USRE22941E - X-substituted - Google Patents
X-substituted Download PDFInfo
- Publication number
- USRE22941E USRE22941E US22941DE USRE22941E US RE22941 E USRE22941 E US RE22941E US 22941D E US22941D E US 22941DE US RE22941 E USRE22941 E US RE22941E
- Authority
- US
- United States
- Prior art keywords
- group
- parts
- ether
- hydroxyl
- acid
- 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 154
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 75
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 69
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 66
- 239000002253 acid Substances 0.000 description 41
- 239000000203 mixture Substances 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000003795 chemical substances by application Substances 0.000 description 35
- 239000000047 product Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- 125000000468 ketone group Chemical group 0.000 description 30
- 238000006460 hydrolysis reaction Methods 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- -1 acyloXy Chemical group 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- 229960000583 Acetic Acid Drugs 0.000 description 23
- 150000007513 acids Chemical class 0.000 description 23
- 239000012362 glacial acetic acid Substances 0.000 description 22
- PNEYBMLMFCGWSK-UHFFFAOYSA-N al2o3 Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 21
- 150000002576 ketones Chemical class 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 229910052799 carbon Inorganic materials 0.000 description 17
- 230000003301 hydrolyzing Effects 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- 150000004820 halides Chemical class 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 238000000034 method Methods 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 125000004432 carbon atoms Chemical group C* 0.000 description 11
- 150000001734 carboxylic acid salts Chemical class 0.000 description 11
- 239000007800 oxidant agent Substances 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 238000007792 addition Methods 0.000 description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- KRVSOGSZCMJSLX-UHFFFAOYSA-L Chromic acid Chemical compound O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 8
- 238000009835 boiling Methods 0.000 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 7
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 7
- 229910001884 aluminium oxide Inorganic materials 0.000 description 7
- 229960005363 aluminium oxide Drugs 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 239000000155 melt Substances 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- 239000011736 potassium bicarbonate Substances 0.000 description 7
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 7
- 229940094025 potassium bicarbonate Drugs 0.000 description 7
- 235000015497 potassium bicarbonate Nutrition 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000001187 sodium carbonate Substances 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- OZWKMVRBQXNZKK-UHFFFAOYSA-N Ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000000875 corresponding Effects 0.000 description 5
- YXHKONLOYHBTNS-UHFFFAOYSA-N diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000000727 fraction Substances 0.000 description 5
- 230000002140 halogenating Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000007127 saponification reaction Methods 0.000 description 5
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000005712 crystallization Effects 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 125000005283 haloketone group Chemical group 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 239000004411 aluminium Substances 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 235000010210 aluminium Nutrition 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 229960000539 carbamide Drugs 0.000 description 3
- 235000013877 carbamide Nutrition 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000012433 hydrogen halide Substances 0.000 description 3
- 229910000039 hydrogen halide Inorganic materials 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 3
- 229940031826 phenolate Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 235000011149 sulphuric acid Nutrition 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butanoic acid Chemical class CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N Cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N Palmitic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- NYTOUQBROMCLBJ-UHFFFAOYSA-N Tetranitromethane Chemical compound [O-][N+](=O)C([N+]([O-])=O)([N+]([O-])=O)[N+]([O-])=O NYTOUQBROMCLBJ-UHFFFAOYSA-N 0.000 description 2
- UQSLMEDLPHHJFT-XFNFOBRPSA-N [N+](=[N-])=CC[C@H]1CC[C@@H]2[C@]1(C)CC[C@H]1[C@H]2CCC2CCCC[C@]12C Chemical compound [N+](=[N-])=CC[C@H]1CC[C@@H]2[C@]1(C)CC[C@H]1[C@H]2CCC2CCCC[C@]12C UQSLMEDLPHHJFT-XFNFOBRPSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 230000001476 alcoholic Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 2
- 229910052804 chromium Inorganic materials 0.000 description 2
- 239000011651 chromium Substances 0.000 description 2
- 229940117975 chromium trioxide Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 150000008049 diazo compounds Chemical class 0.000 description 2
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 125000002587 enol group Chemical group 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000001264 neutralization Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000001590 oxidative Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- IJFGLPBXLYRFEJ-INGDRISUSA-N (8R,9S,10S,13R,14S,17S)-17-ethyl-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,14,16,17-tetradecahydrocyclopenta[a]phenanthren-15-one Chemical class C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C(=O)C[C@H](CC)[C@@]1(C)CC2 IJFGLPBXLYRFEJ-INGDRISUSA-N 0.000 description 1
- SJSYJHLLBBSLIH-SDNWHVSQSA-N (E)-3-(2-methoxyphenyl)-2-phenylprop-2-enoic acid Chemical compound COC1=CC=CC=C1\C=C(\C(O)=O)C1=CC=CC=C1 SJSYJHLLBBSLIH-SDNWHVSQSA-N 0.000 description 1
- FUFLCEKSBBHCMO-KJQYFISQSA-N 11-dehydrocorticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 FUFLCEKSBBHCMO-KJQYFISQSA-N 0.000 description 1
- FXBOKASTQKMONI-UHFFFAOYSA-N 2-methyl-5-(2-methylphenoxy)benzenesulfonic acid Chemical compound CC1=CC=CC=C1OC1=CC=C(C)C(S(O)(=O)=O)=C1 FXBOKASTQKMONI-UHFFFAOYSA-N 0.000 description 1
- ZYJSTSMEUKNCEV-UHFFFAOYSA-N 3-diazo-1-diazonioprop-1-en-2-olate Chemical compound [N-]=[N+]=CC(=O)C=[N+]=[N-] ZYJSTSMEUKNCEV-UHFFFAOYSA-N 0.000 description 1
- KPRGOTLNGIBVFL-GINZOMEDSA-N 7-Keto-DHEA Chemical group C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3C(=O)C=C21 KPRGOTLNGIBVFL-GINZOMEDSA-N 0.000 description 1
- 240000000736 Amomum maximum Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N Boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- KZWLJIVNHQVHPZ-AJCIZGFSSA-N C(C)(=O)OCC([C@H]1CC[C@@H]2[C@]1(C)C(C[C@H]1[C@H]2CCC2CC(CC[C@]12C)=O)=O)=O Chemical compound C(C)(=O)OCC([C@H]1CC[C@@H]2[C@]1(C)C(C[C@H]1[C@H]2CCC2CC(CC[C@]12C)=O)=O)=O KZWLJIVNHQVHPZ-AJCIZGFSSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N Corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
- 240000004051 Cosmos caudatus Species 0.000 description 1
- 235000005956 Cosmos caudatus Nutrition 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-N Crotonic acid Chemical class C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N Dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 229940093915 Gynecological Organic acids Drugs 0.000 description 1
- 241001190717 Hea Species 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N Martius yellow Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N Phenylacetic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N Phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
- LJCNRYVRMXRIQR-UHFFFAOYSA-L Potassium sodium tartrate Chemical compound [Na+].[K+].[O-]C(=O)C(O)C(O)C([O-])=O LJCNRYVRMXRIQR-UHFFFAOYSA-L 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000212342 Sium Species 0.000 description 1
- ASCUXPQGEXGEMJ-GPLGTHOPSA-N [(2R,3S,4S,5R,6S)-3,4,5-triacetyloxy-6-[[(2R,3R,4S,5R,6R)-3,4,5-triacetyloxy-6-(4-methylanilino)oxan-2-yl]methoxy]oxan-2-yl]methyl acetate Chemical compound CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](COC(=O)C)O[C@@H]1OC[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](NC=2C=CC(C)=CC=2)O1 ASCUXPQGEXGEMJ-GPLGTHOPSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000011717 all-trans-retinol Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000012223 aqueous fraction Substances 0.000 description 1
- WPUJEWVVTKLMQI-UHFFFAOYSA-N benzene;ethoxyethane Chemical compound CCOCC.C1=CC=CC=C1 WPUJEWVVTKLMQI-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000004059 degradation Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- 125000001145 hydrido group Chemical group *[H] 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- XGZVLEAZGCUUPH-UHFFFAOYSA-N methylamino(methylimino)methanesulfonic acid Chemical compound CNC(=NC)S(O)(=O)=O XGZVLEAZGCUUPH-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 150000004707 phenolate Chemical class 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003128 pregnanes Chemical class 0.000 description 1
- 150000003130 pregnenes Chemical class 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 230000000576 supplementary Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 125000005039 triarylmethyl group Chemical group 0.000 description 1
- OPSWAWSNPREEFQ-UHFFFAOYSA-K triphenoxyalumane Chemical compound [Al+3].[O-]C1=CC=CC=C1.[O-]C1=CC=CC=C1.[O-]C1=CC=CC=C1 OPSWAWSNPREEFQ-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Definitions
- the process comprises converting into the corresponding acid halides, saturated or unsaturated derivatives of 3-hydroxy-etio-cholanic acid or derivatives of the same, which are further substituted in the ring system, and whose hydroxyl groups in the ring are protected by etherification or acylation; these acid halides are introduced into an excess of diazomethane solution and the 2l-diazo ketones obtained subjected, if desired after preliminary alkaline saponification, to the action of aqueous inorganic acids containing oxygen or organic sulphonic acids, hydrohalic acids or organic carboxylic acids; or diazomethane is slowly added to the acid halides mentioned and the product obtained subjected, if desired, to acid saponification; in the case 2l-hydroxy ketones are obtained they may be subjected after etherification to alkaline saponification, and in the case of 2l-halo-ketones, the halogen atoms may be replaced by monovalent radicals containing oxygen.
- lit-substituted side chain ketones of the cyclopentanopolyhydrophenanthrene series can also be obtained by starting from cyclopentanopolyhydrophenanthrenel'l-carboxylic acid halides of the said series which contain, in ring A in 3-position a group convertible into hydroxyl by hydrolysis and, in ring C, in 11- and/or 12-position, keto groups, groups convertible by hydrolysis into hydroxyl groups or a double bond in which the carbon atom 11 participates.
