AT374205B - METHOD FOR PRODUCING A NEW DELTA 1,4,17-BISNOVCHOLANIC ACID DERIVATE - Google Patents
METHOD FOR PRODUCING A NEW DELTA 1,4,17-BISNOVCHOLANIC ACID DERIVATEInfo
- Publication number
- AT374205B AT374205B AT0078481A AT7848180A AT374205B AT 374205 B AT374205 B AT 374205B AT 0078481 A AT0078481 A AT 0078481A AT 7848180 A AT7848180 A AT 7848180A AT 374205 B AT374205 B AT 374205B
- Authority
- AT
- Austria
- Prior art keywords
- chloride
- sep
- bisnovcholanic
- producing
- acid
- Prior art date
Links
- 239000002253 acid Substances 0.000 title description 5
- 238000004519 manufacturing process Methods 0.000 title description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 150000003431 steroids Chemical group 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- LUJVUUWNAPIQQI-QAGGRKNESA-N androsta-1,4-diene-3,17-dione Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 LUJVUUWNAPIQQI-QAGGRKNESA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NRESKKGDHRQEMH-HPGXARPTSA-N 2-[(8r,9s,10s,13s,14s,17r)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]propanoic acid Chemical class C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(C)C(O)=O)[C@@]1(C)CC2 NRESKKGDHRQEMH-HPGXARPTSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000005899 aromatization reaction Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
Classifications
-
- 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
- C07J13/007—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 17 (20)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
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Die Überführung von Carbonsäuren in Säurechloride mittels Thionylchlorid oder Oxalylchlorid ist an sich eine seit langem bekannte und allgemein benutzte Reaktion, auch in der Reihe der 20-Carboxypregnan-Derivate.
Wendet man aber die in der Literatur-s. hiezu beispielsweise Fiat Final Report No. 996, S. 24 ff sowie P. L. Julian, E. W. Meyer und H. C. Printy, J. Amer. Chem. Soc. 70, 887 [1948]-für die Umsetzung von 3-Acetoxybisnorcholensäure mit Thionylchlorid angegebenen Reaktionsbedingungen auf #1,4,#BNC (Bisnorcholansäure) an, verestert danach das so erhaltene Säurechlorid mit Methanol und analysiert das Rohprodukt, so findet man im Gaschromatogramm die Gegenwart von unerwünschten Nebenprodukten.
Grund hiefür ist vermutlich eine Chlorierung mit eventuell anschliessender Aromatisierung auch des A-Ringes im Steroidgerüst, wie sie z. B. für die Umsetzung von Androsta-1, 4-dien-3, 17- - dion (ADD) mit Oxalylchlorid bekannt ist ; s. hiezu G. W. Moersch et al., J. Org. Chemistry, 29,2495 [1964 ].
Es wurde überraschend gefunden, dass die Bildung des gewünschten A ' -BNC-Chlorids bereits unter aussergewöhnlich milden Reaktionsbedingungen durchgeführt werden kann, bei denen die unerwünschte Mitreaktion anderer reaktiver Stellen der mehrfach ungesättigten Ausgangssäure noch nicht stattfindet. So zeigte sich das überraschende Ergebnis, dass eine praktisch quantitative Säurechloridbildung stattfindet, wenn die folgenden Reaktionsbedingungen eingehalten werden : Reaktionstemperaturen unter 10, vorzugsweise unter 5OC, stöchiometrische Mengen der Reaktanten oder nur sehr begrenzter Überschuss des Thionylchlorids, der nicht über 20, vorzugsweise nicht über 10 Mol-%, beträgt, sowie kurze Reaktionszeiten, die vorzugsweise 30 min nicht überschreiten.
Als Umsetzungsbedingungen ist besonders die folgende Kombination geeignet : 0 C, Thionylchlorid-Überschuss von 0 bis 10 Mol-% und Reaktionsdauer von 15 bis 20 min in Gegenwart eines inerten Lösungsmittels, beispielsweise in Gegenwart halogenierter Kohlenwasserstoffe, wie Methylenchlorid.
Das erfindungsgemässe Verfahren betrifft ein Verfahren zur Herstellung von neuem Pregna-
EMI1.1
l, 4, 17-trien-3-on-20-oarbonylchlorid (AEs ist kein Zusatz eines Katalysators - beispielsweise Pyridin oder Dimethylformamid - oder der Zusatz einer grösseren Menge an Base, wie beispielsweise tertiäres Amin oder Alkalicarbonat, erforderlich. Verestert man das unter diesen Bedingungen hergestellte Säurechlorid mit Methanol, so erhält man den erwarteten Methylester mit einer Ausbeute von mindestens 95% der Theorie. Das Säurechlorid eignet sich als Ausgangsmaterial für nachfolgende Reaktionen zur weiteren strukturellen Umwandlung des Seitenkettensubstituenten in 17-Stellung des Steroidringgerüstes.
