DE1076683B - Process for the preparation of the formic acid esters of 1-alkynylcycloalkanols - Google Patents
Process for the preparation of the formic acid esters of 1-alkynylcycloalkanolsInfo
- Publication number
- DE1076683B DE1076683B DESCH25202A DESC025202A DE1076683B DE 1076683 B DE1076683 B DE 1076683B DE SCH25202 A DESCH25202 A DE SCH25202A DE SC025202 A DESC025202 A DE SC025202A DE 1076683 B DE1076683 B DE 1076683B
- Authority
- DE
- Germany
- Prior art keywords
- alkynylcycloalkanols
- formic acid
- acid esters
- preparation
- alkali metal
- 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.)
- Pending
Links
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 title claims description 12
- 238000000034 method Methods 0.000 title claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 7
- NHGVZTMBVDFPHJ-UHFFFAOYSA-N formyl fluoride Chemical compound FC=O NHGVZTMBVDFPHJ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 description 8
- -1 Formic acid ester Chemical class 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229960004719 nandrolone Drugs 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 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 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- CFLVUFWHXWSGII-UHFFFAOYSA-N (1-ethynylcyclohexyl) formate Chemical compound O=COC1(C#C)CCCCC1 CFLVUFWHXWSGII-UHFFFAOYSA-N 0.000 description 1
- QYLFHLNFIHBCPR-UHFFFAOYSA-N 1-ethynylcyclohexan-1-ol Chemical compound C#CC1(O)CCCCC1 QYLFHLNFIHBCPR-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 238000006661 Meyer-Schuster rearrangement reaction Methods 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000006178 Rupe rearrangement reaction Methods 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
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- WKHJZIRDAONVML-UHFFFAOYSA-N dichloromethane;tetrachloromethane Chemical compound ClCCl.ClC(Cl)(Cl)Cl WKHJZIRDAONVML-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- SHSFXAVQBIEYMK-UHFFFAOYSA-N hept-1-yn-3-ol Chemical compound CCCCC(O)C#C SHSFXAVQBIEYMK-UHFFFAOYSA-N 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical group OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000005406 washing Methods 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
Es ist bekannt, daß man die Ameisensäureester des l-Äthinylcyclohexanols oder des 1-Äthinylpentanols nach den gebräuchlichsten Methoden zur Formylierung alkoholischer Hydroxjiverbindungen nicht erhalten kann. Beim Erwärmen der genannten, gegebenenfalls cyclischen tertiären 1-Äthinylalkanole mit konzentrierter Ameisensäure beobachtet man an Stelle der erwarteten Veresterung intramolekulare Umlagerungen (z. B. Rupe-Umlagerang oder Meyer-Schuster-Umlagerung). Es lag nahe, diese Ausweichreaktion der genannten tertiären Äthinylcarbinole in erster Linie mit der Einbeziehung des zentralen Carbinolkohlenstoffatoms in einen Ring in ursächlichen Zusammenhang zu bringen, da das offenkettige Methyläthyläthinylcarbinol oder in anderer Bezeichnung 3-Methylpentin-(l)-ol-(3) unter vergleichbaren Bedingungen in normaler Reaktion noch den Ameisensäureester liefert.It is known that the formic acid esters of l-ethynylcyclohexanol or 1-ethynylpentanol can be used the most common methods for the formylation of alcoholic hydroxy compounds cannot be obtained. When the mentioned, optionally cyclic tertiary 1-ethynylalkanols are heated with concentrated formic acid instead of the expected esterification, one observes intramolecular rearrangements (e.g. Rupe rearrangement or Meyer-Schuster rearrangement). It was obvious that this evasive reaction of the mentioned tertiary Ethynyl carbinols primarily with the inclusion of the central carbinol carbon atom in a ring in to bring the causal connection, as the open-chain Methyläthyläthinylcarbinol or in other Name 3-methylpentine- (l) -ol- (3) under comparable conditions in normal reaction nor the Formic acid ester supplies.