- These starting materials which also may 01,775, dated June February 5, 1943. September 10, 1946, Switzerland October 5,
- the diazo-ketones or halo-ketones obtained the protected hydroxyl group in 3-position is set free by means of, in particular, hydrolyzing agents, and converted in known manner into a keto group, if necessary with temporary protection of carbon double bonds which may be present, and subsequently, or before oxidation of the free hydroxyl group, the diazoketone or halo-ketone grouping is converted into a free or esterified ketol group by means of organic or inorganic acids or alkalis or carboxylic acid salts; then a double bond is introduced, if desired, in the 4,5-position in a known way and the product finally treated, if desired, with hydrolyzing and/or esterifying agents.
- the starting materials may contain, in addition to those already mentioned, for example, the following substituents: substituted hydroxyl or carbinol groups, carbonyl or amino groups, halogen atoms, hydrocarbon residues, etc. They may be saturated, unsaturated in one or more places and may be of any steric configuration.
- the following substances may, for example, be used as starting materials: halides of saturated or unsaturated, esterified or etherified, 3hydroxy, 3,7- or 3,17-dihydroxy, 3,7,l7-trihydroxy, 3-hydroxy- '7-keto etiocholanic acids or the corresponding cholanic, nor-cholanic or bis-nor-cholanic acids, which contain in ring C in the 11- and/or 12- position keto groups, esterified or etherified hydroxyl groups, or a double bond in which the carbon atom 11 participates, i. e., located in the 9,11- or 11,12-position.
- the protected hydroxyl groups for example, can be esterified with inorganic or organic acids such as carboxylic acids, sulphonic acids or hydrohalic acids, or etherified with alcohols such as triarylmethyl or benzyl alcohols, or with phenols or enolized or acetalized carbonyl compounds.
- inorganic or organic acids such as carboxylic acids, sulphonic acids or hydrohalic acids
- alcohols such as triarylmethyl or benzyl alcohols
- phenols or enolized or acetalized carbonyl compounds instead of the starting products mentioned, their derivatives, e. g., enol derivatives or acetals of the compounds containing keto groups, may be used.
- the carboxylic acids used to start with may be obtained for example by degradation of bile acids, sterols,
- aliphatic diazo compounds used for the reaction with the acid halides may be ketone group.
- aliphatic diazo compounds are only added gradually to the acid halides, halo-ketones (COCH.Hlg) are produced which are also obtainable by subsequent action of a hydro-halide on the diazo ketones.
- the application of the diazoketones or haloketones obtained takes place in crude condition or after their separation and purification.
- the protected hydroxyl group in 3-positicn is set free.
- hydrolyzing agents are generally used; reducing agents may also be used, however, e. g. if benzyl ethers are present. If there are other protected hydroxyl groups in the molecule, e. g. ester groups in ring C, these may remain unchanged on using mild hydrolyzing agents, such as bicarbcnates, or .may be simultaneously saponified on stronger hydrolysis, e. g. with alkali hydroxides. Halo-"ketone are best hydrolyzed with acidic agents.
- the free 3-hydroxylgroup is converted, in a manner itself known, into a keto group, oxidizing agents such as chromic acid in glacial acetic acid or with dehydrogenating agents, e. g. heating with copper powder, action of metal alcoholates or phenolates in the presence of ketones, such as acetone or cyclohexanone. If necessary, carbon double-bonds Which may be present, are temporarily protected, e. g. by addition and later elimination of halogen or hydrohal'de.
- Other free hydroxyl groups, e, g. present in ring C may be converted at the same time as the 3- hydroxyl group .into keto groups. .On the other hand, with cautious dehydrogenation, e. g. using aluminium alcoholate or phenolate in the presence of ketones, a number of free nuclear hydroxyl groups may be only partly converted into keto groups, particularly the one in 3-position.
- the diazo-keto grouping which may be present, is converted into .a free or esterified ketol grouping by the .actionof anhydrous or diluted organic or inorganic'acids, e. g. acetic acid, propionic acid, butyric acids, crotonic acids, palmitic acid, benzoic acid, phenyl-acetic acid, sulphuric acids, methane-sulphonic acid, toluenesulphonic acid, hydrohalicacids, phosphoric acids or boric acid. Acylates, halides or sulphonic acid esters thus can be obtained for example.
- anhydrous or diluted organic or inorganic'acids e. g. acetic acid, propionic acid, butyric acids, crotonic acids, palmitic acid, benzoic acid, phenyl-acetic acid, sulphuric acids, methane-sulphonic acid, toluenesulphonic acid, hydrohalicacids
- halogen-ketone group is present instead of the diazothe former is converted, before or after the described oxidation, into a free or esterified ketol group by means of alkaline agents, e. g. bicarbonates or of carboxylic acid salts.
- ester groups which may be present can be saponified with hydrolyzing agents.
- the relative sensitiveness of the u-hydroxy ketone group to alkali should be taken into e. g. with consideration, so that it is preferable to work with acids or very weak alkalis. such as bicarbonates.
- esteri'fying agents can :be allowed to act. Radicals ,of..the above mentioned acids, but also, for example, of polycarboxylic acids, such as :phthalic or succinic acid, or of carbonic acid or its derivatives, thus may be introduced. If several hydroxyl-eroups ;are present, a complete or only a partial esterification, particularly in the 21-pos'ition, can be undertaken.
- R' esteerified hydroxyl group
- X oue or two keto or substituted or free hydroxyl groups, or one double bond.
- Halogen 5 parts of etio-desoxycholic acid diacetate, M. Pt. 202-204 C.,' are dissolved in 26.5 parts of pure thionyl chloride, the solution is allowed to stand for 39 minutes at C., then for 20 hours at room temperature and then evaporated to dryness in vacuo with exclusion of moisture.
- the crystalline residue is dissolved in 30 parts of dry benzene and added at about 15 C. to a solution of diazomethane in about 250 parts of dry ether (prepared from 16 parts of nitroso-methyl carbamide and dried by repeated distillation over solid potassium hydroxide). The mixture is allowed to stand, with exclusion of moisture, first for 2 hours at 0 C., then for 22 hours at room temperature.
- the golden yellow, oily residue consists of 5.87 parts of crude 21-diazo pregnane-3a, 12pdiol-ZO-one-diacetate and is worked up directly.
- the same triketone is further obtainable by oxidation with chromic acid of the pregnanc- 12;3,21-diol-3,20-dione-2l-monoacetate, prepared as described in Example 2.
- pregnane-21-ol-3,12,20-trione-acetate are dissolved in 950 parts of pure glacial acetic acid and a solution of bromine in glacial acetic acid, equivalent to 1 mol. bromine, is added. After an induction period of a few minutes, the solution rapidly becomes decolourized. It is then evaporated down in vacuo at 30 C. when transparent crystals separate out which are washed with absolute ether and a mixture of ether and petroleum ether. The bromide obtained in this way melts at l82-18'l.5 C. The mother-liquors give, after evaporating down in vacuo, an amorphous substance which can be reducedto the initial parent product by heating with zinc dust,
- the crystallized bromine compound is boiled with very pure pyridine for 5 hours under reflux. The mixture is then evaporated down in vacuo, the residue dissolved in ether, the ether solution washed with hydrochloric acid, sodium carbonate solution and water, dried and evaporated down. The residue is recrystallized from a mixture of acetone and ether and gives pale yellow prisms which are dissolved in benzene and chromatographed by running through a column of alum-inium oxide.
- Example 2 To 2.45 parts of pregnane-iia, 12,8,21-trlol-20- one-Zl-monoacetate, prepared as described in Example 1, benzene is added and the latter evaparatiom The productzis; now boiled, excluding moisture, with 12.4 parts of aluminiumrphenolate (freshly recrystallized froma mixture. of:benzenei and petroleum ether) 50.0 I parts. of .dry; benzene and: 1.70; parts of dry acetone for 2.0. hours under; refiuxon a'boiling water-bath.v After Cooling; the, mixture is evaporated down in vacuo, the residue. extracted with plenty ofxether, the.
- aluminiumrphenolate freshly recrystallized froma mixture. of:benzenei and petroleum ether
- the extracts obtained with mixtures of'benzene. and petroleum ether, benzene, and benzene and ether give oily products or ones which do not meltsharply.
- the extracts obtained with benzene and ether, ether, and ether and chloroform give on evaporating down and recrystallizing from benzene, pregnane-l2p,2l-dlol 3,20 dione 21 monoacetate as colourless crystals, M.
- the substance is A -pregnene-l2,B,2l-diol-3,2O dione-Zl-monoacetate;
- The: substanceshowsj in the'ultraviolet absorption spectrum; a band with a. maximum at 244 m or which g,f,e 4:l2' (in absolute alcohol).
- the substance is presumably a hydrate of A pregnene-l2d21-diol 3,20- dione.
- a stereoisomeric product can be obtained .by usingas starting. material for the synthesis the corresponding substance, isomeric in 12-position.
- the ether solution is washed. with'water, dried over sodiumsulphate and evaporated down.
- the brown amorphous residue consists mainly of 21-diazo-pregnane-3a,l2/3- diol-20-one-lz-monoacetate.
- Example 1 They consistof pregnane-3a,l2fi- 2-l-triol-20-one-12,2l-diacetate. From further extractions with chloroform, a small quantity of the 2l-monoacetate described: in Example 1 is also'obtained'.
- this compound may first be de- 5 hydrogenated to 2l-diazo-pregnane-3,20-dione- 12B-ol-acetate, for example by means of an aluminium alcoholate or phenolate in presence of acetone or cyclohexanone, and the latter then be acetolyzed to the pregnane-12B,21-diol-3,20-dione-diacetate.
- the substance shows in the ultraviolet absorption spectrum a band with a maximum at 244 m and 10g 5:4.15 (in alcohol) and thus consists of A -pregnene-12 S,21-diol 3,20 dione diacetate.
