GB2199325A - 16-dehydro-20-oxopregnane derivatives - Google Patents
16-dehydro-20-oxopregnane derivatives Download PDFInfo
- Publication number
- GB2199325A GB2199325A GB08730269A GB8730269A GB2199325A GB 2199325 A GB2199325 A GB 2199325A GB 08730269 A GB08730269 A GB 08730269A GB 8730269 A GB8730269 A GB 8730269A GB 2199325 A GB2199325 A GB 2199325A
- Authority
- GB
- United Kingdom
- Prior art keywords
- dinor
- oxo
- oic acid
- dione
- dehydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000002253 acid Substances 0.000 claims abstract description 47
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000005977 Ethylene Substances 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 150000003431 steroids Chemical class 0.000 claims abstract description 5
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 5
- 150000004715 keto acids Chemical class 0.000 claims abstract description 4
- 230000007935 neutral effect Effects 0.000 claims abstract description 4
- 150000003624 transition metals Chemical class 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 15
- 239000007858 starting material Substances 0.000 claims description 14
- QWMFKVNJIYNWII-UHFFFAOYSA-N 5-bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine Chemical compound CC1=CC=C(C)N1C1=CC=C(Br)C=N1 QWMFKVNJIYNWII-UHFFFAOYSA-N 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
- 150000004685 tetrahydrates Chemical class 0.000 claims description 3
- 241000237519 Bivalvia Species 0.000 claims 1
- 235000020639 clam Nutrition 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 230000003595 spectral effect Effects 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000003246 corticosteroid Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 229960001334 corticosteroids Drugs 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000002211 ultraviolet spectrum Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229930182558 Sterol Natural products 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 150000003432 sterols Chemical class 0.000 description 4
- 235000003702 sterols Nutrition 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000005187 foaming Methods 0.000 description 3
- -1 keels Chemical class 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- VRRHHTISESGZFN-RKFFNLMFSA-N 16,17-didehydroprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC=C(C(=O)C)[C@@]1(C)CC2 VRRHHTISESGZFN-RKFFNLMFSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 241000203720 Pimelobacter simplex Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- TXHIDIHEXDFONW-UHFFFAOYSA-N benzene;propan-2-one Chemical compound CC(C)=O.C1=CC=CC=C1 TXHIDIHEXDFONW-UHFFFAOYSA-N 0.000 description 2
- 235000010633 broth Nutrition 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 229940032007 methylethyl ketone Drugs 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- JWMFYGXQPXQEEM-WZBAXQLOSA-N pregnane group Chemical group [C@@H]12CC[C@H](CC)[C@@]1(C)CC[C@H]1[C@H]2CCC2CCCC[C@]12C JWMFYGXQPXQEEM-WZBAXQLOSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000003637 steroidlike Effects 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
- KZJWDPNRJALLNS-VPUBHVLGSA-N (-)-beta-Sitosterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@@H](C(C)C)CC)C)CC4)CC3)CC=2)CC1 KZJWDPNRJALLNS-VPUBHVLGSA-N 0.000 description 1
- CSVWWLUMXNHWSU-UHFFFAOYSA-N (22E)-(24xi)-24-ethyl-5alpha-cholest-22-en-3beta-ol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(CC)C(C)C)C1(C)CC2 CSVWWLUMXNHWSU-UHFFFAOYSA-N 0.000 description 1
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- KLEXDBGYSOIREE-UHFFFAOYSA-N 24xi-n-propylcholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CCC)C(C)C)C1(C)CC2 KLEXDBGYSOIREE-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- LPZCCMIISIBREI-MTFRKTCUSA-N Citrostadienol Natural products CC=C(CC[C@@H](C)[C@H]1CC[C@H]2C3=CC[C@H]4[C@H](C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C LPZCCMIISIBREI-MTFRKTCUSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- ARVGMISWLZPBCH-UHFFFAOYSA-N Dehydro-beta-sitosterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)CCC(CC)C(C)C)CCC33)C)C3=CC=C21 ARVGMISWLZPBCH-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- XYNPYHXGMWJBLV-VXPJTDKGSA-N Tomatidine Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)C[C@@H]4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@@]11CC[C@H](C)CN1 XYNPYHXGMWJBLV-VXPJTDKGSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 description 1
- 229960005471 androstenedione Drugs 0.000 description 1
