NO170545B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITIES 6,21-DIMETHYL-19-NOR-PREGNA-DIENER - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITIES 6,21-DIMETHYL-19-NOR-PREGNA-DIENER Download PDFInfo
- Publication number
- NO170545B NO170545B NO892652A NO892652A NO170545B NO 170545 B NO170545 B NO 170545B NO 892652 A NO892652 A NO 892652A NO 892652 A NO892652 A NO 892652A NO 170545 B NO170545 B NO 170545B
- Authority
- NO
- Norway
- Prior art keywords
- pregna
- dimethyl
- diene
- methyl
- isomer
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title claims description 5
- 230000001225 therapeutic effect Effects 0.000 title 1
- 239000002253 acid Substances 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 6
- WYRXPAAHXDCEGC-LIEJCIORSA-N (8s,9s,10r,13s,14s)-6,13-dimethyl-2,8,9,10,11,12,14,15,16,17-decahydro-1h-cyclopenta[a]phenanthren-3-one Chemical class C([C@@H]12)CC(=O)C=C1C(C)=C[C@@H]1[C@@H]2CC[C@]2(C)CCC[C@H]21 WYRXPAAHXDCEGC-LIEJCIORSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000012285 osmium tetroxide Substances 0.000 claims description 4
- 229910000489 osmium tetroxide Inorganic materials 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound 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 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 150000001204 N-oxides Chemical class 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- -1 alkyl radical Chemical class 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000002211 ultraviolet spectrum Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical group [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 229960003387 progesterone Drugs 0.000 description 3
- 239000000186 progesterone Substances 0.000 description 3
- 150000000318 19-norprogesterones Chemical class 0.000 description 2
- 235000018185 Betula X alpestris Nutrition 0.000 description 2
- 235000018212 Betula X uliginosa Nutrition 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000003245 coal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 102000003998 progesterone receptors Human genes 0.000 description 2
- 108090000468 progesterone receptors Proteins 0.000 description 2
- 230000000962 progestomimetic effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- CEYWPVCZMDVGLZ-UHFFFAOYSA-N (+-)-Senecinsaeure Natural products CC=C(C(O)=O)CC(C)C(C)(O)C(O)=O CEYWPVCZMDVGLZ-UHFFFAOYSA-N 0.000 description 1
- SCGILXXYXVPRAK-KTGOFWQSSA-N (8r,9r,10s,13s,14s)-1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16-hexadecahydrocyclopenta[a]phenanthren-17-one Chemical compound C([C@@H]12)CC3CCCC[C@@H]3[C@H]2CC[C@H]2[C@H]1CCC2=O SCGILXXYXVPRAK-KTGOFWQSSA-N 0.000 description 1
- NUPLBTPPIOMJPG-PNKHAZJDSA-N (8r,9s,10r,13s,14s)-13-methyl-1,2,7,8,9,10,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthrene Chemical class C1C=C2C=CCC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 NUPLBTPPIOMJPG-PNKHAZJDSA-N 0.000 description 1
- JFEPJTGMGDGPHJ-PNKHAZJDSA-N (8r,9s,10r,13s,14s)-13-methyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 JFEPJTGMGDGPHJ-PNKHAZJDSA-N 0.000 description 1
- BCWWDWHFBMPLFQ-VXNCWWDNSA-N (8r,9s,13s,14s)-3-methoxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-17-one Chemical compound C1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2CCC3=CC(OC)=CC=C3[C@H]21 BCWWDWHFBMPLFQ-VXNCWWDNSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- JJYWRQLLQAKNAD-UHFFFAOYSA-N 2-methylpent-2-enoic acid Chemical compound CCC=C(C)C(O)=O JJYWRQLLQAKNAD-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 208000019255 Menstrual disease Diseases 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 206010036618 Premenstrual syndrome Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical class [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- YWGHUJQYGPDNKT-UHFFFAOYSA-N hexanoyl chloride Chemical compound CCCCCC(Cl)=O YWGHUJQYGPDNKT-UHFFFAOYSA-N 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- NRUBUZBAZRTHHX-UHFFFAOYSA-N lithium;propan-2-ylazanide Chemical compound [Li+].CC(C)[NH-] NRUBUZBAZRTHHX-UHFFFAOYSA-N 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VHWYCFISAQVCCP-UHFFFAOYSA-N methoxymethanol Chemical compound COCO VHWYCFISAQVCCP-UHFFFAOYSA-N 0.000 description 1
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- HNAUTGHTMNMTJD-UHFFFAOYSA-N n,n-diethylethanamine oxide;hydrogen peroxide Chemical compound OO.CC[N+]([O-])(CC)CC HNAUTGHTMNMTJD-UHFFFAOYSA-N 0.000 description 1
- KZUIYQJTUIACIG-YBZCJVABSA-N nomegestrol Chemical compound C1=C(C)C2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 KZUIYQJTUIACIG-YBZCJVABSA-N 0.000 description 1
- 229960004911 nomegestrol Drugs 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical class [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
- C07J13/007—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 17 (20)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Denne oppfinnelse angår fremstilling av nye, terapeutisk virksomme 6,21-dimethyl-19-nor-pregna-diener med den generelle formel I: This invention relates to the production of new, therapeutically effective 6,21-dimethyl-19-nor-pregna-dienes with the general formula I:
hvor R er hydrogen eller syreresten av en alifatisk eller aromatisk carboxylsyre med 1-7 carbonatomer. where R is hydrogen or the acid residue of an aliphatic or aromatic carboxylic acid with 1-7 carbon atoms.