Überraschenderweise wurde nun gefunden, daß man die 1-Alkinylcycloalkanole der allgemeinen FormelSurprisingly, it has now been found that the 1-alkynylcycloalkanols of the general formula
Z C-C=C-RZ C-C = C-R
Verfahren zur HerstellungMethod of manufacture
der Ameisensäureester
von 1 -Alkinylcycloalkanolenthe formic acid ester
of 1-alkynylcycloalkanols
Anmelder:Applicant:
Schering Aktiengesellschaft,
Berlin N 65, Müllerstr. 170-172Schering Aktiengesellschaft,
Berlin N 65, Müllerstr. 170-172
Dr. Ulrich Kerb, Berlin-Charlottenburg,Dr. Ulrich Kerb, Berlin-Charlottenburg,
und Dr. Martin Schenck, Berlin-Frohnau,and Dr. Martin Schenck, Berlin-Frohnau,
sind als Erfinder genannt wordenhave been named as inventors
OHOH
worin R Wasserstoff oder einen beliebigen einwertigen Kohlenwasserstoffrest und Z einen beliebigen zweiwertigen substituierten oder nicht substituierten Kohlenwasserstoffrest mit vorzugsweise 4 bis 6 Kohlenstoffatomen, der auch Teil eines Cyclopentanopolyhydrophenanthrenringsystems sein kann, bedeutet, in ihre entsprechenden Ameisensäureester der allgemeinen Formelwherein R is hydrogen or any monovalent hydrocarbon radical and Z is any divalent substituted or unsubstituted hydrocarbon radical with preferably 4 to 6 carbon atoms, which can also be part of a Cyclopentanopolyhydrophenanthrenringsystem, means in their corresponding formic acid ester of the general formula
Z C-C = C-RZ C-C = C-R
O-CO-HO-CO-H
überführen kann, wenn man die genannten 1-Alkinylcycloalkanole, vorzugsweise in Form ihrer Alkalialkoholate, mit Formylfluorid in einem inerten organischen Lösungsmittel, wie Tetrahydrofuran, Dioxan oder Äther, bei niederen Temperaturen, vorzugsweise bei —80 bis —600C, behandelt. Die Bereitung der hierzu benötigten Alkalialkoholate geschieht zweckmäßig durch Eintragen der im organischen Lösungsmittel gelösten Äthinylcycloalkanole in eine Lösung von etwa 1 Mol Alkaliamid in flüssigem wasserfreiem Ammoniak und anschließendes Verjagen des Ammoniaks durch Einleiten von trockenem Stickstoff. Gegebenenfalls im Molekül des Cycloalkanols vorhandene empfindliche Gruppen, wie α,/3-ungesättigte Ketogruppen von Steroiden, wird man während der Umsetzung zweckmäßig durch intermediäre Überführung in geeignete Derivate, wie Ketale oder Enoläther, in an sich bekannter Weise gegen unerwünschte Veränderungen schützen.can be converted, if the 1-mentioned Alkinylcycloalkanole preferably treated in the form of their alkali metal, with formyl fluoride in an inert organic solvent such as tetrahydrofuran, dioxane or ether, at low temperatures, preferably at -80 to -60 0 C. The alkali metal alcoholates required for this purpose are expediently prepared by introducing the ethynylcycloalkanols dissolved in the organic solvent into a solution of about 1 mole of alkali metal amide in liquid anhydrous ammonia and then driving off the ammonia by introducing dry nitrogen. Any sensitive groups present in the molecule of the cycloalkanol, such as α, / 3-unsaturated keto groups of steroids, will expediently be protected against undesired changes during the reaction by intermediate conversion into suitable derivatives, such as ketals or enol ethers, in a manner known per se.
In die verbleibende Lösung bzw. Suspension des Alkoholate wird das Formylfluorid dann unter Kühlen zweckmäßig auf —80 bis —600C und Rühren eingeleitet. Nach beendeter Umsetzung, die trotz der niedrigen Temperaturen in kurzer Zeit beendet ist, wird das gebildete Formiat in üblicher Weise, z. B. durch Abdampfen des Lösungsmittels, zweckmäßig bei niedriger Temperatur und vermindertem Druck, abgetrennt und erforderlichenfalls unter Anwendung bekannter Methoden gereinigt, worauf man gegebenenfalls die intermediär geschützten empfindlichen Gruppen in üblicher Weise wieder freisetzt.In the remaining solution or suspension of the alcoholates formyl fluoride is then introduced under cooling expedient to -80 to -60 0 C and stirring. After completion of the reaction, which is completed in a short time despite the low temperatures, the formate formed is in the usual way, for. B. separated off by evaporation of the solvent, expediently at low temperature and reduced pressure and, if necessary, purified using known methods, whereupon the intermediately protected sensitive groups are optionally released again in the usual way.