- AEMFNILZOJDQLW-UHFFFAOYSA-N androstenedione Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-UHFFFAOYSA-N 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- MJVXAPPOFPTTCA-UHFFFAOYSA-N beta-Sistosterol Natural products CCC(CCC(C)C1CCC2C3CC=C4C(C)C(O)CCC4(C)C3CCC12C)C(C)C MJVXAPPOFPTTCA-UHFFFAOYSA-N 0.000 description 1
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 1
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 229940093476 ethylene glycol Drugs 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000007483 microbial process Effects 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- PWRIIDWSQYQFQD-UHFFFAOYSA-N sisunine Natural products CC1CCC2(NC1)OC3CC4C5CCC6CC(CCC6(C)C5CCC4(C)C3C2C)OC7OC(CO)C(OC8OC(CO)C(O)C(OC9OC(CO)C(O)C(O)C9OC%10OC(CO)C(O)C(O)C%10O)C8O)C(O)C7O PWRIIDWSQYQFQD-UHFFFAOYSA-N 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 235000015500 sitosterol Nutrition 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- NLQLSVXGSXCXFE-UHFFFAOYSA-N sitosterol Natural products CC=C(/CCC(C)C1CC2C3=CCC4C(C)C(O)CCC4(C)C3CCC2(C)C1)C(C)C NLQLSVXGSXCXFE-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 1
- KWVISVAMQJWJSZ-VKROHFNGSA-N solasodine Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CN1 KWVISVAMQJWJSZ-VKROHFNGSA-N 0.000 description 1
- JXWLYDNHVXFBJA-UHFFFAOYSA-N solasodine Natural products CC1CCC2(NC1)NC3CC4C5CC=C6CC(O)CCC6(C)C5CCC4(C)C3C2C JXWLYDNHVXFBJA-UHFFFAOYSA-N 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- XYNPYHXGMWJBLV-OFMODGJOSA-N tomatidine Natural products O[C@@H]1C[C@H]2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]5[C@@H](C)[C@]6(O[C@H]5C4)NC[C@@H](C)CC6)CC3)CC2)CC1 XYNPYHXGMWJBLV-OFMODGJOSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/005—Ketals
- C07J21/006—Ketals at position 3
-
- 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)
-
- 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
- C07J13/007—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 17 (20)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
- C07J41/0016—Oximes
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
A new process for preparing 16-dehydro-20-oxopregnane derivatives characterized by reacting a steroid having 17(20)-dehydro-23,24-dinorcholan-22-oic acid structure or a salt thereof with hydrogen peroxide in neutral or alkaline medium in the presence of salts of oxo-acids of transition metals as catalysts. Compounds prepared include the novel compounds 9 alpha -hydroxy-4, 16-pregnadiene-3,20-dione; 1,4,9(11), 16-pregnatetraene-3,20-dione; 3-methoxyimino-4, 9(11), 16-pregnatrien-20-one and 5,9(11), 16-pregratriene-3, 20-dione 3-ethylene ketal.
Description
PROCESS FOR PREPARING 16-DEHYDRO-20-OXIPREGNANE DERIVATIVES
The invention relates to a new process for preparing 16-dehydro-20-oxopregnane derivatives.
Since 1950, 16-dehydro-20-oxopregnane derivatives have been used as intermediates in the synthesis of corticosteroids / P. L. Julian et awl. : J. Am. Chem. Soc.
72, 5145 (1950)7. They may be advantageously prepared by the oxidative chemical degradation of various sapcgenines, e.g. diosgenine, tigogenine or hecogenine / R. E. Marker et al.--: 3. Am. Chem. Soc. 61, 3592 (1939); ibid. 62, 51E (1940); ibid. 69, 2167 (1947)7 as well as from the aglycones of some steroidal alkaloids, e.g. solasodine or tomatidine / Y. Sato et awl. : J. Org. Chem. 22, 1496 (1558)7.
From the middle of the sixties besides sapogenines end steroidal alkaloids, sterols of plant origin, especially sitosterol, have been used as starting materials in the synthesis of drugs, owing to their lower price and easier availability.
It is known that 3-oxo-23,24-dinor-4,17(20)-choladien -22-oic acid (U. S. Patent specification No. 3,994,933) and 9α-hydroxy-3-oxo-23,24-dinor-4,17(20)-choladien-22-oic acid (British Patent specification No. 2,098,218) are prepared by the partial microbial side-chain degradation of sterols of animal or plant origin.
Intermediates of a pregnane skeleton were attempted to be prepared from sterol degradation products having a 23,24-dinor-cholane skeleton for the synthesis of corticosteroids.
We found that 3-oxo-23,24-dinor-4,17(20)-choladien -22-cic acid could be transformed by hydrogen peroxide into 4,16-pregnadiene-3,20-dione and 9α-hydroxy-3-oxo- -23,24-dinor-4,17(20)-choladien-22-oic acid into the novel compound 9α-hydroxy-4,16-pregnadiene-3,20-dione with a hich yield in neutral or alkaline aqueous medium, in the presence cf the salts of oxo acids of transition metals (tunsten, molybdenum, vanadium, titanium)
This type of transforration has not been found in tne literature.It enables to prepare 16-dehydro-20-ox3- -pregnane derivatives which can be advantageously applied as intermediates in the synthesis of corticostercids from natural sterols, with high yield.
