NO761516L - PROCEDURES FOR THE MANUFACTURE OF STEROIDS - Google Patents
PROCEDURES FOR THE MANUFACTURE OF STEROIDSInfo
- Publication number
- NO761516L NO761516L NO761516A NO761516A NO761516L NO 761516 L NO761516 L NO 761516L NO 761516 A NO761516 A NO 761516A NO 761516 A NO761516 A NO 761516A NO 761516 L NO761516 L NO 761516L
- Authority
- NO
- Norway
- Prior art keywords
- dione
- solution
- formula
- dioxane
- chloroform
- Prior art date
Links
- 150000003431 steroids Chemical class 0.000 title claims description 14
- 238000000034 method Methods 0.000 title claims description 7
- 238000004519 manufacturing process Methods 0.000 title claims 2
- 150000001875 compounds Chemical class 0.000 claims description 52
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
- 239000011737 fluorine Chemical group 0.000 claims description 10
- 229910052731 fluorine Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 150000004965 peroxy acids Chemical class 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 88
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- 239000000203 mixture Substances 0.000 description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- QIEPWCSVQYUPIY-LEKSSAKUSA-N Delta(1)-progesterone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 QIEPWCSVQYUPIY-LEKSSAKUSA-N 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 10
- 239000012362 glacial acetic acid Substances 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 230000018044 dehydration Effects 0.000 description 5
- 238000006297 dehydration reaction Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- 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 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- -1 2-oxopropoxy Chemical group 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000003862 glucocorticoid Substances 0.000 description 3
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- RJKFOVLPORLFTN-UHFFFAOYSA-N progesterone acetate Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 RJKFOVLPORLFTN-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 229940037128 systemic glucocorticoids Drugs 0.000 description 2
- GILOHIFOCBAZMZ-XYSHCKNMSA-N (8s,10s,13s,14s,16r,17s)-17-(2-chloroacetyl)-17-hydroxy-10,13-dimethyl-16-(2-oxopropoxy)-7,8,12,14,15,16-hexahydro-6h-cyclopenta[a]phenanthren-3-one Chemical compound C([C@H]12)CC3=CC(=O)C=C[C@]3(C)C1=CC[C@@]1(C)[C@H]2C[C@@H](OCC(=O)C)[C@]1(O)C(=O)CCl GILOHIFOCBAZMZ-XYSHCKNMSA-N 0.000 description 1
- LSOSHPOZTQLSAZ-MRYBABCUSA-N (8s,10s,13s,14s,16r,17s)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-16-phenacyloxy-7,8,12,14,15,16-hexahydro-6h-cyclopenta[a]phenanthren-3-one Chemical compound O([C@@H]1C[C@H]2[C@H]3C([C@]4(C=CC(=O)C=C4CC3)C)=CC[C@@]2([C@@]1(O)C(=O)CO)C)CC(=O)C1=CC=CC=C1 LSOSHPOZTQLSAZ-MRYBABCUSA-N 0.000 description 1
- QQCBOIWDENXRLP-BYZMTCBYSA-N (8s,9s,10r,13r,14s,17s)-17-ethyl-10,13-dimethyl-6,7,8,9,11,12,14,15,16,17-decahydro-3h-cyclopenta[a]phenanthrene Chemical compound C1CC2=CCC=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 QQCBOIWDENXRLP-BYZMTCBYSA-N 0.000 description 1
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- JYGXADMDTFJGBT-VWUMJDOOSA-N Hydrocortisone Natural products O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 201000009053 Neurodermatitis Diseases 0.000 description 1
- 206010037083 Prurigo Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000005336 allyloxy group Chemical group 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- VEVJTUNLALKRNO-TYHXJLICSA-N benzoyl-CoA Chemical compound O=C([C@H](O)C(C)(COP(O)(=O)OP(O)(=O)OC[C@@H]1[C@H]([C@@H](O)[C@@H](O1)N1C2=NC=NC(N)=C2N=C1)OP(O)(O)=O)C)NCCC(=O)NCCSC(=O)C1=CC=CC=C1 VEVJTUNLALKRNO-TYHXJLICSA-N 0.000 description 1
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 1
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- KQTXIZHBFFWWFW-UHFFFAOYSA-L disilver;carbonate Chemical compound [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 125000000109 phenylethoxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])O* 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Description
Denne oppfinnelse vedrører nye steroidale 9, ll|3-dihalogen-[16a;, 17-b ]-l, 4-dioksaner som er nyttige som anti-inf lammatoriske midler. This invention relates to novel steroidal 9,11|3-dihalo-[16a;,17-b]-1,4-dioxanes which are useful as anti-inflammatory agents.
Forbindelsene i henhold til foreliggende oppfinnelse har formelen The compounds according to the present invention have the formula
hvor Z er hydrogen, hydroksy, alkyl where Z is hydrogen, hydroxy, alkyl
eller halogen, or halogen,
X er klor eller fluor, A, erX is chlorine or fluorine, A, is
0 0
ii ii
eller R^C-O-CH-CI^-, R-^ er hydrogen, alkyl eller aryl, R er hydro-or R^C-O-CH-CI^-, R-^ is hydrogen, alkyl or aryl, R is hydro-
gen eller alkyl, R^ er alkyl, cykloalkyl eller aryl, P og Q er uavhengige av hverandre hydrogen, metyl eller halogen'og de prikkede linjene i 1,2- og 6,7-stillingene betyr eventuelle dobbeltbindinger. gen or alkyl, R^ is alkyl, cycloalkyl or aryl, P and Q are independently of each other hydrogen, methyl or halogen' and the dotted lines in the 1,2- and 6,7-positions mean any double bonds.
Denne oppfinnelse tilveiebringer også en fremgangsmåteThis invention also provides a method
for fremstilling av et steroid med strukturenfor the preparation of a steroid with the structure
hvor Z er hydrogen, hydroksy, eller halogen, X er klor eller fluor, A, er 0 eller er hydrogen, alkyl eller aryl,R^er hydrogen eller alkyl,R^er alkyl, cykloalkyl eller aryl, P og Q er uavhengig av hverandre hydrogen, metyl eller halogen og de prikkede linjene i 1,2- og 6,7-stillingene betyr eventuelle dobbeltbindinger, hvilken omfatter å omsette en forbindelse med formelen hvor Ax er -CH2CH2~, R20-CH-CH2-, med N-klorsuccinimid og en syre med.formelenHX, hvor X er klor eller fluor, for å danne en forbindelse med formel I hvor A-, er -CH-CH--, R20-CH-CH2- ellér ved å omsette en forbindelse med formelen hvor R, er alkyl eller aryl, Z' er hydrogen, "eller halogen og P og Q er som definert ovenfor, med N-klorsuccinimid og en syre med formelen HX hvor X er klor eller fluor, fulgt av omsetning med. en sterk syre for å danne en forbindelse med formelen hvorR^er alkyl eller aryl, eller ved å omsette en forbindelse med formelen hvor P, Q ogZ' er som definert ovenfor, med N-klorsuccihimid og en syre med formelen HX hvor X er klor eller fluor, fulgt av omsetning med suksessivt en persyre, et oksydasjonsmiddel og en sterk syre for å danne en forbindelse med formelen where Z is hydrogen, hydroxy, or halogen, X is chlorine or fluorine, A, is 0 or is hydrogen, alkyl or aryl, R^ is hydrogen or alkyl, R^ is alkyl, cycloalkyl or aryl, P and Q are independent of each other hydrogen, methyl or halogen and the dotted lines in the 1,2- and 6,7-positions mean any double bonds, which includes reacting a compound with the formula where Ax is -CH2CH2~, R20-CH-CH2-, with N- chlorosuccinimide and an acid of the formula HX, where X is chlorine or fluorine, to form a compound of the formula I wherein A-, is -CH-CH--, R20-CH-CH2- or by reacting a compound of the formula where R, is alkyl or aryl, Z' is hydrogen, "or halogen and P and Q are as defined above, with N-chlorosuccinimide and an acid of the formula HX where X is chlorine or fluorine, followed by reaction with a strong acid for to form a compound of the formula wherein R^ is alkyl or aryl, or by reacting a compound of the formula wherein P, Q and Z' are as defined above, with N-chlorosucciimide and a sy re of the formula HX where X is chlorine or fluorine, followed by reaction with successively a peracid, an oxidizing agent and a strong acid to form a compound of the formula
hvor R er hydrogen, og om ønskes forsåpe forbindelsen med formel VII eller formel Vila for å danne den tilsvarende 21-hydroksy-forbindelse. where R is hydrogen, and if desired saponify the compound with formula VII or formula VIIa to form the corresponding 21-hydroxy compound.
Uttrykket "alkyl", så som det brukes gjennom hele beskrivelsen, refererer til både forgrenede og rettkjedede alkylgrupper med 1 til 8 karbonatomer. Alkylgrupper med 1 til 4 karbonatomer er foretrukket. The term "alkyl", as used throughout the specification, refers to both branched and straight chain alkyl groups of 1 to 8 carbon atoms. Alkyl groups with 1 to 4 carbon atoms are preferred.
Uttrykket "cykloalkyl", så som det brukes gjennom hele beskrivelsen, refererer til cykloalkylgrupper som har 3 til 6 karbonatomer. The term "cycloalkyl", as used throughout the specification, refers to cycloalkyl groups having 3 to 6 carbon atoms.
Uttrykket "aryl", så som anvendt gjennom hele beskrivelsen, refererer til fenyl eller fenyl substituert med halogen, alkyl eller alkyl-0-.Fenyl er den foretrukne arylgruppe. The term "aryl" as used throughout the specification refers to phenyl or phenyl substituted with halogen, alkyl or alkyl-O-. Phenyl is the preferred aryl group.