Durch das erfindungsgemäße Verfahren werden bestimmte Ameisensäureester erstmalig zugänglich, die gegenüber den entsprechenden Estern anderer Carbonsäuren in vielen Fällen überlegene Eigenschaften besitzen, wie verbesserte Löslichkeiten, erleichterte Freisetzbarkeit der veresterten Hydroxylgruppe, wo ein intermediärer Schutz bei Verwendung von Cycloalkanolen als Zwischenprodukte für die Herstellung technisch wertvoller Endprodukte erwünscht ist, oder verstärkte physiologische Wirksamkeit der Formiate im Vergleich zu den entsprechenden Estern anderer Carbonsäuren.The process according to the invention makes certain formic acid esters accessible for the first time, the in many cases have superior properties compared to the corresponding esters of other carboxylic acids, such as improved solubility, easier releasability of the esterified hydroxyl group where a intermediate protection when using cycloalkanols as intermediates for the production technically valuable end products is desired, or increased physiological effectiveness of the formates in comparison to the corresponding esters of other carboxylic acids.
Beispiel 1
17a-Äthinvl-19-nortestosteronformiatexample 1
17a-ethinvl-19-nortestosterone formate
Etwa 100 ecm flüssiges Ammoniak werden unter Rühren bei —80 bis —6O0C mit einer Spur Eisen(III)-nitrat versetzt und 250 mg Natrium eingetragen. Sobald die dunkelblaue Farbe verschwunden ist, wird eine Lösung von 3,4 g lTa-Äthinyl-lQ-nortestosteronäthylenketal in 60 ecm absolutem Tetrahydrofuran innerhalb 15 Minuten zugetropft, das Gemisch 30 Minuten gerührt, das Kältebad entfernt und so lange unter Einleiten vonAbout 100 cc of liquid ammonia are added to -6O 0 C with a trace of iron (III) nitrate with stirring at -80 and added 250 mg of sodium. As soon as the dark blue color has disappeared, a solution of 3.4 g of lTa-ethynyl-lQ-nortestosterone ethyl ketal in 60 ecm of absolute tetrahydrofuran is added dropwise over the course of 15 minutes, the mixture is stirred for 30 minutes, the cold bath is removed and so long while passing in
909 758/548909 758/548
trockenem Stickstoff gerührt, bis alles Ammoniak verdampft ist.stirred with dry nitrogen until all the ammonia has evaporated.
Anschließend wird die Lösung wieder auf —80 bis —60" C gekühlt und unter langsamen Rühren Formylfluorid eingeleitet. Nach lstündigem Rühren im Kältebad wird das Gemisch durch Verdünnen mit Methylenchlorid, Waschen mit Wasser, Trocknen und Abdampfen der Lösungsmittel aufgearbeitet. Der ölige Rückstandkristallisiert beim Verreiben mit Äther. Durch L'rnki istallisation aus Methanol werden 0,57 g eines Formiats des 17a-Äthiiiyl-19-nori:estusteronätliylenketals vom Schmelzpunkt 201 bis 205: C abgetrennt. Durch Chromatographie der eingedampften Mutterlaugen an Kieselsäuregel werden 1,26 g eine:; zweiten isomeren Formiats des 17«-Athinyl-19-nortestosteroniithylenketaIs vom Schmelzpunkt 161 bis 163:C isoliert. Beide Verbindungen liefern nach der Ketnlspaltung durch etwa 20 Minuten dauerndes Erhitzen in 90° oiger Essigsäure auf dem Dampfbad, wobei stets ein Teil des Formiats wieder verseift wird, 17«-Äthinyl-19-nortestosteronfoimiat.Schmelzpunkt 156bis 158 C; 2a UV-Absorptionsmaximum bei 239 ma; ε = 17060. Ausbeute 0,479 g.The solution is then cooled again to -80 to -60 "C and formyl fluoride is introduced with slow stirring. After stirring for 1 hour in a cold bath, the mixture is worked up by diluting with methylene chloride, washing with water, drying and evaporating the solvent. The oily residue crystallizes on trituration with ether. 0.57 g of a formate of 17α-ethyl-19-nori: estusteronethylenketal with a melting point of 201 to 205 : C are separated by crystallization from methanol. Chromatography of the evaporated mother liquors on silica gel gives 1.26 g of a: .; second isomeric formate of 17 "-Athinyl-19 nortestosteroniithylenketaIs of melting point 161 to 163 C, isolated Both compounds provide after Ketnlspaltung by approximately 20 minutes lasting heating at 90 ° o acetic acid on the steam bath, always a part of the formate is saponified again, 17 «-ethynyl-19-nortestosterone foimiate. Melting point 156 to 158 C; 2a UV absorption maximum at 23 9 ma; ε = 17060. Yield 0.479 g.