- the same product can be obtained by acetylation of A -pregnene-12B,21-diol-3,20-dione (see Example 2) with acetic anhydride and absolute pyridine for 1 hour at 95 C.
- Example 4 The preparation of the parent material in this example can be carried out as follows:
- the product melts indefinitely and consists of a mixture of the stereo-isomeric 30L- and 3fi,11-dihydroxy-etio-cholanic acids. It is partially acetylated by boiling under reflux for one hour with 5 parts of glacial acetic acid and 1 part of acetic anhydride; 2 parts of Water are then added, a drop at a time, while the mixture is still hot, and boiling is continued for another 15 minutes. After the addition of more water, the mixture is considerably concentrated in vacuo and the acid completely precipitated by a further addition of water; filtered off by suction and dried in vacuo.
- the yellow crystalline substance has the formula C22H34O5 and melts indefinitely, as it consists of a mixture of the stereo-isomeric 341- and 3e-acetoxy-l1 hydroxy etio cholanic acids.
- the yield is 1.1 parts.
- the well-dried product is dissolved in 6 parts of pure thionyl chloride and allowed to stand for 16 hours at room temperature, excluding moisture. The solution is then evaporated down in vacuum and the residue, crude A -3-acetoxyetio-cholenic acid-chloride, dissolved in 10 parts of dry benzene.
- the benzene solution of the parent material thus obtained is introduced at 0 C. into a dry ether solution of diazomethane prepared from 5 parts of nitrosomethyl carbamide. This mixture is first allowed to stand for 2 hours at 0 C., then for 12 hours at room temperature, is then evaporated down at a bath temperature of 50 C. and the residue dried in vacuo.
- the obtained 1.15 parts of crude yellow diazoketone are dissolved in 15 parts of methyl alcohol, a solution of 0.75 part potassium hydroxide in 1 part of water and 35 parts of methyl alcohol is added, and thewhole allowed to stand for 8 hours at room temperature.
- the colourless crystals have an empirical formula of (3231-13204; they rapidly reduce alkal ne .silver-diamine solution at room tem- 11 perature and give, when dissolved in a little chloroform, a pronounced yellow colour with tetra-nitro-methane.
- the latter maybe acetolyzed to the;21- :aceto-xy-ketone and then be oxidized, for example with chromium trioxide in-glacial acetic-acid, the nuclear double bond being protected before the 'oxidation, e. g. by addition of bromine, and regeneratedafterwards, for example by reacting with zinc dust or analkali iodide.
- the product is now brominated in glacial acetic acid with 2 mols bromine and then debrominated by boiling for 5 hours'with absolute pyridine or by heating to 150C. forg-2 hours with dimethylaniline.
- Thecrude product is heated to 80 C.
- the -substance has the empirical formula (3231-13004, reduces alkaline silver-diamine solution rapidly and markedly at room temperature; dissolved in 'a little chloroform, it gives apronounced yellow colour on the addition of tetranitromethane.
- the product, A -21- acetoxy-pregnadiene-3,20-'dione, is distinguished by a veryhigh activity onadrenalectomized rats.
- the crude .21-,diazowpregnane-ic l-l1 ,20edione-acetate . is dissolved 1300 parts of .methyl alcohol, a solution of 15 partsbf ,potassiumfhydroxide in 20 parts of water and 700 parts of rnethylalcohol added, and th e whole allowed to stand for 3 hoursat 20 C.
- a solution of 32 parts of potassium bicarbonate in 1000 parts of Water is then added, the methylalcohol removedin vacuo and theremaining suspension extracted with a largev quantity of ether.
- the ether solution after washing with water and drying over 12 sodium sulphate; is concentrated "at a bath-temperature of 50 C. and then completely evaporated -dow-n in vacuof24parts of crude 21-dia'zopregnane-Be-ol-l1,20-dioneremaining-as a light brown resin.
- this compound may first be dehydrogenated to- -21- diazo-pregnane-3,11,20 trione, for example by means of ,an aluminium :alcoholateor .phenolate in presence of acetoneroreyclohexanone,gandthe latterthen.be acetolyzed tothe 211acetoxy-pregnane-,3,1l,20-trione.
- a normal bromine solution is :firstvprepared by mixing 10 parts ,of bromine with ⁇ 1384 parts of glacial acetic acid. .9.6 ;*parts :of the pregnanc- This bromide is bollediurrder refluxfforfi hours with looparts'of'absolute pyridine. After evaporating down in vacuo, the residue is dissolved in a large quantity of ether, the ether solution washed with a little dilute hydrochloric acid, sodium carbonate solution and water, dried over sodium sulphate and evaporated down. The residue is purified chromatographically over a column of aluminium oxide, when the first benzene extracts give crystals which melt indefinitely at a low temperature.
- an ester stereoisomeric in 3-position can be used as starting product. If the process is started, however, from a 3,1l-diacyloxy-etiocholanic acid (if desired with different ester groups in 3- and ll-position), corticosterone, llisocorticosterone, or their ll-mono-esters or 11,21-diesters may be obtained in an analogous way, whereby the possibility exists of preparing mixed diesters.
- the intermediate products in the latter syntheses are for example the pregnane- -ones, containing in ll-position a hydroxyl group or a group convertible into hydroxyl by hydrolysis, in 3-position the said groups or a keto group and in 2l-position a halogen or a diazo group.
- a process for the manufacture of an asubstituted side-chain ketone of the cyclopentanopolyhydrophenanthrene series which comprises reacting with an aliphatic diazo compound a .cyclopentanopolyhydrophenanthrene l7 carboxylic acid halide which containsin ring A in 3-position a group convertible into hydroxyl by hydrolysis and in ring C in at least one of the positions 11 and 12 a member of the group consisting of a keto group and a group convertible by hydrolysis into hydroxyl, subjecting the resultant diazoketone to the action of a hydrolyzing agent whereby the group present in 3-position is converted into free hydroxyl, and then reacting the resultant product with a member of the group consisting of oxidizing agents and dehydrogenating agents whereby the free hydroxy in 3- position is converted into keto and then with a member of the group consisting of acids, alkalis and carboxylic acid salts whereby the diazo-keto radical is converted into a keto
- a process for the manufacture of an oc-Sllbstituted side-chain ketone of the cyclopentanopolyhydrophenanthrene series which comprises reacting with an aliphatic diazo compound a cyclopentanopolyhydrophenanthrene l7 carboxylic acid halide which contains in ring A in 3-position a group convertible into hydroxyl by hydrolysis and in ring C in at least one of the positions 11 and 12 a member of the group consisting of a keto group and a group convertible by hydrolysis into hydroxyl, and subjecting the resultant diazoketone to the action of a hydrolyzing agent whereby the group present in 3-position is converted into free hydroxyl, and then reacting the resultant product with a member of the group consisting of acids, alkalis and carboxylic acid salts whereby the diazoketo radical is converted into a ketol radical and then with a member of the group consisting 0t oxidizing agents and dehydrogenating agents whereby the free hydroxy
- a process for the manufacture of an oc-Sllbstituted side-chain ketone of the cyclopentanopolyhydrophenanthrene series which comprises reacting with an aliphatic diazo compound an unsaturated oyclopentanopolyhydrophenanthrenell-carboxylic acid halide which contains in ring A in 3-position a group convertible into hydroxyl by hydrolysis and in ring C in at least one of the positions 11 and 12 a member of the group consisting of a keto group and a group convertible by hydrolysis into hydroxyl, subjecting the resultant diazoketone to the action of a hydrolyzing agent whereby the group present in 3-position is converted into free hydroxyl, reacting the resultant product with halogen to saturate carbon double bonds present; and reacting the resultant prodnot with a member of the group consisting of oxidizing agents and dehydrogenating agents whereby the free hydroxyl in 3-position is converted into keto, reacting the resultant product with a
- a process for the manufacture of an a-Sllbstituted side-chain ketone of the cyclopentanopolyhydrophenanthrene series which comprises reacting with an aliphatic diazo compound an unsaturated cyclopentanopolyhydrophenanthrene l'l-carboxylic acid halide which contains in ring A in 3-position a group convertible into hydroxyl by hydrolysis and in ring C in at least one of the positions 11 and 12 a member of the group consisting of a keto group and a group convertible by hydrolysis into hydroxyl, subjecting the resultant diazoketone to the action of a hydrolyz ing agent whereby the group present in 3-position is converted into free hydroxyl, reacting the re- .15 sult'ant 'product'with a member of the group consisting of :acids, alkalis and carboxylic acid salts whereby the diazoketo radical is converted into-a *ketol radical, reacting the resultant productwit
- cyclopentanopolyhydrophenanthrene- 1'7 -carboxylic acid halide which is saturated in the rings A and B and which contains in ring A in 3-position a group convertible into hydroxyl by hydrolysis and in ring C in at least one of the positions 11 and .12 amember of the group consisting of a lketo group and a group convertible by hydrolysis into hydroxyl, subjecting the resultant diazoketone to the action of a hydrolyzing agent whereby the group present in 3-position is converted into free hydroxyl, reacting-the product with a member of the group consisting of oxidizing agents and dehydrogenating agents whereby the free hydroxyl in 3-position is converted into keto,
- a process for the manufacture of an lX-Substituted side-chain ketone of the cyclopentanopolyhydrophenanthrene series which comprises reacting with-an aliphatic diazo compound a cyclopen-tanopolyhydrophenanthrene 17 carbox- ,ylicacid halide which is saturated in the rings .A ancLB and which contains in ring A in 3-position a group convertible into hydroxyl by hydrolysis-and inring-C- in, at least one of the positions 11 and 12 a member of the group consisting of aketo group and ra group convertible by hydrolysis into hydroagyl, subjecting the resultant diazoketone to .theaction ofa mild .hydrolyzing agent whereby only the group pr-esent, in 3-posi-tion is .sele ctively converted: into free hydroxyl, reacting the product with a member-ofthegroup consistingpf-oxidizing agents and dehydrogenating agents whereby .the free ket
- a process for the manufacture-of an a-substituted side-chain ketone of the cyclopentanopolyhydrophenanthrene series which comprises reacting with an aliphatic diazo compounds, cyc1opentanopolyhydrophenanthrene 17 -carboxylic'acid halide which is'saturated in the rings A and B and which contains in ring A in 3-position a group convertible into hydroxyl by hydrolysis and in ring C in at least one of the positions 11 and 12 a member of the group consisting of a keto group and a group convertible by hydrolysis into hydroxyl, subjecting the resultant dia-zoketcne to the action of a strong hydrolyzing agent whereby all groups which are convertible into hydroxyl by hydrolysis are so-converted,'reacting the product with a member of the group consisting of oxidizing agents and dehydrogenating agents whereby the free hydroxyl in 3-position is converted intoketo, then reacting the resultant product with a
- the compounds of the pregnene series containing a ketonic oxygen at the carbon atom 3 and, as sole substituent in ring C, at the carbon atom 12 a member of the group consisting of hydroxyl, a group convertible into hydroxyl by hydrolysis and a ketonio oxygen, at the carbon atom 20 a ketonic oxygen and at the carbon atom 21 a member of the group consisting of a hydroxyl and an esterified hydroxyl.