Steroidene med formel I er fysiologisk aktive substanser som har glukokortikoid og "anti-inflammatorisk aktivitet, og som følgelig kan anvendes i stedet for kjente glukokprtikoider ved behandling av revmatisk arteritt, og for dette formål kan de admini-streres på samme måte som for eksempel- hydrokortison, idet dosisen blir justert i overensstemmelse med den relative kraft til det spesielle steroid. Dessuten kan steroidene i henhold til denne oppfinnelse anvendes topisk i stedet for kjente glukokortikoider ved behandling av hudsykdommer, f.eks. dermatitt, psoriasis, solfor-brenning, nevrodermatitt, eksem og anogenital prurigo. The steroids of formula I are physiologically active substances that have glucocorticoid and "anti-inflammatory activity, and which can therefore be used instead of known glucocorticoids in the treatment of rheumatic arteritis, and for this purpose they can be administered in the same way as for example- hydrocortisone, the dose being adjusted according to the relative potency of the particular steroid. Furthermore, the steroids of this invention can be used topically instead of known glucocorticoids in the treatment of skin diseases, e.g. dermatitis, psoriasis, sunburn, neurodermatitis , eczema and anogenital prurigo.
Når forbindelsene i henhold til oppfinnelsen blir gitt oralt, kan de anvendes i et dosisområde på 0,1 til 200 milligram fortrinnsvis 0,3 til 100 milligram. Ved topisk administrasjon kan forbindelsene i henhold til oppfinnelsen anvendes i området0,01 til 5,0 vekt%, fortrinnsvis 0,05 til 2,0 vekt%, i en konvensjonell krem eller oppløsning. When the compounds according to the invention are given orally, they can be used in a dose range of 0.1 to 200 milligrams, preferably 0.3 to 100 milligrams. For topical administration, the compounds according to the invention can be used in the range of 0.01 to 5.0% by weight, preferably 0.05 to 2.0% by weight, in a conventional cream or solution.
De steroider med formel I hvor A, er -CH0-CH~-, R_0-CH-CHo-, The steroids of formula I where A, is -CH0-CH~-, R_0-CH-CHo-,
blir fremstilt fra det tilsvarende 11/3-hydroksy-steroid med strukturen is prepared from the corresponding 11/3-hydroxy steroid with the structure
Dehydrat iser ing av 11/3-hydroksy-steroider med formel II Dehydration of 11/3-hydroxysteroids of formula II
for å gi A ^^ ^-steroider som har strukturento give A ^^ ^ steroids having the structure
kan utføres ved anvendelse av hvilken som helst av flere fremgangsmåter som er kjent i industrien. Eksempler på slike- fremgangsmåter er: can be performed using any of several methods known in the industry. Examples of such methods are:
1) dehydratisering méd fosforoksyklorid og pyridin, og1) dehydration with phosphorus oxychloride and pyridine, and
2) dehydratisering med metansulfonylklorid og pyridin. 2) dehydration with methanesulfonyl chloride and pyridine.
Omsetning av et A -steroid av formel III med N-klorsuccinimid og en syre med formelen Reaction of an A-steroid of formula III with N-chlorosuccinimide and an acid of the formula
hvor X er klor eller fluor, gir elet tilsvarende steroidale 9,11/3-dihalogen-[16a,17b]-l,4-dioksan med strukturen hvor A1er -CH2CH2-, R20-CH-CH2-, Omsetningen kan utføres i et oppløsningsmiddel, f.eks. iseddik, ved en temperatur på fra 0 til 30°C i 1 til 6 timer. ■ De steroider med formel I hvor A, er blir fremstilt fra det tilsvarende 11/3-hydroksy-steroid med strukturen I formlene VI og VII, og gjennom hele beskrivelsen, er R, alkyl eller aryl og Z' er hydrogen, eller halogen. - Omdannelse av et 11/3-hydroksy-steroid med formel VI til det tilsvarende 9,11/3-dihalogen-steroid kan utføres ved anvendelse av fremgangsmåtene beskrevet ovenfor (d.v.s. dehydratisering av 11/3-hydroksy-steroidet fulgt av halogener ing) . Det resulterende 9,11/3-dihalogen-steroid kan omsettes med en oppslemning eller opp-løsning av en sterk uorganisk eller organisk syre, 'f.eks. p-toluensulfonsyre, i et organisk oppløsningsmiddel, f.eks. benzen, for å gi det tilsvarende steroid med strukturen VIII hvor R^er alkyl eller aryl. Omdannelse av et 11/3-hydroksy-steroid med formel VII til -'det tilsvarende 9,11/3-dihalogen-steroid kan utføres ved anvendelse av fremgangsmåtene beskrevet ovenfor (d.v.s. dehydratisering av 11/3-hydroksy-steroidet fulgt av halogener ing) . Det resulterende 9,11/3-dihalogen-steroid kan omsettes suksessivt med en persyre, et oksydasjonsmiddel og en oppslemning av en sterk syre i et oppløs-ningsmiddel, f.eks. benzen, for å gi et steroid med strukturen where X is chlorine or fluorine, the molecule gives the corresponding steroidal 9,11/3-dihalo-[16a,17b]-1,4-dioxane with the structure where A1 is -CH2CH2-, R20-CH-CH2-, The reaction can be carried out in a solvent, e.g. glacial acetic acid, at a temperature of from 0 to 30°C for 1 to 6 hours. ■ The steroids of formula I where A is are prepared from the corresponding 11/3-hydroxysteroid of the structure I formulas VI and VII, and throughout the description, R is alkyl or aryl and Z' is hydrogen or halogen. - Conversion of a 11/3-hydroxysteroid of formula VI to the corresponding 9,11/3-dihalosteroid can be carried out using the methods described above (i.e. dehydration of the 11/3-hydroxysteroid followed by halogenation) . The resulting 9,11/3-dihalosteroid can be reacted with a slurry or solution of a strong inorganic or organic acid, e.g. p-toluenesulfonic acid, in an organic solvent, e.g. benzene, to give the corresponding steroid of structure VIII where R^ is alkyl or aryl. Conversion of a 11/3-hydroxysteroid of formula VII to the corresponding 9,11/3-dihalosteroid can be carried out using the methods described above (i.e., dehydration of the 11/3-hydroxysteroid followed by halogenation ). The resulting 9,11/3-dihalosteroid can be reacted successively with a peracid, an oxidizing agent and a slurry of a strong acid in a solvent, e.g. benzene, to give a steroid with the structure
hvorR^er hydrogen. De tilsvarende 21-hydroksy-steroider kan frem-stilles ved forsåpning av 21-acyloksy-steroider. where R^ is hydrogen. The corresponding 21-hydroxy steroids can be prepared by saponification of 21-acyloxy steroids.
Fremstillingen av steroider med formlene II, VI og VII er The preparation of steroids of formulas II, VI and VII is
beskrevet i søknad nr.described in application no.
De følgende eksempler er spesifikke utførelser av denne oppfinnelse. The following examples are specific embodiments of this invention.
Eksempel 1Example 1
A. 21- hydroksypregna- l, 4, 9( 11)- trieno[ 16a, 17- b ]-[ 1, 4 ] dioksan- 3, 20- dion, 21- acetat A. 21- hydroxypregna- l, 4, 9( 11)- trieno[ 16a, 17-b ]-[ 1, 4 ] dioxane- 3, 20-dione, 21- acetate
En blanding av 1,5 g 11/3,21-dihydroksypregna-l,4-dieno [16a,174jb] [1, 4 ]-dioksan-3, 20-dion, 21-acetat, 75 ml dimetylformamid, 37,5 ml pyridin og 15 ml metansulfonylklorid blir rørt ved 0°C i 75 minutter, blir så hellet inn i kald, fortynnet saltsyre og den resulterende blanding ble ekstrahert med kloroform. Kloroform-oppløsningen blir tørket og inndampet i vakuum. Residuet blir opp-løst .i kloroform og kromatografert på en 60 g silikagel-kolpnne. Eluering med 1:1 heksan-kloroform gir 1,2 g med 21-hydroksypregna-1,4, 9(11)-trieno [16a, 17-b][1,4]dipksan-3,20-dion, 21-acetat. A mixture of 1.5 g of 11/3,21-dihydroxypregna-1,4-dieno [16a,174jb] [1, 4 ]-dioxane-3, 20-dione, 21-acetate, 75 ml of dimethylformamide, 37.5 ml of pyridine and 15 ml of methanesulfonyl chloride are stirred at 0°C for 75 minutes, then poured into cold dilute hydrochloric acid and the resulting mixture is extracted with chloroform. The chloroform solution is dried and evaporated in vacuo. The residue is dissolved in chloroform and chromatographed on a 60 g silica gel column. Elution with 1:1 hexane-chloroform gives 1.2 g of 21-hydroxypregna-1,4, 9(11)-trieno [16a, 17-b][1,4]dipxane-3,20-dione, 21- acetate.
