GB2155477A - Tricyclic aliphatic diones for use in preparing 19-norandrostenedione - Google Patents
Tricyclic aliphatic diones for use in preparing 19-norandrostenedione Download PDFInfo
- Publication number
- GB2155477A GB2155477A GB08508480A GB8508480A GB2155477A GB 2155477 A GB2155477 A GB 2155477A GB 08508480 A GB08508480 A GB 08508480A GB 8508480 A GB8508480 A GB 8508480A GB 2155477 A GB2155477 A GB 2155477A
- Authority
- GB
- United Kingdom
- Prior art keywords
- norandrostenedione
- diones
- preparing
- enedione
- tricyclic aliphatic
- 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.)
- Granted
Links
- 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 title abstract description 3
- 241000551547 Dione <red algae> Species 0.000 title description 2
- 125000001931 aliphatic group Chemical group 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 125000004825 2,2-dimethylpropylene group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[*:1])C([H])([H])[*:2] 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- VOYADQIFGGIKAT-UHFFFAOYSA-N 1,3-dibutyl-4-hydroxy-2,6-dioxopyrimidine-5-carboximidamide Chemical compound CCCCn1c(O)c(C(N)=N)c(=O)n(CCCC)c1=O VOYADQIFGGIKAT-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- -1 (-O) - Chemical class 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
Classifications
-
- 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
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/04—Saturated compounds containing keto groups bound to acyclic carbon atoms
- C07C49/16—Saturated compounds containing keto groups bound to acyclic carbon atoms containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/126—Acids containing more than four carbon atoms
- C07C53/128—Acids containing more than four carbon atoms the carboxylic group being bound to a carbon atom bound to at least two other carbon atoms, e.g. neo-acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/80—Unsaturated compounds containing keto groups containing rings other than six-membered aromatic rings
- C07C59/82—Unsaturated compounds containing keto groups containing rings other than six-membered aromatic rings the keto group being part of a ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Steroid Compounds (AREA)
Abstract
The compounds of the formulae <IMAGE> wherein A is 2,2-dimethylpropylene, are useful in the synthesis of 19-norandrostenedione
Description
SPECIFICATION
Tricyclic aliphatic diones
This invention relates to tricyclic alkanones which may be used in the synthesis of 19norandrostenedione.
US-A-3646151 and US-A-4024166 disclose compounds of the formulae
wherein A is alkylidene and, specifically, ethylene, and their conversion to 1 9-norandrostenedione. The ethylene ketal of formula (A) is also disclosed in US-A-4158012.
Novel compounds according to the present invention are the enedione of formula (A), and the dione of formula (B), in which A is 2,2dimethylpropylene.
The novel enedione is prepared from the trione of the formula
which is disclosed and claimed in British Patent Application No 820571 2 (Serial No.
2116165). The trione, preferably without separation from the mixture which is prepared by the process described in GB-A-2116165, is dissolved in a solvent and refluxed with aqueous sodium carbonate for between 1 and 1 8 hours. Suitable solvents include methanol, ethanol, isopropanol and tert-butyl alcohol; methanol is preferred.
The enedione can be recovered from the reaction mixture by conventional methods such as evaporation, crystallisation, filtration and chromatography, and combinations thereof. The enedione has the feature that it is solid and can therefore easily be isolated as a pure product.
The novel dione is prepared by reducing the novel enedione. Methods for conducting this reduction are known in the art. The preferred method is by hydrogenation in the presence of a catalyst such as palladium-on-carbon.
The novel dione can be used by dissolving it in a solvent and reacting it with a strong acid, to yield 1 9-norandrostenedione. Reaction conditions and methods for recovering the product from the reaction mixture are known in the art.
The following Examples 1 and 2 illustrate the invention, while Example 3 illustrates the utility of the dione.