Firstly 3-oxo-23,24-dinor-4,9(11),17(20)-cholatrien- -22-oic acid not described in the literature was prepared from the known 9 9α-hydroxy-3-oxo-23,24-dinor-4,17(20)- -choladien-22-oic acid, by eliminating the 9 -hydroxy group. The presence of the 9(11)-double bond in this molecule opens the way for the formation of 11 llp-hydroxy or ll-oxo group, characteristic features of corticosteroid drugs, or for the introduction of a halogen substituent into position C-9, known to increase the antiinflammatcry effect Gf corticosteroids.
By microbial dehydrogenation with Arthrobacter
simplex a double bond was also introduced into 3-oxo -23.24-dinor-4,9(11),17(20)-cholatrien-22-oic acid in position 1, frequently occurring in corticosteroids.
The new method suitable for the conversion of
23,24-dinorcholanoic acids unsaturated at position 17(20) to compounds with a pregnane skeleton was applied for preparing the known 4,9(11),16-pregnatriene-3,20-dione / S. BernsTein: J. Am. Chem. Soc. 81, 4956 (1955)? from 3-oxo-23,24-dinor-4,9(11),17(20)-cholatrien-22-oic acid and the new intermediate of corticosteroid synthesis, 1,4,9(11),16-Frenatetraene-3,20-dione from 3-oxo-23,24 -dinor-1,4,9(11),17(20)-cholatetraen-22-oic acid.
It may be advantageous to protect the 3-oxc group ouring the transformation of 16-dehydro-20-oxo-pregnane derivatives, prepared from 3-oxo-23, 24-dinor-4 ,17(20)- -choladien-22-oic acid or from its derivatives substituted at the sterane-skeletoR to corticosteroids. Namely, in this case an epoxide can be selectively formed at the 16 double bond and the 16cL,l7-oxydo derivative-is easily transformed into the 17 α-hydroxy compound having the characteristic 17oL-hydroxy feature of corticosteroids / P. L. Julian et al.:
J. Am. Chem. Soc. 72, 5145 (1950)7.Thus the 3-oxo group of the steroids having a 3-oxo-23,24-dinor-4,17(20)choladien-22-oic acid structure is protected by blocking groups (oximes, keels, enol-ethers) and the derivatives obtained are converted into the respective 16-dehydro-20- -oxopregnane derivatives.
Based on the above the invention relates to a process for preparing 16-dehydro-20-oxcpregnane derivatives, in which a steroid having 17(20)-dehydro-23,24-dinorcholan -22-oic acid structure or a salt thereof is reacted with hydrogen peroxide in neutral or alkaline medium in the presence of salts of oxo-acids of transition metals as catalyst.
In the process of the invention any steroid having the 23,24-dinorcholan-22-oic acid sttucture with a double bond in the 17(20)-position may serve as starting material.
To prepare intermediates of 16-dehydro-2G-oxopregnane structure which are most advantageous for the synthesis of natural corticosteroid hormones and drugs it is preferred to modify the l7(20)-dehydro-23,24-dinorcholane skeleton, before applying it in the process of the invention, in a way which promotes the introduction of the 17 S and 21- -hydroxy groups characteristic for corticosteroids.
Economically it is advantageous to develop a synthesis strategy wherein the characteristic structural elements of the designed corticosteroid are already introduced to the skeleton of dinorcholanoic acids which can be inexpensively prepared by a microbial process.
According to a preferred embodiment of the present invention at first 20 to 50 mole . amounts of the ammonium or alkali metal salt of the transition metal oxo-acids, used as catalyst, are added to the aqueous solution of a salt formed, if desired, in situ with an inorganic or organic base, preferably with sodium hydroxide, of 17(20) -behydro-23,24-dinorcholanoic acid, used as starting material, then a 30 z aqueous hydrogen peroxide solution is added to the reaction mixture in 5 to 50 fold molar e-xcess.
It is preferred to apply ammonium paramolybdenate or sodium tungstate as catalyst.
Unlike the dinorcholanoic acid salts, used as starting materials, the products having a 16-detydro-20-oxopregnane skeleton are practically insaluble in water and are precIpItated from the reaction mixture.
The products can be advantageously purified by recrystallization. The con-stituents of the mother liquor can be purified by column and by preparative thin-layer chromatography.
The structure of the products prepared by the process of the invention was confirmed by ultraviolet, infrared, 1H-NMR and mass spectroscopic methods.
The process of the invention is further illustrated by the following non-limiting Examples.
Example 1
Preparation of 9α-hydroxy-4,16-pregnadiene-3,20- -dione from 9α-hydroxy-3-oxo-23,24-dinor-4,17(20)- -choladien-22-oic acid
1076 mg (3 mmoles) of 9α-hydroxy-3-oxo-23,24-dinor- -4,17(20)-choladien-22-oic acid are dissolved in a mixture of 30 ml of water and 3 ml of 1 N sodium hydroxide. Then 531 mg of ammonium paramolybdenate tetrahydrate are dissolved in 6 ml of water, the pH is adjusted to 8.0 with concentrated ammonium hydroxide, and the two solutions are combined To this reaction mixture, having pH 8.5, 20 ml of 25 % hydrogen peroxide are added dropwise at room terrperature within 2.5 hours.The foaming of the reaction mixture is reduced by the addit-ion of a few drops of dichlorcmethane.