B. 9, ll/ ?- diklor- 21- hydroksypregna- l, 4- dieno [ 16g, 17- b] [ 1, 4]-dioksan- 3, 20- dion, 21- acetat B. 9, ll/ ?- dichloro- 21- hydroxypregna- l, 4- dieno [ 16g, 17- b] [ 1, 4]-dioxane- 3, 20- dione, 21- acetate
En oppløsning av 1,2 g 21-hydroksypregna-l,4,9(11)-trieno [16a, 17-b ] [1,4 ]-dioksan-3,20-dion, 21-acetat og 5,0 g litiumklorid i 50 ml iseddik blir rørt ved 0-5°C og det blir tilsatt 413 mg N-klorsuccinimid. Det blir tilsatt en oppløsning av 126 mg tørt hydrogenklorid i 2 ml tetrahydrofuran og den resulterende blanding blir rørt ved romtemperatur i 2 timer, hellet inn i 600,ml kaldt vann og ekstrahert med kloroform. Kloroform-oppløsningen A solution of 1.2 g of 21-hydroxypregna-1,4,9(11)-trieno [16a, 17-b] [1,4]-dioxane-3,20-dione, 21-acetate and 5.0 g lithium chloride in 50 ml of glacial acetic acid is stirred at 0-5°C and 413 mg of N-chlorosuccinimide is added. A solution of 126 mg of dry hydrogen chloride in 2 ml of tetrahydrofuran is added and the resulting mixture is stirred at room temperature for 2 hours, poured into 600 ml of cold water and extracted with chloroform. The chloroform solution
blir vasket med vann, tørket og inndampet i vakuum for å gi 1,31 g med urenset produkt. Dette materialet blir plate-kromatografert på tre 2 mm's silikagelplater med dimensjonene 20 x 20 cm. Etter to fremkallinger med 1:1 kloroform-etylacetat, blir det UV-aktive bånd for den intermediære R f verdsatt og det blir eluert med etylacetat og det oppnås 735 mg materiale. Omkrystallisering fra metanol gir 540 mg med materialé som har smeltepunkt på 256-258°C, spaltning. Dette blir forenet med 137 mg med materiale oppnådd ved omkromatografering av moderluten, og omkrystallisering fra metanol gir 575 mg med 9,ll/3-diklor-21-hydroksypregna-l,4-dieno [16a, 17-b ]-[1,4 ]-dioksan-3,20-dion, 21-acetat, sm.p. 256-258°C (spaltning). is washed with water, dried and evaporated in vacuo to give 1.31 g of crude product. This material is plate chromatographed on three 2 mm silica gel plates with dimensions 20 x 20 cm. After two developments with 1:1 chloroform-ethyl acetate, the UV-active band for the intermediate R f is appreciated and it is eluted with ethyl acetate and 735 mg of material is obtained. Recrystallization from methanol gives 540 mg of material which has a melting point of 256-258°C, cleavage. This is combined with 137 mg of material obtained by rechromatography of the mother liquor, and recrystallization from methanol gives 575 mg of 9,11/3-dichloro-21-hydroxypregna-1,4-dieno [16a, 17-b]-[1, 4 ]-dioxane-3,20-dione, 21-acetate, m.p. 256-258°C (decomposition).
Analytisk beregning for C25H3oC^2°6*C'6°'3é>»H, 6,08; Cl, 14,26 Funnet: C, 60,09; H, 5,83;Cl, 14^:23 Analytical calculation for C25H3oC^2°6*C'6°'3é>»H, 6.08; Cl, 14.26 Found: C, 60.09; H, 5.83; Cl, 14:23
Eksempel 2Example 2
A.. 5' i- etoksy- 21- hydroksypregna- 4, 9( ll)- dieno[ 16g, 17- b][ 1, 4]-dioksan- 3, 20- dion, 21- propionat A.. 5' i- ethoxy- 21- hydroxypregna- 4, 9( ll)- dieno[ 16g, 17- b][ 1, 4]-dioxane- 3, 20-dione, 21- propionate
En blanding av 5 'I -etoksy-11/3,21-dihydroksypregn-4-eno [16a,-17-b] [1,4]-dioksan-3,20-dion, 21-^ropionat (4 mmol), 75 ml dimetylformamid, 37,5 ml pyridin og 15 mr^metansulfonylklorid blir rørt ved 0°C i 75 minutter og hellet inn i kald fortynnet saltsyre, og den resulterende blanding blir ekstrahert med kloroform.Kloroform-^oppløsningen blir tørket og inndampet i vakuum for å gi tittel-forbindelsen. A mixture of 5' I -ethoxy-11/3,21-dihydroxypregn-4-eno [16a,-17-b][1,4]-dioxane-3,20-dione, 21-^ropionate (4 mmol) , 75 ml of dimethylformamide, 37.5 ml of pyridine and 15 ml of methanesulfonyl chloride are stirred at 0°C for 75 minutes and poured into cold dilute hydrochloric acid, and the resulting mixture is extracted with chloroform. The chloroform solution is dried and evaporated in vacuum to give the title compound.
B. 9, llff- diklor- 5' g- etoksy- 21- hydroksypregn- 4- eno [ 16g, 17- ?b ]-[| 1, 4 ]- dioksan- 3, 2o- dion, 21- propionat B. 9, llff- dichloro- 5' g- ethoxy- 21- hydroxypregn- 4- eno [ 16g, 17- ?b ]-[| 1, 4 ]- dioxane- 3, 2o-dione, 21- propionate
En oppløsning av 5' £ -etoksy-21-hydroksypregna^4,9 (11) -r dieno[16a,17-b][1,4]dioksan-3,20-dion, 21-propionat (1,4 mmol) og 2,5 g litiumklorid i 25 ml iseddik blir rørt ved 0-5°C og det blir tilsatt 207 mg N-klorsuccinimid. Det blir tilsatt en oppløsning av 63 mg tørt hydrogenklorid i 1 ml tetrahydrofuran og den resulterende blanding blir rørt ved romtemperatur i 2 timer, så hellet inn i 300ml kaldt vann og ekstrahert med kloroform. Kloroform-oppløs-ningen blir vasket med vann, tørket og inndampet i vakuum for å gi tittel-forbindelsen. A solution of 5' £ -ethoxy-21-hydroxypregna^4,9 (11) -r dieno[16a,17-b][1,4]dioxane-3,20-dione, 21-propionate (1.4 mmol ) and 2.5 g of lithium chloride in 25 ml of glacial acetic acid are stirred at 0-5°C and 207 mg of N-chlorosuccinimide are added. A solution of 63 mg of dry hydrogen chloride in 1 ml of tetrahydrofuran is added and the resulting mixture is stirred at room temperature for 2 hours, then poured into 300 ml of cold water and extracted with chloroform. The chloroform solution is washed with water, dried and evaporated in vacuo to give the title compound.
Eksempel 3Example 3
A. 5' £- etoksy- 21- hydroksypregna- 4, 9( ll)- dieno-[ 16g, 17- b] [ 1, 4 ] dioksan- 3, 20- dion, 21- mesylat En blanding av 5 '^-etoksy-ll/J, 21-dihydroksypregn-4-eno-[16a,17-b][1,4]dioksan-3,20-dion (4 mmol), 75 ml dimetylformamid, 3 7,5 ml pyridin og 15 ml metansulfonylklorid blir rørt ved 0°C i A. 5' £- ethoxy- 21- hydroxypregna- 4, 9( ll)- dieno-[ 16g, 17- b] [ 1, 4 ] dioxane- 3, 20- dione, 21- mesylate A mixture of 5 '^ -ethoxy-ll/J, 21-dihydroxypregn-4-eno-[16a,17-b][1,4]dioxane-3,20-dione (4 mmol), 75 ml dimethylformamide, 3 7.5 ml pyridine and 15 ml of methanesulfonyl chloride is stirred at 0°C in
75 minutter, blir så hellet inn i kald, fortynnet saltsyre og den 75 minutes, is then poured into cold, diluted hydrochloric acid and it
resulterende blanding blir ekstrahert med kloroform.Kloroform-oppløsningen blir tørket og inndampet i vakuum for å gi tittel-forbindelsen. resulting mixture is extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to give the title compound.
B. 9, llff- diklor- 5' C- etoksypregn- 4- eno [ 16g, 17- b ]-[ 1, 4] dioksan- 3, 20- dion, 21- mesylat B. 9, llff- dichloro- 5' C- ethoxypregn- 4- eno [ 16g, 17- b ]-[ 1, 4] dioxane- 3, 20-dione, 21- mesylate
En oppløsning av 5'£ -etoksy-21-hydroksypregna-4,9(ll)-dieno[16a,17-b][1,4]dioksan-3,20-dion, 21-mesylat (1,4 mmol) og 2,5 g litiumklorid i 25 ml iseddik blir rørt ved 0-5°C bg det blir tilsatt 207 mg N-klorsuccinimid. Det blir tilsatt en oppløsning av 63 mg tørt hydrogenklorid i 1 ml tetrahydrofuran og den resulterende blanding blir rørt ved romtemperatur i 2 timer, hellet inn i 300 ml kaldt vann og ekstrahert med kloroform.Kloroform-oppløsningen blir vasket med vann, tørket og inndampet i vakuum for å gi tittel-forbindelsen. A solution of 5'£ -ethoxy-21-hydroxypregna-4,9(11)-dieno[16a,17-b][1,4]dioxane-3,20-dione, 21-mesylate (1.4 mmol) and 2.5 g of lithium chloride in 25 ml of glacial acetic acid are stirred at 0-5°C while 207 mg of N-chlorosuccinimide are added. A solution of 63 mg of dry hydrogen chloride in 1 ml of tetrahydrofuran is added and the resulting mixture is stirred at room temperature for 2 hours, poured into 300 ml of cold water and extracted with chloroform. The chloroform solution is washed with water, dried and evaporated in vacuum to give the title compound.
C . 9, 11/ 3,, 21- triklor- 5 ' f - etoksy- pregn-* 4- eno-C. 9, 11/ 3,, 21- trichloro- 5 ' f - ethoxy- pregn-* 4- eno-
116g, 17- b 1 [ L, 4 ] dioksan- 3, 20- dion116g, 17- b 1 [ L, 4 ] dioxane- 3, 20-dione
En oppløsning av 0 ,8 mmol 9, ll/S-diklor-5 'S-etoksy-21-hydroksypregn-4-eno [16g,17-b ] [1,4]dioksan-3 ,20-dion, 21-mesylat i 20 ml dimetylformamid blir rørt ved 100°C sammen med 2 g litiumklorid i 30 minutter, og blir så avkjølt og hellet inn i is-vann. Det resulterende materiale blir filtrert-, vasket med vann og tørket i vakuum for å gi tittel-forbindelsen. A solution of 0.8 mmol of 9,11/S-dichloro-5'S-ethoxy-21-hydroxypregn-4-eno [16g,17-b] [1,4]dioxane-3,20-dione, 21- mesylate in 20 ml of dimethylformamide is stirred at 100°C together with 2 g of lithium chloride for 30 minutes, and is then cooled and poured into ice-water. The resulting material is filtered, washed with water and dried in vacuo to give the title compound.
