CA1122591A - .delta. sun15 xx-steroid - Google Patents
.delta. sun15 xx-steroidInfo
- Publication number
- CA1122591A CA1122591A CA314,900A CA314900A CA1122591A CA 1122591 A CA1122591 A CA 1122591A CA 314900 A CA314900 A CA 314900A CA 1122591 A CA1122591 A CA 1122591A
- Authority
- CA
- Canada
- Prior art keywords
- group
- carbon
- formula
- double bond
- ethynyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 12
- -1 chloro-ethynyl group Chemical group 0.000 claims abstract description 12
- 125000000468 ketone group Chemical group 0.000 claims abstract description 9
- 125000002252 acyl group Chemical group 0.000 claims abstract description 8
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 125000004665 trialkylsilyl group Chemical group 0.000 claims abstract description 5
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims abstract description 3
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims abstract description 3
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims abstract description 3
- 241000284466 Antarctothoa delta Species 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 19
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 10
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims description 6
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 5
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical group FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims 2
- 229930194542 Keto Natural products 0.000 claims 1
- 239000003377 acid catalyst Substances 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 125000000962 organic group Chemical group 0.000 claims 1
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 229960003563 calcium carbonate Drugs 0.000 description 4
- 235000010216 calcium carbonate Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-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
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- UKDOTCFNLHHKOF-FGRDZWBJSA-N (z)-1-chloroprop-1-ene;(z)-1,2-dichloroethene Chemical group C\C=C/Cl.Cl\C=C/Cl UKDOTCFNLHHKOF-FGRDZWBJSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical group [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000002902 organometallic compounds Chemical class 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JRIZOGLBRPZBLQ-QXUSFIETSA-N 19-Norandrostenedione Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JRIZOGLBRPZBLQ-QXUSFIETSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229960001040 ammonium chloride Drugs 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- YWVOYVKNISJERC-UHFFFAOYSA-N chloroethyne Chemical compound ClC#[C-] YWVOYVKNISJERC-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ARNWQMJQALNBBV-UHFFFAOYSA-N lithium carbide Chemical compound [Li+].[Li+].[C-]#[C-] ARNWQMJQALNBBV-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001641 magnesium iodide Inorganic materials 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- LROBJRRFCPYLIT-UHFFFAOYSA-M magnesium;ethyne;bromide Chemical compound [Mg+2].[Br-].[C-]#C LROBJRRFCPYLIT-UHFFFAOYSA-M 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- LEVJVKGPFAQPOI-UHFFFAOYSA-N phenylmethanone Chemical compound O=[C]C1=CC=CC=C1 LEVJVKGPFAQPOI-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical group CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J33/005—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton spiro-condensed
- C07J33/007—Cyclic thioketals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
- C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
- C07J1/0096—Alkynyl derivatives
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention provides in a process for the production of a .DELTA.15-steroid having the general formula I
(I), wherein R1 represents a hydrogen atom, a trialkyl silyl group or an acyl group and R2 represents an ethynyl group, a chloro-ethynyl group or a propynyl group, which comprises introducing the R2 group into the 17.alpha.position of a 17- oxo steroid having the general formula II
(II), wherein Y represents a ketalised keto group and one of the ----bonds in the 4, 5-, 5, 6- or 7, 10- position is a carbon-carbon double bond and the others represent carbon-carbon single bonds and A-B represents a carbon-carbon double bond or the grouping wherein R' represents a hydrogen atom, a silyl, acyl, sulphonyl or nitro group, the improvement in which Y in formula II
represents a keto group protected with ethane dithiol - (1,2) and the carbon-carbon double bond is in the 4,5-position.
The present invention provides in a process for the production of a .DELTA.15-steroid having the general formula I
(I), wherein R1 represents a hydrogen atom, a trialkyl silyl group or an acyl group and R2 represents an ethynyl group, a chloro-ethynyl group or a propynyl group, which comprises introducing the R2 group into the 17.alpha.position of a 17- oxo steroid having the general formula II
(II), wherein Y represents a ketalised keto group and one of the ----bonds in the 4, 5-, 5, 6- or 7, 10- position is a carbon-carbon double bond and the others represent carbon-carbon single bonds and A-B represents a carbon-carbon double bond or the grouping wherein R' represents a hydrogen atom, a silyl, acyl, sulphonyl or nitro group, the improvement in which Y in formula II
represents a keto group protected with ethane dithiol - (1,2) and the carbon-carbon double bond is in the 4,5-position.
