solution of 9-fluoro-ll~J21-dihydroxypregna-1-,4,16-triene-3,20-dione (1.7g) is dissolved in - methanol (300ml) by warming and the solution is cooled to room temperature. Copper acetate (lOOmg) is added and a stream of air is passed into the solution under stirring. In about 20 minutes the startiny material disappears to give less polar compounds as indicated by thin layax chromatography. The solution is then evaporated ln vacuo, the residual solid is washed successively with a dilute ammonium chloride solution and water and i5 dried to afford an essentially equimolar mixkure (1.9g) oE the title aldehyde (as its hydrate) and the title acetal as indicated by the ~R spectrum. When dried ln vacuo (125-130C, 0.5mm of H~) for 2.0 hours, this material is converted into an essentially equimolar mixture (1.77g) of the title aldehyde and acetal as shown by NMR and IR spectra.
~1.4 Z9 ~ ~ K570 B) 9-Fluoro~ -hydroxy-3,20-dioxopregna-1,4 16-trieno-21-oic acid, me-thyl ester , To a stirred solution of the mix-ture of ~d~hyde and acetal prepared in part A, in a mix-ture of anhydrous dichloromethane (lOOml) and anhydrous methanol (20ml) ls added successively activated manganese dioxide (4.0g), potassium c~anide (500mg) and glacial acetic acid (0.5ml). In less than 1.0 hour, the starting materials disappear to give essentially a single less polar compound as indicated by thin layer chromatography. The reaction mixture is filtered through a bed of diatomaceous earth and the filter cake is washed with several small portions of a warm mixture of dichloromethane-methanol. The filtrate and the washings are combined and evaporated to a solid residue which is washed with water and dried.
Crystallization of the resulting material from methanol-dichloromethane (with evaporative removal of dichlorornethane) yields 1.4g of the title compound, melting point 284-286C.
C) ll~-~Acetyloxy)-9~f _ oro-3,20-dioxo~re~na-~5 1,4,16-trieno-21-oic acid! methyl f~ster A solution of 9-fluoro-11~-hydroxy-3,20-dioxopregna-1,4,16-trieno-21-oic acid, methyl ester (400mg) in a mixture of glac~ial acetic acid ~9.Oml) and acetic anhydride ~9 n Oml) containing p-toluenesulfonic acid (200mg) is stirred at room temperature for 24 hours. Sodium acetate (300mg) is added and the mixture is pour2d into ice water ~200ml) with stirring.
The solid that separates is isolated by filtration, washed with water and dried to yield 400mg of the title compound that is contaminated with only trace amount impurities as judged by thin layer chromatography. Crystallization of this material from ethyl acetate-hexane yields 350mg of the title compound, melting point 235-236C.
D) ll~-(Acetyloxy)-9-fluoro-1'~ 2'-dimethyl-3,20-dioxopregna-1,4-dieno-[16~, 17 d]cyclohexen-21-oic acid, methyl ester To a stirred solution of ll~-(acetyloxy)-9-fluoro-3 t 20-dioxopregna 1,4,16-trieno-21-oic acid, methyl ester (320mg) in anhydrous dichloromethane (25ml) containing aluminum chloride (lOOmg) is added 2,3-dimethyl-1,3-butadiene (0.25~1).
The mixture is stirred at room -temperature for 1.5 hour, poured into water and extractéd wl-th dichloromethane. The dichloromethane extract is washed with ~later, dried over anhydrous magnesium sulfate and evaporated to a residue (300mg). This is subjected to chromatography on a column of silica gel (lOg) to isolate the title compound (265mg). Crystallization from ethyl acetate-hexane gives need]es (160mg), melting point 172-173C.
~34-E) 9-Fluoro-ll~-hydroxy-1',2'-d1methyl-3,20-dioxopre~na-1,4-dieno~16~,17-d]cyclohexen-21-oic acid A solution o~ -(acetyloxy)-9-fluoro-1', 2'-dimethyl-3,20-dioxopregna-1,4-dieno[16~,17-d]
cyclohexen-21-oic acid, methyl ester (235mg) in a mixture of 90% methanol (lOOml) and tetrahydrofuran (lOml) containing 3M sodium hydroxide (2.Oml) is stirred under an atmosphere of nitrogen in a bath at 60-70C for 2-3 hours. The mixture is acidified with the minimum amount of 5~ hydrochloric acid and evaporated in vacuo. The residue is worked up with water and dried to yield 195mg of the title compound. Crystalliaation from a mixture of chloroform-methanol gives the analytical s~ecimen of the title compound, melting point 236-239C.
