GB2065660A - Anti inflammatory 2- bromo-6 beta -fluoro-9 alpha -halo steroids of the pregna-1,4-dien-3-one series - Google Patents
Anti inflammatory 2- bromo-6 beta -fluoro-9 alpha -halo steroids of the pregna-1,4-dien-3-one series Download PDFInfo
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- GB2065660A GB2065660A GB8035829A GB8035829A GB2065660A GB 2065660 A GB2065660 A GB 2065660A GB 8035829 A GB8035829 A GB 8035829A GB 8035829 A GB8035829 A GB 8035829A GB 2065660 A GB2065660 A GB 2065660A
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- United Kingdom
- Prior art keywords
- alpha
- bromo
- dione
- pregnadiene
- carbon atoms
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- 230000003110 anti-inflammatory effect Effects 0.000 title claims abstract description 4
- -1 -halo steroids Chemical class 0.000 title description 4
- SNHKWZAAMYPZLN-NWSAAYAGSA-N (8s,9s,10r,13r,14s,17s)-17-ethyl-10,13-dimethyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-one Chemical class C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 SNHKWZAAMYPZLN-NWSAAYAGSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000002252 acyl group Chemical group 0.000 claims abstract description 9
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 9
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 229940070710 valerate Drugs 0.000 claims abstract description 7
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
- 239000011737 fluorine Substances 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 5
- 230000031709 bromination Effects 0.000 claims abstract description 5
- 238000005893 bromination reaction Methods 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 5
- 150000003128 pregnanes Chemical class 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims description 2
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000032050 esterification Effects 0.000 abstract description 2
- 238000005886 esterification reaction Methods 0.000 abstract description 2
- 150000007524 organic acids Chemical class 0.000 abstract description 2
- 238000010931 ester hydrolysis Methods 0.000 abstract 1
- 125000004043 oxo group Chemical group O=* 0.000 abstract 1
- 238000001228 spectrum Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 239000012043 crude product Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000002211 ultraviolet spectrum Methods 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- XUXVVQKJULMMKX-UHFFFAOYSA-N 1,1,1-trimethoxypentane Chemical compound CCCCC(OC)(OC)OC XUXVVQKJULMMKX-UHFFFAOYSA-N 0.000 description 1
- LBKIRBXELMWQRC-UHFFFAOYSA-N 1-methoxypropane-1,1-diol Chemical compound CCC(O)(O)OC LBKIRBXELMWQRC-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- DUCKXCGALKOSJF-UHFFFAOYSA-N pentanoyl pentanoate Chemical compound CCCCC(=O)OC(=O)CCCC DUCKXCGALKOSJF-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
- C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
A process for the preparation of the title compounds, which are of general formula: <IMAGE> in which: X is an oxo group, a beta -hydroxyl group or a chlorine atom; Y is a fluorine or a chlorine atom but is not fluorine when X is a beta -chlorine atom; Z is a hydrogen atom or an alpha -hydroxyl or alpha - or beta -methyl group; R'is a hydrogen atom or an alkanoyl group having from 2 to 8 carbon atoms; and when Z is alpha -hydroxyl and R' is hydrogen, the corresponding 16 alpha , 17 alpha -acetonides and 16 alpha -alkanoyl derivatives, the alkanoyl radical having from 2 to 8 carbon atoms; and R is hydrogen or the acyl radical of a mono- or di-carboxylic organic acid having from 2 to 8 carbon atoms, of metasulfobenzoic acid or of phosphoric acid, comprises the bromination of the corresponding 2- unsubstituted- DELTA <1,4>-dienes (wherein R is C2-8 acyl) dissolved or suspended in a suitable solvent by reaction with excess of bromine in the cold, to give the corresponding 1,2-dibromo- derivative, which is then reacted with a basic agent to give the desired product (I) which is isolated and purified in known manner, and subjected to ester hydrolysis and re- esterification when required. Claimed per se are the anti inflammatory 17,21 dipropionate, 17-propionate- 21-acetate, and 17-propionate-21- valerate of 2-bromo-6 beta , 9 alpha - difluoroprednisolone.