I den generelle formel I kan substituenten R f.eks. være acetyl, propionyl, butyryl, pentanoyl, hexanoyl eller benzoyl eller en syrerest avledet fra en umettet syre, som f.eks. senecinsyre eller 2-methyl-pentensyre. In the general formula I, the substituent R can e.g. be acetyl, propionyl, butyryl, pentanoyl, hexanoyl or benzoyl or an acid residue derived from an unsaturated acid, such as e.g. senecic acid or 2-methyl-pentenoic acid.
Spesielt angår oppfinnelsen fremstilling av de føl-gende forbindelser, som for tiden foretrekkes: 17a-hydroxy-6,21-dimethyl-3,20-dioxo-19-nor-pregna-4,6-dien, 17a-acetoxy-6,21-dimethyl-3,20-dioxo-19-nor-pregna-4,6-dien, 17a-butyryloxy-6,21-dimethyl-3,20-dioxo-19-nor-pregna-4,6-dien, In particular, the invention relates to the production of the following compounds, which are currently preferred: 17a-hydroxy-6,21-dimethyl-3,20-dioxo-19-nor-pregna-4,6-diene, 17a-acetoxy-6, 21-dimethyl-3,20-dioxo-19-nor-pregna-4,6-diene, 17a-butyryloxy-6,21-dimethyl-3,20-dioxo-19-nor-pregna-4,6-diene,
17a-caproyloxy-6,21-dimethyl-3,20-dioxo-19-nor-pregna-4,6-dien, 17α-caproyloxy-6,21-dimethyl-3,20-dioxo-19-nor-pregna-4,6-diene,
17a-heptanoyloxy-6,21-dimethyl-3,20-dioxo-19-nor-pregna-4,6-dien. 17α-heptanoyloxy-6,21-dimethyl-3,20-dioxo-19-nor-pregna-4,6-diene.
Det er allerede kjent derivater av 19-nor-progesteron med en methylsubstituent i 6-stillingen, f.eks. "Nomegestrol", som er et sterkt progestativt middel med rene progesteronegen-skaper. Derivatives of 19-nor-progesterone with a methyl substituent in the 6-position are already known, e.g. "Nomegestrol", which is a strong progestative agent with pure progesterone gene creators.
Det er likeledes tidligere kjent derivater av 19-nor-progesteron hvis kjede i 17-stillingen omfatter 3 carbonatomer, spesielt 3,20-dioxo-17a-21-dimethyl-19-nor-pregna-4,9-dien, som er omtalt i fransk patentskrift nr. 2 077 877. Denne type forbindelser oppviser bare moderate progestomimetiske There are also previously known derivatives of 19-nor-progesterone whose chain in the 17-position comprises 3 carbon atoms, in particular 3,20-dioxo-17a-21-dimethyl-19-nor-pregna-4,9-diene, which is discussed in French patent document no. 2 077 877. This type of compound exhibits only moderate progestomimetic
egenskaper sammenlignet med deres lavere homologe. properties compared to their lower homologs.
Det har nu vist seg at forbindelsene med den generelle formel I oppviser meget interessante progestomimetiske egenskaper, spesielt gitt oralt, og at deres sterke binding til progesteronmottakerne innebærer en sterk progestativ virkning . It has now been shown that the compounds of the general formula I exhibit very interesting progestomimetic properties, especially given orally, and that their strong binding to the progesterone receptors implies a strong progestative effect.
De nye 6,21-dimethyl-19-nor-pregna-diener fremstilles ved at et 3-oxo-6-methyl-estra-4,6-dienderivat med formel VI: i form av en E- eller Z-isomer bis-hydroxyleres under anvendelse av et bis-hydroxyleringsmiddel fremstilt fra osmiumtetroxyd og et hydroperoxyd i et inert medium, for dannelse av det tilsvarende 17a-hydroxy-20-ketonderivat med formelen: som, når nødvendig, acyleres under anvendelse av et funksjon-elt derivat av en alifatisk eller aromatisk carboxylsyre med 1-7 carbonatomer i nærvær av et surt medium. The new 6,21-dimethyl-19-nor-pregna-dienes are produced by a 3-oxo-6-methyl-estra-4,6-diene derivative of formula VI: in the form of an E- or Z-isomer bis- is hydroxylated using a bis-hydroxylating agent prepared from osmium tetroxide and a hydroperoxide in an inert medium, to form the corresponding 17α-hydroxy-20-ketone derivative of the formula: which, when necessary, is acylated using a functional derivative of a aliphatic or aromatic carboxylic acid with 1-7 carbon atoms in the presence of an acidic medium.
Bis-hydroxyleringsreaksjonen utføres fortrinnsvis ved bruk av osmiumtetroxyd og et hydroperoxyd av et N-oxyd av tertiært eller sekundært amin, som f.eks. N-oxydet av trimethyl-amin, N-oxydet av triethylamin eller N-oxydet av morfolin. Acyleringen av 17a-hydroxyderivatet utføres fortrinnsvis ved hjelp av et syreklorid eller -anhydrid i nærvær av en sterk mineralsyre, som f.eks. saltsyre eller svovelsyre, eller en Lewis-syre, som f.eks. bortrifluorid. The bis-hydroxylation reaction is preferably carried out using osmium tetroxide and a hydroperoxide of an N-oxide of a tertiary or secondary amine, such as e.g. The N-oxide of trimethylamine, the N-oxide of triethylamine or the N-oxide of morpholine. The acylation of the 17a-hydroxy derivative is preferably carried out with the aid of an acid chloride or anhydride in the presence of a strong mineral acid, such as e.g. hydrochloric or sulfuric acid, or a Lewis acid, such as boron trifluoride.
Alkyleringen av 17a-hydroxyderivatet utføres fortrinnsvis med methoxymethanol eller dihydropyran i nærvær av p-toluensulfonsyre i et inert oppløsningsmiddel. The alkylation of the 17a-hydroxy derivative is preferably carried out with methoxymethanol or dihydropyran in the presence of p-toluenesulfonic acid in an inert solvent.
Farmakologiske undersøkelser har vist at bindingen av de nye forbindelser til progesteronmottakerne, målt for liv-morens mottakere mot merket progesteron, er 2,5 ganger ster-kere enn progesteronets binding til disse. Pharmacological investigations have shown that the binding of the new compounds to the progesterone receptors, measured for the uterine receptors against labeled progesterone, is 2.5 times stronger than the progesterone's binding to these.
Effektiviteten av de nye forbindelser kan tilskrives den steroidale ringstruktur som bærer to voluminøse substi-tuenter, nemlig en methylgruppe i 6-stillingen og en methylgruppe i 21-stillingen, som, uten å endre forbindelsenes evne til å bindes til mottakersentrene, hindrer eller forsinker den metabolisering av forbindelsen i kroppen som forårsakes av reduserende eller hydrogenerende enzymer. The effectiveness of the new compounds can be attributed to the steroidal ring structure which carries two bulky substituents, namely a methyl group in the 6-position and a methyl group in the 21-position, which, without changing the ability of the compounds to bind to the receptor centers, prevents or delays the metabolism of the compound in the body caused by reducing or hydrogenating enzymes.
Farmasøytiske preparater inneholdende de nye 6,21-dimethyl-19-nor-pregnadiener som aktiv bestanddel er virksomme for behandling av gynekologiske forstyrrelser knyttet til en utilstrekkelighet i luteum, som f.eks. menstruasjonsforstyr-relser, dysmenorrhea, det premenstruelle syndrom og menopause-forstyrrelser. Pharmaceutical preparations containing the new 6,21-dimethyl-19-nor-pregnadienes as an active ingredient are effective for the treatment of gynecological disorders linked to an insufficiency in the luteum, such as e.g. menstrual disorders, dysmenorrhea, the premenstrual syndrome and menopause disorders.
De farmasøytiske preparater er beregnet for administrering parenteralt, oralt, rectalt, gjennom slimhin-nene, percutant eller pernasalt. The pharmaceutical preparations are intended for administration parenterally, orally, rectally, through the mucous membranes, percutaneously or pernasally.
De vanlige doser varierer fra 0,05 til 25 mg aktiv forbindelse pr. enhet, og den daglige dose varierer fra 0,1 til 50 mg aktiv forbindelse ved administrering kontinuerlig eller med intervaller. The usual doses vary from 0.05 to 25 mg of active compound per unit, and the daily dose ranges from 0.1 to 50 mg of active compound when administered continuously or at intervals.
3-oxo-6-methyl-estra-4,6-dienderivatet med formel VI som anvendes som et utgangsmateriale ved analogifremgangsmåten ifølge oppfinnelsen, kan fremstilles som følger: The 3-oxo-6-methyl-estra-4,6-diene derivative of formula VI, which is used as a starting material in the analog method according to the invention, can be prepared as follows:
Et 17-keto-18-methyl-gonadien valgt blant 3-alkoxy-estra-1,3,5-trienene med den generelle formel IIa: hvor R2 er et lavere alkylradikal med 1-6 carbonatomer, og 3-alkoxy-estra-3,5-dienene med den generelle formel IIb: hvor R er som ovenfor,angitt, omsettes med et (triarylpropyl)-fosfoniumhalogenid eller dettes ylid, med de generelle form-ler: for fosfoniumhalogenidet: for det tilsvarende ylid: hvor Ar er et usubstituert eller substituert fenylradikal og Hal er et halogenatom som ikke er fluor, for dannelse av et propylidenderivat valgt fra gruppen be-stående av: estra-1,3,5-dien-derivatene med den generelle formel IIIa: A 17-keto-18-methyl-gonadiene selected from the 3-alkoxy-estra-1,3,5-trienes of the general formula IIa: where R2 is a lower alkyl radical with 1-6 carbon atoms, and the 3-Alkoxy-estra-3,5-dienes with the general formula IIb: where R is as stated above, is reacted with a (triarylpropyl)-phosphonium halide or its ylide, with the general formulas: for the phosphonium halide: for the corresponding ylid: where Ar is an unsubstituted or substituted phenyl radical and Hal is a halogen atom other than fluorine, for the formation of a propylidene derivative selected from the group consisting of: the estra-1,3,5-diene derivatives of the general formula IIIa:
i form av en E- eller Z-isomer, hvor Rx er som ovenfor angitt, og in the form of an E or Z isomer, where Rx is as indicated above, and
estra-3,5-dien-derivatene med den generelle formel IIIb: the estra-3,5-diene derivatives of the general formula IIIb:
i form av en E- eller Z-isomer, hvor Rx er som ovenfor angitt-Forbindelsen med den generelle formel IIIa underkas-tes så en hydrogenering etter Birchs metode for dannelse av et 3-oxo-estra-4-en, som overføres til en forbindelse med den generelle formel IIIb ved omsetning med et alkyleringsmiddel i et surt medium, og forbindelsen med den generelle formel IIIb omsettes med et formyleringsmiddel av Vilsmeier-Hack-type for dannelse av det tilsvarende 6-formylerte derivat med den generelle formel IV: i form av en E- eller Z-isomer, hvor Rx er som ovenfor angitt. Det 6-formylerte derivat reduseres med et blandet alkalime-tallhydrid, hvoretter det derved dannede 6-hydroxymethylerte derivat dehydratiseres i et surt medium for dannelse av et 3-oxo-6-methylenderivat med formel V: in the form of an E- or Z-isomer, where Rx is as indicated above-The compound with the general formula IIIa is then subjected to a hydrogenation according to Birch's method to form a 3-oxo-estra-4-ene, which is transferred to a compound of the general formula IIIb by reaction with an alkylating agent in an acidic medium, and the compound of the general formula IIIb is reacted with a formylating agent of the Vilsmeier-Hack type to form the corresponding 6-formylated derivative of the general formula IV: i form of an E or Z isomer, where Rx is as indicated above. The 6-formylated derivative is reduced with a mixed alkali metal hydride, after which the 6-hydroxymethylated derivative thus formed is dehydrated in an acidic medium to form a 3-oxo-6-methylene derivative of formula V:
i form av en E- eller Z-isomer. in the form of an E or Z isomer.
Den sistnevnte forbindelse isomeriseres ved at den omsettes med en isomeriseringskatalysator, for dannelse av 3-oxo-6-methyl-estra-4,6-dienderivatet med formel VI: The latter compound is isomerized by reacting it with an isomerization catalyst, to form the 3-oxo-6-methyl-estra-4,6-diene derivative of formula VI:
i form av en E- eller Z-isomer. in the form of an E or Z isomer.
Reaksjonen mellom forbindelsen med formel IIa eller IIb og triarylpropylfosfoniumhalogenidet eller dettes ylid gir hovedsakelig Z-isomeren i 17-stillingen. Imidlertid kan E-isomeren, som fåes bare i begrensede mengder, isoleres under anvendelse av fysikalske metoder, og syntesen kan fortsettes uten noen særlig forskjell, enten med Z-isomeren eller med E-isomeren. The reaction between the compound of formula IIa or IIb and the triarylpropylphosphonium halide or its ylide gives mainly the Z-isomer in the 17-position. However, the E-isomer, which is obtained only in limited quantities, can be isolated using physical methods, and the synthesis can proceed without much difference, either with the Z-isomer or with the E-isomer.
De følgende utførelser og betingelser foretrekkes ved de ovenfor omtalte reaksjoner som fører frem til utgangsmaterialet med formel VI: Omsetningen av 17-oxo-gonanet med formel IIa eller IIb med et triarylpropylfosfoniumhalogenid utføres i et basisk medium i et polart oppløsningsmiddel. The following embodiments and conditions are preferred for the above-mentioned reactions leading to the starting material of formula VI: The reaction of the 17-oxo-gonane of formula IIa or IIb with a triarylpropylphosphonium halide is carried out in a basic medium in a polar solvent.
Det basiske reagens er natriumhydrid, lithiumisopro-pylamid, kalium-tert-butylat eller natriumamid. The basic reagent is sodium hydride, lithium isopropylamide, potassium tert-butylate or sodium amide.
Det polare oppløsningsmiddel er dimethylsulfoxyd eller hexamethylfosfortriamid. The polar solvent is dimethylsulfoxide or hexamethylphosphoric triamide.
Reduksjonen av forbindelsen med formel IIIa i henhold til Birchs metode utføres ved reduksjon i flytende ammoniakk med påfølgende behandling med en sterk syre, som f.eks. saltsyre. The reduction of the compound of formula IIIa according to Birch's method is carried out by reduction in liquid ammonia followed by treatment with a strong acid, such as e.g. hydrochloric acid.
Vilsmeier-Hack-reagenset dannes ved omsetning av fosforoxyklorid med et tertiært amin, som f.eks. dimethylanilin, eller med et disubstituert amid, som f.eks. dimethylformamid. The Vilsmeier-Hack reagent is formed by reacting phosphorus oxychloride with a tertiary amine, such as dimethylaniline, or with a disubstituted amide, such as e.g. dimethylformamide.
Reduksjonen av den 6-formylerte forbindelse utføres under anvendelse av et alkalimetallaluminohydrid eller et alkalimetallborhydrid i et ikke-reaktivt oppløsningsmiddel, som f.eks. en syklisk ether eller en alkanol. The reduction of the 6-formylated compound is carried out using an alkali metal aluminohydride or an alkali metal borohydride in a non-reactive solvent, such as e.g. a cyclic ether or an alkanol.