F) 9-Fluoro-11~-hydroxy-1',2'-dimethyl-3,20-dioxopre~na-1,4-dieno[16~tl7_d]c~clohexen-21-oic acld, n-butyl ester.
To a solution of 9-fluoro~ -hydroxy-1', 2'-dimethyl-3,20-dioxopregna-1,4~dieno[16~tl7-d]
cyclohexen-21-oic acid (175mg) in dichloromethane (40ml) containing a few drops of methanol is added an excess of an ethereal solution of diazobutane.
After 5 minutes, the excess diaxobutane is destroyed by the addition of a few drops of acetic acid.
The solution is evaporated to dryness and the residue is crystallized from acetone-hexane to yield 127mg of the title compound melting point 209-~11C.
~z~
Example 16 16~)-9-Fluoro-1~2',3'~4'-tetrahydro-ll-hydroxy ... . _ _ .
3,20-dioxopregna-1,4-dienol16,17-b]naphthalen-21-oic _ _ . . .. .. _ acid, octyl ester A solution of 500 mg (0.96 mmole) of 11~,16~-9-fluoro-1',2',3',4'-tetra-11-hydroxy-3,20-dioxopregna-1,4-dieno[16,17-b]naphthalen-21-oic acid, l-methylethyl ester and 40 mg of sodium cyanide in 40 ml of dry octanol-l (distilled over calcium hydride) was stirred at 130 under nitrogen atmosphere for 1.5 hour. The resulting solution was evaporated in vacuo. The residue was dissolved in dichloromethane, washed wi-th water, dried over anhydrous Na2SO4 and evaporated in vacuo to give a residue which was dissolved in chloroform-hexane (7:3) and chromatographed on a 20g silica gel column. Elution with chloroform-hexane (7:3) gave 485 mg (97%) of product. Crystallization from acetone-hexane gave 370 my (74%) of product, m.p.
215-216.
Anal~ Calcd- ~or c37H47FO5: C~ 75-22; El~8-02 F, 3,22 Found: C,75.34; H,8.23;
F,3.21
Claims (40)
1. A process for preparing a steroid of the formula and esters thereof, or the 1,2-dehydro derivative thereof, wherein X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or R4 and R5 together are =O; R2 and R3 are the same or different and are hydrogen, alkyl or aryl, or taken together with the double bond to which they are attached, form a benzene ring; R6 and R7 are the same or different and are hydrogen, alkyl, alkoxy, formyl, phenyl or cyano and in addition hydroxy, halogen, carboalkoxy and alkylcarbonyl when R2 and R3 are separate with the proviso that when R6 and R7 are different, one of R6 and R7 is hydrogen; R8 is hydrogen or -CH-R9R10 wherein R9 and R10 are the same or different and are hydrogen or alkyl, characterized by oxidizing the corresponding 21-hydroxysteroid of the formula or by oxidizing the 21-hydroxy group of a steroid of the formula to a 21-carboxylic acid group and then fusing the cyclo-hexane and tetrahydronaphthalene group having the formula in the 16,17-position.
2. A process according to claim 1 wherein R2 and R3 are the same or different and are hydrogen, alkyl or aryl.
3. A process according to claim 1 wherein R2 and R3 taken toyether with the double bond to which they are attached form a benzene ring.
4. A process according to claim 1 wherein R2 and R3 are the same or different and are hydrogen, alkyl or aryl;
R4 is hydrogen and R5 is hydroxy or together R4 and R5 are =O; Y is hydroyen, methyl or fluorine and R6, R7 and R8 are hydrogen.
R4 is hydrogen and R5 is hydroxy or together R4 and R5 are =O; Y is hydroyen, methyl or fluorine and R6, R7 and R8 are hydrogen.