After the reaction is completed the mixture is kept at 45 C for 30 minutes to remove the dichloromethane, then it is cooled to room temperature. The precipitated product is filtered and dried. Yield: 650 mg of 9 aS-hydroxy-4,16- -pregnadien-3,20-dione which are recrystallized first from acetone and subsequently from benzene.
M. p. : 186 to 192 cc Ultraviolet spectrum (ethanol): #max 242 nm ( & 25,400)
Infrared spectral data (KBr): OH 3530, #C=O 1665, 1650, C=C 1610, 1585 cm-1 H-NMR spectral data (COCl3, #, TMS): 6.75 m (H-16), 5.90 s (H-4), 2.25 s (3H-21), 1.30 s (3H-19), 0.95 s (3H-18) ppm.
Analysis: Calculated Found
C 76.79 % 76.67 %
H 8.59 % 8.54 %
ExamPle 2
Preparation of 4.9(11).16-pregnatriene-3,20-dione from 3-oxo-23,24-dinor-4.9(11),17(20)-cholatrien- -22-oic acid
1703 mg (5 mmoles) of 3-oxo-23,24-dinor-4,9(11),17(20)- -chclatrien-22-oic acid are dissolved in a mixture of 50 ml of water and 5 ml of 1 N sodium hydroxide. Then 8E5 mg of ammonium paramolybdenate tetrahydrate are dissolved in 15 ml of water, the pH is adjusted to 7.5 with concentrated ammonium hydroxide, and the two solutions are combined. To this reaction mixture, having pH 8.0, 15 ml of a 25 % aqueous hydrogen peroxide- solution (110 mmoles) are added dropwise at room temperature within 2 hours.The product starts to precipitate during this period, it is filtered and dried subsequently. Yield: 975 mg of crude 4,9(11),16- -pregnatriene-3,20-dione which are recrystallized first from acetone and then from methanol.
M. p.: 202 to 205 C.
[α]D = +237 (c=l, chloroform) Preparation of the starting material 3-oxo-23,24 -dinor-4,9(11),17(20)-cholatrien-22-oic acid: 1752 mg (5 mmoles) of 9 eL-hydroxy-3-oxo-23,24-dinor- 4,17(20)-choladien-22-oic acid are dissolved in 18 ml of dichloromethane, then 1.08 ml of chlorosulfonic acid are added dropwise to the stirred solution at -5 C and stirring is continued at this temperature for 30 minutes.
Thereafter 22 ml of water are added under stirring to the reaction mixture and the layers formed are separated. The aqueous layer is extracted twice with 10 ml of dichloromethane. The dichlcromethane extracts are combined and evaporated at reduced pressure. The residue, 1.84 g, is purified t) preparative thnn-layer chromatography (developing solvent: benzene-acetone 8:2). The obtained chromatographical- ly pure product is dissolved in 30 ml of methanol and 2 ml of 10 % methanolic hydrochloric acid are added. This acidic methanolic solution is diluted with 120 ml cf ethyl acetate ard the mixture is twice washed with 25 ml of water, the.
it is evaporated at reduced pressure. Yield: 1.44 g of 3-oxo -23,24-dinor-4,9(11),17(20)-cholatrien-22-oic acid which are recrystallized from methanol.
M. p. : 238 to 239 C Ultraviolet spectrum (ethanol): # max 236 nm
max Infrared spectral data (KBr): 9 OH 3400-2400, 9 C=C 1675 (COOH and 3-keto), 2 C=C 1610 cm H-NMR spectral data (COCl3, #, TMS): 5.70 s (H-4), 5.50 m (H-ll), 2.00 s (3 H-21), 1.30 s (3 H-19), 0.90 s (3 H-1B) ppm
Mass spectral data: M+ 340, m/z: 340, 325, 307, 295, 227, 213, 105, 91.
Example 3
Preparation of 4116-preonadiene-3,20-dione from 3-oxo-23,24-dinor-4.17(20)-choladien-22-oic acid
1028 mg (3 mmoles) of 3-oxo-23,24-dinor-4,17(20)choladien-22-oic acid are dissolved in a mixture of 30 ml of water and 3 ml of 1 N sodium hydroxide. To this solution 160 mg (0.5 mmole) of sodium tungstate dihydrate are added in 1 ml of water. Then 4.0 ml of a 30 % aqueous hydrogen peroxide solution are added dropwise to the reaction mixture at 60 C under stirring within one hour Heavy foaming is reduced by the addition of a few drops of methyl-ethyl -ketone. Thereafter the mixture is kept overnight at 5 OC.