Beispiel 2
1 -Äthinylcyclohexan-l -olf ormiatExample 2
1-Ethynylcyclohexan-1 -olf ormiat
In 100 ecm flüssiges Ammoniak werden nach Zusatz einer Spatelspitze Eisen(III)-nitrat 1,2 g Natrium in kleinen Stücken eingetragen. In die Natriumamidlösung wird innerhalb von 10 Minuten eine Lösung von 6,8 g Äthinylcyclohexanol in 50 ecm absolutem Tetrahydrofuran eingetropft und, wie im Beispiel 1 beschrieben, weitergearbeitet. Das erhaltene Öl wird in Tetrachlorkohlenstoff gelöst und an Kieselsäuregel (100Z0 Wasser) chromatographiert. Mit Methylenchlorid—Tetrachlorkohlenstoff 1 : 1 wird das Formiat eluiert. 1-Athinylcvclohexan-1-olformiat siedet bei 16 Torr zwischen 84 und 857C; Ausbeute 3,72 g.After adding a spatula tip of iron (III) nitrate, 1.2 g of sodium are added in small pieces to 100 ecm of liquid ammonia. A solution of 6.8 g of ethynylcyclohexanol in 50 ecm of absolute tetrahydrofuran is added dropwise to the sodium amide solution over a period of 10 minutes and the process is continued as described in Example 1. The oil obtained is dissolved in carbon tetrachloride and chromatographed on silica gel (10 0 Z 0 water). The formate is eluted with methylene chloride-carbon tetrachloride 1: 1. 1-Ethynyl cyclohexan-1-ol formate boils at 16 Torr between 84 and 85 7 C; Yield 3.72g.
4040
Beispiel 3
17a-Äthinyl-19-nortestosteronformiatExample 3
17a-ethynyl-19-nortestosterone formate
In 100 ecm flüssiges Ammoniak werden unter Rühren bei —80 bis —60:C nach Zusatz einer Spur Eisen(III)-nitrat 400 mg Kalium eingetragen. Sobald die dunkelblaue Lösung sich entfärbt hat, wird eine Lösung von 3,3 g ^«-Äthinyl-lQ-nortestosteron-S-äthylenoläther (F. 171 bis 172:C) in 80 ecm absolutem Dioxan innerhalb von 15 Minuten zugetropft, das Kältebad entfernt und so lange unter Einleiten von trockenem Stickstoff gerührt, bis alles Ammoniak verdampft ist. Anschließend wird auf —80 bis —60: C abgekühlt und unter langsamem Rühren Formylfluorid eingeleitet.400 mg of potassium are added to 100 ml of liquid ammonia with stirring at -80 to -60 : C after adding a trace of iron (III) nitrate. As soon as the dark blue solution has become discolored, a solution of 3.3 g of ethynyl-lQ-nortestosterone-S-ethylenol ether (F. 171 to 172 : C) in 80 ecm of absolute dioxane is added dropwise within 15 minutes, the cold bath removed and stirred while passing in dry nitrogen until all the ammonia has evaporated. The mixture is then cooled to -80 to -60 : C and formyl fluoride is introduced with slow stirring.