5. A process according to claim 1 wherein R2 and R3 taken together with the double bond to which they are attached form a benzene ring; R4 is hydrogen and R5 is hydroxy or together R4 and R5 are =O; Y is hydrogen, methyl or fluorine and R6, R7 and R8 are hydrogen.
6. A process according to claim 1 wherein X is fluorine and R6, R7 and R8 are hydrogen.
7. A process according to claim 1 wherein R4 is hydroxy, R5 is hydrogen and R6, R7 and R8 are hydrogen.
8. A process according to claim 1 wherein R4 is hydroxy; R5 is hydrogen, R6, R7 and R8 are hydrogen;
and X is hydrogen or fluoroine.
and X is hydrogen or fluoroine.
9. The process in accordance with claim 1 wherein 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b]naphthalene-21-oic acid, methyl ester is produced.
10. The process in accordance with claim 1 wherein 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b]naphthalen-21-oic acid, 1-methylethyl ester is produced.
11. The process in accordance with claim 1 wherein 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b]naphthalen-21-oic acid, butyl ester is produced.
12. The process in accordance with claim 1 wherein 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b]naphthalene-21-oic acid, 1,1-dimethylethyl ester is produced.
13. The process in accordance with claim 1 wherein 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b]naphthalen-21-oic acid, 2,2-dimethylpropyl ester is produced.
14. The process in accordance with claim 1 wherein 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno-[16.alpha.,l7-d]cyclohexen-21-oic acid, methyl ester is produced.
15. The process in accordance with claim 1 wherein 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno-[16.alpha.,17-d]cyclohexen-21-oic acid, 1-methylethyl ester is produced.
16. The process in accordance with claim 1 wherein 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno-[16.alpha.,17-d]cyclohexen-21-oic acid, butyl ester is produced.
17. The process in accordance with claim 1 wherein 9-fluoro-11.beta.-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[l6.alpha.,17-d]cyclohexen-21-oic acid, methyl ester is produced.
18. The process in accordance with claim 1 wherein 9-fluoro-11.beta.-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[l6.alpha.,17-d]cyclohexen-21-oic acid, ethyl ester is produced.
19. The process in accordance with claim 1 wherein 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno-[16.alpha.-17-d]cyclohexen-21-oic acid, 2,2-dimethylpropyl ester is produced.
20. The process in accordance with claim 1 wherein 9-fluoro-11.beta.-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[16.alpha.,17-d]cyclohexen-21-oic acid, 1,1-dimethyl-ethyl ester is produced.
21. A steroid having the formula and esters thereof, or the 1,2-dehydro derivative thereof, wherein X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or R4 and R5 toyether are =O; R2 and R3 are the same or different and are hydrogen, alkyl or aryl, or taken together with the double bond to which they are attached, form a benzene ring; R6 and R7 are the same or different and are hydrogen, alkyl, alkoxy, formyl, , phenyl or cyano and in addition hydroxy, halogen, carboalkoxy and alkylcarbonyl when R2 and R3 are separate with the proviso that when R6 and R7 are different, one of R6 and R7 is hydrogen; R8 is hydrogen or -CH-R9R10 wherein R9 and R10 are the same or different and are hydrogen or alkyl, whenever prepared by the process of claim 1.
22. A compound according to claim 21 wherein R2 and R3 are the same or different and are hydrogen, alkyl or aryl, whenever prepared by the process of claim 1.
23. A compound according to claim 21 wherein R2 and R3 taken together with the double bond to which they are attached form a benzene ring, whenever prepared by the process of claim 3.
24. A compound according to claim 21 wherein R2 and R3 are the same or different and are hydrogen, alkyl or aryl; R4 is hydrogen and R5 is hydroxy or together R4 and R5 are =O; Y is hydrogen, methyl or fluorine and R6, R7 and R8 are hydrogen, whenever prepared by the process of claim 4.
25. A compound according to claim 21 wherein R2 and R3 taken together with the double bond to which they are attached form a benzene ring; R4 is hydrogen and R5 is hydroxy or together R4 and R5 are =O; Y is hydrogen, methyl or fluorine and R6, R7 and R8 are hydrogen, whenever prepared by the process of claim 5.