The precipitate is filtered and dried. Yield: 623 mg of 4,16-pregnadiene-3,20-dione which are recrystallized from acetone for analytical purposes.
M. p.: 186 to 189 C [α]D = +1750 (c=0.9, chloroform)
Ultraviolet spectrum (ethanol): # max 241 nm ( = 28,100)
Infrared spectrum (KBr): 9 C=C 1650, 1680, 9 C=C 1585, 1615 cm~l.
Analysis: Calculated Found
C 80.72 % 80.90 %
H 9.03 % 9.12 %
Example 4
Preparation of 1,4,9(11),16-pregnatetraene-3,20-dione
from 3-oxo-23,24-dinor-1,4,9(11),17(20)-cholatetraen-
-22-oic acid
1015 mg (3 mmoles) of 3-oxo-23,24-dinor-1,4,9(11),17(20)- -cholatetraen-22-oic acid are dissolved in a mixture of 30 ml cf water and 3 ml of 1 N sodium hydroxide. To this solution 160 mg (0.5 mmole) of sodium tungstate dihydrate are added in 1 ml of water. Then 3.2 ml of a 25 % aqueous hydrogen peroxide solution are added dropwise to the reaction mixture within 1.5 hours, at 60 OC under constant stirring.
Thereafter the reaction mixture is cooled to room temperature, the precipitate formed is filtered and dried. 534 g of crude 1,4,9(11),16-pregnatetraene-3,20-dione are obtained which are purified at first by preparative thin-layer chromatography (adsorbent: 2:1 mixture of Kieselgel G and Kieselgel 60
HF254+366, REANAL, Budapest; developing solvent: 4:1 mixture of benzene and acetone), then by two repeated recrystallizations from benzene.
M. p.: 204 to 208 C Ultraviolet spectrum (ethanol): k max 240 nm (= 24,300)
Infrared spectral data (KBr): #C=O 1670, 1660, PC=C 1630, 1610, 1590 cm1 H-NMR spectral data (COCl3, THS): 7.20 (lH-l), 6.30 (1H-2), 6.05 (1H-4), AMXm (J1,2 = 12 Hz, 32,4 2 2 Hz, J1,4 = Hz), 6.70 t (1H16), 5.60 m (lH-1l), 2.30 s (3H-21), 1.45 s (3H-19), 0.95 s (3H-18) ppm
Mass spectral data: M 308 m/z: 308, 293, 265, 172, 157, 121, 91, 43.
Analysis: Calculated Found
C 81.78 8 81.70 %
H 7.84 a 7.74 %
Preparation of the starting material 3-oxo-23,24 -dinor-1,4,9(11),17(20)-cholatetraen-22-oic acid
10 ml portions of an Arthrobacter simplex culture induced by 4-androstene-3,17-dione for the formation of the 3-oxo-steroid-l-dehydrogenase enzyme are measured at sterile conditions into ten 500 ml Erlenmeyer flasks. Then each culture is diluted with 90 ml of 1 % (w/w) aqueous p-cyclodextrine solution. Thereafter 100 mg of 3-oxo-23,24 -dinor-4,5(1l),17(20)-cholatrien-22-oic acid, dissolved in 2 ml of ethanol, are added to each culture which are shaken on a rotary shaker at 37 OC for two days.Then the broths are combined, their pH is adjusted to 2 with 2N sulfuric acid and the fermentation broth is extracted three times with 200 ml of ethyl acetate. The ethyl acetate extracts are combined and evaporated at reduced pressure. The 960 mg of crude product obtained are purified by preparative thin -layer chromatography in a developing solvent of benzene -acetone (8:2). The 710 mg of chromatographically pure product are dissolved in 20 ml of methanol, then 1 ml of 10 0 hydrochloric acid is added in methanol at O OC. Thereafter the acidic solution is diluted with 100 ml of ethyl acetate, washed twice with 25 ml of water and evaporated at reduced pressure. The product obtained, 3-oxo-23,24 -dinor-1,4,9(11),17(20)-cholatetraen-22-oic acid, is recrystallized from methanol.
M. p. : 240 to 244 cc Ultraviolet spectrum (ethanol): #max 235 nm Infrared spectral data (KBr): # OH 3600-2500, # C=C 1690 (COOH), 1665 (3-keto), # C=C 1630, 1610 cm 1 H-NMR spectral data (CDCl3, C, TMS): 7.20 (H-l), 6.30 (H-2), 6.10 (H-4), 4Xm (J1,2 = iO Hz, 2,4 = 2 Hz, J1,4 ~ O Hz), 5.50 m (H-ll), 1.95 s (3H-2i), 1.40 s (3H-19), 0.95 s (3H-18) pD Mass spectral data: M + 338 m/z: 338, 323, 310, 211, 165, 145, 121, 91.