Description
SPECIFICATION
Process for the preparation of 2-bromo-6ss-fluoro 3-keto-A 4-steroids of the pregnane series and products obtained thereby.
The present invention relates to a process for the preparation of steroid derivatives of the pregnane series and to products obtained thereby.
More particularly, the present invention relates to a process for the preparation of 2-bromo-6p4luoro-3- keto-AR4-steroids of the pregnane series of the general structural formula:
in which: Xis a keto- or a B-hydroxyl-group or a chlorine atom;
Y is a fluorine or a chlorine atom, but is not fluorine when Xis a chlorine atom;
Z is a hydrogen atom, or an a-hydroxyl- or a- or p-methyl-grnup; R' is a hydrogen atom or an alkanyl group having from 2 to 8 carbon atoms; and when Z is a -hydroxyl and
R' is hydrogen, the corresponding 16a, 17a-acetonides and 16a -alkanoyl-derivatives, the alkanoyl group having from 2 to 8 carbon atoms; and
R is hydrogen or the alkanoyl radical of a mono- or di-carboxyl organic acid having from 2 to 8 carbon atoms, of metasulfobenzoic acid or of phosphoric acid.
The compounds of formula I which possess valuable pharmacological properties particularly antiinflammatory and anti-rheumatoid arthritic activity are described and claimed in my U.K. Patent No.
1504132, No. 1504133 and No.1504134.
I have now surprisingly found that the compounds of formula I can be prepared in a more simple and advantageous manner in comparison with the process described and claimed in my above mentioned U.K.
patents.
This new process, the object of the present invention, which will be illustrated in detail hereinafter, comprises the bromination of a compound of the formula:
in which X, Y, Z, have the same significance as in formula I above, R is an alkanoyl group having from 2 to 8 carbon atoms, and R' is hydrogen or an alkanoyl group having from 2 to 8 carbon atoms, and when Z is a-hydroxyl and R' is hydrogen, the corresponding 16a-17a-acetonides and 16a-alkanoyl-derivatives,the alkanoyl group having from 2 to 8 carbon atoms.
The compounds of formula A, starting materials for the new process of the present invention, are described in detail and claimed in my U.K. Patent Nos. 1504294 and 1504295.
The process of the present invention may be represented by the following reaction scheme:
A compound of formula A, dissolved or suspended in a suitable solvent, such as dioxantetrahydrofuran or dimethylsulfoxide, is reacted with an excess of bromine in the cold, preferably at room temperature, to give the corresponding 1 ,2-dibromo-derivative (1'). This intermediate may be isolated as such, but it is preferred to convert it directly into the desired end product (1).
This conversion can be achieved by splitting off hydrogen bromide by means of a suitable basic agent such as an organic tertiary base, for instance pyridine, lutidine or collidine, or an inorganic base such as sodium or potassium acetate, and by operating generally at room temperature. After the reaction is completed, the mixture is poured into ice-cooled water and the desired crude product can be recovered by filtration, washing with water and drying at 40 C "in vacuo" to a constant weight.
Alternatively, the crude product can be extracted from the aqueous mixture with a water-immiscible solvent such as chloroform. The combined chloroform extracts are washed with water, dried over anhydrous sodium sulfate and evaporated "in vacuo" to dryness to a constant weight.
On crystallization of the crude product from a suitable solvent, or from a mixture of solvents, the desired pure compound (I) is obtained.
If desired, the alkanoyl, group R of the compound (I), thus obtained can be converted via the corresponding 21 -free-hydroxy-derivative into anotheralkanoyl group deriving from a mono ordi-carboxylic acid having from 2 to 8 carbon atoms of metasulfobenzoic or of phosphoric acid, by a method well known to those skilled in the art.
Alkali and alkaline earth metal salts of these compounds when the alkanoyl group is derived from a polybasic organic acid, such as succinic acid, tartaric acid, citric acid, metasulfobenzoic acid, or an inorganic acid, such as phosphoric acid, are also included within the scope of the present invention.