- the saturated compounds of the pregnane series containing a ketonic oxygen at the carbon atom 3 and, as sole substituent in ring C, at the carbon atom 12 a member of the group consisting of hydroxyl, a group convertible into hydroxyl by hydrolysis and a ketonic oxygen, at the carbon atom 20 a ketonic oxygen and at the carbon atom 21 a member of the group consisting of a hydroxyl and an esterified hydroxyl.
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Description
Reissued Nov. 25 1947 tX-SUBSTITUTED SIDE-CHAIN KETONES OF THE CYCLOPENTANOPOLYHYDRO- PHENANTHRENE SERIES AND PROC- ESS OF MAKING SAME Tadeus Reichstein, Basel, Switzerland No Drawing. Original No. 2,4 11, 1946, Serial No. 474,892, Application for reissu Serial No. 695,834. 1942 16 Claims.
In U. S. patent application Serial No. 195,161, a process is described for the manufacture of saturated and unsaturated derivatives of pregnane-3-ol-20-0ne which contain in the Zl-position a diazo group, halogen or a monovalent oxygen radical and which may be further substituted in the ring system, in particular with hydroxyl, acyloXy, alkoxy or oxide groups. The process comprises converting into the corresponding acid halides, saturated or unsaturated derivatives of 3-hydroxy-etio-cholanic acid or derivatives of the same, which are further substituted in the ring system, and whose hydroxyl groups in the ring are protected by etherification or acylation; these acid halides are introduced into an excess of diazomethane solution and the 2l-diazo ketones obtained subjected, if desired after preliminary alkaline saponification, to the action of aqueous inorganic acids containing oxygen or organic sulphonic acids, hydrohalic acids or organic carboxylic acids; or diazomethane is slowly added to the acid halides mentioned and the product obtained subjected, if desired, to acid saponification; in the case 2l-hydroxy ketones are obtained they may be subjected after etherification to alkaline saponification, and in the case of 2l-halo-ketones, the halogen atoms may be replaced by monovalent radicals containing oxygen.
In French Patent No. 840,417 an analogous process is described, starting from earboxylic acid halides which are derived from ring ketones of the cyclopentanopolyhydrophenanthrene series or their enol derivatives.
In none of these patents are there mentioned asstarting products carboxylic acids of the cyclopentanopolyhydrophenanthrene series or their halides which contain a ring A in the 3-position an esterified or etherified hydroxyl group, and in ring in the 11- and/or 12-position, keto groups, esterified or etherified hydroxyl groups or a double bond in which the carbon atom 11 participates.
It has now been found that lit-substituted side chain ketones of the cyclopentanopolyhydrophenanthrene series can also be obtained by starting from cyclopentanopolyhydrophenanthrenel'l-carboxylic acid halides of the said series which contain, in ring A in 3-position a group convertible into hydroxyl by hydrolysis and, in ring C, in 11- and/or 12-position, keto groups, groups convertible by hydrolysis into hydroxyl groups or a double bond in which the carbon atom 11 participates. These starting materials, which also may 01,775, dated June February 5, 1943. September 10, 1946, Switzerland October 5,
. ZED-397.4)
be further substituted, are caused to react with aliphatic diazo compounds; in the diazo-ketones or halo-ketones obtained the protected hydroxyl group in 3-position is set free by means of, in particular, hydrolyzing agents, and converted in known manner into a keto group, if necessary with temporary protection of carbon double bonds which may be present, and subsequently, or before oxidation of the free hydroxyl group, the diazoketone or halo-ketone grouping is converted into a free or esterified ketol group by means of organic or inorganic acids or alkalis or carboxylic acid salts; then a double bond is introduced, if desired, in the 4,5-position in a known way and the product finally treated, if desired, with hydrolyzing and/or esterifying agents.
The starting materials may contain, in addition to those already mentioned, for example, the following substituents: substituted hydroxyl or carbinol groups, carbonyl or amino groups, halogen atoms, hydrocarbon residues, etc. They may be saturated, unsaturated in one or more places and may be of any steric configuration. The following substances may, for example, be used as starting materials: halides of saturated or unsaturated, esterified or etherified, 3hydroxy, 3,7- or 3,17-dihydroxy, 3,7,l7-trihydroxy, 3-hydroxy- '7-keto etiocholanic acids or the corresponding cholanic, nor-cholanic or bis-nor-cholanic acids, which contain in ring C in the 11- and/or 12- position keto groups, esterified or etherified hydroxyl groups, or a double bond in which the carbon atom 11 participates, i. e., located in the 9,11- or 11,12-position. The protected hydroxyl groups, for example, can be esterified with inorganic or organic acids such as carboxylic acids, sulphonic acids or hydrohalic acids, or etherified with alcohols such as triarylmethyl or benzyl alcohols, or with phenols or enolized or acetalized carbonyl compounds. Finally, instead of the starting products mentioned, their derivatives, e. g., enol derivatives or acetals of the compounds containing keto groups, may be used. The carboxylic acids used to start with, may be obtained for example by degradation of bile acids, sterols,
enins from cardiac glucosides, etc., or synthetically starting from the corresponding ring ketones. The surprising observation was made that acid halides of 11- or l2-keto acids can be prepared without difficulty and with a much better yield than, for example, those of 3-keto acids.
Amongst the aliphatic diazo compounds used for the reaction with the acid halides may be ketone group.
however, the aliphatic diazo compounds are only added gradually to the acid halides, halo-ketones (COCH.Hlg) are produced which are also obtainable by subsequent action of a hydro-halide on the diazo ketones.
The application of the diazoketones or haloketones obtained takes place in crude condition or after their separation and purification. As next step the protected hydroxyl group in 3-positicn is set free. For this purpose hydrolyzing agents are generally used; reducing agents may also be used, however, e. g. if benzyl ethers are present. If there are other protected hydroxyl groups in the molecule, e. g. ester groups in ring C, these may remain unchanged on using mild hydrolyzing agents, such as bicarbcnates, or .may be simultaneously saponified on stronger hydrolysis, e. g. with alkali hydroxides. Halo-"ketone are best hydrolyzed with acidic agents.
The free 3-hydroxylgroup is converted, in a manner itself known, into a keto group, oxidizing agents such as chromic acid in glacial acetic acid or with dehydrogenating agents, e. g. heating with copper powder, action of metal alcoholates or phenolates in the presence of ketones, such as acetone or cyclohexanone. If necessary, carbon double-bonds Which may be present, are temporarily protected, e. g. by addition and later elimination of halogen or hydrohal'de. Other free hydroxyl groups, e, g. present in ring C, may be converted at the same time as the 3- hydroxyl group .into keto groups. .On the other hand, with cautious dehydrogenation, e. g. using aluminium alcoholate or phenolate in the presence of ketones, a number of free nuclear hydroxyl groups may be only partly converted into keto groups, particularly the one in 3-position.
After, or even before, oxidation of the 3-hydroxyl group, the diazo-keto grouping, which may be present, is converted into .a free or esterified ketol grouping by the .actionof anhydrous or diluted organic or inorganic'acids, e. g. acetic acid, propionic acid, butyric acids, crotonic acids, palmitic acid, benzoic acid, phenyl-acetic acid, sulphuric acids, methane-sulphonic acid, toluenesulphonic acid, hydrohalicacids, phosphoric acids or boric acid. Acylates, halides or sulphonic acid esters thus can be obtained for example. If a halogen-ketone group is present instead of the diazothe former is converted, before or after the described oxidation, into a free or esterified ketol group by means of alkaline agents, e. g. bicarbonates or of carboxylic acid salts.
If a double bond is to be introduced in the 4,5- position, this can be done in a known way, e. g. by halogenation and subsequent elimination of hydrohalide.
In a further step, ester groups which may be present can be saponified with hydrolyzing agents. The relative sensitiveness of the u-hydroxy ketone group to alkali should be taken into e. g. with consideration, so that it is preferable to work with acids or very weak alkalis. such as bicarbonates.
Finally esteri'fying agents can :be allowed to act. Radicals ,of..the above mentioned acids, but also, for example, of polycarboxylic acids, such as :phthalic or succinic acid, or of carbonic acid or its derivatives, thus may be introduced. If several hydroxyl-eroups ;are present, a complete or only a partial esterification, particularly in the 21-pos'ition, can be undertaken.
The most important stages of the reaction may .be illustrated by the following formulas:
00.0mm 00.01am
" yin Hlg l cosmos -R;group convertible into hydroxyl by hydrolysis.
R'=esterified hydroxyl group.
X=oue or two keto or substituted or free hydroxyl groups, or one double bond.