Eksempel 4Example 4
A. 5' £, 21- dihydroksypregna- 4, 9( ll)- dieno[ 16g, 17- b]-[ 1, 4] dioksan- 3, 20- dion, 5', 21- diacetat A. 5' £, 21- dihydroxypregna- 4, 9( ll)- dieno[ 16g, 17- b]-[ 1, 4] dioxane- 3, 20-dione, 5', 21- diacetate
En blanding av 5'? , 11/3,21-trihydroksypregn-4-eno^ [16a, 17-b ]-[1,4 ]dioksan-3,20-dion, 5',21-diacetat (4 mmol), 75 ml dimetylformamid, 37,5 ml pyridin og 15 ml metansulfonylklorid blir rørt ved 0°C i 75 minutter, blir så hellet inn i kald, fortynnet saltsyre og den resulterende blanding blir ekstrahert med kloroform. Kloroform-oppløsningen blir tørket og inndampet i vakuum for å gi tittel-forbindelsen. A mix of 5'? , 11/3,21-trihydroxypregn-4-eno^ [16a, 17-b]-[1,4]dioxane-3,20-dione, 5',21-diacetate (4 mmol), 75 ml dimethylformamide, 37 .5 ml of pyridine and 15 ml of methanesulfonyl chloride are stirred at 0°C for 75 minutes, then poured into cold dilute hydrochloric acid and the resulting mixture is extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to give the title compound.
B. 9 , ll/ 3- diklor- 5 ' F , 21- dihydroksypregn- 4- eno-[ 16g, 17- b ] [ 1, 4 } dioksan- 3, 20- dion, 5', 21- diacetat B. 9 , ll/ 3- dichloro- 5 ' F , 21- dihydroxypregn- 4- eno-[ 16g, 17- b ] [ 1, 4 } dioxane- 3, 20-dione, 5', 21- diacetate
En oppløsning av 5'£,21-dihydroksypregna-4,9(ll)-dieno-[16a, 17-b ]-[l,4 ]dioksan-3,20-dion, 5', 21-diacetat (2,1 mmol) og 3,75g litiumklorid i 37,5 ml iseddik blir rørt ved 0-5°C og det blir tilsatt 310 mg N-klorsuccinimid. En oppløsning av 95 mg tørt hydrogenklorid i 1,5 ml tetrahydrofuran blir tilsatt og den resulterende blanding blir rørt ved romtemperatur i 2 timer, hellet inn i 450ml kaldt vannbg ekstrahert med kloroform. Kloroform-oppløsningen blir vasket med vann, tørket og inndampet i vakuum for å gi tittel-forbindelsen. A solution of 5'£,21-dihydroxypregna-4,9(11)-dieno-[16a,17-b]-[1,4]dioxane-3,20-dione, 5',21-diacetate (2, 1 mmol) and 3.75 g of lithium chloride in 37.5 ml of glacial acetic acid are stirred at 0-5°C and 310 mg of N-chlorosuccinimide are added. A solution of 95 mg of dry hydrogen chloride in 1.5 ml of tetrahydrofuran is added and the resulting mixture is stirred at room temperature for 2 hours, poured into 450 ml of cold water bg extracted with chloroform. The chloroform solution is washed with water, dried and evaporated in vacuo to give the title compound.
Eksempel 5 Example 5
9, ll/ 3- diklor- 6g- f luor- 5 ' £ , 21- dihydroksypregn&- l, 4-dieno- [ 16g, 17- b] [ 1, 4 ] dioksan- 3, 20- dion, 5'' 5 »21- diacetat Ved å innsette 6g-fluor-5'f ,21-dihydroksypregna-l,4,9(ll)-trieno- [16g,17-b] [1,4]dioksan-3,20-dion-5'21-diacetat i stedet for steroidreaktanten og gå frem som beskrevet i eksempel 4B, oppnås tittel-forbindelsen. 9, ll/ 3- dichloro- 6g- f luor- 5 ' £ , 21- dihydroxypregn&- l, 4-dieno- [ 16g, 17- b] [ 1, 4 ] dioxane- 3, 20- dione, 5'' 5 »21- diacetate By inserting 6g-fluoro-5'f ,21-dihydroxypregna-1,4,9(11)-trieno- [16g,17-b] [1,4]dioxane-3,20-dione -5'21-diacetate in place of the steroid reactant and proceed as described in Example 4B, the title compound is obtained.
Eksempel 6Example 6
A. 21- klor- 5 '€ , ri/ 3- dihydroksypregna- l, 4- dieno-A. 21- chloro-5 '€ , ri/ 3- dihydroxypregna- l, 4- dieno-
[ 16g, 17- b ] [ 1, 4 ldioksan- 3, 20- dion, 5' £ - benzoat En blanding av 21-klor-5'?,110-dihydrqksypregna-l,4-dieno-[16a,17-bj[1,4]dioksan-3,20-dion, 5'S-benzoat (2,8 mmol), 52 ml dimetylformamid, 26 ml pyridin og 11 ml metansulfonylklorid blir rørt ved 0°C i 75 minutter, hellet inn i kald, fortynnet saltsyre og den resulterende blanding blir ekstrahert med kloroform. Kloroform-oppløsningen blir tørket og inndampet i vakuum for å gi tittel-forbindelsen. [ 16g, 17- b ] [ 1, 4 ldioxane- 3, 20- dione, 5' £ - benzoate A mixture of 21-chloro-5'?,110-dihydrqxypregna-1,4-dieno-[16a,17- bj[1,4]dioxane-3,20-dione, 5'S-benzoate (2.8 mmol), 52 ml of dimethylformamide, 26 ml of pyridine and 11 ml of methanesulfonyl chloride are stirred at 0°C for 75 minutes, poured into cold, dilute hydrochloric acid and the resulting mixture is extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to give the title compound.
B. 9, 11/ 3, 21- triklor- 5' £ - hydroksypregna- 1, 4- dieno-[ 16g, 17- b ] [ 1, 4 ] dioksan- 3 , 20- dion, 5 ' £ - benzoat B. 9, 11/ 3, 21- trichloro- 5' £ - hydroxypregna- 1, 4- dieno-[ 16g, 17- b ] [ 1, 4 ] dioxane- 3 , 20- dione, 5 ' £ - benzoate
En oppløsning av 21-klor-5-hydroksypregna-1,4,9(11)-trieho [16a,17-b ] [1,4]dioksan-3,20-dion, 5'5-benzoat (2 mmol) og 3,6 g litiumklorid i 36 ml iseddik blir rørt ved 0-5°C og det blir tilsatt 296vmg N-klorsuccinimid. Det blir tilsatt en oppløsning av 90 mg tørt hydrogenklorid i 1,45 ml tetrahydrofuran og den resulterende blanding blir rørt ved romtemperatur i 2 timer, hellet inn i 220ml kaldt vann og ekstrahert med kloroform. Klofoformoppløs-ningen blir vasket med vann, tørket og inndampet i vakuum for å gi tittel-forbindelsen. A solution of 21-chloro-5-hydroxypregna-1,4,9(11)-trieho [16a,17-b] [1,4]dioxane-3,20-dione, 5'5-benzoate (2 mmol) and 3.6 g of lithium chloride in 36 ml of glacial acetic acid are stirred at 0-5°C and 296 vmg of N-chlorosuccinimide are added. A solution of 90 mg of dry hydrogen chloride in 1.45 ml of tetrahydrofuran is added and the resulting mixture is stirred at room temperature for 2 hours, poured into 220 ml of cold water and extracted with chloroform. The clofoform solution is washed with water, dried and evaporated in vacuo to give the title compound.
Eksempel 7 Example 7
A. 17, 21- dihydroksy- 16g-( 2- okso- 2- fenyletoksy)-pregna- 1, 4, 9( 11)- trien- 3, 20- dion, 21- acetat A. 17, 21- dihydroxy- 16g-( 2- oxo- 2- phenylethoxy)-pregna- 1, 4, 9( 11)- trien- 3, 20-dione, 21- acetate
En oppløsning av 11/3,17, 21-trihydroksy-16a-(2-okso-2-fenyl-etoksy)pregna-1,4-dien-3,20-dion, 21-acetat (4 mmol) i 40 ml dimetylformamid og 20 ml pyridin blir rørt sammen med 10 ml metansulfonylklorid i, 60 minutter ved 0°C, og blir så hellet inn i fortynnet saltsyre og ekstrahert med kloroform. Kloroform-oppløsningen blir vasket med vann, tørket og inndampet for å gi tittel-forbindelsen. A solution of 11/3,17, 21-trihydroxy-16α-(2-oxo-2-phenyl-ethoxy)pregna-1,4-diene-3,20-dione, 21-acetate (4 mmol) in 40 mL dimethylformamide and 20 ml of pyridine are stirred together with 10 ml of methanesulfonyl chloride for 60 minutes at 0°C, and then poured into dilute hydrochloric acid and extracted with chloroform. The chloroform solution is washed with water, dried and evaporated to give the title compound.