Preferred carboxylic acids which esterify the hydroxyl group in the 21-position are: acetic, propionic,
butyric, isobutyric, valeric, trimethyl-acetic, succinic, tartaric, citric, maleic, glutaric, pimelic, aminoacetic,
cyclopentylpropionic, benzoic, phenylacetic, nicotinic and isonicotinic acid.
Preferred carboxylic acids which esterify the hydroxyl group in the 17-position are: acetic, propionic,
butyric, isobutyric, valeric, cyclopentylpropionic, benzoic and phenylacetic.
The preparation of the 17-monoesters of 17a,21-dihydroxy-2-bromo-6ss-fluoro-3,20-diketo-1,4- pregnadienes of formula (I) in which R=R'=hydrogen with one of the above mentioned acids may be carried
out according to methods already known from the literature, for instance through the corresponding cyclic 17,21 -ortho-esters which, on acidic hydrolysis, give the desired 17-mono-esters (British Patent Nos. 996,079 and 996,080). The 17-monoesters thus obtained, having a free hydroxyl group in the 21-position, can be converted according to methods known per se, into the corresponding 17,21 -diesters, having the alkanoyl radical in the 21-position equal to or different from that in the 17-position.
Also following within the scope of the present invention are a few 17, 21-di-esters of formula (I) wherein
the radicals R and R' are equal or different. Such compounds comprise:
1. 2-Brnmo-69a-difluorn-1 ,4-pregnadiene-1 1 17a,21-tnol-3,20-dione-1 7,21 -dipropionate.
2. 2-Bromo-6ss,9α-difluoro-1,4-pregnadiene-11 P,1 7cr,21 -triol-3,20-dione-l 7-propionate-21-acetate.
3. 2-Bromo-6ss,9α-difluoro-1,4-pregnadiene-11 p,1 7a,2l4riol-3,20-dione-1 7-propionate-21 -valerate.
The present invention also comprises a pharmaceutical composition comprising one or more of the above
three specific compounds in admixture with a suitable carrier for local or parenteral administration.
The following examples illustrate methods of carrying out the present invention, but it is to be understood
that these Examples are given for the purpose of illustration and not of limitation.
EXAMPLE 1 2-Bromo-6ss,9a-difluoro- t,4-pregnadiene- t I 17a,214r1o13, 20-dione- 17,2 t-diacetate (Compound 1, R = R' = -acetyl; X = -OH; Y= FJ.
15 g of 6ss,9a-difluoro-prednisolone-17a,21-diacetate, prepared according to Example 9 of my British
Patent No. 1,504,294 is suspended in 900 ml of peroxides-free dioxan. 31.9 g (10 ml) of bromine was added dropwise to this suspension at 20 C over a period of 30 minutes with stirring. The reaction mixture was kept at 20 C with stirring for a further 48 hours. Then 100 ml of pyridine was added to the reaction mixture which was kept overnight with stirring at 200C.
The dark-coloured resultant mass was slowly poured into 5 litres of ice-cooled water with stirring. After 3 hours the precipitate was collected by filtration, washed with water and dried at 40 C "in vacuo" to a constant weight.
Yield = -16.2 g of crude title product.
Upon crystallization from acetone-hexane, 14.3 g of pure 2-bromo-6ss,9α-difluoro-1,4-pregnadiene-11ss, 17a, 21-triol-3,20-dione-17,21-diacetate was obtained showing the following characteristics:
UV - Spectrum #maxmeOH = 246m ; E1cm1% = 240
IR - Spectrum (Nujol): 3500-1760-1730-1700-1650-1615-1240 cm-1 [alD = -46 (c = 0.5, dioxan) M.P. 312-315 C Molecular weight 559.5
Analysis Calculated for C25H29BrF2O7 C 53.68% H 5.22%
Br 14.29% F6.8 %
Found C 53.65% H 5.13%
Br 14.0 % F6.65% The N.M.R. analysis confirmes the presence of 2-bromo-3-keto-A1,4, and the epimeric ss-configuration of the 6-fluoro-substituent.