Halogen 5 parts of etio-desoxycholic acid diacetate, M. Pt. 202-204 C.,' are dissolved in 26.5 parts of pure thionyl chloride, the solution is allowed to stand for 39 minutes at C., then for 20 hours at room temperature and then evaporated to dryness in vacuo with exclusion of moisture. The crystalline residue is dissolved in 30 parts of dry benzene and added at about 15 C. to a solution of diazomethane in about 250 parts of dry ether (prepared from 16 parts of nitroso-methyl carbamide and dried by repeated distillation over solid potassium hydroxide). The mixture is allowed to stand, with exclusion of moisture, first for 2 hours at 0 C., then for 22 hours at room temperature. It is then concentrated consider ably on a water-bath and finally completely dried in vacuo. The golden yellow, oily residue consists of 5.87 parts of crude 21-diazo pregnane-3a, 12pdiol-ZO-one-diacetate and is worked up directly.
For saponification of the two acetate groups, it is mixed with a solution of 3.37 parts potassium hydroxide (4.5 mol.) in 5 parts of water and '75 parts of methyl alcohol and allowed to stand for 22 hours at room temperature. A solution of about 6 parts of potassium bicarbonate in 120 parts of water is then added, the mixture freed from methyl alcohol in a vacuum and extracted with much ether. The ether solution is washed with water, dried over sodium sulphate and evaporated down. The product obtained consists of 4.39 parts of a crude 21-diazo-pregnane-3a,l2pdiol-ZO-one.
This preparation is heated in 25 parts of pure glacial acetic acid to 100 C. After 55 minutes the calculated quantity of gas is liberated and the reaction finished. The light brown solution is evaporated to dryness in vacuo, the residue dissolved in dry benzene and separated chromatographically by running through a column of aluminium oxide. After some oily material has been eluted, a compound is obtained with mixtures of ether and chloroform which gives on crystallisation from a mixture of ether and methyl alcohol,
needles with a double melting point 94-110 C.
and 144-1485 C. When recrystallized from aqueous methyl alcohol it melts at 149.5-150.5 C. and has a specific rotation of [a] =+139.7- -4 (in acetone). The product is pregnane-3u,12li,21- triol-20-one-21-monoacetate. With a mixture of chloroform, ethyl acetate and methyl alcohol a further amorphous product is extracted which contains the same monoacetate.
6 parts of the above mentioned compound are dissolved in 160 parts of pure glacial acetic acid, a solution of 3 parts of chromium trioxide in 160 parts of glacial acetic acid is added and the whole allowed to stand for 16 hours at 18 C. The mixture is evaporated down in vacuo at 30 C., a little water added to the residue and the latter extracted with plenty of ether. The ether solution is washed with dilute sulphuric acid, sodium carbonate solution and water, dried over sodium sulphate and evaporated down. Crystals are ob tained from a mixture of benzene and ether, precipitation of which is completed by the addi- 6 tion of petroleum ether. They melt at 189-191" C. and have a specific rotation of [a] =+153.O- 3 (in acetone). The substance is pregnane-Zl-ol- 3,12,20-trione-acetate.
Considerable quantities of the same triketone can also be obtained by oxidation of the amorphous pregnane-3a,l2;3,2l-triol-20-one-21-mono acetate.
The same triketone is further obtainable by oxidation with chromic acid of the pregnanc- 12;3,21-diol-3,20-dione-2l-monoacetate, prepared as described in Example 2.
parts of pregnane-21-ol-3,12,20-trione-acetate are dissolved in 950 parts of pure glacial acetic acid and a solution of bromine in glacial acetic acid, equivalent to 1 mol. bromine, is added. After an induction period of a few minutes, the solution rapidly becomes decolourized. It is then evaporated down in vacuo at 30 C. when transparent crystals separate out which are washed with absolute ether and a mixture of ether and petroleum ether. The bromide obtained in this way melts at l82-18'l.5 C. The mother-liquors give, after evaporating down in vacuo, an amorphous substance which can be reducedto the initial parent product by heating with zinc dust,
and sodium acetate in glacial acetic acid.
The crystallized bromine compound is boiled with very pure pyridine for 5 hours under reflux. The mixture is then evaporated down in vacuo, the residue dissolved in ether, the ether solution washed with hydrochloric acid, sodium carbonate solution and water, dried and evaporated down. The residue is recrystallized from a mixture of acetone and ether and gives pale yellow prisms which are dissolved in benzene and chromatographed by running through a column of alum-inium oxide.
The fractions eluted with mixtures of benzene and petroleum ether and the first ones with benzene give a product which melts indefinitely at about -180 C. The further fractions extracted with absolute benzene, and mixtures of benzene and ether give, on recrystallization from a mixture of acetone and ether, the N-pregnene- 21-ol-3,12,20-trione-monoacetate as colourless prisms of melting point 182-184 C. and specific rotation [a] =-+228.6i3 (in acetone).
6 parts of this preparation are dissolved in 65 parts of methyl alcohol, a solution of 7 parts of potassium bicarbonate in 22 parts of water is added, and the whole allowed to stand for 23 hours at room temperature. A little water is then added and the methyl alcohol completely removed in vacuo. The material which separates out in crystalline form is filtered off with suction, washed with water and dried in vacuo. By extracting the aqueous fractions with a mixture of ether and chloroform (5:1) a small supplementary amount can be obtained. Double recrystallization from a mixture of benzene and ether gives colourless long needles which melt at 180- 183 C. and have a specific rotation of Example 2 To 2.45 parts of pregnane-iia, 12,8,21-trlol-20- one-Zl-monoacetate, prepared as described in Example 1, benzene is added and the latter evaparatiom The productzis; now boiled, excluding moisture, with 12.4 parts of aluminiumrphenolate (freshly recrystallized froma mixture. of:benzenei and petroleum ether) 50.0 I parts. of .dry; benzene and: 1.70; parts of dry acetone for 2.0. hours under; refiuxon a'boiling water-bath.v After Cooling; the, mixture is evaporated down in vacuo, the residue. extracted with plenty ofxether, the. ethersolution washed with a concentrated: solution or sodium potassium tartrate, with diluteihydrochloricacid; potassium bicarbonatesolutiom and water, dried; over sodium sulphate andevaporated down. The free phenol is then first removed as far. as possible by-heating in ahigh vacuum-at .95? C; The crystalline' residue, which stillcontains-some phenol, is-dissolved in.120 parts-of dry benzene, diluted with the same quantity ofpetroleum' ether and chromatographed by allowing to run through a column of aluminium oxide preparedwith petroleum ether.
The extracts obtained with mixtures of'benzene. and petroleum ether, benzene, and benzene and ether give oily products or ones which do not meltsharply. The extracts obtained with benzene and ether, ether, and ether and chloroform give on evaporating down and recrystallizing from benzene, pregnane-l2p,2l-dlol 3,20 dione 21 monoacetate as colourless crystals, M. Pt, 199- 192 C., [ot] =+146.3' -3 (in acetone), With chloroform anda mixture of chloroform, ethyl acetate and methyl alcohol, a yellow amorphous product is eluted, which can be oxidized with; chromic acid as may be the pure product, to pregnane-Z1 ol-3j12,20 trionoatletate '(see ExampIe'Dl.
4 parts of pregnane-l2fl,2l-diol-3,20-dione-21-. m-onoacetate are dissolved in 60 parts of pure" lacial aceticacid andbrominatedwith a normal solution of bromine in glacial aceticacid as described in Example 1; The mixtureis then immediately evaporated down in vacuoat 25 C. and a little absolute ether added to theresidue, when crystallization occurs. The crystals, after-wash= ing with some ether and a mixture of? ether. and petroleum ether, melt at 171-1720. with decomposition. The crystallized-bromideiswell dried and boiledu-nder reflux with 50 parts of absolute pyridine for 5-hours. The mixture-is then evaporated down in vacuo, the residue dissolved in ether, the ethersolution washed until neutral, dried and evaporated down. The crude, crystalline aggregate is recrystallized once froma mixtureof acetone and ether, then dissolvedin benzene and purified chromatographically over' a column of aluminium oxide, The extracts thus obtained with benzene and ether, absolute ether, and ether and chloroform (up to 114;) crystallize from a mixture of-acetoneand ether in needles which melt, after washing with' ether, at 182-184? C. and show a specific rotation-of The substance is A -pregnene-l2,B,2l-diol-3,2O dione-Zl-monoacetate; The: substanceshowsj in the'ultraviolet absorption spectrum; a band with a. maximum at 244 m or which g,f,e=4:l2' (in absolute alcohol).
In quite an analogous Way another 2l-ester, for example the propionat'e; butyrates, palmitate or benzoate, is obtained, when the SYntheSiSflS started with the. corresponding. ester.
6' parts of the. said 'zbmonoacetate' are dis;-
reform).
solved; in. 60v parts ofmethyl alcohol, asolution of .62 parts: of; potassium bicarbonate in 20.- parts of. water is added, andthe whole allowed to stand: Some more.
The substance is presumably a hydrate of A pregnene-l2d21-diol 3,20- dione. A stereoisomeric productcan be obtained .by usingas starting. material for the synthesis the corresponding substance, isomeric in 12-position.
Example 3.
5.8 parts of crude 21-diazo-pregnane=31,12 3, diol20 .-one-.-diacetate, prepared as described in. Example 1 from 4.7 parts of etio-desoxycholic. acid diacetate, are-mixed witha solution of 2.8, parts potassium carbonate and 0.7 part potasa sium bicarbonate in 51 partsof Water and 115. parts of methylalcohol, in order to saponify one. of the two acetate groups, and the whole allowed to. stand at room temperature for 44 hours. Water is added to the mixture which then is freed from methyl alcohol in vacuo andextracted with. plenty: of ether, when flocculent. impurities re main undissolved. The ether solution is washed. with'water, dried over sodiumsulphate and evaporated down. The brown amorphous residue consists mainly of 21-diazo-pregnane-3a,l2/3- diol-20-one-lz-monoacetate.
The latter is heated to C. with 22- parts of pure anhydrous glacial acetic acid. After 30. minutes approximately the calculated amount oi nitrogen has been liberated and the reaction is finished. The light brown solution is evaporat ed. down-to dryness in vacuo, the residue dissolved in 100 parts of benzene, diluted with 300 parts. of petroleum ether and chromatographed through a column of aluminium oxide. On elution with amixture of benzene and-ether crystals areobtained which, on recrystallization from a mixture of acetone and ether, melt at 156-158 C. and. have a specific rotation of- [u] =+150.7:2 (in acetone). They consistof pregnane-3a,l2fi- 2-l-triol-20-one-12,2l-diacetate. From further extractions with chloroform, a small quantity of the 2l-monoacetate described: in Example 1 is also'obtained'.
2 parts of the diacetateare dissolved in 221 parts of pure glacial acetic acid, 23 parts; of,a12; per cent solution of chromium trioxidein glacial acetic acid is added and the whole allowed to stand for 16 hours at 20 C. The mixture is evaporated down in vacuo almost to dryness, (temperature of the bath 25 0.), water added to. the residue, and the mixture extracted, with, plenty of ether. The ethersolution is washed until neutral, dried' and; considerably concert: trated. By the addition of petroleum-ether, 1.4 parts of long; colourless rods are obtained wh ch, on-recr-ystallization from a mixture'of ether and petroleum-ether, melt at -122 C; and have a specific. rotation of [aJ =+142.4:4- (in chlo- They consist of pregnane-12p,2l.-diol.-, 3,2 0-dione-diacetate. The sameproduct. canalso be obtained bythe acetylation; of pregnane-dfid 21-diol-3,20-dione-2l-monoacetate (see Example 2).
Instead of first acetolyzing and then oxidizing the 21-diazo-pregnane 3a,12}3dl01 20 one-12- monoacetate, this compound may first be de- 5 hydrogenated to 2l-diazo-pregnane-3,20-dione- 12B-ol-acetate, for example by means of an aluminium alcoholate or phenolate in presence of acetone or cyclohexanone, and the latter then be acetolyzed to the pregnane-12B,21-diol-3,20-dione-diacetate.
2 parts of the diacetate are dissolved in 14 parts of pure glacial acetic acid and brominated with a normal solution of bromine in glacial acetic acid, as described in Example 1. The mix- 5 ture is then immediately evaporated down in vacuo at 30 C. 0n the addition of absolute ether, the residue crystallizes and melts, after washing with ether and a mixture of ether and benzine, at 165176 C. with decomposition. The crystalline bromide is heated to boiling with 18 parts of pure pyridine for 5 hours under reflux. The solution is then evaporated down in vacuo, the residue dissolved in ether, the ether solution washed with hydrochloric acid, sodium carbonate solution and water, dried and evaporated down. The crystalline residue is recrystallized once from acetone-ether, the crystals, which do not melt sharply, dissolved in 20 parts of benzene, the solution diluted with 80 parts of petroleum ether and chromatographed by allowing to run through a column of aluminium oxide. From the fractions eluted with absolute benzene, and benzene-ether, colourless, glossy, double pyramids, M. Pt. 158-159 C., are obtained by recrystallization from a mixture of acetone, ether and hexane. The specific rotation is [a] =+197.7i5 (in acetone).
The substance shows in the ultraviolet absorption spectrum a band with a maximum at 244 m and 10g 5:4.15 (in alcohol) and thus consists of A -pregnene-12 S,21-diol 3,20 dione diacetate. The same product can be obtained by acetylation of A -pregnene-12B,21-diol-3,20-dione (see Example 2) with acetic anhydride and absolute pyridine for 1 hour at 95 C.
7 parts of the diacetate are dissolved in 550 parts of methyl alcohol, a solution of 12 parts of potassium bicarbonate in 300 parts of water is added, and the whole allowed to stand for 17 hours at 20 C. Some water is then added, the methyl alcohol removed in vacuo and the amorphous residue dissolved in a mixture of ether and chloroform (9:1). The ether and chloroform solution is washed several times with a little water, dried over sodium sulphate and evaporated down. The residue, after recrystallization from a mixture of benzene and ether, and from acetone and ether, gives colourless octahedrons, which melt at 188-192 C. and have a specific rotation of [m] =+185.3i2; I
l ma 6.3 i 3 (in acetone) Example 4 The preparation of the parent material in this example can be carried out as follows:
1 part of 3,1l-diketo-etio-cholanic acid methylester (M. Pt. 184 C.) is hydrogenated in 20 parts of pure glacial acetic acid after the addition of 0.4 part platinum oxide until the absorption of hydrogen ceases completely, which requires about 8 hours. After filtration, the solution is evaporated down and the residue boiled under reflux for 4 hours with a solution of 2- parts of potassium hydroxide in 2 parts of water and 20 parts of methyl alcohol. After the addition of 10 parts of water, the methyl alcohol is removed in vacuo, hydrochloric acid added to the residue, cooling continually, until acid reaction to congo is reached, and the precipitated crystalline acid filtered oil by suction, washed with water and dried in vacuo. The product melts indefinitely and consists of a mixture of the stereo-isomeric 30L- and 3fi,11-dihydroxy-etio-cholanic acids. It is partially acetylated by boiling under reflux for one hour with 5 parts of glacial acetic acid and 1 part of acetic anhydride; 2 parts of Water are then added, a drop at a time, while the mixture is still hot, and boiling is continued for another 15 minutes. After the addition of more water, the mixture is considerably concentrated in vacuo and the acid completely precipitated by a further addition of water; filtered off by suction and dried in vacuo. The yellow crystalline substance has the formula C22H34O5 and melts indefinitely, as it consists of a mixture of the stereo-isomeric 341- and 3e-acetoxy-l1 hydroxy etio cholanic acids. The yield is 1.1 parts. The well-dried product is dissolved in 6 parts of pure thionyl chloride and allowed to stand for 16 hours at room temperature, excluding moisture. The solution is then evaporated down in vacuum and the residue, crude A -3-acetoxyetio-cholenic acid-chloride, dissolved in 10 parts of dry benzene.
The benzene solution of the parent material thus obtained is introduced at 0 C. into a dry ether solution of diazomethane prepared from 5 parts of nitrosomethyl carbamide. This mixture is first allowed to stand for 2 hours at 0 C., then for 12 hours at room temperature, is then evaporated down at a bath temperature of 50 C. and the residue dried in vacuo. The obtained 1.15 parts of crude yellow diazoketone are dissolved in 15 parts of methyl alcohol, a solution of 0.75 part potassium hydroxide in 1 part of water and 35 parts of methyl alcohol is added, and thewhole allowed to stand for 8 hours at room temperature. A solution of 1.6 parts of potassium bicarbonate in 50 parts of water is then added, the methyl 5 alcohol removed in vacuo and the product thoroughly dried by evaporating off with dry benzene. It is then allowed to stand for 20 days in a sealed ampoule with 200 parts of dry benzene, parts of dry acetone and 5 parts of aluminium phenolate. It is then concentrated down considerably,
the residue extracted with ether and the ether solution washed with very dilute hydrochloric acid, sodium carbonate solution and water, dried over sodium sulphate and evaporated down. The residue is very well evacuated until the free phenol has been completely removed. This crude product is heated for 30 minutes to C. with 15 parts of pure anhydrous glacial acetic acid, when nitrogen escapes freely. Evaporation in vacuo gives crude A -21-acetoxy-pregnene- 3,20-dione. It is purified chromatographically by allowing a solution of it to run through A1203. The diketone is removed from the column with absolute benzene and can be obtained in a pure condition by re- 0 crystallization from a mixture of ether and petroleum ether. A product Which does not melt quite sharply at C. is suitable, however, for working up. The colourless crystals have an empirical formula of (3231-13204; they rapidly reduce alkal ne .silver-diamine solution at room tem- 11 perature and give, when dissolved in a little chloroform, a pronounced yellow colour with tetra-nitro-methane.
'Instead of dehydrogenating the 3-hydroxy diazoketone, the latter maybe acetolyzed to the;21- :aceto-xy-ketone and then be oxidized, for example with chromium trioxide in-glacial acetic-acid, the nuclear double bond being protected before the 'oxidation, e. g. by addition of bromine, and regeneratedafterwards, for example by reacting with zinc dust or analkali iodide.
The product is now brominated in glacial acetic acid with 2 mols bromine and then debrominated by boiling for 5 hours'with absolute pyridine or by heating to 150C. forg-2 hours with dimethylaniline. Thecrude product is heated to 80 C.
"for 15 minutes with 0.5 part of zinc dust and parts of glacial acetic acid, rotating continually. After filtration it is evaporated down in vacuo, extracted with ether, the solution Washed with dilute hydrochloric acid, sodium carbonate solution and water, dried over sodium sulphate and evaporated down. The residue is purified chromatographically. From the; fractions eluted with benzene, and With benzene and ether (99:1), colourless thin prisms are obtained, on recrystallizationfrom ether, which melt at 158-159" C. and have a specific rotation of lul=+129 C. '(acetone). The -substance has the empirical formula (3231-13004, reduces alkaline silver-diamine solution rapidly and markedly at room temperature; dissolved in 'a little chloroform, it gives apronounced yellow colour on the addition of tetranitromethane. The product, A -21- acetoxy-pregnadiene-3,20-'dione, is distinguished by a veryhigh activity onadrenalectomized rats.
Starting from M -'31P 'or A -3fi-acetoxyetio-cholenic acid, A -2l-acetoxy-pregnadiene-3,20-dione, melting at 141 C. and crystallizing 'from ether in fine needles, can be obtained in a similar Way. It shows "a specific rotation [al -|-98 (in acetone).
Example. 5
.23 parts not .offl-acctoxydl keto etio cholanic acid, .M. -P.t. 110-112" C. (obtainable-as described in U. S. Patent No. 2,403,683) ,are dissolved at 0 C. in 1-40 parts of very pure thionyl chloride, and allowed tostand, with-exclusion ofmoisture, at first for 30 minutes at 0 C., and the-n for v16 hoursat 18 C. The solutionis then concentrated downin vacuo (temperature of the bath 910 C.), the residue dissolved in 500 parts of dry benzene and the solution added .at 0 C. to ,a freshly distilledsolution of diazomethane in ether whichhas been prepared from 100 parts of nitrosomethyl carbamide and dried Over potassium hydroxide; gas is immediately liberated. The mixture is allowed to stand, at first for 2 hours at .0 0., with exclusionof moisture, and then for .16 hou-rs at 18 C.,; itiis.thenconcentratedi down considerablyat a bath temperature of. 50' 9., and finally, completely dried in .Vacuo. The residue-weighszfi parts.
The crude .21-,diazowpregnane-ic l-l1 ,20edione-acetate .is dissolved 1300 parts of .methyl alcohol, a solution of 15 partsbf ,potassiumfhydroxide in 20 parts of water and 700 parts of rnethylalcohol added, and th e whole allowed to stand for 3 hoursat 20 C. A solution of 32 parts of potassium bicarbonate in 1000 parts of Water is then added, the methylalcohol removedin vacuo and theremaining suspension extracted with a largev quantity of ether.
The ether solution, after washing with water and drying over 12 sodium sulphate; is concentrated "at a bath-temperature of 50 C. and then completely evaporated -dow-n in vacuof24parts of crude 21-dia'zopregnane-Be-ol-l1,20-dioneremaining-as a light brown resin.
The latter is =then'hea'ted-for 30 minutes=ito -100 C. with'300 partsof pure anhydrous glacial acetic acid and the-nitrogenliberatednollected' over water in a measuringcylinder. When the liberation of nitrogen is complete,-the solution is evaporated down in vacuo. -The 24 parts of residue which remain are purified in the-known way chromatographical ly overalurninium oxide.
The extracts obtained with mixtures of benzene and-ether 'give, on recrystallization from-ether and petroleum-ether pregnane-3532l-diol-1 1, "20- dione-Zl-monoacetate in colourless plateletsmelting at 178-181-C, Acetylation with acetic-anhydride and pyridine gives thecorresporiding-diacetate 169-171" C.
6.5 partsof the monoacetatedescribed=are-dissolved inlOO- partsofglaciailacetic acid, IOU-parts of a 2% solution of chromium trioxidei-n glacial acetic acid (2 parts CrOs) added, and:the whole is allowedto stand-for 16 hours at 20 C. 'It=is then concentratedxdown inv'acuo-at-a bath temperature of 39C., waterraddedand the whole extracted with ether. The ether solution is washed with dilute sulphuric acid, sodium ':car-
bonat'e solution :and "water, dried =over =so"d'iu-m sulphate and concentrated. Crystallization, whichsoon sets in, is completed-by theaddition of'some-petroleumether. In this way pregnanc- '3,11 ,20-tri'one-"2l-ol acetate is obtained in'colourless needles, M. Pt. 1"5'3-1'55" C., which show .-a specific rotation [e]5 =+.I0 7-:2i*4 tcon'centr-ation 0.783 in acetone).
Instead of first-acetolyzingand then oxidizing the 21-diazo-pregnane-3,6-ol 11,20-.dione, .this compound may first be dehydrogenated to- -21- diazo-pregnane-3,11,20 trione, for example by means of ,an aluminium :alcoholateor .phenolate in presence of acetoneroreyclohexanone,gandthe latterthen.be acetolyzed tothe 211acetoxy-pregnane-,3,1l,20-trione.
Instead of adding-the 3.;8- acetoxy-l1 ketoetiocholanic acid-chloride: to ail-excess ofdiazomethane solution, the latter :solution may be .added slowly to the benzene solution of the .-said acidchloride. -In this 163.88 the box-responding .21- chloro-20-.ketone is obtained,:-which-after sapon- .ification and oxidation .101 ,the 'substituent in 3- ,position, f or example bymeans. of 1 alcoholic .-hydrochloric. acid and of chromic-acid, can be converted also to the pregnane-3,11,20+trione-21--olacetate by means-for example, of an;alkali ace- :tate in acetoneor glacial. acetioacid' or 'of -silver acetate.
A normal bromine solution is :firstvprepared by mixing 10 parts ,of bromine with {1384 parts of glacial acetic acid. .9.6 ;*parts :of the pregnanc- This bromide is bollediurrder refluxfforfi hours with looparts'of'absolute pyridine. After evaporating down in vacuo, the residue is dissolved in a large quantity of ether, the ether solution washed with a little dilute hydrochloric acid, sodium carbonate solution and water, dried over sodium sulphate and evaporated down. The residue is purified chromatographically over a column of aluminium oxide, when the first benzene extracts give crystals which melt indefinitely at a low temperature. The further benzene, and benzene and ether fractions give, after recrystallizing twice from a mixture of acetone and ether, colourless needles melting at 1'75-1'78 C. and having a specific rotation [a] =+Z10.7'i:3 (concentration 0.676 in acetone). They consist of A -pregnene-3,l1,20-trione-2l-ol-acetate (dehydro-corticosterone-acetate) A sample of very pure natural dehydro corticosterone acetate melts, under the same conditions, at PVT-179 C., has the above specific rotation and a mixture with the synthetic product gives no melting point depression. Saponification with methyl alcoholic HCl or potassium bicarbonate in aqueous methyl alcohol gives the free dehydro-corticosteroneacetate, melting at I'M-180 C.
Instead of the 3 3-acetoxy-ll-keto-etio-cholanic acid an ester stereoisomeric in 3-position can be used as starting product. If the process is started, however, from a 3,1l-diacyloxy-etiocholanic acid (if desired with different ester groups in 3- and ll-position), corticosterone, llisocorticosterone, or their ll-mono-esters or 11,21-diesters may be obtained in an analogous way, whereby the possibility exists of preparing mixed diesters. The intermediate products in the latter syntheses are for example the pregnane- -ones, containing in ll-position a hydroxyl group or a group convertible into hydroxyl by hydrolysis, in 3-position the said groups or a keto group and in 2l-position a halogen or a diazo group.
Having thus described the invention what is claimed is:
1. In a process for the manufacture of an asubstituted side-chain ketone of the cyclopentano-polyhydrophenanthrene series, the steps of reacting with an aliphatic diazo compound a cyclopentanopolyhydrophenanthrene l7 carboxylic acid halide which contains in ring A in 3-posltion a group convertible into hydroxyl by hydrolysis and in ring C in at least one of the positions 11 and 12 a member of the group consisting of a keto group and a group convertible by hydrolysis into hydroxyl, and subjecting the resultant diazo-ketone to the action of a hydrolyzing agent whereby the group present in 3'-position is converted into free hydroxyl.
2. In a process for the manufacture of an acsubstituted side-chain ketone of the cyclopentanopolyhydrophenanthrene series, the step of reacting a cyclopentanopolyhydrophenanthryll7) diazomethyl-ketone which contains in ring A in .3-position a member of the group consisting of a hydroxyl group and a keto group, and a ring C in at least one of the positions 11 and 12 a member of the group consisting of a keto group and a group convertible by hydrolysis into hydroxyl, with a member of the group consisting of acids, alkalis and carboxylic acid salts.
3. A process for the manufacture of an asubstituted side-chain ketone of the cyclopentanopolyhydrophenanthrene series, which comprises reacting with an aliphatic diazo compound a .cyclopentanopolyhydrophenanthrene l7 carboxylic acid halide which containsin ring A in 3-position a group convertible into hydroxyl by hydrolysis and in ring C in at least one of the positions 11 and 12 a member of the group consisting of a keto group and a group convertible by hydrolysis into hydroxyl, subjecting the resultant diazoketone to the action of a hydrolyzing agent whereby the group present in 3-position is converted into free hydroxyl, and then reacting the resultant product with a member of the group consisting of oxidizing agents and dehydrogenating agents whereby the free hydroxy in 3- position is converted into keto and then with a member of the group consisting of acids, alkalis and carboxylic acid salts whereby the diazo-keto radical is converted into a ketol radical.
4. A process for the manufacture of an oc-Sllbstituted side-chain ketone of the cyclopentanopolyhydrophenanthrene series, which comprises reacting with an aliphatic diazo compound a cyclopentanopolyhydrophenanthrene l7 carboxylic acid halide which contains in ring A in 3-position a group convertible into hydroxyl by hydrolysis and in ring C in at least one of the positions 11 and 12 a member of the group consisting of a keto group and a group convertible by hydrolysis into hydroxyl, and subjecting the resultant diazoketone to the action of a hydrolyzing agent whereby the group present in 3-position is converted into free hydroxyl, and then reacting the resultant product with a member of the group consisting of acids, alkalis and carboxylic acid salts whereby the diazoketo radical is converted into a ketol radical and then with a member of the group consisting 0t oxidizing agents and dehydrogenating agents whereby the free hydroxyl in 3-position is converted into keto.
5. A process for the manufacture of an oc-Sllbstituted side-chain ketone of the cyclopentanopolyhydrophenanthrene series, which comprises reacting with an aliphatic diazo compound an unsaturated oyclopentanopolyhydrophenanthrenell-carboxylic acid halide which contains in ring A in 3-position a group convertible into hydroxyl by hydrolysis and in ring C in at least one of the positions 11 and 12 a member of the group consisting of a keto group and a group convertible by hydrolysis into hydroxyl, subjecting the resultant diazoketone to the action of a hydrolyzing agent whereby the group present in 3-position is converted into free hydroxyl, reacting the resultant product with halogen to saturate carbon double bonds present; and reacting the resultant prodnot with a member of the group consisting of oxidizing agents and dehydrogenating agents whereby the free hydroxyl in 3-position is converted into keto, reacting the resultant product with a halogen eliminating agent to regenerate the protected double bonds, and then with a member of the group consisting of acids, alkalis and carboxylic acid salts whereby the diazoketo radical is converted into a ketol radical,
6. A process for the manufacture of an a-Sllbstituted side-chain ketone of the cyclopentanopolyhydrophenanthrene series, which comprises reacting with an aliphatic diazo compound an unsaturated cyclopentanopolyhydrophenanthrene l'l-carboxylic acid halide which contains in ring A in 3-position a group convertible into hydroxyl by hydrolysis and in ring C in at least one of the positions 11 and 12 a member of the group consisting of a keto group and a group convertible by hydrolysis into hydroxyl, subjecting the resultant diazoketone to the action of a hydrolyz ing agent whereby the group present in 3-position is converted into free hydroxyl, reacting the re- .15 sult'ant 'product'with a member of the group consisting of :acids, alkalis and carboxylic acid salts whereby the diazoketo radical is converted into-a *ketol radical, reacting the resultant productwit-h reacting with an aliphatic diazo compound, a
cyclopentanopolyhydrophenanthrene- 1'7 -carboxylic acid halide which is saturated in the rings A and B and which contains in ring A in 3-position a group convertible into hydroxyl by hydrolysis and in ring C in at least one of the positions 11 and .12 amember of the group consisting of a lketo group and a group convertible by hydrolysis into hydroxyl, subjecting the resultant diazoketone to the action of a hydrolyzing agent whereby the group present in 3-position is converted into free hydroxyl, reacting-the product with a member of the group consisting of oxidizing agents and dehydrogenating agents whereby the free hydroxyl in 3-position is converted into keto,
-then,reacting the resultant product with a member of .the group consisting of acids, alkalis and .carboxylic acid salts whereby the diazoketo radical is converted into a ketol radical, and finally introducing a double bond into the 4,5-position by reaction with a halogenating agent followed by reaction with a reagent for eliminating hydrogen halide.
8. -A process for the manufacture of an a-Sllbstituted side-chain ketone of the cyclopentanopolyhydrophenanthrene series, which comprises reacting with analiphatic diazo compound a cyclopentanopolyhydrophenanthrene 17 carboxylic acid halide which is saturated in the rings A and B and which contains in ring A in 3-position algroup convertible into hydroxyl by hydrolysis and inring C in at least one of the positions 11 and 11 2 amember of the group consisting of a keto group and a group convertible by hydrolysis into hydroxyhsubjecting the resultant diazoketone to the actionof la hydrolyzing agent whereby the group present in 3-position is converted into free hydroxyl, reacting theproduct with a member of the group consisting of acids, alkalis and carboX- ylic acid salts whereby the diazoketo radical is converted into a ketol radical, then with a member of the group consisting of oxidizing agents and dehydrogenating agents whereby the free hydroxyl in 3-position is converted into keto, and finally introducing a double bond into the 45-130- sition by reaction with a halogenating agent followed by reaction with a reagent for eliminating hydrogen halide.
9. A process for the manufacture of an lX-Substituted side-chain ketone of the cyclopentanopolyhydrophenanthrene series, which comprises reacting with-an aliphatic diazo compound a cyclopen-tanopolyhydrophenanthrene 17 carbox- ,ylicacid halide which is saturated in the rings .A ancLB and which contains in ring A in 3-position a group convertible into hydroxyl by hydrolysis-and inring-C- in, at least one of the positions 11 and 12 a member of the group consisting of aketo group and ra group convertible by hydrolysis into hydroagyl, subjecting the resultant diazoketone to .theaction ofa mild .hydrolyzing agent whereby only the group pr-esent, in 3-posi-tion is .sele ctively converted: into free hydroxyl, reacting the product with a member-ofthegroup consistingpf-oxidizing agents and dehydrogenating agents whereby .the free hydroxy-llin 3-positionlis:converted into keto, then reacting the resultant'product -witha member of *the'group consisting'of acids, alkalis and carboxyl-ic acid salts whereby the diazoketo radical-is converted into a ketolradical andfinally introducing a double bondinto the 4,5: position by reaction with a halogenating agent followed by-reaction with a'reagent for eliminating hydro.- gen halide.
10. Aprocess.forthamanufaoture of an oc-Sllbstituted side-chain :ketone of the ,cyclopentanopolyhydrophenanthrene series, which comprises reacting with-an aliphatic-diazo compound acyclopentanopolyhydrophenanthrene .1'7 -carboX- ,ylic halide which ,issaturatedin the rings -A and B and which contains in ring vAlin 3-position a group convertible into hydroxyl by hydrolysis and in ring C in at=least .oneofthe positions 11 and 12 a member of the group consisting-Ora keto group and a group convertiblebyhydrolysis into hydroxyl, subjecting the resultant diazoketone to the action of ,a mild hydrolyzing agent whereby only the .group present in 3-,position is selectively converted .into ,free lhydroxyl, reacting theproduct with amember ofthe group consisting of acids, ,alkalis ,and carboxylic acid salts whereby thediazoketo radical is converted into a ketol-radical, then with ,a member ofthe group consisting of oxidizingagents and dehydrogenating agents whereby the free hydroxyl in 3-position is converted into keto, and finally introducing a double bondlintothe 4,5-position by reaction ,witha halogenating agent followed-by reaction with a reagent for eliminatinghydrcgen halide.
11. A process for the manufacture-of an a-substituted side-chain ketone of the cyclopentanopolyhydrophenanthrene series, which comprises reacting with an aliphatic diazo compounds, cyc1opentanopolyhydrophenanthrene 17 -carboxylic'acid halide which is'saturated in the rings A and B and which contains in ring A in 3-position a group convertible into hydroxyl by hydrolysis and in ring C in at least one of the positions 11 and 12 a member of the group consisting of a keto group and a group convertible by hydrolysis into hydroxyl, subjecting the resultant dia-zoketcne to the action of a strong hydrolyzing agent whereby all groups which are convertible into hydroxyl by hydrolysis are so-converted,'reacting the product with a member of the group consisting of oxidizing agents and dehydrogenating agents whereby the free hydroxyl in 3-position is converted intoketo, then reacting the resultant product with a member of thegroup consisting of acids, alkalis'and carboxylic acid-salts whereby the diazoketo radical is converted into 'a-ketol radical,
and finally introducing a double bond into the polyhydrophenanthren-e series, which comprises reacting with an :aliphatic 'diazo compound "a cylopentanopolyhydrophenanthrene l7 carboxylic acid halide which i's'saturated in the rings .A and B and which contains in ring-Alin 3 1ccsition a group convertible into hydroxyl :by'hy ,drolysis endearing C in at leastonerojfthe ,po- ,sitions .111 1and1a member of the roup cansisting of a keto group and a group convertible by hydrolysis into hydroxyl, subjecting the resultant diazoketone to the action of a strong hydrolyzing agent whereby all groups which are convertible into hydroxyl by hydrolysis are so converted, reacting the product with a member of the group consisting of acids, alkalis and carboxylic'acid salts whereby the diazoketo radical is converted into a ketol radical, then with a member of the group consisting of oxidizing agents and dehydrogenating agents whereby the free hydroxyl in 3-position is converted into keto, and finally introducing a double bond into the 4,5- position by reaction with a halogenating agent followed by reaction with a. reagent for eliminating hydrogen halide.
13. The compounds of the pregnene series, containing a ketonic oxygen at the carbon atom 3 and, as sole substituent in ring C, at the carbon atom 12 a member of the group consisting of hydroxyl, a group convertible into hydroxyl by hydrolysis and a ketonio oxygen, at the carbon atom 20 a ketonic oxygen and at the carbon atom 21 a member of the group consisting of a hydroxyl and an esterified hydroxyl.
14. The saturated compounds of the pregnane series, containing a ketonic oxygen at the carbon atom 3 and, as sole substituent in ring C, at the carbon atom 12 a member of the group consisting of hydroxyl, a group convertible into hydroxyl by hydrolysis and a ketonic oxygen, at the carbon atom 20 a ketonic oxygen and at the carbon atom 21 a member of the group consisting of a hydroxyl and an esterified hydroxyl.
15. A member of the group consisting of the .A -pregnene-3,12,20-trione-21-ol and its esters.
16. A member of the group consisting of the A -pregnene-3,20-dione-12,21-di-ols and their 21- mono-esters.
TADEUS REICHSTEIN',
REFERENCES CITED The following references are of record in the file of this patent:
UNITED STATES PATENTS Number Name Date 2,312,480 Reichstein Mar. 2, 1943 2,312,483 Reichstein Mar. 2, 1943
Publications (1)
Publication Number | Publication Date |
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USRE22941E true USRE22941E (en) | 1947-11-25 |
Family
ID=2089882
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Application Number | Title | Priority Date | Filing Date |
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US22941D Expired USRE22941E (en) | X-substituted |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2771475A (en) * | 1954-12-17 | 1956-11-20 | Upjohn Co | Steroids |
US2840572A (en) * | 1955-12-02 | 1958-06-24 | Merck & Co Inc | Chemical compounds and processes for preparing the same |
US2947765A (en) * | 1955-12-07 | 1960-08-02 | Pfizer & Co C | Preparation of the 12-keto isomer of cortisone |
US2950281A (en) * | 1952-09-17 | 1960-08-23 | Merck & Co Inc | delta5-3-ethylenedioxy-11, 20-diketo-21-iodopregnene |
-
0
- US US22941D patent/USRE22941E/en not_active Expired
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2950281A (en) * | 1952-09-17 | 1960-08-23 | Merck & Co Inc | delta5-3-ethylenedioxy-11, 20-diketo-21-iodopregnene |
US2771475A (en) * | 1954-12-17 | 1956-11-20 | Upjohn Co | Steroids |
US2840572A (en) * | 1955-12-02 | 1958-06-24 | Merck & Co Inc | Chemical compounds and processes for preparing the same |
US2947765A (en) * | 1955-12-07 | 1960-08-02 | Pfizer & Co C | Preparation of the 12-keto isomer of cortisone |
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