B. 9, ll/ 3- diklor- 17, 21- dihydroksy- 16a- ( 2- okso- 2- fenyletoksy)-pregna- 1, 4- dien- 3, 20- dion, 21- acetat B. 9, ll/ 3- dichloro- 17, 21- dihydroxy- 16a-( 2- oxo- 2- phenylethoxy)-pregna- 1, 4- diene- 3, 20-dione, 21- acetate
En oppløsning av 17,21-dihydroksy-16a-(2-okso-2-fenyl-etoksy) pregna-1,4,9(11)-trien-3,20-dion, 21-acetat (1,4 mmol) og 2,52 g litiumklorid i 25 ml iseddik blir rørt ved0-5°C og det blir tilsatt 209 mg N-klorsuccinimid. Det blir så tilsatt en oppløsning av 63 mg tørt hydrogenklorid i 1 ml tetrahydrofuran og den resulterende blanding blir rørt ved romtemperatur i 2 timer, hellet inn i 130ml kaldt vann og ekstrahert med kloroform.Kloroform-oppløs-ningen blir vasket med vann, tørket og inndampet for å gi tittel-forbindelsen. A solution of 17,21-dihydroxy-16α-(2-oxo-2-phenyl-ethoxy)pregna-1,4,9(11)-triene-3,20-dione, 21-acetate (1.4 mmol) and 2.52 g of lithium chloride in 25 ml of glacial acetic acid are stirred at 0-5°C and 209 mg of N-chlorosuccinimide are added. A solution of 63 mg of dry hydrogen chloride in 1 ml of tetrahydrofuran is then added and the resulting mixture is stirred at room temperature for 2 hours, poured into 130 ml of cold water and extracted with chloroform. The chloroform solution is washed with water, dried and evaporated to give the title compound.
C. 9, lljS- diklor- 2 *', 3 ' - dihydro- 21- hydroksy- 5 ' - f enyl- pregna-1, 4- dieno [ 16oi, 17- b] [ 1, 4 jdioksinT3, 20- dion, 21- acetat En oppslemning av 100 rag p-toluensulfonsyre i 100 ml benzen blir tilbakeløpsbehandlet i 1 time med en Dean-Stark-felle fylt med en molekylar-sikt. Oppløsningen blir,avkjølt og man tilsetter .1 , C. 9, lljS- dichloro- 2 *', 3 ' - dihydro- 21- hydroxy- 5 ' - phenyl- pregna-1, 4- dieno [ 16oi, 17- b] [ 1, 4 jdioxinT3, 20- dione , 21-acetate A slurry of 100 mg of p-toluenesulfonic acid in 100 ml of benzene is refluxed for 1 hour with a Dean-Stark trap filled with a molecular sieve. The solution is cooled and .1 is added,
9, ll)8-diklor-21-hydroksy-16a- (2-okso-2-f enyletoksy) pregna-1,4-dien-3,20-dion, 21-acetat (1 mmol). Etter tilbakeløp i 30 minutter under nitrogen, blir oppløsningen avkjølt, vasket med 5% natriumbikarbo-nat-oppløsning, tørket og inndampet i vakuum for å gi tittel-forbindelsen. 9,11)8-Dichloro-21-hydroxy-16α-(2-oxo-2-phenylethoxy)pregna-1,4-diene-3,20-dione, 21-acetate (1 mmol). After refluxing for 30 minutes under nitrogen, the solution is cooled, washed with 5% sodium bicarbonate solution, dried and evaporated in vacuo to give the title compound.
Eksempel 8 Example 8
A. 21- klor- 17- hydroksy- 16 a-( 2- oksopropoksy)-pregna- 1;4, 9( 11)- trien- 3, 20- dion A. 21- chloro- 17- hydroxy- 16 a-( 2- oxopropoxy)-pregna- 1;4, 9( 11)- trien- 3, 20-dione
En oppløsning av 21-klor-110, 17-dihydroksy-16o!-(2-okso-propoksy)pregna-1,4-dien-3,20-dion (10 mmol) i 40 ml dimetylformamid og 20 ml pyridin blir rørt ved 0°C i 75 minutter sammen med lo ml metansulfonylklorid.Blandingen blir hellet inn i kald, fortynnet saltsyre og blir ekstnahert med kloroform. Klproformgoppløs-ningen, blir tørket pg inndampet for å gi tittel-forbindelseri. A solution of 21-chloro-110,17-dihydroxy-16o!-(2-oxo-propoxy)pregna-1,4-diene-3,20-dione (10 mmol) in 40 ml of dimethylformamide and 20 ml of pyridine is stirred at 0°C for 75 minutes together with 10 ml of methanesulfonyl chloride. The mixture is poured into cold, dilute hydrochloric acid and is extracted with chloroform. The kproform solution is dried and evaporated to give the title compound.
B. 9, 11/ 3, 21- triklor- 17- hydroksy- 16tt- ( 2-oksopropoksy) pregna- 1, 4- dien- 3, 20- dion B. 9, 11/ 3, 21- trichloro- 17- hydroxy- 16tt- ( 2-oxopropoxy) pregna- 1, 4- diene- 3, 20-dione
En oppløsning av 21-klor-17-hydroksy-l6a-(2-oksopropoksy)-pregna-1,4,9(11)-trien-3,20-dion (4 mmol) og 7,2 g litiumklorid i 72 ml iseddik blir rørt ved 0-5°C og det blir tilsatt 592 mg N-klorsuccinimid. Det blir tilsatt en oppløsning av 180 mg tørt hydrogenklorid i 2,9 ml tetrahydrofuran og den resulterende blanding blir rørt ved romtemperatur i 2 timer, hellet inn i 400 ml kaldt vann og ekstrahert med kloroform.Kloroform-oppløsningen blir vasket med vann, tørket og inndampet for å gi tittel-forbindelsen. A solution of 21-chloro-17-hydroxy-16a-(2-oxopropoxy)-pregna-1,4,9(11)-triene-3,20-dione (4 mmol) and 7.2 g of lithium chloride in 72 ml glacial acetic acid is stirred at 0-5°C and 592 mg of N-chlorosuccinimide is added. A solution of 180 mg of dry hydrogen chloride in 2.9 ml of tetrahydrofuran is added and the resulting mixture is stirred at room temperature for 2 hours, poured into 400 ml of cold water and extracted with chloroform. The chloroform solution is washed with water, dried and evaporated to give the title compound.
C. 9, 11/ 3, 21- triklor- 2 ' , 3 ' - dihydro- 5' - metylpregna-1, 4- dieno [ 16a;, 17- b ] [ 1, 4 ] dioksin- 3, 20- dion C. 9,11/3,21-trichloro-2',3'-dihydro-5'-methylpregna-1,4-dieno [16a;,17-b] [1,4]dioxin-3,20-dione
En oppslemning av 200 mg p-toluensulfonsyre i 200 ml benzen blir tilbakeløpsbehandlet i 1 time med en Dean-Stark-felle fylt med en molekylar-sil. Den resulterende oppløsning blir avkjølt og 9,lip,21-trikldr-17-hydroksy-16a-(2-oksopropoksy)pregna-1,4-dien-3,20-dion (3 mmol) blir tilsatt. Etter tilbakeløpsbehandling i 2 timer blir oppløsningen avkjølt, vasket med fortynnet natriumbi-karbonat-oppløsning og tørket. Fjerning av oppløsningsmiddel gir tittel-forbindelsen. A slurry of 200 mg of p-toluenesulfonic acid in 200 ml of benzene is refluxed for 1 hour with a Dean-Stark trap filled with a molecular sieve. The resulting solution is cooled and 9,lip,21-tricldr-17-hydroxy-16a-(2-oxopropoxy)pregna-1,4-diene-3,20-dione (3 mmol) is added. After refluxing for 2 hours, the solution is cooled, washed with dilute sodium bicarbonate solution and dried. Removal of solvent gives the title compound.
Eksempel 9Example 9
A. 16g-( allyloksy)- 17, 21- dihydroksypregna-4, 9( 11)- dien- 3, 20- dion, 21- acetat A. 16g-(allyloxy)-17,21-dihydroxypregna-4,9(11)-diene-3,20-dione,21-acetate
En oppløsning av 16a-(allyloksy)-11/3,17,21-trihydroksypregn-4-en-3,20-dion, 21-acetat (10mmol) i 100 ml dimetylformamid og 50 ml pyridin blir rørt i 90 minutter ved 0°C sammen med 20 ml A solution of 16α-(allyloxy)-11/3,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate (10 mmol) in 100 ml of dimethylformamide and 50 ml of pyridine is stirred for 90 minutes at 0 °C together with 20 ml
metansulfonylklorid. Oppløsningen blir hellet inn i overskudd av 5% saltsyre og blir ekstrahert med kloroform. Kloroform-oppløsningen methanesulfonyl chloride. The solution is poured into an excess of 5% hydrochloric acid and is extracted with chloroform. The chloroform solution
..blir tørket og inndampet for å gi tittel-forbindelsen...is dried and evaporated to give the title compound.
B. 16oi- ( allyloksy) - 9- klor- llft- f luor- 17, 21- dihydroksypregn- 4- en- 3, 20- dion, 21- acetat B. 16oi- (allyloxy) - 9- chloro- llft- fluoro- 17, 21- dihydroxypregn- 4- ene- 3, 20- dione, 21- acetate
En oppløsning av 16a-(allyloksy)-17,21-dihydroksypregna-4,9(11)-dien-3,20-dion, 21-acetat (0,5 mmol) og N-klorsuccinimid (67 mg, 0,5 mmol) i diklormetan blir satt til en blanding av vannfritt hydrogenfluorid (3,42 g) og vannfritt tetrahydrofuran (6 g) i en polyetylen-flaske ved -80°C. Etter 1 time blir blandingen rørt i 30 minutter ved -20°Cog blir så sakte satt til en kald natrium-karbonat-oppløsning. Ekstrahering med kloroform, tørking av ekstrakt-et og fjerning av oppløsningsmidlet gir tittel-forbindelsen. A solution of 16α-(allyloxy)-17,21-dihydroxypregna-4,9(11)-dien-3,20-dione, 21-acetate (0.5 mmol) and N -chlorosuccinimide (67 mg, 0.5 mmol) in dichloromethane is added to a mixture of anhydrous hydrogen fluoride (3.42 g) and anhydrous tetrahydrofuran (6 g) in a polyethylene bottle at -80°C. After 1 hour, the mixture is stirred for 30 minutes at -20°C and is then slowly added to a cold sodium carbonate solution. Extraction with chloroform, drying the extract and removing the solvent gives the title compound.