Nach lstündigem Rühren im Kältebad wird das Gemisch mit Methylenchlorid verdünnt, mit Wasser neutral gewaschen, die Methylenchloridlösung über Natriumsulfat getrocknet und das Lösungsmittel im Vakuum abdestilliert. Durch Chromatographie an Kieselsäuregel mit Methylenchlorid wird das ^«-Äthinyl-lQ-nortestosteronformiat isoliert. Ausbeute 0,48 g; F. 157 bis 158DC; hi 2o' = —37,6" (CHCl3); U" V-Absorptionsmaximum bei 239 ma; ε = 17 000.After stirring for 1 hour in the cold bath, the mixture is diluted with methylene chloride and washed neutral with water, the methylene chloride solution is dried over sodium sulfate and the solvent is distilled off in vacuo. Chromatography on silica gel with methylene chloride is used to isolate the ^ «- ethynyl-lQ-nortestosterone formate. Yield 0.48g; M.p. 157 to 158 D C; hi 2 o ' = -37.6 "(CHCl 3 ); U" V absorption maximum at 239 ma; ε = 17,000.
1 -Propinylcyclohexan-l -olf ormiat1-Propinylcyclohexan-l -olf ormiat
In 150 ecm flüssiges Ammoniak weiden unter Rühren bei —80 bis —60° C nach Zusatz einer Spur Eisen(III)-nitrat 1,2 g Natrium in kleinen Stücken eingetragen. In die Natriumamidlösung werden 6,9 g 1 -Propinylcyclohexanol-1-ol, gelöst in 110 ecm absolutem Tetrahydrofuran, innerhalb von 15 Minuten zugetropft.In 150 ecm of liquid ammonia we graze with stirring at -80 to -60 ° C after adding a trace of iron (III) nitrate 1.2 g sodium entered in small pieces. 6.9 g of 1-propynylcyclohexanol-1-ol, dissolved in 110 ecm of absolute tetrahydrofuran, added dropwise within 15 minutes.
Nach 21.i 2stündigem Rühren wird das Kältebad entfernt, das Ammoniak mit Stickstoff abgeblasen, anschließend das Gemisch auf —80 bis — 60: C gekühlt und Formylfluorid eingeleitet. Die Aufarbeitung erfolgt wie im Beispiel 1 beschrieben. Das erhaltene Öl wird im Vakuum destilliert.After 2 1 . i 2 hours of stirring, the cooling bath was removed, blown off the ammonia with nitrogen, then the mixture to -80 to - 60: C cooled and introduced formyl fluoride. Working up is carried out as described in Example 1. The oil obtained is distilled in vacuo.
1-Propinylcyclohexan-l-olföiiniat ist ein farbloses C>1 von angenehmem Geruch und siedet bei 4 Torr zwischen und 78CC. Ausbeute 4,1 g.1-Propynylcyclohexan-1-olföiiniat is a colorless C> 1 with a pleasant odor and boils at 4 Torr between and 78 C C. Yield 4.1 g.
Claims (3)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DESCH25202A DE1076683B (en) | 1958-12-16 | 1958-12-16 | Process for the preparation of the formic acid esters of 1-alkynylcycloalkanols |
| CH8035759A CH379487A (en) | 1958-12-16 | 1959-11-07 | Process for the preparation of the formic acid esters of 1-alkynyl-cycloalkanols |
| FR836543A FR238M (en) | 1958-12-16 | 1960-08-23 | Medicinal product based on steroid compound. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DESCH25202A DE1076683B (en) | 1958-12-16 | 1958-12-16 | Process for the preparation of the formic acid esters of 1-alkynylcycloalkanols |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1076683B true DE1076683B (en) | 1960-03-03 |
Family
ID=7430082
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DESCH25202A Pending DE1076683B (en) | 1958-12-16 | 1958-12-16 | Process for the preparation of the formic acid esters of 1-alkynylcycloalkanols |
Country Status (3)
| Country | Link |
|---|---|
| CH (1) | CH379487A (en) |
| DE (1) | DE1076683B (en) |
| FR (1) | FR238M (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU197746B (en) * | 1985-09-05 | 1989-05-29 | Sandoz Ag | Process for producing xantin derivatives and pharmaceutical compositions containing them |
-
1958
- 1958-12-16 DE DESCH25202A patent/DE1076683B/en active Pending
-
1959
- 1959-11-07 CH CH8035759A patent/CH379487A/en unknown
-
1960
- 1960-08-23 FR FR836543A patent/FR238M/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CH379487A (en) | 1964-07-15 |
| FR238M (en) | 1961-02-27 |
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