Dehydratiseringen av det 6-hydroxymethylerte derivat til et 6-methylenderivat utføres ved at det behandles med en sterk syre, som f.eks. saltsyre, perklorsyre eller svovelsyre. The dehydration of the 6-hydroxymethylated derivative to a 6-methylene derivative is carried out by treating it with a strong acid, such as e.g. hydrochloric acid, perchloric acid or sulfuric acid.
Isomeriseringsreagenset er et metall av platinagrup-pen absorbert på en inert bærer, som f.eks. palladium på kull, platina på kull eller palladium på kalsiumcarbonat. The isomerization reagent is a metal of the platinum group absorbed on an inert carrier, such as e.g. palladium on coal, platinum on coal or palladium on calcium carbonate.
De følgende eksempler illustrerer fremstillingen av de nye 6,21-dimethyl-19-nor-pregnadiener. Først vises imidlertid fremstillingen av utgangsmaterialet med formel VI. The following examples illustrate the preparation of the new 6,21-dimethyl-19-nor-pregnadienes. First, however, the preparation of the starting material with formula VI is shown.
Eksempel A Example A
Fremstilling av et utqanqsmateriale, 6, 21- dimethyl- 3- oxo- 19-nor- preqna- 4, 6, 17( 20)- trien. Preparation of a starting material, 6, 21-dimethyl-3-oxo-19-nor-preqna-4, 6, 17(20)-triene.
Trinn A: 3-alkoxy-21-methyl-19-nor-pregna-3,5,17(20)-trien. Step A: 3-Alkoxy-21-methyl-19-nor-pregna-3,5,17(20)-triene.
Under anvendelse av fremgangsmåten beskrevet av A.M. Krubiner og medarbeidere i J.Org.Chem. 33 (1968) 1713 fåes, ved at det startes med 3-methoxy-17-keto-estra-l,3,5(10)-trien, først 3-methoxy-21-methyl-estra-l, 3, 5 (10)17(20)-tetraen (sm.p. = 76°C; [a]D = +59°), deretter 3-keto-21-methyl-19-nor-pregna-4,17(20)-dien, som etter reduksjon i henhold til meto-den ifølge Birch-Nelson fåes i form av en flytende, strågul olje ([a]D = +47°). Denne forbindelse overføres - ved omsetning med triethylorthoformiat i nærvær av spor av p-toluensulfonsyre i et ethanolisk medium - til 3-ethoxy-21-methyl-19-nor-pregna-3,5,17(20)-trien. Using the method described by A.M. Krubiner and colleagues in J.Org.Chem. 33 (1968) 1713 is obtained, by starting with 3-methoxy-17-keto-estra-1,3,5(10)-triene, first 3-methoxy-21-methyl-estra-1, 3,5 ( 10)17(20)-tetraene (m.p. = 76°C; [a]D = +59°), then 3-keto-21-methyl-19-nor-pregna-4,17(20)- diene, which after reduction according to the Birch-Nelson method is obtained in the form of a liquid, straw-yellow oil ([a]D = +47°). This compound is transferred - by reaction with triethylorthoformate in the presence of traces of p-toluenesulfonic acid in an ethanolic medium - to 3-ethoxy-21-methyl-19-nor-pregna-3,5,17(20)-triene.
På samme måte overføres 3-keto-21-methyl-19-nor-pregna-4,17(20)-dien til 3-methoxy-21-methyl-19-nor-pregna-3,5,17(20)-trien ved bruk av trimethylorthoformiat i et metha-nolisk medium i nærvær av spor av p-toluensulfonsyre. In the same way, 3-keto-21-methyl-19-nor-pregna-4,17(20)-diene is transferred to 3-methoxy-21-methyl-19-nor-pregna-3,5,17(20)- triene using trimethylorthoformate in a methanolic medium in the presence of traces of p-toluenesulfonic acid.
Utbytte = 79%. Smeltepunkt 118°C. Yield = 79%. Melting point 118°C.
Trinn B: 3-ethoxy-6-formyl-21-methyl-19-nor-pregna-l,5,17(20)-trien (Z-isomer). Step B: 3-ethoxy-6-formyl-21-methyl-19-nor-pregna-1,5,17(20)-triene (Z-isomer).
Til 30 g 3-ethoxy-21-methyl-19-nor-pregna-3,5,17(20)-trien (Z-isomer) og 300 ml dimethylformamid settes et Vilsmeier-Hack-reagens fremstilt av 15,5 ml fosforoxyklorid og 124 ml dimethylformamid ved +5°C. Reaksjonsblandingen holdes under omrøring i 75 minutter, og det tilsettes 140 ml av en mettet vandig oppløsning av natriumacetat. Det fremkommer en krystallinsk, gul utfeining. Etter henstand i 15 minutter filtreres blandingen, og det vaskes med vann. Etter filtrering og vaskning fåes 20,2 g 3-ethoxy-6-formyl-21-methyl-19-nor-pregna-1,5,17(20)-trien (Z-isomer) som gule krystaller. Utbytte = 62%. Smeltepunktet for den rene forbindelse er 99°C. Dreiningsevne: [a]D = -21,5° (C = 1% dioxan). To 30 g of 3-ethoxy-21-methyl-19-nor-pregna-3,5,17(20)-triene (Z-isomer) and 300 ml of dimethylformamide is added a Vilsmeier-Hack reagent prepared from 15.5 ml of phosphorus oxychloride and 124 ml of dimethylformamide at +5°C. The reaction mixture is kept under stirring for 75 minutes, and 140 ml of a saturated aqueous solution of sodium acetate are added. A crystalline, yellow precipitate appears. After standing for 15 minutes, the mixture is filtered and washed with water. After filtration and washing, 20.2 g of 3-ethoxy-6-formyl-21-methyl-19-nor-pregna-1,5,17(20)-triene (Z-isomer) are obtained as yellow crystals. Yield = 62%. The melting point of the pure compound is 99°C. Twistability: [a]D = -21.5° (C = 1% dioxane).