Example 5
Preparation of 3-methoxyimino-4,9(11),16-pregnatrien-
-20-one fron 3-methoxyimino-23,24-dinor-4,9(11j,17(20 -cholatrien-22-oic acid
1109 mg (3 mmoles) of 3-methoxyimino-23,24-dinor -4,9(11),17(20)-cholatrien-22-oic acid are dissolved in a mixture of 25 ml of water, 3 ml of 1 N sodium hydroxide and 3 ml of dichloromethane. To this solution firstly 500 mg (1.5 mmoles) of sodium tungstate dihydrate are added in 3 ml water. Then 5.5 ml of a 25 % aqueous hydrogen peroxide solution are added dropwise to the reaction mixture within two hours at 55 cc under constant stirring. During the addition the product is precipitated at heavy foaming.
The precipitate formed is filtered and dried. Yield: 967 mg of 3-methoxyimino-4,9(11),16-pregnatrien-20-one, a mixture of E and Z isomers.
Infrared spectral data (KBr): ; C=O 1659, 9 C=C 1620 cm Analysis: Calculated Found
C 77.84 % 77.61 %
H 8.61 % 8.59 %
N 4.13 % 4.53 %
Preparation of the starting material 3-methoxyimino -23,24-dinor-4,9(11) ,17(20)-cholatrien-22-oic acid
2.04 g (6 mmoles) of 3-oxo-23,24-dinor-4,9(11),17(20)- -chblatrien-22-oic acid and 0.55 g (6.3 mmoles) of methoxy gamine hydrochloride are stirred in 15 ml of pyridine at rcom temperature for 20 hours. Then the reaction mixtu-re is poured to 60 ml of water and extracted three times with 20 ml of dichloromethane. The combined extracts are evaporated at reduced pressure and traces of residual pyridine are removed by azeotropic distillation first by with toluene, then with methanol. Yield: 2.13 g of 3-methoxyimino-23,24 -dinor-4,9(11),17(20)-cholatrien-22-oic acid.
Example 6 5,9(11) ,16-Preqnatriene-3,20-dion-3-ethylene ketal
1.920 mg (5 mmoles) of 3-oxo-23,24-dinor-chola -5,9(11),17(20)-trien-22-oic acid 3-ethylene ketal are dissolved in a mixture of 8.6 ml of methanol, 4.3 ml of methylethylketone, 5.2 ml of 10 M sodium hydroxide and 86 ml of water. To this solution 0.21 g of sodium tungstate dihydrate in 4.3 ml of water are added. Then 12.9 ml of a 30 % aqueous hydrogen peroxide solution are added dropwise within one hour at 60 C under constant stirring.
Thereafter the reaction mixture is heated to 85 C to remove organic solvents, then it is slowly cooled and left to stand at 5 cc overnight. Yield: 1.01 g (60 %) of 5,9(11),16-pregnatriene-3,20-dione-3-ethylene ketal which is recrystallized from methanol for analytical purposes.
M. p.: 210 to 214 C Ultraviolet spectrum (ethanol): # max 239 nm ( E.= 9600) Infrared spectral data (KBr): 9 C=O 1657, # c=c 1589 cm 1 1H-NMR spectral data (CDC13, #, TMS): 5.45 m (1H-6, lH-il), 6.70 t (lH-16), 2.25 5 (3H-21), 1.20 s (3H-19), 0.80 (3H-18) Analysis:Calculated Found
C 77.92 % 77.66 %
H 8.59 % 8.29 %
Preparation of the starting material 3-oxo-23,24 -dinor-5,9(11),17(20)-cholatrien-22-oic acid 3-ethylene
ketal
1.022 mg (3 mmoles) of 3-oxo-23,24-dinor-4,9(11),17(20)- -cholatrien-22-oic acid are dissolved in 10 ml of dichloromethane, then 20 mg of p-toluenesulfonic acid, 1 ml of ethyleneglycol, and 0.5 ml of trimethylorthoformiate are added. The reaction mixture is stirred at room temperature for 4 hours, then it is heated at 40 C until it is concentrated to half its volume. After the addition of one drop of triethylamine the solution is diluted with dichloro methane, washed with sodium hydrogen carbonate solution and water, dried over sodium sulfate and evaporated at reduced pressure. The product obtained in near quantitative yield is recrystallized from methanol for analytical purposes.
M. p.: 240 to 243 C
Infrared spectral data (KBr): 9 = 1701 cm 1 1H-NMR spectral data (CDCl3, g TMS): 11.05 (1H, -COOH), 5.45 m (1H-6, H-ll), 3.95 s (4H-dioxolane), 1.95 s (3H-21), 1.20 s (3H-19), 0.90 s (3H-18) ppm
Analysis Calculated Found
C 74.97 % 75.02 %
H 8.39 % 8.45 %
Claims (15)
1. A process for preparing 16-dehydro-20-oxopregnane derivatives, which co mpri ses reacting a steroid having 17(20)-dehydro-23,24-dinorcholan-22-oic acid structure or a salt therecf with hydrogen peroxide in neutral or alkaline medium in the presence of salts of oxoacids of transition metals as catalysts.