# (Me2SO) 0.87 (3H,s, 18 CH3)
1.55 (3H,d,18CH3) 1.97 (3H, s, CH3COO-)
2.06 (3H, s, CH3COO-)
4.77 (2H, s, -CO-CH2-O-CO)
6.47 (1H, d, =C(4)-H)
7.84 (1 H, s, =0(1) - H) p.p.m.
Analogous results can be achieved when, instead of pyridine, the intermediate product formed after bromination is shaken with an aqueous solution of sodium acetate.
EXAMPLE 2 2-Bromo-6ss, 9α-difluoro-1,4-pregnadiene-11ss, 16α 17α 21-tetrol-3,20-dione-21-acetate 16,17-acetonide
To a suspension of 10 g of ss, 9a-difluoro-16a-hydroxy-prednisolone-16,17-acetonide-21-acetate (prepared according to Example 17 of my British Patent No. 1,504,294 in 500 ml of tetrahydrofu ran, 21.25 g of bromine is added dropwise at 20 C over a period of 15 minutes with stirring. The reaction mixture was kept at 20 C with stirring for a further 36 hours. Then 70 ml of lutidine was added to the reaction mixture which was kept at room temperature overnight with stirring, and then it was slowly poured into 4 liters of ice-cooled water with stirring.
After 4 hours the precipitate was filtered, washed with water and dried at 40 C "in vacuo" to a constant weight.
Yield = 9.6 g of crude title compound.
Upon crystallization from acetone-ethyl ether, 8.3 g of pure 2-bromo-8ss,9α-difluoro-1,4-pregnadiene- 11ss,1 6a,17a, 21 -tetrol-3,20-dione-21 -acetate-1 6, 1 7-acetonide was obtained, and having the following characteristics:
UV Spectrum #maxMeOH = 245 m : E1cm1% = 221
IR Spectrum (Nujol): 3500-1760-1730-1670-1640-1610-1235 cm-1.
[a]D = +0.2 (c=1, dioxan) M.P. = 148 - 151 C
Analogous results can be achieved when, instead of pyridine, the intermediate formed after bromination is shaken with an aqueous solution of potassium acetate.
EXAMPLE 3 2-Bromo-6ss-fluoro-9α, 1 1(3-dichloro- 1,4-pregnadiene- 17a2 1-diol-3,20-dione- 17,2 l -diacetate.
20 grams of 6(34luoro-9a, 11 (3-dichloro-1 ,4-pregnadiene-17a, 21 -diol-3,20-dione-1 7,21 -diacetate, prepared according to Example 18 of my British Patent No. 1,504,294 was suspended in 1000 ml of peroxides-free dioxan. 42.5 g (13.3 ml) of bromine was added dropwise to this suspension at 20 C over a period of 30 minutes with stirring.
The reaction mixture was kept at 20 with stirring for a further 48 hours. Then 133 ml of pyridine was added to the reaction mixture which was kept overnight with stirring at 20 C and then it was slowly poured into 6.7 litres of ice-cooled water with stirring.
After 4 hours the precipitate was collected by filtration, washed with water and dried at 40 C "in vacuo" to a constant weight.
Yield = 21.6 g of crude title compound.
Upon crystallization of the crude product from aqueous acetone, 15.8 g of pure 2-bromo-6ss-fluoro-9α, 11ss-dichloro-1,4-pregnadiene-17α, 21-diol-3,20-dione-17,21-diacetate was obtained, and having the following characteristics:
UV - Spectrum #maxMeOH = 244 m : E1cm1% = 215
IR - Spectrum (Nujol): 1760-1745-1675-1650-1610-1230 cm-1 [a]D = +0.2 (c=1, dioxan) M.P. = 268 - 272 C.
