DE1115247B - Process for the preparation of 6ª ‡ -Methyl-11ª ‰, 21-dioxy-4, 17 (20) -pregnadien-3-one by alkaline hydrolysis of the 3-pyrrolidyleneamine of 6ª ‡ -Methyl-11ª ‰, 21-dioxy-4, 17 (20) -pregnadien-3-ons - Google Patents
Process for the preparation of 6ª ‡ -Methyl-11ª ‰, 21-dioxy-4, 17 (20) -pregnadien-3-one by alkaline hydrolysis of the 3-pyrrolidyleneamine of 6ª ‡ -Methyl-11ª ‰, 21-dioxy-4, 17 (20) -pregnadien-3-onsInfo
- Publication number
- DE1115247B DE1115247B DEU6769A DEU0006769A DE1115247B DE 1115247 B DE1115247 B DE 1115247B DE U6769 A DEU6769 A DE U6769A DE U0006769 A DEU0006769 A DE U0006769A DE 1115247 B DE1115247 B DE 1115247B
- Authority
- DE
- Germany
- Prior art keywords
- acid
- dioxy
- methyl
- pregnadien
- preparation
- 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
- 238000000034 method Methods 0.000 title claims description 11
- 238000005904 alkaline hydrolysis reaction Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 6
- 150000003839 salts Chemical class 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- -1 hydrocarbyl carboxylic acid Chemical class 0.000 claims description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- ALLSOOQIDPLIER-UHFFFAOYSA-N 2,3,4-trichlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C(Cl)=C1Cl ALLSOOQIDPLIER-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims 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 claims 1
- 239000005711 Benzoic acid Substances 0.000 claims 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims 1
- 235000011054 acetic acid Nutrition 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- 235000010233 benzoic acid Nutrition 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims 1
- 229940106681 chloroacetic acid Drugs 0.000 claims 1
- 235000019253 formic acid Nutrition 0.000 claims 1
- 229910017604 nitric acid Inorganic materials 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 claims 1
- 235000019260 propionic acid Nutrition 0.000 claims 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 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- QDAUEUYWLREWPI-FFZBTMFNSA-N O=C1C=C2CC[C@H]3[C@@H]4CCC(=CC)[C@]4(CC([C@@H]3[C@]2(CC1)C)=O)C Chemical compound O=C1C=C2CC[C@H]3[C@@H]4CCC(=CC)[C@]4(CC([C@@H]3[C@]2(CC1)C)=O)C QDAUEUYWLREWPI-FFZBTMFNSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 240000001987 Pyrus communis Species 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
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- RVEZZJVBDQCTEF-UHFFFAOYSA-N sulfenic acid Chemical compound SO RVEZZJVBDQCTEF-UHFFFAOYSA-N 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Description
Verfahren zur Herstellung von 6 a-Methyl-11 ß,2 1 -dioxy-4,17(20)-pregnadien-3-on durch alkalische Hydrolyse des 3-Pyrrolidylenamins des 6 a-Methyl-11ß,21-diöxy-4,17(20)-pregnadien-3-ons Die Erfindung betrifft ein Verfahren zur alkalischen Hydrolyse des 3-Pyrrolidyl-enamins des 6a-Methyl-11P,21-dioxy-4,17(20)-pregnadien-3-ons, wobei das 3- namin vor der alkalischen Hydrolyse in das entsprechende Säureadditionssalz übergeführt werden muß.Process for the preparation of 6α-methyl-11β, 2 1 -dioxy-4,17 (20) -pregnadien-3-one by alkaline hydrolysis of the 3-pyrrolidyleneamine of 6α-methyl-11β, 21-dioxy-4,17 (20) -pregnadien-3-one The invention relates to a process for the alkaline hydrolysis of 3-pyrrolidyl-enamine des 6a-methyl-11P, 21-dioxy-4,17 (20) -pregnadien-3-one, the 3-namin before the alkaline hydrolysis can be converted into the corresponding acid addition salt got to.