2. A process as claimed in claim 1, which r r;p r i s e s using 3-oxo-23,24-dinor-4,17(20)-choladier,- -22-cic acid as starting material.
3. A process as claimed in claim 1, which c o m pr i s e s using 9 i-hydroxy-3-cxo-23,24-cinrr-4,17(20,-choiadien-22- -oic acid as starting material.
4. A process as claimed in claim 1, which comprises using 3-oxo-23,24-dinor-4,9(11),17(20) -cholatrien-22-oic acid as starting material.
5. A process as claimed in claim 1, which comprises using 3-oxo-23,24-dinor-1,4,9(11),17(20) -cholatetraen-22-oic acid as starting material.
6. A process as claimed in claim 1, which comprises using 3-methoxyimino-23 ,24-dinor -4,9(11),17(20)-cholatrien-22-oic acid as starting material.
1. A process as claimed in claim 1, which comprises using 3-oxo-23,24-dinor-5,9(11),17(20)- -cholatrien-22-oic acid 3-ethylene ketal as starting material.
8. A process as claimed in claim 1, which comprises applying ammonium paramolybdenate tetra hydrate as catalyst.
9. A process as claimed in claim 1, which compr ise s applying sodium tungstate dihydrate as catalyst.
10. 9s -Hydroxy-4,16-pregnadiene-3,20-dione.
11. 1,4,9(11),16-Pregnatetraene-3,20-dione.
12. 3-Methoxyimino-4,9(11),16-pregnatrien-20-one.
13. 5,9(t1),16-Pregnatriene-3,20-dione 3-ethylene ketal.
14. k process as claimed in claim 1, substantially as hereinbefore described in any one of Examples 1 to 6.
15. 16-dehydro-20 oxopregnane derivatives made by the process defined in any one of claims 1 to 9 or 14.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU549986A HU198736B (en) | 1986-12-29 | 1986-12-29 | Process for producing 16-dehydro-20-oxopregnane derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8730269D0 GB8730269D0 (en) | 1988-02-03 |
| GB2199325A true GB2199325A (en) | 1988-07-06 |
| GB2199325B GB2199325B (en) | 1990-04-25 |
Family
ID=10970368
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8730269A Expired - Lifetime GB2199325B (en) | 1986-12-29 | 1987-12-29 | Process for preparing 16-dehydro-20-oxopregnane derivatives and such derivatives |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPH0830076B2 (en) |
| GB (1) | GB2199325B (en) |
| HU (1) | HU198736B (en) |
| NL (1) | NL8703151A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0685487A1 (en) * | 1994-06-02 | 1995-12-06 | Roussel-Uclaf | A new method of preparation of a 16-beta-steroid and new intermediates of said preparation |
| CN1907998B (en) * | 2005-08-05 | 2010-05-26 | 天津天药药业股份有限公司 | Refining process of intermediate 21-methyltetraene of dexamethasone series products |
| US8017793B2 (en) | 2004-05-14 | 2011-09-13 | Shionogi & Co., Ltd. | Oxidation of alcohol with use of hydrogen peroxide and tungsten catalyst |
| CN105622700A (en) * | 2016-01-29 | 2016-06-01 | 山东赛托生物科技股份有限公司 | Method for synthesizing steroid intermediate 17-Acetyl-10, 13-dimethyl-6, 7, 8, 10, 12, 13, 14, 15octahydro-cyclopenta[a]phenathren-3 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4189430A (en) * | 1978-07-31 | 1980-02-19 | The Upjohn Company | Epoxide process |
| DE2966511D1 (en) * | 1978-07-31 | 1984-02-02 | Upjohn Co | Epoxypregnadienes, hydroxypregnatrienes, process for their preparation and process for their conversion to precursors of useful anti-inflammatory agents |
-
1986
- 1986-12-29 HU HU549986A patent/HU198736B/en not_active IP Right Cessation
-
1987
- 1987-12-29 NL NL8703151A patent/NL8703151A/en not_active Application Discontinuation
- 1987-12-29 GB GB8730269A patent/GB2199325B/en not_active Expired - Lifetime
-
1988
- 1988-01-04 JP JP4788A patent/JPH0830076B2/en not_active Expired - Lifetime
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0685487A1 (en) * | 1994-06-02 | 1995-12-06 | Roussel-Uclaf | A new method of preparation of a 16-beta-steroid and new intermediates of said preparation |
| FR2720747A1 (en) * | 1994-06-02 | 1995-12-08 | Roussel Uclaf | Novel process for the preparation of a 16beta-methyl steroid and novel intermediates |
| US5596108A (en) * | 1994-06-02 | 1997-01-21 | Roussel Uclaf | Process for the preparation of 16β-methylsteroids |