EXAMPLE 4 2-Bromo-6ss-fluoro-9α, 11ss-dichloro-16α-methyl-1, 4-pregnadiene-17α, 21-diol-3,20-dione-17, 21-diacetate By starting from 6ss-fluoro-9α, 11ss-dichloro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,20-dione-17, 21-diacetate prepared according to Example 19 of my British Patent No. 1,504,294 and by operating as indicated in Example 3, the title compound was prepared having the following characteristics:
UV - Spectrum #maxMeOH = 244 M : E1cm1% = 196
IR - Spectrum (Nujol): 1735-1605-1570-1235 cm1.
M.P. = 242 - 246 C.
EXAMPLE 5 2-bromo-6ss,9α-difuloro-16α-methyl-predisolone-21-pivalate By starting from 6ss, 9α-difluoro-16α-methyl-prednisolone prepared according to Example 11 of my British
Patent No. 1,504,294 and by operating as indicated in the previous Examples, the title compound was prepared.
EXAMPLE 6 2-Bromo-6ss,9α-difluoro-1,4-pregnadiene-11ss, 17α 21-triol-3,20-dione
A 10% aqueous solution of potassium carbonate was added dropwise with stirring to a solution of 2 g of 2-bromo-GP, 9a-difluoro-1,4-pregnadiene-l 1P, 17a, 21-trio13, 20-dione-17, 21-diacetate in 20 ml of methanol at 0 C under nitrogen. After 1 hour, the reaction mixture was neutralized with acetic acid, concentrated "in vacuo" to a small volume. The crude title product was collected by filtration, washed with water and dried "in vacuo" at 40 C to a constant weight.On crystallization from aqueous acetone, the pure product was obtained having the following characteristics:
UV - Spectrum #maxMeOH = 246 m ; E1cm1% = 251
IR - Spectrum (Nujol): 3420-1720-1665-1640-1600-1245 cm-1.
M.P. = 225 - 228 C [α]D = -5.0 (c = 1, dioxan).
EXAMPLE 7 2-Bromo-6ss-fluoro-9α, 11ss-dichloro-1,4-pregnadiene-17α,21-diol-3, 20-dione
By operating as described in Example 6, and by employing 2-bromo-6ss-fluoro-9α, 11ss-dichloro-1,4- pregnadiene-17α 21-diol-3,20-dione-17,21-diacetate as starting material, obtained according to Example 3, the title compound was obtained having the following characteristics:
UV - Spectrum #maxMeOH = 245 mil; E1cm1% = 235
IR - Spectrum (Nujol): 3500-1715-1675-1645-1 605 cm-1 [a]D = +35 (c=0.5, dioxan).
EXAMPLE 8 2-Bromo-6ss-fluoro-9α 11ss-dichloro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3, 20-dione By operating as described in the previous Examples 6 and 7, and by emplying 2-bromo-6ss-fluoro-9α, 11ss- dichloro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,20-dione-17,21-diacetate as starting material obtained according to Example 4, the title compound was prepared, showing the following characteristics: UV - Spectrum #maxMeOH = 244 m ; E1cm1% = 182
IV - Spectrum (Nujol): 3640-3500-3400-1705-1665-1642-1605 cm-1 [cr]D = +21 (c=0.5, dioxan).
EXAMPLE 9
By operating as described in the previous Examples, the 16ss-methyl-derivatives may also be obtained.
EXAMPLE 10 2-Bromo-6ss, 9α-difluoro-1,4-pregnadiene-11ss, t7a, I-triol-3, 20-dione- 17-propionate A) 2-Bromo-6ss, 9α-difluoro-1,4-pregnadiene-11ss, 17α, 21-triol-3, 20-dione-17,21-cyclic orthopropionate: To a suspension of 5 g- of 2-bromo-6ss, 9α-difluoro-1,4-pregnadiane-11 ss,17a,21 -triol-3, 20-dione (prepared according to Example 6) in 100 ml of ethyl acetate, gently warmed to 40 C there was added 6 g of methyl orthopropionate and 0.3 g of p-toluensulfonic- acid monohydrate, with stirring. After a few minutes a complete solution was obtained. The reaction mixture was stirred and kept under nitrogen for about one hour. Completion of the desired conversion into cyclic 17a, 21-orthopropionatewas checked at T.L.C.