Description
~ZZ5~L
The present invention relates to the production of D steroids.
In applicants copending application No. 263,032 filed October 8, 1976 Q15-steroids having the ~eneral ormula I
~ ~ 2 / ` (I) in which, Rl represents a hydrogen atom, a trialkyl silyl group or an acyl group and R represents an ethynyl group, a chloro-ethynyl group or a propynyl group are inter alia described.
Acyl radicals of physiological compatible acids are suitable as acyl radicals Rl. Preferred acids are organic carboxylic and sulphonic acids containing 1 to 16, particularly 1 to 11 carbon atoms, which belong to the aliphatic, cycloaliphatic, aromatic~
aromatic-aliphatic or heterocyclic series. These acids can also be saturated or unsaturated, monobasic or polybasic and/or sub-stituted in the usual manner. Alkyl, hydroxy, alkoxy, oxo or amino groups or halogen atoms are mentioned as examples of the substituents.
Each of the alkyl groups of the trialkyl silyl group must contain 1 to 4 carbon atoms, the trimethyl silyl group being preferred.
The ~15-steroids having the general formula I have valuable steroid-hormone properties and can be used as pharma-ceutics.
According to copending Application Ser. No. 263,032 the ~15-steroids having the general formula I are produced by introducing the R2 radical into a 17-oxo steroid having the - 1- ~
~eneral formula II
B
A
~ ` ~ ~ (II) wherein Y represents a free keto group or a ketalised keto group and one of the ---- bonds in the 4, 5-, 5, 6- or 9, 10- position, is a carbon-carbon double bond and each of the other carbon-carbon single bonds and A-B represents a carbon-carbon double bond or the grouping C15 - C16, wherein R represents a hydrogen OR
atom, a silyl, acyl, sulphonyl or nitro group, by means of con-ventional methods with the aid of an agent yielding the radical R2, while forming a tertiary carbinol group at the 17-carbon atom, HORl being split off in the 15, 16-double bond, any primarily introduced protective group being split off and depen-din~ on the eventually desired meanin~ of Rl in the final pro-duct, the 17-hydroxy group is esterified if required, either prior to or after splitting off the protective group.
Trialkyl silyl radicals, particularly trimethyl silyl radicals or dialkyl silyl radicals, particularly dimethyl silyl radicals are suitable as silyl radicals Rl.
The radicals of organic carboxylic acids are suitable as acyl radicals Rl. Acyl radicals containing approximately 1 to 10 carbon atoms, for example, the acetyl, trifluoro-acetyl, propionyl, butyryl, valeryl, heptanoyl and benzoyl radical, are particularly suitable. Again, for example, the mesyl, ethane-sulphonyl, propionyl-sulphonyl and p-tosyl radical are suitable sulphonyl radicals R .
2S9~
The introduction of the radical R can be carried out by conventional methods with an organo-metallic ethynyl, chloro-ethynyl or propynyl compound. Such organo-metallic compounds are, for example, alkali metal acetylides, such as for example, potassium and lithium acetylide or potassium and lithium chloro-or methyl acetylide.
The organo-metallic compound can also be formed in situ and reacted with the 17-ketone having the for~ula II.
Thus, for example, acetylene and an alkali metal, particularly potassium, sodium or lithium, can be allowed to act on the 17-ketone in a suitable so'vent, in the presence of a C4- or C5-alcohol or of ammonia, or in the form of e.g. butyl lithium.
Li-thium chloro-acetylide can be formed from 1, 2-dichloro ethylene and an ethereal lithium-methyl solution. Ethinyl-magnesium or ethinyl-zinc halides, particularly ethinyl-magnes-ium bromide or iodide, are also suitable as organo-metallic ethinyl compounds. Dialkyl ether, tetrahydrofuran, dioxane, benzene and toluene are suitable solvents.