Die alkalische Hydrolyse von 3-Enaminen ist bekannt (vgl. Hogg und Mitarbeiter, J. Am. Chem. Soc., 77, S. 4436 [l955]). Wird jedoch diese Reaktion auf das 3-Pyrrolidyl-enamin des 6x-Methyl-llß,21-dioxy-4,17(20)-pregnadien-3-ons übertragen (vgl. S p e r o und Mitarbeiter, J. Am. Chem. Soc., 78, S. 6213 [1956]), so ist die Ausbeute an 6a-Methyl-llß,21-dioxy-4,17(20)-pregnadien-3-on beträchtlich geringer als diejenige, die bei der entsprechenden Hydrolyse des 3-Pyrrolidyl-enamins des llß,21-Dioxy-4,17(20)-pregnadien-3-ons erhalten wird. Während bei der Hydrolyse der letztgenannten Verbindung bei Raumtemperatur befriedigende Ausbeuten erzielt wurden, ergab die Hydrolyse der zuvor genannten Verbindung unter denselben Bedingungen nur eine 20°/oige Ausbeute an dem gewünschten Produkt, berechnet auf das Ausgangsmaterial 3,11-Diketo-6x-methyl-4,17(20)-[cis]-pregnadien-21-carbonsäure-methylester. Selbst durch längeres Erhitzen wurde die Ausbeute nur leicht erhöht.The alkaline hydrolysis of 3-enamines is known (cf. Hogg and Coworkers, J. Am. Chem. Soc., 77, p. 4436 [1955]). However, this reaction will on the 3-pyrrolidyl-enamine of 6x-methyl-11ß, 21-dioxy-4,17 (20) -pregnadien-3-one transferred (see. S per o and coworkers, J. Am. Chem. Soc., 78, p. 6213 [1956]), the yield of 6a-methyl-11ß, 21-dioxy-4,17 (20) -pregnadien-3-one is considerable lower than that which occurs in the corresponding hydrolysis of 3-pyrrolidyl-enamine des llß, 21-dioxy-4,17 (20) -pregnadien-3-one is obtained. While in hydrolysis the last-mentioned compound achieved satisfactory yields at room temperature resulted in hydrolysis of the aforementioned compound under the same conditions only a 20% yield of the desired product calculated on the starting material 3,11-Diketo-6x-methyl-4,17 (20) - [cis] -pregnadiene-21-carboxylic acid methyl ester. Self prolonged heating increased the yield only slightly.
Es wurde gefunden, daß eine Gesamtausbeute von 40 bis 5001, berechnet auf die Ausgangsverbindung 3,11- Diketo - 6x - methyl - 4,17(20) - [cis] - pregnadien-21-carbonsäure-methylester, selbst ohne Erhitzen erzielt werden kann, wenn das 3-Pyrrolidyl-enamin des 6x - Methyl -11ß,21-dioxy - 4,17(20) - [cis] - pregnadien 3-ons, d. h. das 3-Pyrrolidyl-6-methyl-llß,21-dioxy-3,5,17(20)-[cis]-pregnatrien vor der Hydrolyse in eines seiner Säureadditionssalzeumgewandelt wird. Während für die Hydrolysereaktion ohne die Säureadditionssalzstufe eine chromatographische Trennung erforderlich ist, um das gewünschte Produkt zu isolieren, wird nach dem Verfahren gemäß Erfindung mehr als die doppelte Menge an Produkt durch direkte Kristallisation erzielt, ein Vorteil, der von besonderer Bedeutung bei der Produktion im großen ist. Diese Ausbeuteerhöhung bei einem Zwischenprodukt zur Herstellung des hochaktiven entzündungshemmenden Mittels 6x - Methyl - 11ß,17x,21 - trioxy - 4 - pregnan-3,20-dion-21-acetats ist besonders wichtig im Hinblick auf die Anzahl von Stufen, die für dessen Herstellung notwendig sind (vgl. S p e r o und Mitarbeiter, a. a. O.).It has been found that a total yield of 40 to 500 liters, calculated on the starting compound 3,11-diketo-6x-methyl-4,17 (20) - [cis] - pregnadiene-21-carboxylic acid methyl ester, is achieved even without heating can, if the 3-pyrrolidyl-enamine des 6x - methyl -11ß, 21-dioxy - 4,17 (20) - [cis] - pregnadien 3-one, ie the 3-pyrrolidyl-6-methyl-11ß, 21- dioxy-3,5,17 (20) - [cis] -pregnatriene is converted into one of its acid addition salts before hydrolysis. While chromatographic separation is required for the hydrolysis reaction without the acid addition salt stage in order to isolate the desired product, more than twice the amount of product is achieved by direct crystallization according to the process according to the invention, an advantage which is of particular importance in large-scale production is. This increase in the yield of an intermediate for the preparation of the highly active anti-inflammatory agent 6x-methyl-11β, 17x, 21-trioxy-4-pregnane-3,20-dione-21-acetate is particularly important in view of the number of steps required for it Production are necessary (see S pero and coworkers, loc. Cit.).