C. 9- klor- llff- fluor- 17, 21- dihydroksy- 16a-( oksiranyl-metoksy) pregn- 4- en- 3, 20- dion, 21- acetat C. 9- chloro- llff- fluoro- 17, 21- dihydroxy- 16a-( oxiranyl- methoxy) pregn- 4- ene- 3, 20- dione, 21- acetate
Ehoppløsning av 16a-(allyloksy)-9-klor-ll/3-fluor-17,21-dihydroksypregn-4-en-3,20-dion, 21-acetat (1,4 mmol) i 20ml diklormetan blir rørt sammen med 300 mg m-klorperbenzosyre i 72 timer. Oppløsningen blir vasket med en kald blanding av fortynnet natrium-bikarbonat- og fortynnet natriumsulfittoppløsning og blir tørket. Fjerning av oppløsningsmiddel gir tittel-forbindelsen. A solution of 16α-(allyloxy)-9-chloro-11/3-fluoro-17,21-dihydroxypregn-4-ene-3,20-dione, 21-acetate (1.4 mmol) in 20 ml of dichloromethane is stirred with 300 mg of m-chloroperbenzoic acid for 72 hours. The solution is washed with a cold mixture of dilute sodium bicarbonate and dilute sodium sulfite solution and is dried. Removal of solvent gives the title compound.
D. 9- klor- llj8- fluor- 5 ' £ , 21- dihydroksypregn- 4-eno [ 16a, 17- b] [ 1, 4 ] dioksan- 3, 20- dion, 21- acetat En oppløsning av 9-klor-ll/3-fluor-17,21-dihydroksy-16a- D. 9- chloro- llj8- fluoro- 5 ' £ , 21- dihydroxypregn- 4-eno [ 16a, 17- b] [ 1, 4 ] dioxane- 3, 20- dione, 21- acetate A solution of 9-chloro -ll/3-fluoro-17,21-dihydroxy-16a-
(dksiranyImetoksy)pregn-4-en-3,20-dion, 21-acetat (1 mmol) i 20 ml tetrahydrofuran blir rørt sammen med 1 g perjodsyre i 4 ml vann i 7 timer. Oppløsningen blir fortynnet med vann og ekstrahert med kloroform. Tørking av denne oppløsning og fjerning av oppløsnings-middel gir tittel-forbindelsen. (dxiranyImethoxy)pregn-4-ene-3,20-dione, 21-acetate (1 mmol) in 20 ml of tetrahydrofuran is stirred with 1 g of periodic acid in 4 ml of water for 7 hours. The solution is diluted with water and extracted with chloroform. Drying this solution and removing the solvent gives the title compound.
Eksempel 10Example 10
A* 21- klor- 5'%- hydroksypregna- 4, 9( 11)- dieno-[ 160;, 17- b] [ 1, 4 ] dioksan- 3 , 20- dion, 5'- butyrat En blanding av 21-klorr-5 , ll/3-dihydroksypregn-4-eno-[ 16a,17-b][l,4]-dioksan-3,20-dion, 5'-butyrat (4 mmol), 75 ml dimetylformamid, 37,5 ml pyridin og 12 ml metansulfonylklorid blir rørt ved 0°C i 75 minutter, blir så hellet inn i kald,fortynnet saltsyre og den resulterende blanding blir ekstrahert med kloroform. Kloroform-oppløsningen blir tørket og inndampet i vakuum for å gi tittel-forbindelsen. A* 21- chloro- 5'%- hydroxypregna- 4, 9( 11)- dieno-[ 160;, 17- b] [ 1, 4 ] dioxane- 3 , 20- dione, 5'- butyrate A mixture of 21 -chloror-5, 11/3-dihydroxypregn-4-eno-[16a,17-b][1,4]-dioxane-3,20-dione, 5'-butyrate (4 mmol), 75 ml dimethylformamide, 37 .5 ml of pyridine and 12 ml of methanesulfonyl chloride are stirred at 0°C for 75 minutes, then poured into cold dilute hydrochloric acid and the resulting mixture is extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to give the title compound.
B. 9, 21- diklor- ll/ 3- f luor- 5- hydroksypregn- 4-eno- [ 16o?, 17- b ] [ 1, 4 ] dioksan- 3, 20- dion, 5'- butyrat En blanding av 21-klor-5'^-hydroksypregna-4,9(ll)-dieno-[16a;, 17-b) [1,4]dioksan-3,20-dion, 5'-butyrat (2 mmol) og N-klorsuccinimid (260 mg, 2 mmol) i tørr diklormetan blir satt til én blanding av 10,13 g vannfritt hydrogenfluorid og 18 g vannfritt tetrahydrofuran i en polyetylen-flaske ved -80°C. Etter 1 time blir blandingen rørt i ytterligere 2 timer ved 0°c og blir hellet for-siktig inn i en kald natriumkarbonat-oppløsning.Ekstrahering med kloroform gir tittel-forbindelsen. B. 9, 21- dichloro- ll/ 3- f fluoro- 5- hydroxypregn- 4-eno- [ 16o?, 17- b ] [ 1, 4 ] dioxane- 3, 20- dione, 5'- butyrate A mixture of 21-chloro-5'^-hydroxypregna-4,9(ll)-dieno-[16a;, 17-b) [1,4]dioxane-3,20-dione, 5'-butyrate (2 mmol) and N-chlorosuccinimide (260 mg, 2 mmol) in dry dichloromethane is added to a mixture of 10.13 g of anhydrous hydrogen fluoride and 18 g of anhydrous tetrahydrofuran in a polyethylene bottle at -80°C. After 1 hour, the mixture is stirred for a further 2 hours at 0°C and is carefully poured into a cold sodium carbonate solution. Extraction with chloroform gives the title compound.
Eksempel 11Example 11
A. 21- klorpregna- l, 4, 9( ll) trieno [ 16a;, 17- b ]-[ 1, 4] dioksan- 3, 20- dion A. 21-chlorpregna-l,4,9(ll)trieno [16a;,17-b]-[1,4]dioxane-3,20-dione
En blanding av 21-klor-lljS-hydroksypregna-1,4-dieno-[16a;, 17-b ] [1,4 ]dioksan-3,20-dion (4 mmol), 40 ml dimetylformamid, 20 ml pyridin og 10 ml metansulfonylklorid blir rørt ved 0°C i 75 minutter, hellet inn i kald, fortynnet saltsyre og den resulterende blanding blir ekstrahert med kloroform.Kloroform-oppløsningen blir tørket og inndampet i vakuum for å gi tittel-forbindelsen. A mixture of 21-chloro-lljS-hydroxypregna-1,4-dieno-[16a;, 17-b] [1,4]dioxane-3,20-dione (4 mmol), 40 ml of dimethylformamide, 20 ml of pyridine and 10 ml of methanesulfonyl chloride is stirred at 0°C for 75 minutes, poured into cold dilute hydrochloric acid and the resulting mixture is extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to give the title compound.
B. 9, 11- diklor- llff- fluorpregna- 1, 4- diéno-B. 9, 11- dichloro- llff- fluoropregna- 1, 4- dieno-
[ 160;, 17- b ] [ 1, 4 ] dioksan- 3, 20- dion[ 160;, 17- b ] [ 1, 4 ] dioxane- 3, 20-dione
En blanding av 21-klorpregna-l,4,9(ll)-trieno-[16a,17-b]-[1,4 ]dioksan-3,20-dion (1,9 mmol) og N-klorsuccinimid (247 mg, 1,9 mmol) i tørt metylenklorid blir satt sakte til en blanding av 10,2 g vannfritt hydrogenfluorid og 18 ,g tetrahydrofuran ved -80°C. Etter 1 time blir blandingen rørt i ytterligere 1 time ved 0°C og blir hellet inn i kald natriumbikarbonatoppløsning. Tittel-forbindelsen oppnås ved ekstrahering med kloroform, tørking og fjerning av opp-løsningsmiddel i vakuum. A mixture of 21-chloropregna-1,4,9(11)-trieno-[16a,17-b]-[1,4]dioxane-3,20-dione (1.9 mmol) and N-chlorosuccinimide (247 mg, 1.9 mmol) in dry methylene chloride is added slowly to a mixture of 10.2 g of anhydrous hydrogen fluoride and 18 g of tetrahydrofuran at -80°C. After 1 hour, the mixture is stirred for a further 1 hour at 0°C and is poured into cold sodium bicarbonate solution. The title compound is obtained by extraction with chloroform, drying and removal of solvent in vacuo.