Accordin~ to copending application NQ . 263,032 in a ! 20 preferred method the reaction of the 17-oxo steroid is carried ' out with the aid of an agent yielding the radical R when the 3-; keto group is present as a protected ketal. The ketal radicals are derived from the alcohols usually used for the protection of oxo groups. Ethylene glycol and 2,2-dimethyl-1,3-propane-diole are mentioned as examples.
; It has now been found that the formation of ketal in the 3 position is particularly favourable if the 3,17-diketone is reacted with ethane dithiol-(1,2~.
The present invention thus is a development of the process of applicantscopending Application No.263,032 for producing ~15-steroids having the general formula I by R -alkinylation of compounds having the general formula II, in zzs9~
which ~ in formula II represent a keto group protected with ethane dithiol-(1,2) and that the carbon-carbon double bond ~s in the 4, 5-position.
a The advantages of the process o the present invention lie in that the 3,3-dithio~thylene ketal is formed in almost ~ quantitative yields and that a compound with a stable protec-¦ tive group is formed which can be easily split off again after ; the R -~lkinylation.
In tne protection of the 3-keto group with ethane dithiol-(1,2) according to the invention a homogenous compouna having a 4-en structure is formed. This compound can be puri-fied in a simple manner by crystallization. In the process of the copending application a substance mixture having 5(6)- and 5(10)-en structure in formed by protection of the 3-keto group with 2,2-dimethyl-1,3-propane diol. This substance mixture must be purified by chromatography.
' According to "Synthesis" 1974, page 32 the thioketal is formed in polar solvents, as for example, in a lower alcohol, particularly methanol, or in a lower carboxylic acid, particul-, arly glacial acetic-acid, in the presence of an acid, catalyst, as for example, boron trifluorid~ etherate, at temperatures of approximately o to 50C.
! According to "Tetrahedron letters" 1972, page 1989 the thioketal is split with methyl iodide in an aqueous lower alcohol while adding calcium carbonate.
~ The process according to the invention is further described followed by the Examples:
Example 1 50.0 g of 15~-hydroxy-18-methyl~4-oestren-3,17-dione ~ 30 in 750 ml of methanol are mixed with 25 ml of ethane diol-(1,2)t and 10 ml of boron trifluoride etherate under argon at room temperature. A portion of the product crystallizes out wi~hin ~L:lZZ593L
an hour while the remaining substance is crystallized by cooling with ice/water. The crystallizate is filtered with suction, washed with waterr dried in vacuo and recrystallized from acetone/hexane. 54 0 g o~ 3,3-ethylene dithio-15a-hydroxy-18-methyl-4-oestren-17-one are obtained.
Melting point: 213.5C
Example 2 15 ml of methane sulphonyl chloride are slowly added dropwise to 14.6 g of 3,3-ethylene-dithio-15a-hydroxy-18-methyl-4-oestren-17-one in 75 ml of pyridine while cooling with ice and stirring. After 1.5 hours 75 ml of dimethyl formamide and 45 g of anhydrous sodium acetate are added. The mixtute is stirred for 28 hours at room temperature, whereupon it is put in ice/
water. The precipitated product is ~iltered with suction, dis-solved in acetic ester and dried over sodium sulphate. The solution is treated with active carbon. 12.1 g of 3,3-ethylene-dithio-18-methyl-4,15-oestradien-17-one are obtained. A sample recrystallized from acetone/hexane had a melting point of 215.8C.
Example 3 Acetylene is passed through an ice/water-cooled solution of 140 ml of butyl lithium (15% in hexane) in 450 ml of tetrahydrofuran, whereupon 12.1 g of 3,3-ethylene~dithio-18-methyl-4,15-oestradien-17-one in 450 ml of tetrahydrofuran are added dropwise, followed by stirring for 30 minutes at room ! . temperature. The solution is then carefully mixed with satur-! ated ammonium-chloride solution dilutedwith acetic ester, washed with water and dried over sodium sulphate. The crude product i5 purified in acetone with active carbon. 12.0 g of 17~-ethynyl-3,3-ethylene-dithio-18-methyl-4,15-oestradien-17~-ol are obtain-ed. A sample recrystallized from acetone/hexane has a melting point of 152.2C.