Ausgangsverbindung in dem Verfahren gemäß Erfindung ist das 3-Pyrrolidyl-enamin des 6x-Methyll lß,21-dioxy-4,17(20)-pregnadien-3-ons und insbesondere das 3-Pyrrolidyl-enamin des 6x-Methylllß,21-dioxy-4,17(20)-[cis]-pregnadien-3-ons, das aus 3,11 - Diketo - 4,17(20) - pregnadien -_ 21 - carbonsäure methylester hergestellt wird (S p e r o und Mitarbeiter, a. a. O.).The starting compound in the process according to the invention is 3-pyrrolidyl-enamine des 6x-methyllß, 21-dioxy-4,17 (20) -pregnadien-3-one and especially 3-pyrrolidyl-enamine des 6x-Methylllß, 21-dioxy-4,17 (20) - [cis] -pregnadien-3-one, which from 3,11 - Diketo - 4,17 (20) - pregnadiene -_ 21 - carboxylic acid methyl ester is produced (S p e r o and employees, a. a. O.).
Diese Enamine werden mit einer anorganischen oder organischen Säure in der für die Säureadditionssalze von Aminen üblichen Weise in ein Säureädditionssalz übergeführt. Wenn jedoch unter wäßrigen Bedingungen gearbeitet wird, wird zweckmäßig die Säureadditionssalz enthaltende Lösung oder Suspension, sofort alkalisch gemacht, da die Ausbeute an gewünschtem Produkt vermindert. wird, wenn das 3-Enamin unter wäßrigen, sauren Bedingungen längere Zeit gehalten wird. Außerdem sollte wegen der labilen 3ß-Oxygruppe ein Erhitzen unter wäßrigen sauren Bedingungen vermieden werden.These enamines are made with an inorganic or organic acid in the manner customary for the acid addition salts of amines into an acid addition salt convicted. However, if it is carried out under aqueous conditions, it is appropriate the solution or suspension containing the acid addition salt, immediately made alkaline, since the yield of the desired product is reduced. will when the 3-enamine is under aqueous, acidic conditions is maintained for a long time. Also, because of the unstable 3ß-oxy group heating under aqueous acidic conditions can be avoided.
Unter die Säureadditionssalze, die gemäß Erfindung benutzt werden können, fallen sowohl anorganische als auch organische Säureadditionssalze, vorzugsweise die letzteren und insbesondere niedere Kohlenwasserstoffcarbonsäureadditionssalze, die z. B. 1 bis 8 C- Atome enthalten. Einige Beispiele für Säureadditionssalze, die z. B. aus dem entsprechenden 3-Enamin und Säure hergestellt werden, sind das Hydrochlorid, Hydrobromid, Sulfat, Phosphat, Nitrat, Acetat, Formtat, Propionat, Butyrat, Chloracetat, Benzoat, Trichlorbenzoat oder Trifluoracetat.Among the acid addition salts used according to the invention Both inorganic and organic acid addition salts are preferred the latter and in particular lower hydrocarbon carboxylic acid addition salts, the z. B. 1 to 8 C- Contain atoms. Some examples of acid addition salts, the z. B. are prepared from the corresponding 3-enamine and acid, are Hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, formtat, propionate, Butyrate, chloroacetate, benzoate, trichlorobenzoate or trifluoroacetate.
Das erfindungsgemäße Verfahren wird durch die nachfolgenden Beispiele erläutert.The process according to the invention is illustrated by the following examples explained.