After cooling, the reaction mixture was neutralized with about 1 ml of pyridine and evaporated "in vacuo" to dryness.
B) 2-Bromo-6ss, 9a-difluoro- 1,4-pregnadiene- 11(3, 170,2 21-triol-3,20-dione- 17-propionate
The oily residue obtained in A) was dissolved in 30 ml of methanol and to this solution 0,5 ml of diluted aqueous sulfuric acid (3% by weight) was added. The reaction mixture was refluxed for 30 minutes, filtered in the warm and left overnight in a refrigerator to crystallize.
The crystalline product was collected by filtration, washed with little ice-cooled methanol and dried "in vacuo". Yield about 3,75 g of product undertitle B) having the following characteristics:
UV - Spectrum #maxMeOH = 246 m ; E1cm1% = 231
IR - Spectrum (Nujol): 3410-3320-1680-1660-1630-1620-1565-1220 cm-1.
[a]D = -74.8 (c=1, dioxan).
EXAMPLE 11 2-Bromo-6ss, 9a-difluoro- 1,4-pregnadiene- 11(3, 17a, 2 14r1o1-3, 20-dione- 17-valerate
A) 2-Bromo-6ss, 9a-difluoro- 1,4-pregnadiene- 11(3, 17α, 2 1-triol-3, 20-dione- 17,21-cyclic orthovalerate
To a solution of 5 g of 2-bromo-6ss, 9α-difluoro-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione in 20 ml of anhydrous dimethylformamide, there was added 6 ml of methylorthovalerate, 0.2 g of p-toluensulfonic acid.
The reaction mixutre was stirred and kept under nitrogen at 120 C for about 3 hours. After cooling, the reaction mixture was neutralized with about 1 ml of pyridine and was poured in 100 ml of ice-cooled water.
The precipitate was collected by filtration, washed with water and dried in vacuo to constant weight.
B) 2-Bromo-6(3, 9a-difluoro- 1,4-pregnadiene- 11ss, 17α 21-triol-3, 20-dione- 17-valerate
The crude product obtained in A) was dissolved in 30 ml of methanol and to this solution 0.6 ml of diluted aqueous- sulfuric acid (3% by weight) was added. The reaction mixture was refluxed for 40 minutes and then poured in 100 ml of ice-cooled water and it was kept overnight at room temperature. The precipitate was collected by filtration, washed with water and dried "in vacuo" to a constant weight. The crude product was recrystallized from acetone-hexane. Yield = #3g of pure product, having the following characteristics;
UV - Spectrum #maxMeOH = 246 m ; E1cm1% = 225
IR - Spectrum (Nujol) 3500-1725-1718-1668-1645-1580 cm-1 [a]D = -73.8" (c=1, dioxan).
EXAMPLE 12
By operation as described in Examples 10 and 11 and by suitably varying the methyl orthoester and the "steroid-17α, 21-diol" the following compounds were prepared: P-bromo-GP, Sa-difluoro-l P-pregnadiene-11P, 17a, 21-trioi-3, 20-dione-17-butyrate; 2-Bromo-6ss, 9α-difluoro-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-benzoate; EXAMPLE 13 2-Bromo-6ss,9α-difluoro-1,4-pregnadiene-11ss, 17α 21-triol-3, 20-dione-21-propionate
1 g of 2-Bromo-6ss, 9α-difluoro-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione (prepared according to
Example 6) was dissolved in 10 ml of anhydrous pyridine.To this solution 6 ml of propionic anhydride was added and the reaction mixture was kept overnight at room temperature, and then poured in about 400 ml of -ice-cooled water. The crude product was collected by filtration, washed with water and dried at 40 C "in vacuo" to a constant weight.