1122S9l Example 4 7.4 g of 17~ ethynyl-3r3 ethylene-dioxy-18-methyl-4, 15-oestradien-17~-ol in 200 ml of a 95~ aqueous methanol are stirred with 20 ml of methyl iodide and 3.5 g of calcium carbonate for 19 hours with reflux. The reaction mixture is concentrated in vacuo, the resiaue is dissolved in acetic ester, washed with water and dri~d over sodium sulphate. After chro-matographing the crude product on silica gel with 15 to 20~ of acetone/hexane 4.7 g of 17a-ethynyl-17~-hydroxy-18-methyl-4,15-oestradien-3-one having a melting point of 198C are obtained.
Example 5 320 ml of a 5% ethereal lithium-methyl solution are added dropwise to 65 ml of 1,2-dichloro-ethylene in 325 ml of ether at 0C while injecting argon. After 1 hour 28.2 g of 3.3-ethylene-dithio-18-methyl-4,15-oestradien-17-one in 700 ml of tetrahydrofuran are added, followed by stirring at room temper-ature. After 2.5 hours the solution is carefully mixed with saturated ammonium-chloride solution, diluted with acetic ester, washed with water and dried over sodium sulphate. After concen-trating in vacuo, 33.2 g of 3,3-ethylene-dithio-17~-chloro-ethynyl-18-methyl-4,15-oestradien-17~-ol are obtained a~ an oily product.
~]D = -115.2C
Example 6 33.2 g of 3.3-ethylene-dithio-17~-chloro-ethynyl-18-methyl-4,15-oestradien-17~-ol in 500 ml of 95% methanol are ` stirred with 70 ml of methyl iodide and 15 g of calcium carbon-ate for 22 hours with reflux. The reaction mixture is concen-, trated in vacuo, the residue is dissolved in acetic ester, ! 30 washed with water and dried over sodium sulphate. After chroma tographing the crude product on silica gel with 13 to 15% of acetone/hexane 16.5 g of 17~-chloro-ethynyl-17~-hydroxy-18-~ Z59~
methyl-4,15-oestradien-3-one having a melting poin~ of 155C
are obtained.
Example 7 Methyl acetylene is passed through an ice-water-cooled solution of 50 ml of n-butyl lithium (15~ in hexane~ in 100 ml of tetrahydrofuran for 30 minutes. After stirring and injecting argon 2.0 g of 3;3-ethylene-dithio-18-methyl-4,15-oestradien-17-one in 20 ml of tetrahydrofuran are added. After 1.5 hours the solution is carefully mixed with a saturated ammonium-chloride io solution, diluted with acetic ester, washed with water until neutral and dried over sodium sulphate. The crude product is chromatographed on silica gel. With 10% of acetone in hexane 1.9 g of 3,3-ethylene-dithio-18-methyl-17a-propyn-1-yl-4,15-oestradien-17~-ol are extracted as an oily product.
[a]D = -66C
Example 8 1.0 g of 3,3-ethylene-dithio-18-methyl-17a-propyn-1-yl-4,15-oestradien-17~-ol in 40 ml of 95~ aqueous methanol are reacted with methyl iodide and calcium carbonate and further treated analogously to example 6. After recrystallizing the crude product from acetone/isopropyl ether 320 mg of 17~-hydroxy-18 -methyl-17a-propyn-1-yl-4,15-oestradien-3-one having a melt-ing point of 82C are obtained.
The present invention relates to the production of D steroids.
In applicants copending application No. 263,032 filed October 8, 1976 Q15-steroids having the ~eneral ormula I
~ ~ 2 / ` (I) in which, Rl represents a hydrogen atom, a trialkyl silyl group or an acyl group and R represents an ethynyl group, a chloro-ethynyl group or a propynyl group are inter alia described.