Example 1 Enedione Ill
The residue of the trione prepared in the
Example of GB-B-2116165 is taken up in 50 ml methanol and stirred at gentle reflux under nitrogen for 5 minutes. Then 1.01 ml saturated aqueous sodium carbonate solution is added, and the mixture is stirred at reflux for 1 6 hours. TIc shows complete conversion of the trione to the enedione. The reaction mixture is allowed to cool to 25 C and is then added to 150 ml water and 10 ml of a saturated sodium chloride solution. This is extracted with two-100 ml portions of methylene chloride, and each organic layer is backwashed sequentially with 100 ml water. The combined organic layers are concentrated on a roto-evaporator to constant weight to provide 13.70 9 of colourless oil Ill; uv max (EtOH) 248 nm for = 9,270).Using an value of 14,470 for pure Ill, this oil represents a 78% chem. yeild of Ill from the dione-carboxylic acid VII (see GB-A-2116165).
The crude enedione is taken up in 50 ml hexane at 50 C. Slow cooling and seeding give solids which, after stirring at - 1 5 C for 1 5 minutes, are collected by filtration. The solids are washed with 50 ml of - 1 5' hexane and dried in vacuo at 45 C for 1 6 hours, to provide 7.54 g (67% yield from the dionecarboxylic acid) of the enedione, mp 90-91
C.Recrystallisation of a sample from 40% aqueous methanol gives the enedione as a solid melting at 92-93.5 C; H nmr (CDCl3) 83.50 (s, 4, -CH,-O), 1.40 (s, 3, CH,C(-O) (-O) -), 1.04 (s, 3, C,3Me) and 0.96 and 0.94 ppm (s,6,gem-dimethyl); uv max (EtOH) 248 nm ( = 14,470).
Example 2 Dione
A 5.50 g aliquot of the trione from Example 1 in 35 ml methanol containing 200 mg 5% palladium-on-carbon (50% water wet) and 27 mg potassium hydroxide is hydrogenated at 13-22 C at atmospheric pressure for 11 2 hours. TIc indicates the reduction is complete.
The catalyst is removed by filtration and washed with methanol.
Example 3 1 9-Norandrostenedione The crude material of Example 2 is stirred at reflux under nitrogen for 5 minutes. 1.0 ml 6N hydrochloric acid is added. Over 4 hours, with stirring, the solution is then slowly concentrated by distillation, to approximately 25 ml. Tlc indicates the reaction is complete. The temperature is adjusted to 50 C and seeded.
Solids form slowly. After 1 5 minutes, 20 ml water are added. The slurry is allowed to stand at 10 C for 30 minutes. The solids are collected by filtration, washed with 10 ml cold 60% water-methanol and dried under reduced pressure at 50 C overnight to afford 1.99 g 1 9-norandrostenedione (61% yield from the dione-carboxylic acid), mp 166-168 C.
Claims (2)
1. The enedione of the formula
2. The dione of the formula
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08508480A GB2155477B (en) | 1981-07-28 | 1985-04-01 | Tricyclic aliphatic diones for use in preparing 19-norandrostenedione |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US28795581A | 1981-07-28 | 1981-07-28 | |
| US06/302,004 US4400524A (en) | 1981-07-28 | 1981-09-15 | Grignard reagents prepared from 5-halopentan-2-one propylene ketals |
| GB08205712A GB2116165B (en) | 1981-07-28 | 1982-02-26 | Preparing 19-norandrostenedione and novel intermediates therefor |
| NL8201083A NL8201083A (en) | 1981-07-28 | 1982-03-16 | PROCESS FOR PREPARING 19-NORANDROSTEENDION. |
| FR8204894A FR2523977A1 (en) | 1981-07-28 | 1982-03-23 | METHOD AND KEY INTERMEDIATE COMPOUNDS FOR THE PREPARATION OF 19-NORANDROSTENEDIONE |
| GB08508480A GB2155477B (en) | 1981-07-28 | 1985-04-01 | Tricyclic aliphatic diones for use in preparing 19-norandrostenedione |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8508480D0 GB8508480D0 (en) | 1985-05-09 |
| GB2155477A true GB2155477A (en) | 1985-09-25 |
| GB2155477B GB2155477B (en) | 1986-05-08 |
Family
ID=27546344
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08508480A Expired GB2155477B (en) | 1981-07-28 | 1985-04-01 | Tricyclic aliphatic diones for use in preparing 19-norandrostenedione |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2155477B (en) |
-
1985
- 1985-04-01 GB GB08508480A patent/GB2155477B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB8508480D0 (en) | 1985-05-09 |
| GB2155477B (en) | 1986-05-08 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |