US3705893A - Process for the 9(11)-enolisation of a steroid 1,4-diene-3,11-dione - Google Patents
Process for the 9(11)-enolisation of a steroid 1,4-diene-3,11-dione Download PDFInfo
- Publication number
- US3705893A US3705893A US92216A US3705893DA US3705893A US 3705893 A US3705893 A US 3705893A US 92216 A US92216 A US 92216A US 3705893D A US3705893D A US 3705893DA US 3705893 A US3705893 A US 3705893A
- Authority
- US
- United States
- Prior art keywords
- enolate
- dione
- diene
- reaction
- steroid
- 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 - Lifetime
Links
- 238000000034 method Methods 0.000 title abstract description 26
- 150000003431 steroids Chemical class 0.000 title abstract description 24
- 238000006243 chemical reaction Methods 0.000 abstract description 28
- 239000002585 base Substances 0.000 abstract description 27
- 239000002904 solvent Substances 0.000 abstract description 10
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 9
- 150000001340 alkali metals Chemical class 0.000 abstract description 9
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052744 lithium Inorganic materials 0.000 abstract description 4
- 229910052736 halogen Inorganic materials 0.000 abstract description 3
- 150000002367 halogens Chemical class 0.000 abstract description 3
- 229960004618 prednisone Drugs 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 15
- -1 enol ester Chemical class 0.000 description 15
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 230000008707 rearrangement Effects 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 229960001810 meprednisone Drugs 0.000 description 5
- 150000003128 pregnanes Chemical class 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000003246 corticosteroid Substances 0.000 description 4
- 229960001334 corticosteroids Drugs 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 4
- QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 239000005977 Ethylene Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- XHFXMNZYIKFCPN-UHFFFAOYSA-N perchloryl fluoride Chemical compound FCl(=O)(=O)=O XHFXMNZYIKFCPN-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000000292 calcium oxide Substances 0.000 description 2
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- SFDZETWZUCDYMD-UHFFFAOYSA-N monosodium acetylide Chemical compound [Na+].[C-]#C SFDZETWZUCDYMD-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- UJTRRNALUYKHQE-UHFFFAOYSA-N sodium;diphenylmethylbenzene Chemical compound [Na+].C1=CC=CC=C1[C-](C=1C=CC=CC=1)C1=CC=CC=C1 UJTRRNALUYKHQE-UHFFFAOYSA-N 0.000 description 2
- SMBZJSVIKJMSFP-UHFFFAOYSA-N trifluoromethyl hypofluorite Chemical compound FOC(F)(F)F SMBZJSVIKJMSFP-UHFFFAOYSA-N 0.000 description 2
- SVYCRJXQZUCUND-PQXSVQADSA-N (6s,8s,9s,10r,13s,14s,17r)-17-hydroxy-17-(2-hydroxyacetyl)-6,10,13-trimethyl-6,7,8,9,12,14,15,16-octahydrocyclopenta[a]phenanthrene-3,11-dione Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2C(=O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 SVYCRJXQZUCUND-PQXSVQADSA-N 0.000 description 1
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Natural products C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 150000000476 acetylides Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- NBZANZVJRKXVBH-GYDPHNCVSA-N alpha-Cryptoxanthin Natural products O[C@H]1CC(C)(C)C(/C=C/C(=C\C=C\C(=C/C=C/C=C(\C=C\C=C(/C=C/[C@H]2C(C)=CCCC2(C)C)\C)/C)\C)/C)=C(C)C1 NBZANZVJRKXVBH-GYDPHNCVSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001440 androstane derivatives Chemical class 0.000 description 1
- 150000001441 androstanes Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 238000003683 electrophilic halogenation reaction Methods 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000012025 fluorinating agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- ZMJJCODMIXQWCQ-UHFFFAOYSA-N potassium;di(propan-2-yl)azanide Chemical compound [K+].CC(C)[N-]C(C)C ZMJJCODMIXQWCQ-UHFFFAOYSA-N 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 150000003146 progesterones Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- FZHAPNGMFPVSLP-UHFFFAOYSA-N silanamine Chemical group [SiH3]N FZHAPNGMFPVSLP-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005039 triarylmethyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
Definitions
- This invention relates to the preparation of steroid enolates and of esters derived therefrom.