Eksempel 12 Example 12
9- klor- llj3- fluor- 2' , 2' - dihydro- 21- hydroksy- preqn- 4-eno [ 16g, 17- b ] [ 1, 4 ] dioksin- 3, 20- dion, 21- acetat En oppløsning av 9-klor-ll/3-fluor-5 ,21-dihydroksy-pregn-4-eno[16a,17-b][1,4]dioksan-3,20-dion, 21-acetåt (0,6 mmol, fremstilt som beskrevet i eksempel 9) blir satt til en vannfri oppløs-ning av 70 mg p-toluensulfonsyre i 60mg benzen. Etter tilbakeløps-behandling i 6 timer blir oppløsningen avkjølt, vasket med fortynnet natriumbikarbonat-oppløsning, tørket og inndampet for å gi tittel-forbindelsen. , 9- chloro- llj3- fluoro- 2' , 2' - dihydro- 21- hydroxy- preqn- 4-eno [ 16g, 17- b ] [ 1, 4 ] dioxin- 3, 20- dione, 21- acetate A solution of 9-chloro-11/3-fluoro-5,21-dihydroxy-pregn-4-eno[16a,17-b][1,4]dioxane-3,20-dione, 21-acetate (0.6 mmol , prepared as described in example 9) is added to an anhydrous solution of 70 mg of p-toluenesulfonic acid in 60 mg of benzene. After refluxing for 6 hours, the solution is cooled, washed with dilute sodium bicarbonate solution, dried and evaporated to give the title compound. ,
Eksempel 13 Example 13
9- klor- llj3- fluor- 21- hydroksypregn- 4- eno-[ 16a, 17- bI[ 1, 4] dioksan- 3, 5, 20- trion, 21- acetat 9- chloro- llj3- fluoro- 21- hydroxypregn- 4- eno-[ 16a, 17- bI[ 1, 4] dioxane- 3, 5, 20- trione, 21- acetate
En oppløsning av 9-klor-ll/3-fluor-5 '§ , 21-dihydroksypregn-r 4-eno-[16a,17-b ] [1,4]dioksan-3,20-dion, 21-acetat (1 mmol, fremstilt som beskrevet i eksempel 9) i 100ml toluen blir tilbakeløps-behiandlet i et Dean-Stark-apparat med 7 g Fetizon's reagens (sølv-karbonat på celitt (diatomé-jord)) under nitrogen i 14 timer, og blir så avkjølt og filtrert. Filtratet blir inndampet for å gi tittel-forbindelsen. A solution of 9-chloro-11/3-fluoro-5'§ , 21-dihydroxypregn-r 4-eno-[16a,17-b ] [1,4]dioxane-3,20-dione, 21-acetate ( 1 mmol, prepared as described in Example 9) in 100 ml of toluene is refluxed in a Dean-Stark apparatus with 7 g of Fetizon's reagent (silver carbonate on celite (diatomaceous earth)) under nitrogen for 14 hours, and then cooled and filtered. The filtrate is evaporated to give the title compound.
Eksempel 14 Example 14
9, llig- diklor- 21- hydroksypr egna- 1, 4- dieno-[ 16a, 17- b ] [ 1, 4 ] dioksan- 3, 20- dion; 9, llig- dichloro- 21- hydroxypr egna- 1, 4- dieno-[ 16a, 17- b ] [ 1, 4 ] dioxane- 3, 20-dione;
En oppløsning av 9, ll/3-diklor-21-hydroksypregna-l ,4-dieno-[16a,17-b] [1,4]dioksan-3,20-dion, 21-acetat ( 2 mmol, fremstilt som beskrevet i eksempel 1) i 40 ml metanol blir rørt ved 0°C sammen med 4 ml av en io% kaliumkarbonat-oppløsning. Den resulterende opp-løsning blir surgjort med 1 ml iseddik og fortynnet med vann for å gi tittel-forbindelseri. A solution of 9,11/3-dichloro-21-hydroxypregna-1,4-dieno-[16a,17-b][1,4]dioxane-3,20-dione, 21-acetate (2 mmol, prepared as described in example 1) in 40 ml of methanol is stirred at 0°C together with 4 ml of a 10% potassium carbonate solution. The resulting solution is acidified with 1 ml of glacial acetic acid and diluted with water to give the title compound.
Eksempel 15 Example 15
9, ll/ 3- diklor- 21- hydroksypregna- l, 4- dieno-[ 16a, 17- b] [ 1, 4 ] dioksan- 3 , 20- dion, 21- cyklo-heksankarboksylat 9, ll/ 3- dichloro- 21- hydroxypregna- 1, 4- dieno-[ 16a, 17-b] [ 1, 4 ] dioxane- 3, 20-dione, 21- cyclohexanecarboxylate
En oppløsning av 9,ll/3-diklor-21-hydroksypregna-l,4-dieno-[ 16a,17-b][1,4]dioksan-3,20-dion (1,6 mmol, fremstilt som beskrevet i eksempel 14) i 20 ml pyridin blir rørt sammen med 400mg cyklo-heksankarbonylklorid i 2 timer. Oppløsningen blir fortynnet med kloroform, vasket med 5% saltsyre, tørket og inndampet for å gi tittel-forbindelsen. A solution of 9,11/3-dichloro-21-hydroxypregna-1,4-dieno-[16a,17-b][1,4]dioxane-3,20-dione (1.6 mmol, prepared as described in example 14) in 20 ml of pyridine is stirred together with 400 mg of cyclohexanecarbonyl chloride for 2 hours. The solution is diluted with chloroform, washed with 5% hydrochloric acid, dried and evaporated to give the title compound.
Eksempel 16Example 16
A. 5'- etoksypregna- 4, 9( ll) dieno[ 16g, 17- b]-[ 1, 4] dioksan- 3, 20- dion A. 5'- ethoxypregna- 4, 9( ll) dieno[ 16g, 17-b]-[ 1, 4] dioxane- 3, 20-dione
En oppløsning av 5'€-etoksy-21-hydroksypregna-4,9(ll)-dieno[16a,17-b][1,4]dioksan-3,20-dion, 21-mesylat (4 mmol, fremstilt som beskrevet i eksempel 3a) i 30 ml dimetylformamid blir tilbake-løpsbehandlet i 2 timer med 2 g litiumjodid. Oppløsningen blir fortynnet med kloroform, vasket med fortynnet saltsyre, vann og nat-riumbisulfitt-oppløsning og blir tørket og inndampet for å gi tittel-forbindelsen. A solution of 5'€-ethoxy-21-hydroxypregna-4,9(ll)-dieno[16a,17-b][1,4]dioxane-3,20-dione, 21-mesylate (4 mmol, prepared as described in example 3a) in 30 ml of dimethylformamide is refluxed for 2 hours with 2 g of lithium iodide. The solution is diluted with chloroform, washed with dilute hydrochloric acid, water and sodium bisulfite solution and is dried and evaporated to give the title compound.
B. 9, llj3- diklor- 5' ?- etoksypregn- 4- eno-[ 16 a , 17- b ] [ 1, 4 ] dioksan- 3, 20- dion B. 9, llj3- dichloro- 5' ?- ethoxypregn- 4- eno-[ 16 a , 17- b ] [ 1, 4 ] dioxane- 3, 20-dione
En oppløsning av 5'S-etoksypregna-4,9(ll)dieno [16a,17-b ]-[1,4]dioksan-3,20-dion (1,4 mmol) og 2,5 g litiumklorid i 25 ml iseddik blir rørt ved 0-5°C og det blir tilsatt 207 mg N-klorsuccinimid. Det blir tilsatt en oppløsning av 63 mg tørt hydrogenklorid i 1 ml tetrahydrofuran og den resulterende blanding blir rørt ved romtemperatur i 2 timer, hellet inn i 300 ml kaldt vann og ekstrahert med kloroform. Kloroform-oppløsningen blir vasket med vann, tørket og inndampet i vakuum for å gi tittel-forbindelsen. A solution of 5'S-ethoxypregna-4,9(ll)dieno [16a,17-b]-[1,4]dioxane-3,20-dione (1.4 mmol) and 2.5 g of lithium chloride in 25 ml of glacial acetic acid is stirred at 0-5°C and 207 mg of N-chlorosuccinimide is added. A solution of 63 mg of dry hydrogen chloride in 1 ml of tetrahydrofuran is added and the resulting mixture is stirred at room temperature for 2 hours, poured into 300 ml of cold water and extracted with chloroform. The chloroform solution is washed with water, dried and evaporated in vacuo to give the title compound.
Eksempel 17 Example 17
9, ll/ 3- diklor- 5, 21- dihydroksypregn- 4-eno [ 16a, 17- b ] [ 1, 4 ] dioksan- 3, 20- dion 9, ll/ 3- dichloro- 5, 21- dihydroxypregn- 4-eno [ 16a, 17- b ] [ 1, 4 ] dioxane- 3, 20-dione
En oppløsning av 9, ll/3-diklor-5 "I", 21-dihydroksypregn-4-eno-[16a,17-b ][1,4]dioksan-3,20-dion, 5',21-diacetat (1 mmol, fremstilt som beskrevet i eksempel 4) i 40 ml metanol ved 0°C blir behandlet med 4 ml med 10%kaliumkarbonat-oppløsriing. Etter 2 timer blir opp-løsningen surg jort med 2 ml eddiksyre, fortynnet med vann og ekstrahert med kloroform for å gi tittel-forbindelsen. A solution of 9,11/3-dichloro-5"I",21-dihydroxypregn-4-eno-[16a,17-b][1,4]dioxane-3,20-dione, 5',21-diacetate (1 mmol, prepared as described in Example 4) in 40 ml of methanol at 0°C is treated with 4 ml of 10% potassium carbonate solution. After 2 hours, the solution is acidified with 2 ml of acetic acid, diluted with water and extracted with chloroform to give the title compound.