| AU689564B2 (en) * | 1994-06-02 | 1998-04-02 | Aventis Pharma S.A. | New preparation process for a 16B-methyl steroid and new intermediates |
| US6117994A (en) * | 1994-06-02 | 2000-09-12 | Hoechst Marion Roussel | Intermediates for 16β-methyl steroids |
| CN1057303C (en) * | 1994-06-02 | 2000-10-11 | 鲁索-艾克勒夫公司 | Process and intermediates for preparing 16β-methyl steroids |
| US8017793B2 (en) | 2004-05-14 | 2011-09-13 | Shionogi & Co., Ltd. | Oxidation of alcohol with use of hydrogen peroxide and tungsten catalyst |
| CN1907998B (en) * | 2005-08-05 | 2010-05-26 | 天津天药药业股份有限公司 | Refining process of intermediate 21-methyltetraene of dexamethasone series products |
| CN105622700A (en) * | 2016-01-29 | 2016-06-01 | 山东赛托生物科技股份有限公司 | Method for synthesizing steroid intermediate 17-Acetyl-10, 13-dimethyl-6, 7, 8, 10, 12, 13, 14, 15octahydro-cyclopenta[a]phenathren-3 |
Also Published As
| Publication number | Publication date |
|---|---|
| HU198736B (en) | 1989-11-28 |
| GB8730269D0 (en) | 1988-02-03 |
| JPS63190898A (en) | 1988-08-08 |
| HUT46035A (en) | 1988-09-28 |
| NL8703151A (en) | 1988-07-18 |
| GB2199325B (en) | 1990-04-25 |
| JPH0830076B2 (en) | 1996-03-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| HU211080B (en) | Process for producing 9(11)-dehydro steroid derivatives | |
| BG61370B2 (en) | SUBSTITUTED ANDROSTA-1,4-DIENE-3,17-DIONES AND METHOD FOR THEIR PREPARATION | |
| EP1274718B1 (en) | A process for the preparation of 7.alpha.-hydroxy 3-aminosubstituted sterols using intermediates with an unprotected 7.alpha.-hydroxy group | |
| JP2812397B2 (en) | 9α-hydroxy-17-methylene steroid, method for producing the same, and method for producing corticosteroid | |
| AU2001253427A1 (en) | A process for the preparation of 7.alpha.-hydroxy 3-aminosubstituted sterols using intermediates with an unprotected 7.alpha.-hydroxy group | |
| NO146865B (en) | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 16-DEHYDRO ANDROSTAND DERIVATIVES | |
| CA2258681C (en) | Process for the preparation of 17-esters of 9.alpha.,21-dihalo-pregnane-11.beta.,17.alpha.diol-20-ones | |
| JP2643943B2 (en) | Novel 6- or 7-methyleneandrosta-1,4-diene-3,17-dione derivative and method for producing the same | |
| JP2677626B2 (en) | 17-Substituted Androsta-1,4-dien-3-one Derivatives | |
| EP0227472B1 (en) | 10 beta-alkynylestrene derivatives and process for their preparation | |
| GB2104899A (en) | New 17oc-(alkanoyloxyhydrocarbyl)-17b-hydroxy steroids with sebum-suppressive activity | |
| FR2569408A1 (en) | NOVEL STEROIDS SUBSTITUTED IN POSITION 10 BY A RADICAL COMPRISING A DOUBLE OR TRIPLE BINDING, THEIR PROCESS OF PREPARATION, THEIR APPLICATION AS MEDICAMENTS, THE PHARMACEUTICAL COMPOSITIONS CONTAINING SAME | |
| GB2199325A (en) | 16-dehydro-20-oxopregnane derivatives | |
| EP0636138A1 (en) | Fluorinated 4-aminoandrostadienone derivatives and process for their preparation | |
| CS250695B2 (en) | Method of pregnane derivatives production | |
| US4771043A (en) | Steroidic aromatase inhibitors | |
| JPS60252494A (en) | Estrogen synthesis inhibitor | |
| Cadot et al. | First synthesis of a steroid containing an unstable 19-nor-androsta-1, 5-dien-3-one system | |
| Pouzar et al. | Synthesis of (19E)-3β, 7α-dihydroxy-17-oxoandrost-5-en-19-al 19-(O-carboxymethyl) oxime, a new hapten for 7α-hydroxydehydroepiandrosterone (3β, 7α-dihydroxyandrost-5-en-17-one) | |
| EP0265119A1 (en) | 1,2-Beta-methylene-4-substituted androstene-3,17-dione derivatives and process for their preparation | |
| US5457097A (en) | Androst-4-eno[4,5-b]pyrrole derivatives | |
| Lourdusamy et al. | Synthesis of Atamestane (SH 489): an Aromatase Inhibitor | |
| PL173451B1 (en) | Novel method of obtaining pregnane derivatives | |
| WO1995001366A1 (en) | Fluorinated 6-methylenandrosta-1,4-dien-3-one derivatives and process for their preparation | |
| CS257790B2 (en) | Method of 20-benzoyl aminopregnane's new derivatives production |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19961229 |