- Steroid 1,4diene-3,11-diones are frequently encountered among the physiologically active steroids, especially the corticosteroids, and it is oten found that the derivatives carrying substituents at the 6- or 9-position possess enhanced activity.
- 9e-fiuoro-16/3-methylprednisone (betamethasone) possesses greater anti-inflamrnatory activity than 16 8-methyl prednisone and 6- methyl prednisone also exhibits greater activity than prednisone.
- the 6- or 9- substituent is usually introduced at a relative early stage, before the 1,4-diene-3,l1-dione system is formed but considerable difiiculty has been experienced in substituting at the sterically hindered 9-position.
- the rearrangement appears to be bimolecular, one molecule of 3-enolate reacting with one molecule of -3,l1-dione to yield one molecule of regenerated -3,1l-di0ne and one molecule of 9(ll)enolate.
- unreacted -3,11-di0ne need only be present in a catalytic quantity since it is constantly regenerated.
- the bimolecular rearrangement is considerably slower than the enolisation and if an excess of base is added, the -3 enolate will be formed quantitatively before rearrangement can take place to a significant extent.
- the bimolecular rearrangement is so slow as to be negligible and at such temperatures substantially only 3-enolate is apparently present (as demonstrated by forming an enol ester). It can thus be seen that if the reaction conditions are selected so that the initially formed 3-enolate cannot come in contact with the unreacted dione, or can only contact the dione under conditions in which rearrangement will not occur, the 3-enolate is obtained as reaction product, whereas if the reaction conditions are selected so that the initially formed 3-enolate can contact unreacted dione under conditions in which rearrangement can occur, the 9(ll)enolate is obtained.
- the present invention therefore we provide a process for the selective 3- or 9( l1)-enolisation of a steriod 1,4-diene-3,11-dione in which the 1,4-dione-3,l1- dione is treated under substantially oxygen-free and anhydrous conditions in a non-hydroxylic solvent with an alkali metal base other than a lithium base soluble in the solvent to form the 3-enolate; when the 9(ll)enolate is required, the dione in non-enolised form being allowed or caused either subsequently or simultaneously to react with the 3-enolate initially formed; when the 3-enolate is required the reaction being carried out at a temperature below 50 C. or the reaction being carried out in a manner whereby contact between the 3-enolate and unreacted dione is reduced or avoided.
- alkali metal base that is a sodium, potassium, rubidium or caesium base, acting as a strong nucleophile under anhydrous non-hydroxylic conditions is required to abstract the desired proton from the 6- and 9-position.
- the enolates formed are advantageously, as indicated above, converted directly into enol esters.
- the reaction with the alkali metal base may be conveniently quenched and the corresponding ester pro,- symbolized, by treating the reaction mixture in situ with an acylating agent, e.g. a reactive ester, for example, the acid halide, or more particularly, the anhydride, of an organic acid such as an aliphatic, araliphatic or aromatic carboxylic or sulphonic acid.
- an acylating agent e.g. a reactive ester, for example, the acid halide, or more particularly, the anhydride, of an organic acid such as an aliphatic, araliphatic or aromatic carboxylic or sulphonic acid.
- an acylating agent e.g. a reactive ester, for example, the acid halide, or more particularly, the anhydride, of an organic acid such as an aliphatic, araliphatic or aromatic carboxylic or
- Any steroid l,4-diene-3,ll-dioue can be enolised by the process according to the present invention, especially corticosteroids of the prednisone type and suitably substituted progesterone and androstane derivatives.
- Particularly desirable enolates are formed from prednisone BMD ,(17,20:20,21-bismethylenedioxyprednisone) and its 160: and l6fi-meth'yl analogues, n -ll-ketoprogesterone ethylene ketal and androstane-l,4-diene-3,l1,17-trione-l7- monoethylene ketal.
- the 3- and 9(ll)-enol esters or the parent 3- and 9(l1)- enolates are, as indicated previously, particularly useful as starting compounds for electrophilic substitution reactions at 6- or 9-positions.
- reaction with sources of positive halogen such as molecular chlorine or bromine, introduces a halogen atom at the 6- or 9'position.
- fluorine especially at the 9a-position, by reacting an enolate or enol ester with an electrophilic fluorinating agent, such as perchloryl fluoride, or a hypofiuorite reagent such as trifluoromethyl hypofiuorite.
- the method according to the invention thus allows 9cz-fill0l0 prednisone or a 16mmethyl or l6fl-methyl derivative to be prepared directly from prednisone or its l-methyl derivatives.