By recrystallization of the crude product from acetone-hexane, 0.80 g of pure product was obtained, showing the following characteristics:
UV - Spectrum #maxMeOH = 246 m ; D1%m = 218
IV - Spectrum (Nujol): 3640-3470-1720-1680-1665-1640-1600-1205 cm-1 [a]D = + 20.9 (c=1, dioxan).
EXAMPLE 14 2-Bromo-6ss,9α-difluoro-1,4-pregnadiene-11ss, 17α, 21-triol-3, 20-dione-17,21-dipropionate
By operating as described in Example 13,2-bromo-6ss, 9α-difluoro-1,4-pregnadiene-11ss, 17α, 21-triol-3, 20-dione-17-propionate when reacted with propionic anhydride was converted to 2-bromo-6ss, 9α-difluoro- 1,4-pregnadiene-ll P, 17a, 21-triol-3, 20-dione-17, P1-dipropionate having the following characteristics:
UV-Spectrum #maxMeOH = 246 m ; E1cm1% = 207
IR-Spectrum (Nujol): 3500-1735-1675-1650-1610-1200 cm-1 [a]D = 37.3 (c=1, dioxan).
EXAMPLE 15 2-Bromo-6ss, 9α-difluoro-1,4-pregnadiene-11ss, 17α, 21-triol-3, 20-dione-17-propionate-21-acetate By operating as described in Example 13,2-bromo-6ss,9α-difluoro-1,4-pregnadiene-11ss, 17α, 21-triol-3, 20-dione-17-propionate when reacted with acetic anhydride was converted to 2-bromo-6ss,9α-difluoro-1,4- pregnadiene-1 1(3, 17α, 21 -triol-3, 20-dione-l 7-pro pionate-21-acetate having the following characteristics: UV - Spectrum #maxMeOH = 246 mu; E1cm1% = 215
IR-Spectrum (Nujol): 3500-1750-1740-1715-1675-1600-1245 cm-1.
[a]D = -43.6 (c=1, dioxan).
EXAMPLE 16 2-Bromo-6ss, 9α-difluoro-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-propionate-21-valerate
By operating as described in Example 13,2-bromo-6ss, 9α-difluoro-1,4-pregnadiene-11ss, 17α, 21-triol-3, 20-dione-17-propionate when reacted with valeric anhydride was converted to 2-bromo-6ss, 9α-difluoro-1,4- pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-propionate-21-valerate, having the following characteristics:
UV Spectrum #maxMeOH = 246 mu; E1cm1% = 199
IR-Spectrum (Nujol): 3470-1755-1730-1720-1670-1645-1610-1215 cm-1.
[a]= -35 (c=1, dioxan).
EXAMPLE 17
By esterification of the products obtained according to Examples 10, 11 and 12 with a suitable anhydride there were obtained the corresponding diesters or "hetero-diesters", i.e. the 17, 21-diesters having the alkanoyl radicals in the 17- and 21-positions either the same or different.
Claims (12)
1. A process for the preparation of a 2-bromp-6ss-fluoro-3-keto-#1,4-steroid of the pregnane series of the general structural formula:
in which: Xis a keto-or a (3-hydroxyl group or a chlorine atom;
Y is a fluorine or a chlorine atom but is not fluorine when X is a chlorine atom;
Z is a hydrogen atom or an a-hydroxyl or a- aor ss- methyl group;
R' is a hydrogen atom or an alkanoyl group having from 2 to 8 carbon atoms; and when Z is a-hydroxyl and R' is hydrogen, the corresponding 1 6a, 1 7a-acetonides and 1 6a-alkanoyl derivatives, the alkanoyl radical having from 2 to 8 carbon atoms; and
R is hydrogen or the alkanoyl radical of a mono- or di-carboxyl organic acid having from 2 to 8 carbon atoms, of metasulfobenzoic acid or of phosphoric acid, comprising the bromination of a compound of the general structural formula:
in which X, Y, Z and R' have the same significance as above and R is an alkanoyl group having from 2 to 8 carbon atoms wherein such compound dissolved or suspended in a suitable solvent is reacted with an excess or bromine in the cold, to give the corresponding 1, 2-dibromo-derivative, which is then reacted with a suitable basic agent to give the desired product (I) which is isolated and purified in manner known "per se".