Herstellung von 3-Pyrrolidyl-6-methyl-1lß,21-dioxy-3,5,17(20)-[cis]-pregnatrien Eine Lösung von 3,7g 6a-Methyl-3,11-diketo-4,17(20)- [cis]-pregnadien-21-carbonsä ure- methylester (Spero und Mitarbeiter Journ. Amer. Chem. Soc., 78, S. 6213 [1956]), 70 mg p-Toluolsulfonsäure und 1,65 ccm Pyrrolidin in 75 ccm Benzol wurde 1 Stunde am Rückfluß erhitzt, wobei das während der Reaktion gebildete Wasser kontinuierlich von dem rückfließenden Benzol in einer Dean-Stark-Falle abgeschieden wurde. Das Lösungsmittel wurde unter Vakuum entfernt, der Rückstand, der praktisch aus 3 -Pyrrolidyl-6-methyl-11-keto-3,5,17(20)- [cis]-pregnatrien-21-carbonsäure-methylester bestand, wurde in 50 ccm trockenem Äther gelöst und dann zu einer Suspension von 1,2 g Lithiumaluminiumhydrid in 100 ccm Äther gegeben. Nach 1 stündigem Erhitzen unter Rückfluß für 1 Stunde wurde die Reaktionsmischung gekühlt; dann wurden vorsichtig 7,5 ccm Essigester und sodann 18 ccm Wasser, um die anorganischen Salze in Form einer dicken Paste zu fällen, zugegeben. Die ätherische Phase enthielt gelöst 3-Pyrrolidyl-6-methyl-1 lß,21-dioxy-3,5,17(20)- [cis]-pregnatrien.Preparation of 3-pyrrolidyl-6-methyl-11, 21-dioxy-3,5,17 (20) - [cis] -pregnatriene A solution of 3.7 g of 6a-methyl-3,11-diketo-4,17 (20) - [cis] -pregnadiene-21-carboxylic acid ure methyl ester (Spero and coworkers Journ. Amer. Chem. Soc., 78, p. 6213 [1956]), 70 mg of p-toluenesulfonic acid and 1.65 cc of pyrrolidine in 75 cc of benzene was used for 1 hour heated to reflux, the water formed during the reaction continuously separated from the refluxing benzene in a Dean-Stark trap. That Solvent was removed under vacuum, the residue, which practically consists of 3 -pyrrolidyl-6-methyl-11-keto-3,5,17 (20) - [cis] -pregnatriene-21-carboxylic acid methyl ester was put in 50 ccm dry Dissolved ether and then to a suspension of 1.2 g of lithium aluminum hydride in 100 cc of ether given. After refluxing for 1 hour for 1 hour, the Reaction mixture cooled; then carefully 7.5 cc of ethyl acetate and then 18 cc of water to precipitate the inorganic salts in the form of a thick paste, admitted. The ethereal phase contained dissolved 3-pyrrolidyl-6-methyl-1, 21-dioxy-3,5,17 (20) - [cis] -pregnatrien.
Das entsprechende trans-Isomere wird bei Verwendung von 3,11-Diketo-4,17(20)-[trans]-pregnadien-21-carbonsäure-methylester als Ausgangsmaterial hergestellt, das seinerseits aus dem entsprechenden cis-Isomeren durch Erhitzen in methanolischer Lösung in Gegenwart von Natriummethylat erhalten wird.The corresponding trans isomer is obtained when using 3,11-diketo-4,17 (20) - [trans] -pregnadiene-21-carboxylic acid methyl ester produced as a starting material, which in turn consists of the corresponding cis-isomer obtained by heating in methanolic solution in the presence of sodium methylate will.
Beispiel 6x-Methyl-11ß,21-dioxy-4,17(20)-[cis]-pregnadien-3-on A. Alte Methode Die gesamte Reaktionsmischung, die nach dem im Abschnitt »Herstellung« beschriebenen Verfahren erhalten wurde und das 3-Pyrrolidyl-6-methyl-l 1ß,21-dioxy-3,5,17(20)-[cis]-pregnatrien enthält, wurde im Vakuum zur Trockene eingedampft und der Rückstand unter Stickstoff gesetzt und sodann mit 125 ccm Methanol versetzt. Nachdem man 5 Minuten bei 25°C gerührt hatte, wurden 10 ccm 5°/oiges Natriumhydroxyd hinzugefügt, die Reaktionsmischung bei 25'C 11/2 Stunden gerührt, der pH-Wert der Mischung mit 3 ccm Essigsäure auf 7 eingestellt und das Lösungsmittel im Vakuum abdestilliert. Eine Lösung von 12,5 ccm konzentrierter Salzsäure in 200 ccm Wasser wurde zugefügt, das Produkt aus der erhaltenen Mischung mit Methylenchlorid extrahiert, die Lösung getrocknet und das Methylenchlorid abdestilliert. Die erhaltenen 3 g Rückstand wurden in Essigester gelöst und angeimpft. Es bildeten sich jedoch keine Kristalle, so daß die Lösung zur Trockene eingedampft, erneut in 400 ccm Methylenchlorid gelöst und über 240 g Magnesiumsilicat (bekannt unter dem Handelsnamen Florisil) chromatographiert wurde. Die Kolonne wurde mit Hexanen (bekannt unter dem Handelsnamen Skellysolve B), die zunehmende Mengen an Aceton enthielten, entwickelt. Mit Hexanen und 20 % Aceton und Hexanen und 301)/, Aceton wurden 1,03 g l lß,21-Dioxy-4,17(20)-[cis]-pregnadien-3-on eluiert. In keiner der anderen Eluatfraktionen war eine bedeutende Menge dieser Verbindung vorhanden. Bei Reinigung dieser Verbindung durch Kristallisation aus Essigester wurden 0,7 g (= 200/, der Theorie, berechnet auf die Ausgangsverbindung 3,11-Diketo-6a-methyl-4,17(20)-[cis]-pregnadien-21-carbonsäuremethylester) Kristalle mit einem Schmelzpunkt von 172 bis 174°C erhalten; [AD -f- 125° (CHC13); 2max C, He O H 242; aal 15,200. B. Neue Methode Das unter A genannte rohe 3-Pyrrolidyl-6-methyl-11ß,21-dioxy-3,5,17(20)-[cis]-pregnatrien in ätherischer Lösung wurde von den ausgefallenen anorganischen Salzen abdekantiert, und die Salze wurden zweimal mit je 25 ccm Äther extrahiert. Die ätherische Phase und die Ätherextrakte wurden vereinigt und dann mit einer Lösung von 3 ccm Essigsäure in 15 ccm Methanol gemischt, wobei sich das Iminium-Säureadditionssalz bildete. 37 ccm einer 10°/oigen wäßrigen Natronlauge wurden sofort zu der sauren Mischung zugegeben, die dann 15 Minuten gerührt wurde. Man fügte 40 ccm Wasser hinzu und trennte die Ätherschicht ab. Die wäßrige Schicht wurde mit 40 ccm Äther extrahiert, der Ätherextrakt und die Ätherschicht vereinigt und nacheinander mit verdünnter Salzsäure, Wasser, wäßrigem Natriumbicarbonat und dann mit gesättigter, wäßriger Natriumchloridlösung gewaschen. Der Äther wurde über Natriumsulfat getrocknet und dann abdestilliert, wobei man 3,2 g Rückstand an 11ß,21-Dioxy-4,17(20)-[cis]-pregnadien-3-on erhielt. Bei Reinigung dieser Verbindung durch Kristallisation aus Essigester erhielt man 1,5 g (= 44°/o der Theorie, berechnet auf die Ausgangsverbindung 3,11-Diketo-6ca-methyl-4,l7(20) - [cis]-pregnadien-21-carbonsäuremethylester) an Kristallen mit einem Schmelzpunkt von 172 bis 174°C; [AD von + 125° (CHC13); ,,nd..C,HSOH 242; ayz 14,850.Example 6x-Methyl-11ß, 21-dioxy-4,17 (20) - [cis] -pregnadien-3-one A. Old method -Pyrrolidyl-6-methyl-l 1ß, 21-dioxy-3,5,17 (20) - [cis] -pregnatriene, was evaporated to dryness in vacuo and the residue was placed under nitrogen and then treated with 125 cc of methanol. After stirring for 5 minutes at 25 ° C., 10 ccm of 5% sodium hydroxide were added, the reaction mixture was stirred at 25 ° C. for 11/2 hours, the pH of the mixture was adjusted to 7 with 3 ccm of acetic acid and the solvent was dissolved in Distilled off under vacuum. A solution of 12.5 cc of concentrated hydrochloric acid in 200 cc of water was added, the product was extracted from the mixture obtained with methylene chloride, the solution was dried and the methylene chloride was distilled off. The 3 g residue obtained was dissolved in ethyl acetate and seeded. However, no crystals formed, so the solution was evaporated to dryness, redissolved in 400 cc of methylene chloride and chromatographed over 240 g of magnesium silicate (known under the trade name Florisil). The column was developed with hexanes (known under the trade name Skellysolve B) containing increasing amounts of acetone. With hexanes and 20 % acetone and hexanes and 301) /, acetone, 1.03 μl, 21-dioxy-4,17 (20) - [cis] -pregnadien-3-one were eluted. No significant amount of this compound was present in any of the other fractions of the eluate. When this compound was purified by crystallization from ethyl acetate, 0.7 g (= 200 /, of theory, calculated on the starting compound 3,11-diketo-6a-methyl-4,17 (20) - [cis] -pregnadiene-21- methyl carboxylate) crystals with a melting point of 172 to 174 ° C; [AD- f- 125 ° (CHCl3); 2max C, He OH 242; eel 15.200. B. New method The crude 3-pyrrolidyl-6-methyl-11ß, 21-dioxy-3,5,17 (20) - [cis] -pregnatriene in ethereal solution was decanted from the precipitated inorganic salts, and the Salts were extracted twice with 25 cc of ether each time. The ethereal phase and the ether extracts were combined and then mixed with a solution of 3 cc acetic acid in 15 cc methanol, the iminium acid addition salt being formed. 37 cc of a 10% aqueous sodium hydroxide solution were immediately added to the acidic mixture, which was then stirred for 15 minutes. 40 cc of water were added and the ether layer was separated off. The aqueous layer was extracted with 40 cc of ether, the ether extract and the ether layer were combined and washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate and then with saturated aqueous sodium chloride solution. The ether was dried over sodium sulfate and then distilled off, giving 3.2 g of residue of 11β, 21-dioxy-4,17 (20) - [cis] -pregnadien-3-one. Purification of this compound by crystallization from ethyl acetate gave 1.5 g (= 44% of theory, calculated on the starting compound 3,11-diketo-6ca-methyl-4, 17 (20) - [cis] -pregnadiene- 21-carboxylic acid methyl ester) on crystals with a melting point of 172 to 174 ° C; [AD of + 125 ° (CHCl3); ,, nd..C, HSOH 242; ayz 14,850.
Bei Anwendung des angegebenen Verfahrens wurden vergleichbare Ergebnisse erhalten, wenn man äquivalente Mengen an methanolischem Chlorwasserstoff an Stelle von Essigsäure oder das entsprechende trans-Isomere als Ausgangsverbindung verwendet.Using the specified procedure gave comparable results obtained when equivalent amounts of methanolic hydrogen chloride in place of acetic acid or the corresponding trans isomer is used as the starting compound.