Eksempel 18 Example 18
9, llff- diklor- 5' 1, 21- dihydroksy- 6g- metylpregna- l, 4-dieno [ 16a;, 17- b ] [ 1, 4 ] dioksan- 3 , 20- dion, 5 ' l , 21- diacetat Ved å innsette 5 ' k , 21-dihydroksy-6g-metylpregna-l,4, 9 (11 )-trieno-[16g,17-b ] [1,4]dioksan-3,20-dion-5'l,21-diacetat i stedet for steroidreaktanten og gå frem som beskrevet i eksempel 4B, oppnås tittel-forbindelsen. 9, llff- dichloro- 5' 1, 21- dihydroxy- 6g- methylpregna- 1, 4-dieno [ 16a;, 17- b ] [ 1, 4 ] dioxane- 3 , 20- dione, 5 ' l , 21- diacetate By inserting 5' k , 21-dihydroxy-6g-methylpregna-1,4,9 (11 )-trieno-[16g,17-b ] [1,4]dioxane-3,20-dione-5'l ,21-diacetate in place of the steroid reactant and proceed as described in Example 4B, the title compound is obtained.
Eksempel 19Example 19
A. 9, llj8- diklor- 17, 21- dihydroksy- l6g-( 2- okso- 2-fenyletoksy) pregna- 1, 4- dien- 3, 20- dion A. 9, llj8- dichloro- 17, 21- dihydroxy- 16g-( 2- oxo- 2-phenylethoxy) pregna- 1, 4- diene- 3, 20-dione
En oppløsning av 9,ll/3-diklor-l7,21-dihydroksy-l'6a-(2-okso-2-fenyletoksy)pregna-1,4-dien-3,20-dion, 21-acetat (2 mmol, fremstilt som beskrevet i eksempel 7B) i 40 ml metanol blir rørt sammen med 4 ml av en 10% kaliumkarbonat-oppløsning ved 0°C i 30 minutter, blir surgjort med 2 ml eddiksyre, fortynnet med vann og ekstrahert med kloroform for å gi tittel-forbindelsen. A solution of 9,11/3-dichloro-17,21-dihydroxy-1'6a-(2-oxo-2-phenylethoxy)pregna-1,4-diene-3,20-dione, 21-acetate (2 mmol , prepared as described in Example 7B) in 40 ml of methanol is stirred with 4 ml of a 10% potassium carbonate solution at 0°C for 30 minutes, acidified with 2 ml of acetic acid, diluted with water and extracted with chloroform to give the title connection.
B. 9, ll/ 7- diklor- 17, 21- dihydroksy- 16g- ( 2- okso- 2-fenyletoksy) pregna- 1, 4- dien- 3, 20- dion- 21- metansulfonat B. 9, ll/ 7- dichloro- 17, 21- dihydroxy- 16g-( 2- oxo- 2-phenylethoxy) pregna- 1, 4- diene- 3, 20- dione- 21- methanesulfonate
En oppløsning av 9,ll/3-diklor-17,21-dihydfoksy-16a-(2-okso-2-fenyletoksy)pregna-1,4-dien-3,20-dion (1,4 mmol) i 20 ml pyridin blir rørt ved 1 0 O C sammen med metansulfo' nylklorid (2 mmol) i 2 ti■ me•r. Oppløsningen blir fortynnet med kloroform, vasket med 5% saltsyre, tørket og inndampet for å gi tittel-forbindelsen. A solution of 9,11/3-dichloro-17,21-dihydphoxy-16a-(2-oxo-2-phenylethoxy)pregna-1,4-diene-3,20-dione (1.4 mmol) in 20 ml pyridine is stirred at 10 O C together with methanesulfonyl chloride (2 mmol) for 2 hours. The solution is diluted with chloroform, washed with 5% hydrochloric acid, dried and evaporated to give the title compound.
C* 9, ilj3>21- triklor- 17- hydroksy- 16a-( 2^ okso-2-* f enyletoksy) pregna- 1, 4- dien-* 3, 20-* dion C* 9, ilj3>21- trichloro- 17- hydroxy- 16a-( 2^ oxo-2-* phenylethoxy) pregna- 1, 4- diene-* 3, 20-* dione
En', oppløsning av 9,ll/3-diklor-17,21-dihydroksy-16a-(2-okso-2-fenyletoksy)pregna-l,4-dien-3,20-dion, 2l-metansulfonat (1 mmol) i 20 ml dimetylformamid blir oppvarmet ved 80°G i 3 timer sammen med 1 g litiumklorid, blir så avkjølt, fortynnet med vann og filtrert for å gi tittel-forbindelsen. En', solution of 9,11/3-dichloro-17,21-dihydroxy-16a-(2-oxo-2-phenylethoxy)pregna-1,4-diene-3,20-dione, 21-methanesulfonate (1 mmol ) in 20 ml of dimethylformamide is heated at 80°G for 3 hours together with 1 g of lithium chloride, then cooled, diluted with water and filtered to give the title compound.
D. 9, lljS, 21- triklor- 2 ' , 3 ' - dihydro- 5' - f enylpregna-1, 4- dieno [ 16g, 17- b][ 1, 4] dioksin- 3, 20- dion D. 9,lljS,21-trichloro-2',3'-dihydro-5'-phenylpregna-1,4-dieno[16g,17-b][1,4]dioxin-3,20-dione
En oppslemning av 100 mg p-toluensulfonsyre i 100 ml benzen blir tilbakeløpsbehandlet i 1 time med en Dean-Stark-felle, fylt med molekylarsil. Oppløsningen blir avkjølt og 9,11/3, 21-triklor-17-hydroksy-16a-(2-okso-2-fenyletoksy)pregna-l,4-dien-3,20-dion (1 mmol) blir tilsatt. Etter tilbakeløpsbehandling i 30 minutter under nitrogen blir oppløsningen avkjølt, vasket med 5% natriumbikarbonat-oppløsning, tørket og inndampet i vakuum for å gi tittel-forbindel^-sen. A slurry of 100 mg of p-toluenesulfonic acid in 100 ml of benzene is refluxed for 1 hour with a Dean-Stark trap filled with molecular sieves. The solution is cooled and 9,11/3,21-trichloro-17-hydroxy-16α-(2-oxo-2-phenylethoxy)pregna-1,4-diene-3,20-dione (1 mmol) is added. After refluxing for 30 minutes under nitrogen, the solution is cooled, washed with 5% sodium bicarbonate solution, dried and evaporated in vacuo to give the title compound.
, ■>, ■>
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO761516A NO761516L (en) | 1976-05-03 | 1976-05-03 | PROCEDURES FOR THE MANUFACTURE OF STEROIDS |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO761516A NO761516L (en) | 1976-05-03 | 1976-05-03 | PROCEDURES FOR THE MANUFACTURE OF STEROIDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO761516L true NO761516L (en) | 1977-11-04 |
Family
ID=19882881
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO761516A NO761516L (en) | 1976-05-03 | 1976-05-03 | PROCEDURES FOR THE MANUFACTURE OF STEROIDS |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO761516L (en) |
-
1976
- 1976-05-03 NO NO761516A patent/NO761516L/en unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI80888C (en) | Process for the preparation of therapeutically effective steroid carboxylic acid esters | |
| US4076708A (en) | Process for the preparation of 7α-halogeno-3-oxo-4-dehydro steroids and novel 7α-halogeno derivatives produced thereby | |
| CS209919B2 (en) | Method of making the esters of the 4-halogen-9-fluor-3-oxo-androst-4-en and 4-halogen-9-fluor-3-oxoandrosta -1,4-dien-17beta-thiocarboxyl acid | |
| CA1056371A (en) | Polyhalogeno-steroids and processes for their manufacture | |
| HU188769B (en) | Process for preparing aromatic heterocyclic esters of 3,20-dioxo-1,4-pregnadien-17alpha-ols | |
| HU182732B (en) | Process for producing corticoid-17-alkyl carbonates | |
| US4226862A (en) | Steroids and process for preparing the same | |
| JPS596880B2 (en) | Method for producing D-homosteroid | |
| NO154268B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTIC AFFECTIVE 6A-FLUOR-9A-CHLORINE-PREDNISOLON-17,21-DIESTERS. | |
| EP0061416B1 (en) | Process for the preparation of delta 9(11)- and delta 16-21-chloro-20-keto steroids of the pregnane and d-homopregnane series and their use as intermediates for the synthesis of highly effective corticoids | |
| KR850001208B1 (en) | Process for preparing 17 -acyloxy-5 -corticoids and 17 -acyloxy-5 -corticoids | |
| US4024131A (en) | 16-Methyl-9α-halo steroid esters, ethers and preparation thereof | |
| HU190746B (en) | Process for producing 6-alpha-methyl-corticoides and pharmaceutical compositions containing them | |
| US4018774A (en) | Steroidal [16α,17-d]isoxazolidines | |
| DK146017B (en) | ANALOGY PROCEDURE FOR PREPARING 17ALFA-ACYLOXY-9ALFA, 21-DIHALOGEN-11BETA-HYDROXY-6ALFA-FLUOR-16BETA-METHYL-PREGNA-1,4-DIEN-3,20-DION COMPOUNDS | |
| JPS6052160B2 (en) | Method for producing pregnane-based D-homosteroids | |
| NO761516L (en) | PROCEDURES FOR THE MANUFACTURE OF STEROIDS | |
| US3971773A (en) | Steroidal 9,11-dihalo-[16α,17-b]1,4-dioxanes | |
| JPH0564158B2 (en) | ||
| US5200518A (en) | Anti-inflammatory carboxycyclic acetal pregnane derivatives | |
| US3932388A (en) | -Azido-4,6-pregnadieno(3,2-c)pyrazoles, processes for their preparation and intermediates useful therein | |
| US4155917A (en) | Process for preparing D-homo oxasteroids | |
| ROTHMAN et al. | Steroidal Sapogenins. LXIV. C-21 Acetoxylation of 12-Keto Steroids2 | |
| US4185101A (en) | 1,3,5(10),6,8-19-Nor-pregnapentaenes, their use as anti-psoriatic agents, and pharmaceutical formulations useful therefor | |
| US3931167A (en) | Process for the manufacture of 3-keto-6-azido-4,6-bis-dehydro-steroids and intermediates useful therein |