Acyl radicals of physiological compatible acids are suitable as acyl radicals Rl. Preferred acids are organic carboxylic and sulphonic acids containing 1 to 16, particularly 1 to 11 carbon atoms, which belong to the aliphatic, cycloaliphatic, aromatic~
aromatic-aliphatic or heterocyclic series. These acids can also be saturated or unsaturated, monobasic or polybasic and/or sub-stituted in the usual manner. Alkyl, hydroxy, alkoxy, oxo or amino groups or halogen atoms are mentioned as examples of the substituents.
Each of the alkyl groups of the trialkyl silyl group must contain 1 to 4 carbon atoms, the trimethyl silyl group being preferred.
The ~15-steroids having the general formula I have valuable steroid-hormone properties and can be used as pharma-ceutics.
According to copending Application Ser. No. 263,032 the ~15-steroids having the general formula I are produced by introducing the R2 radical into a 17-oxo steroid having the - 1- ~
~eneral formula II
B
A
~ ` ~ ~ (II) wherein Y represents a free keto group or a ketalised keto group and one of the ---- bonds in the 4, 5-, 5, 6- or 9, 10- position, is a carbon-carbon double bond and each of the other carbon-carbon single bonds and A-B represents a carbon-carbon double bond or the grouping C15 - C16, wherein R represents a hydrogen OR
atom, a silyl, acyl, sulphonyl or nitro group, by means of con-ventional methods with the aid of an agent yielding the radical R2, while forming a tertiary carbinol group at the 17-carbon atom, HORl being split off in the 15, 16-double bond, any primarily introduced protective group being split off and depen-din~ on the eventually desired meanin~ of Rl in the final pro-duct, the 17-hydroxy group is esterified if required, either prior to or after splitting off the protective group.
Trialkyl silyl radicals, particularly trimethyl silyl radicals or dialkyl silyl radicals, particularly dimethyl silyl radicals are suitable as silyl radicals Rl.
The radicals of organic carboxylic acids are suitable as acyl radicals Rl. Acyl radicals containing approximately 1 to 10 carbon atoms, for example, the acetyl, trifluoro-acetyl, propionyl, butyryl, valeryl, heptanoyl and benzoyl radical, are particularly suitable. Again, for example, the mesyl, ethane-sulphonyl, propionyl-sulphonyl and p-tosyl radical are suitable sulphonyl radicals R .
2S9~
The introduction of the radical R can be carried out by conventional methods with an organo-metallic ethynyl, chloro-ethynyl or propynyl compound. Such organo-metallic compounds are, for example, alkali metal acetylides, such as for example, potassium and lithium acetylide or potassium and lithium chloro-or methyl acetylide.
The organo-metallic compound can also be formed in situ and reacted with the 17-ketone having the for~ula II.
Thus, for example, acetylene and an alkali metal, particularly potassium, sodium or lithium, can be allowed to act on the 17-ketone in a suitable so'vent, in the presence of a C4- or C5-alcohol or of ammonia, or in the form of e.g. butyl lithium.
Li-thium chloro-acetylide can be formed from 1, 2-dichloro ethylene and an ethereal lithium-methyl solution. Ethinyl-magnesium or ethinyl-zinc halides, particularly ethinyl-magnes-ium bromide or iodide, are also suitable as organo-metallic ethinyl compounds. Dialkyl ether, tetrahydrofuran, dioxane, benzene and toluene are suitable solvents.
Accordin~ to copending application NQ . 263,032 in a ! 20 preferred method the reaction of the 17-oxo steroid is carried ' out with the aid of an agent yielding the radical R when the 3-; keto group is present as a protected ketal. The ketal radicals are derived from the alcohols usually used for the protection of oxo groups. Ethylene glycol and 2,2-dimethyl-1,3-propane-diole are mentioned as examples.
; It has now been found that the formation of ketal in the 3 position is particularly favourable if the 3,17-diketone is reacted with ethane dithiol-(1,2~.
The present invention thus is a development of the process of applicantscopending Application No.263,032 for producing ~15-steroids having the general formula I by R -alkinylation of compounds having the general formula II, in zzs9~
which ~ in formula II represent a keto group protected with ethane dithiol-(1,2) and that the carbon-carbon double bond ~s in the 4, 5-position.
a The advantages of the process o the present invention lie in that the 3,3-dithio~thylene ketal is formed in almost ~ quantitative yields and that a compound with a stable protec-¦ tive group is formed which can be easily split off again after ; the R -~lkinylation.