i in
Trinn C: 6-methylen-3-oxo-21-methyl-19-nor-pregna-4,17(20)-dien (Z-isomer). Step C: 6-methylene-3-oxo-21-methyl-19-nor-pregna-4,17(20)-diene (Z-isomer).
14,3 g ethoxy-6-formyl-21-methyl-19-nor-pregna-1, 5,17(20)-trien (Z-isomer) og 140 ml methanol omrøres i 80 minutter med 960 g natriumborhydrid ved 0°C. Det tilsettes så langsomt 15 ml av en 2N saltsyreoppløsning. Blandingen omrøres inntil det dannes krystaller. Det fåes 8,7 g 6-methylen-3-oxo-21-methyl-^19-nor-pregna-4,17(20)-dien (Z-isomer). 14.3 g of ethoxy-6-formyl-21-methyl-19-nor-pregna-1, 5,17(20)-triene (Z-isomer) and 140 ml of methanol are stirred for 80 minutes with 960 g of sodium borohydride at 0° C. 15 ml of a 2N hydrochloric acid solution is then slowly added. The mixture is stirred until crystals form. 8.7 g of 6-methylene-3-oxo-21-methyl-^19-nor-pregna-4,17(20)-diene (Z-isomer) are obtained.
Utbytte-= 71%. Smeltepunkt = 110-114°C. Yield-= 71%. Melting point = 110-114°C.
Dreiningsevne: [a]D = 218° (C = 1% dioxan). Rotability: [a]D = 218° (C = 1% dioxane).
UV-spektrum: Amaks = 261 nm e = 10.600. UV spectrum: Amax = 261 nm e = 10,600.
Trinn D: 6,21-dimethyl-3-oxo-19-nor-pregna-4,6,17(20)-trien (Z-isomer). Step D: 6,21-dimethyl-3-oxo-19-nor-pregna-4,6,17(20)-triene (Z-isomer).
3,5 g 6-methylen-3-oxo-21-methyl-19-nor-pregna-4,17(20)-dien (Z-isomer), 35 g natriumacetat og 1,4 g 5% palladium på kull i 350 ml ethanol kokes med tilbakeløpskjøling i 90 minutter. Reaksjonsmediet filtreres og ekstraheres med kloroform, og den organiske fase vaskes med vann. De organiske faser kromatograferes på silica. Fra eluatene utvinnes 3,1 g 6, 21-dimethyl-3-oxo-19-nor-pregna-4,6,17( 20)-trien (Z-isomer) i form av en svakt gulaktig olje. 3.5 g 6-methylene-3-oxo-21-methyl-19-nor-pregna-4,17(20)-diene (Z-isomer), 35 g sodium acetate and 1.4 g 5% palladium on charcoal in 350 ml ethanol is boiled with reflux cooling for 90 minutes. The reaction medium is filtered and extracted with chloroform, and the organic phase is washed with water. The organic phases are chromatographed on silica. From the eluates, 3.1 g of 6, 21-dimethyl-3-oxo-19-nor-pregna-4,6,17(20)-triene (Z-isomer) are recovered in the form of a slightly yellowish oil.
Utbytte = 88%. Yield = 88%.
Dreiningsevne: [a]D = -31° (C = 1% dioxan). Rotability: [a]D = -31° (C = 1% dioxane).
UV-spekteret: Amaks = 288 nm € = 22.000. The UV spectrum: Amax = 288 nm € = 22,000.
Eksempel 1 Example 1
6, 21- dimethyl- 17a- hydroxy- 3, 20- dioxo- 19- nor- preqna- 4, 6- dien. 6, 21- dimethyl- 17a- hydroxy- 3, 20- dioxo- 19- nor- preqna- 4, 6- diene.
2,9 g 6,21-dimethyl-3-oxo-19-nor-pregna-4,6,17(20 )-trien i 29 ml tert-butanol, 0,58 ml av en 2,5% oppløsning av osmiumtetroxyd i tert-butanol og 4,06 g av komplekset triethylamin-N-oxyd-hydroperoxyd omrøres i 24 timer ved romtempe-ratur. 3 g Celitt tilsettes og deretter 2 g natriumsulfitt oppløst i vann. Blandingen holdes omrørt i ytterligere to timer. 2.9 g of 6,21-dimethyl-3-oxo-19-nor-pregna-4,6,17(20 )-triene in 29 ml of tert-butanol, 0.58 ml of a 2.5% solution of osmium tetroxide in tert-butanol and 4.06 g of the complex triethylamine-N-oxide-hydroperoxide are stirred for 24 hours at room temperature. 3 g of Celite are added and then 2 g of sodium sulphite dissolved in water. The mixture is kept stirred for a further two hours.