- Example 2 Slow addition of steroid to base Prednisone BMD (200 mg., 0.5 mmole) in dry TI-IF (10 ml.) was added dropwise over 30 minutes with vigorous stirring to sodium bistrimethylsilylamide (120.3 mg., 0.55 mmole) in THF (5 ml.) under argon, the mixture remaining at room temperature throughout the addition. The mixture was then stirred a further 2 minutes and benzoic anhydride (452 mg., 2.0 mmoles) added. The mixture was then worked up as before to yield the 3-enol benzoate (207 mg., 0.405 mmole; 82%). Use of triphenylmethylsodium (3 mol.
- the 9(l1)-enol benzoates of l6u-methyl prednisone BMD, IGB-methyl prednisone BMD, A -1l-keto-progesterone-ZO- ethylene ketal and androstrane-1,4-diene-3,l1,17-monoethylene ketal may be prepared.
- Use of triphenylmethylsodium (2 mol. equiv.) or sodium acetylide (2 mol. equiv. dispersed in xylene/tetrahydrofuran) yields the identical 9(11)-eno1 benzoate.
- Example 5 Reaction of prednisone BMD 9(11)-enol benzoate with trifluoromethyl hypofluorite (CF OF)
- Prednisone BMD 9(11)-eno1 benzoate 500 mg. was dissolved in a mixture of Freon (100 ml.) and methylene chloride (50 ml.) and reacted with CF OF in the presence of CaO (200 mg.) under nitrogen at about 78 C.
- the crude product (572 mg.) was chromatographed over alumina (grade 3, 40 g.). Elution with benzene, followed by ether/benzene mixtures up to 10% ether, produced small amounts of several non polar products (total weight 103 mg.) which were not studied further.
- a process for the selective 9(11)-enolisation of a 1,4- diene-3,l1-dione steroid of the androstane or pregnane series in which the 1,4-diene-3,l1-dione is treated under substantially oxygen-free and anhydrous conditions in a non-hydroxylic solvent with an alkali metal base other than a lithium base soluble in the solvent, to form the 3- enolate; the dione in non-enolised form being allowed or caused either subsequently or simultaneously to react with the 3-enolate initially formed.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB5742569 | 1969-11-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3705893A true US3705893A (en) | 1972-12-12 |
Family
ID=10479160
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US92216A Expired - Lifetime US3705893A (en) | 1969-11-24 | 1970-11-23 | Process for the 9(11)-enolisation of a steroid 1,4-diene-3,11-dione |
Country Status (11)
-
1970
- 1970-10-23 BE BE70@@@@@@@@A patent/BE759289A/xx unknown
- 1970-11-23 FR FR7041982A patent/FR2072246A5/fr not_active Expired
- 1970-11-23 JP JP45102645A patent/JPS5111112B1/ja active Pending
- 1970-11-23 DE DE19702057541 patent/DE2057541A1/de active Pending
- 1970-11-23 NL NL7017087A patent/NL7017087A/xx unknown
- 1970-11-23 IL IL35706A patent/IL35706A/en unknown
- 1970-11-23 US US92216A patent/US3705893A/en not_active Expired - Lifetime
- 1970-11-23 DK DK594370AA patent/DK134071B/da unknown
- 1970-11-23 CH CH1731370A patent/CH571540A5/xx not_active IP Right Cessation
- 1970-11-23 ZA ZA707908A patent/ZA707908B/xx unknown
- 1970-11-24 GB GB5742569A patent/GB1325004A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| BE759289A (fr) | 1971-05-24 |
| DK134071C (enrdf_load_stackoverflow) | 1977-02-07 |
| DE2057541A1 (de) | 1971-06-03 |
| CH571540A5 (enrdf_load_stackoverflow) | 1976-01-15 |
| FR2072246A5 (enrdf_load_stackoverflow) | 1971-09-24 |
| GB1325004A (en) | 1973-08-01 |
| IL35706A0 (en) | 1971-01-28 |
| IL35706A (en) | 1974-11-29 |
| DK134071B (da) | 1976-09-06 |
| ZA707908B (en) | 1971-11-24 |
| NL7017087A (enrdf_load_stackoverflow) | 1971-05-26 |
| JPS5111112B1 (enrdf_load_stackoverflow) | 1976-04-08 |
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