In tne protection of the 3-keto group with ethane dithiol-(1,2) according to the invention a homogenous compouna having a 4-en structure is formed. This compound can be puri-fied in a simple manner by crystallization. In the process of the copending application a substance mixture having 5(6)- and 5(10)-en structure in formed by protection of the 3-keto group with 2,2-dimethyl-1,3-propane diol. This substance mixture must be purified by chromatography.
' According to "Synthesis" 1974, page 32 the thioketal is formed in polar solvents, as for example, in a lower alcohol, particularly methanol, or in a lower carboxylic acid, particul-, arly glacial acetic-acid, in the presence of an acid, catalyst, as for example, boron trifluorid~ etherate, at temperatures of approximately o to 50C.
! According to "Tetrahedron letters" 1972, page 1989 the thioketal is split with methyl iodide in an aqueous lower alcohol while adding calcium carbonate.
~ The process according to the invention is further described followed by the Examples:
Example 1 50.0 g of 15~-hydroxy-18-methyl~4-oestren-3,17-dione ~ 30 in 750 ml of methanol are mixed with 25 ml of ethane diol-(1,2)t and 10 ml of boron trifluoride etherate under argon at room temperature. A portion of the product crystallizes out wi~hin ~L:lZZ593L
an hour while the remaining substance is crystallized by cooling with ice/water. The crystallizate is filtered with suction, washed with waterr dried in vacuo and recrystallized from acetone/hexane. 54 0 g o~ 3,3-ethylene dithio-15a-hydroxy-18-methyl-4-oestren-17-one are obtained.
Melting point: 213.5C
Example 2 15 ml of methane sulphonyl chloride are slowly added dropwise to 14.6 g of 3,3-ethylene-dithio-15a-hydroxy-18-methyl-4-oestren-17-one in 75 ml of pyridine while cooling with ice and stirring. After 1.5 hours 75 ml of dimethyl formamide and 45 g of anhydrous sodium acetate are added. The mixtute is stirred for 28 hours at room temperature, whereupon it is put in ice/
water. The precipitated product is ~iltered with suction, dis-solved in acetic ester and dried over sodium sulphate. The solution is treated with active carbon. 12.1 g of 3,3-ethylene-dithio-18-methyl-4,15-oestradien-17-one are obtained. A sample recrystallized from acetone/hexane had a melting point of 215.8C.
Example 3 Acetylene is passed through an ice/water-cooled solution of 140 ml of butyl lithium (15% in hexane) in 450 ml of tetrahydrofuran, whereupon 12.1 g of 3,3-ethylene~dithio-18-methyl-4,15-oestradien-17-one in 450 ml of tetrahydrofuran are added dropwise, followed by stirring for 30 minutes at room ! . temperature. The solution is then carefully mixed with satur-! ated ammonium-chloride solution dilutedwith acetic ester, washed with water and dried over sodium sulphate. The crude product i5 purified in acetone with active carbon. 12.0 g of 17~-ethynyl-3,3-ethylene-dithio-18-methyl-4,15-oestradien-17~-ol are obtain-ed. A sample recrystallized from acetone/hexane has a melting point of 152.2C.
1122S9l Example 4 7.4 g of 17~ ethynyl-3r3 ethylene-dioxy-18-methyl-4, 15-oestradien-17~-ol in 200 ml of a 95~ aqueous methanol are stirred with 20 ml of methyl iodide and 3.5 g of calcium carbonate for 19 hours with reflux. The reaction mixture is concentrated in vacuo, the resiaue is dissolved in acetic ester, washed with water and dri~d over sodium sulphate. After chro-matographing the crude product on silica gel with 15 to 20~ of acetone/hexane 4.7 g of 17a-ethynyl-17~-hydroxy-18-methyl-4,15-oestradien-3-one having a melting point of 198C are obtained.
Example 5 320 ml of a 5% ethereal lithium-methyl solution are added dropwise to 65 ml of 1,2-dichloro-ethylene in 325 ml of ether at 0C while injecting argon. After 1 hour 28.2 g of 3.3-ethylene-dithio-18-methyl-4,15-oestradien-17-one in 700 ml of tetrahydrofuran are added, followed by stirring at room temper-ature. After 2.5 hours the solution is carefully mixed with saturated ammonium-chloride solution, diluted with acetic ester, washed with water and dried over sodium sulphate. After concen-trating in vacuo, 33.2 g of 3,3-ethylene-dithio-17~-chloro-ethynyl-18-methyl-4,15-oestradien-17~-ol are obtained a~ an oily product.
~]D = -115.2C
Example 6 33.2 g of 3.3-ethylene-dithio-17~-chloro-ethynyl-18-methyl-4,15-oestradien-17~-ol in 500 ml of 95% methanol are ` stirred with 70 ml of methyl iodide and 15 g of calcium carbon-ate for 22 hours with reflux. The reaction mixture is concen-, trated in vacuo, the residue is dissolved in acetic ester, ! 30 washed with water and dried over sodium sulphate. After chroma tographing the crude product on silica gel with 13 to 15% of acetone/hexane 16.5 g of 17~-chloro-ethynyl-17~-hydroxy-18-~ Z59~
methyl-4,15-oestradien-3-one having a melting poin~ of 155C
are obtained.
Example 7 Methyl acetylene is passed through an ice-water-cooled solution of 50 ml of n-butyl lithium (15~ in hexane~ in 100 ml of tetrahydrofuran for 30 minutes. After stirring and injecting argon 2.0 g of 3;3-ethylene-dithio-18-methyl-4,15-oestradien-17-one in 20 ml of tetrahydrofuran are added. After 1.5 hours the solution is carefully mixed with a saturated ammonium-chloride io solution, diluted with acetic ester, washed with water until neutral and dried over sodium sulphate. The crude product is chromatographed on silica gel. With 10% of acetone in hexane 1.9 g of 3,3-ethylene-dithio-18-methyl-17a-propyn-1-yl-4,15-oestradien-17~-ol are extracted as an oily product.
[a]D = -66C
Example 8 1.0 g of 3,3-ethylene-dithio-18-methyl-17a-propyn-1-yl-4,15-oestradien-17~-ol in 40 ml of 95~ aqueous methanol are reacted with methyl iodide and calcium carbonate and further treated analogously to example 6. After recrystallizing the crude product from acetone/isopropyl ether 320 mg of 17~-hydroxy-18 -methyl-17a-propyn-1-yl-4,15-oestradien-3-one having a melt-ing point of 82C are obtained.
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. In a process for the production of a .DELTA.15-steroid, having the general formula I
(I) wherein R1 represents a hydrogen atom, a trialkyl silyl group or an acyl group and R2 represents an ethynyl group, a chloro-ethynyl group or a propynyl group, which comprises introducing the R2 group into the 17.alpha. position of a 17-oxo steroid having the general formula II
(II) wherein Y represents a ketalised keto group and one of the ---bonds in the 4, 5-, 5, 6- or 7, 10- position is a carbon-carbon double bond and the others represent carbon-carbon single bonds and A-B represents a carbon-carbon double bond or the grouping , wherein R1 represents a hydrogen atom, a silyl, acyl, sulphonyl or nitro group, the improvement in which Y
in formula II represents a keto group protected with ethane dithiol-(1,2) and the carbon-carbon double bond is in the 4,5-position.
(I) wherein R1 represents a hydrogen atom, a trialkyl silyl group or an acyl group and R2 represents an ethynyl group, a chloro-ethynyl group or a propynyl group, which comprises introducing the R2 group into the 17.alpha. position of a 17-oxo steroid having the general formula II
(II) wherein Y represents a ketalised keto group and one of the ---bonds in the 4, 5-, 5, 6- or 7, 10- position is a carbon-carbon double bond and the others represent carbon-carbon single bonds and A-B represents a carbon-carbon double bond or the grouping , wherein R1 represents a hydrogen atom, a silyl, acyl, sulphonyl or nitro group, the improvement in which Y
in formula II represents a keto group protected with ethane dithiol-(1,2) and the carbon-carbon double bond is in the 4,5-position.
2. A process as claimed in Claim 1, in which the protective group is split off by treatment with methyl iodide in an aqueous lower alcohol in the presence of calcium carbonate.
3. A process as claimed in Claim 1, in which the ketal is formed by reacting the compound of formula II in which Y is keto with ethane dithiol-(1,2) in a polar solvent in the presence of an acid catalyst at a temperature from 0 to 30°C.
4. A process as claimed in Claim 3, in which the solvent is methanol and the catalyst is boron trifluoride ether-ate.
5. A process as claimed in Claim 1, 2 or 3 in which the acyl group represented by R1 is derived from an organic car-boxylic or sulphonic acid containing 1 to 16 carbon atoms.
6. A process as claimed in Claim 1, in which the acyl group represented by R1 is derived from an organic carboxylic or sulphonic acid containing 1 to 11 carbon atoms
7. A process as claimed in Claim 6, in which the trialkylsilyl group represented by R1 is a trimethylsilyl group.
8. The process as claimed in Claim 1, 2 or 3 in which the agent reacted with the compound of formula II is an organo metal ethynyl, chlorethynyl or propynyl compound.
9. A process as claimed in Claim 1, 2 or 3, in which the ketalized compound of formula II is 3,3-ethylene-dithio-18-methyl-4,15-oestradien-17-one,
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2749105A DE2749105C2 (en) | 1977-10-31 | 1977-10-31 | Process for the preparation of Δ → 1 → → 5 → -17α-chloroethinyl and propynyl steroids of the estran series |
| DEP2749105.9 | 1977-10-31 | ||
| DE2749104A DE2749104C2 (en) | 1977-10-31 | 1977-10-31 | Process for the preparation of?? 15? -Steroids |
| DEP2749104.9 | 1977-10-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1122591A true CA1122591A (en) | 1982-04-27 |
Family
ID=25773014
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA314,900A Expired CA1122591A (en) | 1977-10-31 | 1978-10-30 | .delta. sun15 xx-steroid |
Country Status (9)
| Country | Link |
|---|---|
| AT (1) | AT365608B (en) |
| CA (1) | CA1122591A (en) |
| CH (1) | CH639106A5 (en) |
| DD (1) | DD139583A6 (en) |
| DK (1) | DK147005C (en) |
| ES (1) | ES473096A2 (en) |
| HU (1) | HU178117B (en) |
| IT (1) | IT1159936B (en) |
| NL (1) | NL7808509A (en) |
-
1978
- 1978-08-16 NL NL7808509A patent/NL7808509A/en not_active Application Discontinuation
- 1978-09-05 ES ES473096A patent/ES473096A2/en not_active Expired
- 1978-10-17 IT IT28810/78A patent/IT1159936B/en active
- 1978-10-25 DD DD78208663A patent/DD139583A6/en unknown
- 1978-10-30 CA CA314,900A patent/CA1122591A/en not_active Expired
- 1978-10-30 HU HU78SCHE659A patent/HU178117B/en unknown
- 1978-10-30 AT AT0774478A patent/AT365608B/en not_active IP Right Cessation
- 1978-10-31 CH CH1121878A patent/CH639106A5/en not_active IP Right Cessation
- 1978-10-31 DK DK485378A patent/DK147005C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ES473096A2 (en) | 1979-07-01 |
| IT1159936B (en) | 1987-03-04 |
| AT365608B (en) | 1982-02-10 |
| DK147005C (en) | 1984-08-27 |
| DK147005B (en) | 1984-03-12 |
| DK485378A (en) | 1979-05-01 |
| CH639106A5 (en) | 1983-10-31 |
| DD139583A6 (en) | 1980-01-09 |
| ATA774478A (en) | 1981-06-15 |
| NL7808509A (en) | 1979-05-02 |
| HU178117B (en) | 1982-03-28 |
| IT7828810A0 (en) | 1978-10-17 |
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