26. A compound according to claim 21 wherein X
is fluorine and R6, R7 and R8 are hydrogen, whenever prepared by the process of claim 6.
is fluorine and R6, R7 and R8 are hydrogen, whenever prepared by the process of claim 6.
27. A compound according to claim 21 wherein R4 is hydroxy, R5 is hydrogen and R6, R7 and R8 are hydrogen, whenever prepared by the process of claim 7.
28. A compound according to claim 21 wherein R4 is hydroxy; R5 is hydrogen, R6, R7 and R8 are hydrogen;
and X is hydrogen or fluorine whenever prepared by the process of claim 8.
and X is hydrogen or fluorine whenever prepared by the process of claim 8.
29. The steroid in accordance with claim 21 having the name 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b] naphthalene-21-oic acid, methyl ester, whenever prepared by the process of claim 9.
30. The steroid in accordance with claim 21 having the name 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.-17-b]naphthalen-21-oic acid, 1-methylethyl ester, whenever prepared by the process of claim 10.
31. The steroid in accordance with claim 21 having the name 9-fluoro-1'2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b]naphthalen-21-oic acid, butyl ester, whenever prepared by the process of claim 11.
32. The steroid in accordance with claim 21 having the name 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-b]naphthalene-21-oic acid, 1,1-dimethylethyl ester, whenever prepared by the process of claim 12.
33. The steroid in accordance with claim 21 having the name 9-fluoro-1',2',3',4'-tetrahydro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16a,17-b]naphthalen-21-oic acid, 2,2-dimethylpropyl ester, whenever prepared by the process of claim 13.
34. The steroid in accordance with claim 21 having the name 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[l6.alpha.,17-d]cyclohexen-21-oic acid, methyl ester, whenever prepared by the process of claim 14.
35. The steroid in accordance with claim 21 having the name 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[l6.alpha.,17-d]cyclohexen-21-oic acid, 1-methylethyl ester, whenever prepared by the process of claim 15.
36. The steroid in accordance with claim 21 having the name 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[16.alpha.,17-d]cyclohexen-21-oic acid, butyl ester, whenever prepared by the process of claim 16.
37. The steroid in accordance with claim 21 having the name 9-fluoro-11.beta.-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[16.alpha.,17-d]cyclohexen-21-oic acid, methyl ester, whenever prepared by the process of claim 17.
38. The steroid in accordance with claim 21 having the name 9-fluoro-11.beta.-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[16.alpha.,17-d]cyclohexen-21-oic acid, ethyl ester, whenever prepared by the process of claim 18.
39. The steroid in accordance with claim 21 having the name 9-fluoro-11.beta.-hydroxy-3,20-dioxopregna-1,4-dieno[l6.alpha.,17-d]cyclohexen-21-oic acid, 2,2-dimethylpropyl ester, whenever prepared by the process of claim 19.
40. The steroid in accordance with claim 21 having the name 9-fluoro-11.beta.-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[16.alpha.,17-d]cyclohexen-21-oic acid, 1,1-dimethylethyl ester, whenever prepared by the process of claim 20.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US919,006 | 1978-06-26 | ||
US05/919,006 US4160772A (en) | 1978-06-26 | 1978-06-26 | Steroidal[16α,17-d]cyclohexene-21-carboxylic acid esters |