Hele blandingen ekstraheres med toluen, hvoretter den organiske fase kromatograferes på et skikt av silica. Eluatene inndampes, og det tørre residuum taes opp i varm methanol. Etter krystallisering fåes 1,66 g 6,21-dimethyl-17a-hydroxy-3, 20-dioxo-l9-nor-pregna-4,6 dien. The entire mixture is extracted with toluene, after which the organic phase is chromatographed on a layer of silica. The eluates are evaporated, and the dry residue is taken up in hot methanol. After crystallization, 1.66 g of 6,21-dimethyl-17α-hydroxy-3,20-dioxo-19-nor-pregna-4,6-diene are obtained.
Utbytte = 52%. Yield = 52%.
Smeltepunkt = 204°C. Melting point = 204°C.
Eksempel 2 Example 2
17a- acetoxy- 6, 21- dimethyl- 3, 20- dioxo- 19- nor- preqna- 4, 6 dien 17a- acetoxy- 6, 21- dimethyl- 3, 20- dioxo- 19- nor- preqna- 4, 6 diene
1 g 6,21-dimethyl-17a-hydroxy-3, 20-dioxo-19-nor-pregna-4,6-dien, 10 ml kloroform, 0,8 ml eddiksyreanhydrid og 0,15 g p-toluensulfonsyre kokes med tilbakeløpskjøling i 50 minutter. 2 ml methanol og 0,1 ml konsentrert saltsyre tilsettes, og det hele kokes med tilbakeløpskjøling i ytterligere én time. Reaksjonsblandingen ekstraheres med kloroform. Kloro-formoppløsningen vaskes med vann, hvoretter oppløsningen inndampes under redusert trykk. 1 g of 6,21-dimethyl-17α-hydroxy-3, 20-dioxo-19-nor-pregna-4,6-diene, 10 ml of chloroform, 0.8 ml of acetic anhydride and 0.15 g of p-toluenesulfonic acid are boiled with reflux for 50 minutes. 2 ml of methanol and 0.1 ml of concentrated hydrochloric acid are added, and the whole is refluxed for a further hour. The reaction mixture is extracted with chloroform. The chloroform solution is washed with water, after which the solution is evaporated under reduced pressure.
Residuet taes opp i methanol for krystallisering. Det utvinnes 780 mg 17a-åcetoxy-6,21-dimethyl-3,20-dioxo-19-nor-pregna-4,6-dien i form av krystaller. The residue is taken up in methanol for crystallization. 780 mg of 17α-acetoxy-6,21-dimethyl-3,20-dioxo-19-nor-pregna-4,6-diene are recovered in the form of crystals.
Utbytte = 69%. Yield = 69%.
UV-spekteret: Amaks = 288 nm 6 = 23.400. Smeltepunkt: 203°C. The UV spectrum: Amax = 288 nm 6 = 23,400. Melting point: 203°C.
Dreiningsevne: [a]D= -34° (C = 1% dioxan). Rotability: [a]D= -34° (C = 1% dioxane).
NMR-spektrum: i CDC13 NMR spectrum: in CDCl3
0,68 Hz 3H (S) i C180.68 Hz 3H (S) in C18
1,05 Hz 3H (t) 1.05 Hz 3H (h)
J = 7 Hz C22J = 7 Hz C22
1,86 Hz 3H (s) methyl i C61.86 Hz 3H (s) methyl in C6
2,08 Hz 3H (s) CH3C0 2.08 Hz 3H (s) CH3CO
5,95 Hz 1H (s) H i C, 5.95 Hz 1H (s) H in C,
6,05 Hz 1H (s) H i C66.05 Hz 1H (s) H in C6
Ved hjelp av den samme fremgangsmåte ble 6,21-dimethyl-17a-propionyloxy-19-nor-pregna-4,6-dien fremstilt ved bruk av propionylklorid. Smp. 178-180°C. [a]D = -44° (C = 1% dioxan). Using the same procedure, 6,21-dimethyl-17a-propionyloxy-19-nor-pregna-4,6-diene was prepared using propionyl chloride. Temp. 178-180°C. [α]D = -44° (C = 1% dioxane).
Ved bruk av den samme fremgangsmåte og ved bruk av caproylklorid fåes 6,21-dimethyl-17a-caproyloxy-19-nor-pregna-4,6-dien. Smp. 160-161°C. [a]D = -49° (dioxan). Using the same method and using caproyl chloride, 6,21-dimethyl-17a-caproyloxy-19-nor-pregna-4,6-diene is obtained. Temp. 160-161°C. [α]D = -49° (dioxane).
Ved bruk av den samme fremgangsmåte og ved bruk av trimethylacetylklorid fåes 6,21-dimethyl-17a-trimethylacety-loxy-19-nor-pregna-4,6-dien. Smp. 218-219°C. [a]D = -31° (C = 1% dioxan). Using the same method and using trimethylacetyl chloride, 6,21-dimethyl-17a-trimethylacety-loxy-19-nor-pregna-4,6-diene is obtained. Temp. 218-219°C. [α]D = -31° (C = 1% dioxane).