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US788051A US2920085A (en) | 1959-01-21 | 1959-01-21 | Process for the hydrolysis of the 3-enamine of 6alpha-methyl-11beta, 21-dihydroxy-4,17(20)-pregnadien-3-one |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1115247B true DE1115247B (en) | 1961-10-19 |
Family
ID=25143293
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEU6769A Pending DE1115247B (en) | 1959-01-21 | 1959-12-23 | Process for the preparation of 6ª ‡ -Methyl-11ª ‰, 21-dioxy-4, 17 (20) -pregnadien-3-one by alkaline hydrolysis of the 3-pyrrolidyleneamine of 6ª ‡ -Methyl-11ª ‰, 21-dioxy-4, 17 (20) -pregnadien-3-ons |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US2920085A (en) |
| DE (1) | DE1115247B (en) |
| GB (1) | GB869777A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3444160A (en) * | 1967-04-03 | 1969-05-13 | Upjohn Co | Protection of delta**4-3-ketosteroids by the formation of protonated 3-enamines |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2849464A (en) * | 1957-05-27 | 1958-08-26 | Upjohn Co | 6-methyl, delta4, 3-keto androstene derivatives |
-
1959
- 1959-01-21 US US788051A patent/US2920085A/en not_active Expired - Lifetime
- 1959-12-04 GB GB41303/59A patent/GB869777A/en not_active Expired
- 1959-12-23 DE DEU6769A patent/DE1115247B/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| US2920085A (en) | 1960-01-05 |
| GB869777A (en) | 1961-06-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE1618065B2 (en) | 21-OXO-23-DESOXO-CARDENOLIDE, PROCESS FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS MANUFACTURED FROM THEM | |
| DE1115247B (en) | Process for the preparation of 6ª ‡ -Methyl-11ª ‰, 21-dioxy-4, 17 (20) -pregnadien-3-one by alkaline hydrolysis of the 3-pyrrolidyleneamine of 6ª ‡ -Methyl-11ª ‰, 21-dioxy-4, 17 (20) -pregnadien-3-ons | |
| DE1264441B (en) | Process for the production of 17alpha-AEthynyl-delta 5 (10-19-nor-androsten-17beta-ol-3-one and 17alpha-AEthynil-19-nor-testosterone and its esters | |
| DE825686C (en) | Process for the conversion of í¸-20-cyanpregnenes with one or more nucleus-bound hydroxyl groups into 17 alpha-oxy-20-ketopregnanes | |
| DE1012299B (en) | Process for the preparation of a pregnan-3-ol-20-one-3-ether or ester | |
| DE1097986B (en) | Process for the production of 6ª ‡ -Methyl-17ª ‡ -oxyprogesterone and its esters | |
| DE1158507B (en) | Process for the preparation of 6a-methyl-16-methylene-steroids | |
| DE750212C (en) | Process for the production of 3-acyloxybisnorcholenic acid | |
| DE1643020C (en) | 18 Methyl 19 nor 17alpha hydroxy progesterone, their 17 mono ester processes for their production and agents containing them | |
| AT257060B (en) | Process for the preparation of new 3-enol ethers of the 6-methyl-3-oxo-Δ <4> -steroids of the androstane, 19-norandrostane, pregnane and 19-norpregnane series | |
| AT162906B (en) | Process for the preparation of derivatives of the cyclopentano-polyhydro-phenantren- or the polyhydro-chrysen series | |
| DE1468632C (en) | öalpha Acetylthio 4 en 3 on steroids and process for their production | |
| DE1593807C (en) | alpha ascine methyl or ethy (ester, as well as a process for their production | |
| DE954248C (en) | Process for the preparation of new tricyclic ketones | |
| DE2560493C2 (en) | 2,9-Dioxatricyclo [4,3,1,0 → 3 → →, → → 7 →] decane | |
| DE2403985A1 (en) | METHOD OF PREPARING RACEMIC 13BETA-AETHYL-3-METHOXY-8,14-SECOGONA1,3,5 (10), 8-TETRAEN-17BETA-OL-14-ON | |
| DE1113453B (en) | Process for the production of substitution products of Reichsteins-Substance-S or their 21-acylates | |
| CH322615A (en) | Process for the preparation of 1-keto-4-oxy-polyhydrophenanthrenes | |
| CH382734A (en) | Process for the preparation of 17a-haloprogesterones | |
| DE1094258B (en) | Process for the preparation of fluorinated 16-methyl steroids | |
| DE1643928B2 (en) | Process for the preparation of alkylaminoalkyl ethers of cycloalkanols | |
| CH616433A5 (en) | Process for the preparation of 18,18-difluorosteroids. | |
| DE1082909B (en) | Process for the preparation of 16-position unsaturated compounds of the pregnane series | |
| CH364776A (en) | Process for making 16-20 keto steroids | |
| CH380113A (en) | Process for the preparation of 16-methylene-17a-hydroxy steroids |