US05/919,020 US4164504A (en) | 1978-06-26 | 1978-06-26 | Steroidal[16α,17-b]naphthaleno-21-carboxylic acid esters |
US919,020 | 1978-06-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1142916A true CA1142916A (en) | 1983-03-15 |
Family
ID=27129763
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000328182A Expired CA1142916A (en) | 1978-06-26 | 1979-05-23 | STEROIDAL [16.alpha., 17-B]NAPHTHALENO AND CYCLOHEXENE-21-CARBOXYLIC ACID ESTERS |
Country Status (24)
Country | Link |
---|---|
AU (1) | AU524173B2 (en) |
CA (1) | CA1142916A (en) |
CH (1) | CH642087A5 (en) |
CS (2) | CS208160B2 (en) |
DD (1) | DD144550A5 (en) |
DE (1) | DE2925552A1 (en) |
DK (1) | DK267079A (en) |
ES (2) | ES481866A1 (en) |
FI (1) | FI791934A (en) |
FR (1) | FR2429796A1 (en) |
GB (2) | GB2023608B (en) |
GR (1) | GR72244B (en) |
HU (1) | HU180089B (en) |
IE (1) | IE49178B1 (en) |
IL (1) | IL57622A (en) |
IT (1) | IT1162746B (en) |
LU (1) | LU81420A1 (en) |
NL (1) | NL7904510A (en) |
NO (1) | NO792118L (en) |
NZ (1) | NZ190510A (en) |
PL (1) | PL216614A1 (en) |
PT (1) | PT69818A (en) |
SE (1) | SE7905568L (en) |
SU (2) | SU946404A3 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4391755A (en) * | 1982-01-18 | 1983-07-05 | E. R. Squibb & Sons, Inc. | Steroid monohydrates, formulations containing same and method |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2924307A (en) * | 1956-09-27 | 1960-02-09 | Gen Motors Corp | Brake adjusting device |
US3944584A (en) * | 1975-02-03 | 1976-03-16 | E. R. Squibb & Sons, Inc. | Steroidal (16α,17-d)cyclohexenes |
-
1979
- 1979-05-21 NZ NZ190510A patent/NZ190510A/en unknown
- 1979-05-23 CA CA000328182A patent/CA1142916A/en not_active Expired
- 1979-05-25 GB GB7918394A patent/GB2023608B/en not_active Expired
- 1979-05-28 AU AU47481/79A patent/AU524173B2/en not_active Ceased
- 1979-05-29 GR GR59210A patent/GR72244B/el unknown
- 1979-06-07 FR FR7914578A patent/FR2429796A1/en active Granted
- 1979-06-08 NL NL7904510A patent/NL7904510A/en not_active Application Discontinuation
- 1979-06-15 CS CS799420A patent/CS208160B2/en unknown
- 1979-06-15 CS CS794141A patent/CS208159B2/en unknown
- 1979-06-18 FI FI791934A patent/FI791934A/en not_active Application Discontinuation
- 1979-06-22 IL IL57622A patent/IL57622A/en unknown
- 1979-06-25 SE SE7905568A patent/SE7905568L/en not_active Application Discontinuation
- 1979-06-25 ES ES481866A patent/ES481866A1/en not_active Expired
- 1979-06-25 IT IT23840/79A patent/IT1162746B/en active
- 1979-06-25 DE DE19792925552 patent/DE2925552A1/en not_active Withdrawn
- 1979-06-25 CH CH592479A patent/CH642087A5/en not_active IP Right Cessation
- 1979-06-25 ES ES481875A patent/ES481875A1/en not_active Expired
- 1979-06-25 DK DK267079A patent/DK267079A/en not_active Application Discontinuation
- 1979-06-25 HU HU79SU1020A patent/HU180089B/en unknown
- 1979-06-25 LU LU81420A patent/LU81420A1/en unknown
- 1979-06-25 NO NO792118A patent/NO792118L/en unknown
- 1979-06-25 SU SU792781351A patent/SU946404A3/en active
- 1979-06-26 PT PT69818A patent/PT69818A/en unknown
- 1979-06-26 DD DD79213895A patent/DD144550A5/en unknown
- 1979-06-26 PL PL21661479A patent/PL216614A1/xx unknown
- 1979-08-08 IE IE1181/79A patent/IE49178B1/en unknown
-
1980
- 1980-10-23 SU SU802995671A patent/SU1055334A3/en active
-
1982
- 1982-03-19 GB GB08208035A patent/GB2106116B/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