Ved bruk av den samme fremgangsmåte og ved bruk av benzoylklorid fåes 6,21-dimethyl-17a-benzoyloxy-19-nor-pregna-4,6-dien. Smp. 221-222°C. [a]D = -49° (C = 1% pyridin). Using the same method and using benzoyl chloride, 6,21-dimethyl-17a-benzoyloxy-19-nor-pregna-4,6-diene is obtained. Temp. 221-222°C. [α]D = -49° (C = 1% pyridine).
Ved bruk av den samme fremgangsmåte og ved bruk av kloracetylklorid fåes 6,21-dimethyl-17a-kloracetyloxy-19-nor-pregna-4,6-dien. Smp. 217 °C. UV-spektrum Xmaks = 288 nm. 6 = 16.900. [a]D = -45° (C = 1% dioxan). Using the same method and using chloroacetyl chloride, 6,21-dimethyl-17a-chloroacetyloxy-19-nor-pregna-4,6-diene is obtained. Temp. 217 °C. UV spectrum Xmax = 288 nm. 6 = 16,900. [α]D = -45° (C = 1% dioxane).
Claims (3)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8714806A FR2622194B1 (en) | 1987-10-27 | 1987-10-27 | NOVEL 19-NOR PROGESTERONE DERIVATIVES, PROCESS FOR OBTAINING SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| PCT/FR1988/000527 WO1989003839A1 (en) | 1987-10-27 | 1988-10-27 | Derivatives of 19-norprogesterone, their preparation and their use |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO892652D0 NO892652D0 (en) | 1989-06-26 |
| NO892652L NO892652L (en) | 1989-08-23 |
| NO170545B true NO170545B (en) | 1992-07-20 |
| NO170545C NO170545C (en) | 1992-10-28 |
Family
ID=26226285
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO892652A NO170545C (en) | 1987-10-27 | 1989-06-26 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITIES 6,21-DIMETHYL-19-NOR-PREGNA-DIENER |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU624096B2 (en) |
| NO (1) | NO170545C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2645864B1 (en) * | 1989-04-13 | 1991-07-12 | Theramex | NOVEL 17/21 ALKYL DERIVATIVES OF 19-NOR PROGESTERONE, PROCESSES FOR OBTAINING SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
-
1988
- 1988-10-27 AU AU26295/88A patent/AU624096B2/en not_active Ceased
-
1989
- 1989-06-26 NO NO892652A patent/NO170545C/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU2629588A (en) | 1989-05-23 |
| NO892652L (en) | 1989-08-23 |
| AU624096B2 (en) | 1992-06-04 |
| NO892652D0 (en) | 1989-06-26 |
| NO170545C (en) | 1992-10-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2588267B2 (en) | 19,11β-crosslinked steroids, process for producing the same, and pharmaceutical preparations containing the compounds | |
| US5352809A (en) | 9-alpha-hydroxy steroids, process for their preparation, process for the preparation of the corresponding 9(11)-dehydro derivatives and pharmaceutical preparations containing such steroids | |
| US3562260A (en) | 2-carbonyl-estratrienes and method of their preparation | |
| NO168891B (en) | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 11BETA- (4-ISOPROPENYLPHENYL) -OESTRA-4,9-DIENES | |
| JPS6117477B2 (en) | ||
| NO160521B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE 13ALFA ALKYLGONANES. | |
| NO148662B (en) | Conditioning shampoos. | |
| NO178768B (en) | 11 these | |
| NO180451B (en) | Analogous process for the preparation of therapeutically active 13-alkyl-11-phenylgonanes | |
| US3318928A (en) | 7alpha-alkyl-17alpha-alkinyl-estradiols | |
| NO128152B (en) | ||
| EP0227472A1 (en) | 10 Beta-alkynylestrene derivatives and process for their preparation | |
| US4789671A (en) | 14,17β-ethano-14β-estratrienes and estratetraenes, process for their production, and pharmaceutical preparations containing them | |
| US3328432A (en) | Novel progesterone derivatives | |
| NO170545B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITIES 6,21-DIMETHYL-19-NOR-PREGNA-DIENER | |
| US4720357A (en) | New process for manufacturing derivatives of 17 alpha-hydroxy 19-nor progesterone and novel intermediates for use therein | |
| US5223492A (en) | Derivatives of 19-nor progesterone; process for producing them and the pharmaceutical compositions incorporating them | |
| KR970005317B1 (en) | Derivatives of 19-nor progesterone; process for producing them and the pharmaceutical compositions incorporating them | |
| US3483226A (en) | 16-oxa and 17 - oxa - d - homoestra - 1,3,5(10)-trien-3-ols and d-nor-seco-diols corresponding,ethers and esters thereof | |
| US2840574A (en) | Process for producing delta7-3-hydroxy steroids | |
| US3419550A (en) | Pentacyclic steroid intermediates and method of preparing the same | |
| US3351639A (en) | 17-alkyl-20-keto substituted pregnenes, pregnadienes and methods of preparing the same | |
| US3954980A (en) | Chemical compounds | |
| NO140679B (en) | PROCEDURE FOR THE PREPARATION OF ALFA-1,6-GLUCOSIDASES | |
| US3682984A (en) | 17{60 -(2,3-methylene-prop-1-en-1 yl)-steroids and 17{60 -(2,3-monohalomethylene and 2,3-dihalomethylene) derivatives thereof |