2. A process as claimed in claim 1, in which the solvent is dioxan, tetrahydrofuran or dimethylsulfoxide.
3. A process as claimed in claim 1 or 2, in which the reaction with excess bromine is carried out at room temperature.
4. A process as claimed in any preceding claim, in which the basic agent is an organic tertiary base or an inorganic base.
5. A process as claimed in claim 4, in which the organic tertiary base is pyridine, lutidine or collidine.
6. A process as claimed in claim 4, in which the inorganic base is sodium or potassium acetate.
7. A process as claimed in any preceding claim, substantially as hereinbefore described and exemplified.
8. A 2-bromo-6ss-fluoro-3-keto-Z1S4-steroid of the pregnane series of the general formula (I), whenever prepared by a method as claimed in any one of claims 1 to 7.
9. 2-bromo-6ss,9a-difluoro-1,4-pregnadiene-11 ss,17a,21 -triol-3, 20-dione-1 7,21 -dipropionate.
10. 2-bromo-6(3, 9a-difluoro-1 ,4-pregnadiene-1 1(3, 1 7a, 21 -triol-3, 20-dione-1 7-propionate-21 -acetate.
11. 2-bromo-6(3, 9a-difluoro-1 ,4-pregnadiene-1 1(3, 170, 21 -triol-3, 20-dione-1 7-propionate-21 -valerate.
12. A pharmaceutical composition having anti-inflammatory activity comprising one or more compounds of claims 9, 10 or 11 in admixture with a suitable carrier for local or parenteral administration.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT27098/79A IT1193853B (en) | 1979-11-07 | 1979-11-07 | PROCEDURE FOR THE PREPARATION OF STEROID DERIVATIVES AND OBTAINED PRODUCTS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2065660A true GB2065660A (en) | 1981-07-01 |
Family
ID=11220944
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8035829A Withdrawn GB2065660A (en) | 1979-11-07 | 1980-11-07 | Anti inflammatory 2- bromo-6 beta -fluoro-9 alpha -halo steroids of the pregna-1,4-dien-3-one series |
Country Status (7)
| Country | Link |
|---|---|
| BE (1) | BE886045A (en) |
| CH (1) | CH645390A5 (en) |
| DE (1) | DE3041774A1 (en) |
| FR (1) | FR2469418A1 (en) |
| GB (1) | GB2065660A (en) |
| IT (1) | IT1193853B (en) |
| NL (1) | NL8006114A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3373189D1 (en) * | 1982-06-21 | 1987-10-01 | Dainippon Ink & Chemicals | Process for preparation of steroids |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1504132A (en) * | 1974-03-08 | 1978-03-15 | Palladino G | 6beta-fluorosteroids of the pregnane series |
-
1979
- 1979-11-07 IT IT27098/79A patent/IT1193853B/en active
-
1980
- 1980-11-05 FR FR8023601A patent/FR2469418A1/en active Granted
- 1980-11-05 DE DE19803041774 patent/DE3041774A1/en not_active Withdrawn
- 1980-11-06 CH CH825780A patent/CH645390A5/en not_active IP Right Cessation
- 1980-11-06 BE BE0/202711A patent/BE886045A/en not_active IP Right Cessation
- 1980-11-07 NL NL8006114A patent/NL8006114A/en not_active Application Discontinuation
- 1980-11-07 GB GB8035829A patent/GB2065660A/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| BE886045A (en) | 1981-03-02 |
| DE3041774A1 (en) | 1981-05-21 |
| IT1193853B (en) | 1988-08-31 |
| IT7927098A0 (en) | 1979-11-07 |
| CH645390A5 (en) | 1984-09-28 |
| FR2469418B1 (en) | 1983-07-08 |
| NL8006114A (en) | 1981-06-01 |
| FR2469418A1 (en) | 1981-05-22 |
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