ES481866A1 (en) | 1980-06-16 |
NL7904510A (en) | 1979-12-28 |
GB2106116A (en) | 1983-04-07 |
GR72244B (en) | 1983-10-04 |
PT69818A (en) | 1979-07-01 |
IL57622A (en) | 1983-02-23 |
SE7905568L (en) | 1979-12-27 |
HU180089B (en) | 1983-01-28 |
CS208160B2 (en) | 1981-08-31 |
FI791934A (en) | 1979-12-27 |
LU81420A1 (en) | 1979-09-12 |
SU1055334A3 (en) | 1983-11-15 |
DD144550A5 (en) | 1980-10-22 |
DK267079A (en) | 1979-12-27 |
IE49178B1 (en) | 1985-08-21 |
FR2429796A1 (en) | 1980-01-25 |
IT1162746B (en) | 1987-04-01 |
GB2023608A (en) | 1980-01-03 |
PL216614A1 (en) | 1980-03-24 |
IE791181L (en) | 1979-12-26 |
AU4748179A (en) | 1980-01-03 |
CS208159B2 (en) | 1981-08-31 |
GB2106116B (en) | 1983-08-03 |
GB2023608B (en) | 1983-04-27 |
IT7923840A0 (en) | 1979-06-25 |
FR2429796B1 (en) | 1983-01-07 |
CH642087A5 (en) | 1984-03-30 |
NO792118L (en) | 1979-12-28 |
NZ190510A (en) | 1982-03-09 |
DE2925552A1 (en) | 1980-01-17 |
ES481875A1 (en) | 1980-07-01 |
AU524173B2 (en) | 1982-09-02 |
IL57622A0 (en) | 1979-10-31 |
SU946404A3 (en) | 1982-07-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5116983A (en) | Dehydrogenation process intermediates | |
US2541104A (en) | 17(alpha)-hydroxy-20-ketosteroids and process | |
US3499891A (en) | Spiro(steroidal-6,1'-cyclopropanes) and process | |
CA1142916A (en) | STEROIDAL [16.alpha., 17-B]NAPHTHALENO AND CYCLOHEXENE-21-CARBOXYLIC ACID ESTERS | |
CH561739A5 (en) | 4-Hydroxy-2-butenoic acid lactone steroid derivs - cardiotonic, anti-inflammatory, hypocholesterolaemic, mineralocorticoid agents | |
US2837517A (en) | 9, 11beta-epoxy-17-alkyltestosterones | |
US3056809A (en) | Method for introducing an oxygen function into a steroid molecule containing an enol group and compounds thereof | |
US3023227A (en) | 5, 7-seco-b-norandrostane derivatives | |
US3016389A (en) | 3, 17-bisoxygenated-18 nor-1, 3, 5(10)-estratrienes and intermediates | |
US4213912A (en) | Process for preparing steroidal [16α,17-d]cyclohexene-21-carboxylic acid esters | |
McElvain et al. | Interconversion of Nepetalic Acid and Isoiridomyrmecin (Iridolactone) | |
US2862011A (en) | Production of 2-bromo-keto-11-oxygenated-4,17-(20)-pregnadiene-21-oic acid esters | |
US4220588A (en) | Chemical processes | |
HERZIG et al. | INVESTIGATIONS ON STEROIDS. XVII. DEHYDRATION STUDIES IN THE SERIES OF 3β, 5, 19-TRIHYDROXYETIOCHOLANIC ACID | |
US3331868A (en) | A-nor-b-norsteroids and intermediates | |
US2304837A (en) | Hydroxy pregnane derivatives and preparation of same | |
US3040065A (en) | Process for the production of 8(9)-dehydroprogesterone and 9alpha-hydroxyprogesterone | |
US3347854A (en) | Preparation of 11beta-hydroxy-19-nor steroidal-delta1, 3, 5 (10), 6, 8-pentaenes | |
Ellis et al. | 571. Modified steroid hormones. Part XVII. Some 6-methyl-4, 6-dien-3-ones | |
US2683723A (en) | Steroid alkali-metal enolates | |
US3865833A (en) | 1,3-diethers of 2-azaestratrienes and intermediates | |
YANAGITA et al. | Santonin and Related Compounds. XII. 1 Stereoformulas of Tetrahydro-α-santonins2 | |
Evans et al. | Cyclopropano-steroids | |
US4160772A (en) | Steroidal[16α,17-d]cyclohexene-21-carboxylic acid esters | |
Kritchevsky et al. | Novel derivatives of 3α, 7α-dihydroxy-5β-cholan-24-OIC acid (chenodeoxycholic acid) and 3α, 7β-dihydroxy-5β-cholan-24-OIC acid (ursodeoxycholic acid) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MKEX | Expiry | ||
MKEX | Expiry |
Effective date: 20000315 |