Das Ausgangsprodukt kann nach der EP-OS 0033439 hergestellt werden.
Die erfindungsgemäss hergestellte Verbindung ist ein wichtiges Zwischenprodukt für die Partialsynthese von pharmazeutisch wirksamen Steroiden. Ein besonderer Vorteil gegenüber den Verbindungen, die in A 17(20)-Stellung keine Doppelbindung besitzen, liegt darin, dass in die erstgenannte Verbindung leicht Substituenten in 17-Stellung eingeführt werden können.
Beispiel : 17 g (50 mMol) A'-BNC in 100 ml absoluten CH2Cl2 werden bei OOC mit 4, 0 ml (55 mMol) frisch über Squalen destilliertem Thionylchlorid versetzt und 20 min bei OOC gerührt.
Danach werden das Lösungsmittel und überschüssiges Thionylchlorid bei der gleichen Temperatur im Vakuum entfernt. Der Rückstand wird wieder in Methylenchlorid aufgenommen und die Lösung nochmals zur Trockne eingeengt. Der Rückstand ist für weitere Umsetzungen zu verwenden. Um ein zur Analyse geeignetes Säurechlorid zu erhalten, wird das rohe Säurechlorid mit absolutem Äther digeriert und nach dem Abziehen des Äthers sorgfältig an der Ölpumpe getrocknet.
Elementaranalyse :
EMI1.2
<tb>
<tb> her. <SEP> : <SEP> C <SEP> 73, <SEP> 2, <SEP> H <SEP> 8,10, <SEP> Cl <SEP> 9,82; <SEP>
<tb> gef. <SEP> : <SEP> C <SEP> 72, <SEP> 85, <SEP> H <SEP> 8,22, <SEP> Cl10,1 <SEP> . <SEP>
<tb>
H-NMR-Spektrum von A 'R-BNC-Chlorid, gemessen in CDC1,, bei 80 MHZ. a-Werte : 1,01 (18 - CH2,s); 1,24 (19 - CH3, s); 2,07 (21 - CH3,s); 6,07; 6,15; 6,17; 6,26; 6,26; 7, 00 : 7, 11 (olefinische Protonen an C (1), C (2) undC (4).
<Desc / Clms Page number 1>
The conversion of carboxylic acids into acid chlorides using thionyl chloride or oxalyl chloride is in itself a long-known and generally used reaction, also in the series of 20-carboxypregnan derivatives.
But if you apply those in the literature-s. for example Fiat Final Report No. 996, pp. 24 ff as well as P.L. Julian, E.W. Meyer and H.C. Printy, J. Amer. Chem. Soc. 70, 887 [1948] -for the reaction of 3-acetoxybisnorcholenic acid with thionyl chloride to # 1.4, # BNC (bisnorcholanoic acid), then esterify the acid chloride thus obtained with methanol and analyze the crude product, so the gas chromatogram shows Presence of unwanted by-products.
The reason for this is probably a chlorination with possibly subsequent aromatization of the A-ring in the steroid structure, as z. B. for the implementation of Androsta-1, 4-dien-3, 17- - dione (ADD) with oxalyl chloride is known; s. see G. W. Moersch et al., J. Org. Chemistry, 29.2495 [1964].
It has surprisingly been found that the formation of the desired A ′ -BNC chloride can be carried out under extraordinarily mild reaction conditions in which the undesired co-reaction of other reactive sites of the polyunsaturated starting acid does not yet take place. The surprising result was that a practically quantitative formation of acid chloride takes place if the following reaction conditions are observed: reaction temperatures below 10, preferably below 5OC, stoichiometric amounts of the reactants or only a very limited excess of the thionyl chloride, which does not exceed 20, preferably not above 10 Mol%, and short reaction times, which preferably do not exceed 30 minutes.
The following combination is particularly suitable as the reaction conditions: 0 C, excess thionyl chloride of 0 to 10 mol% and reaction time of 15 to 20 min in the presence of an inert solvent, for example in the presence of halogenated hydrocarbons, such as methylene chloride.
The method according to the invention relates to a method for producing new pregna-
EMI1.1
1, 4, 17-trien-3-one-20-oarbonylchloride (AEs does not require the addition of a catalyst - for example pyridine or dimethylformamide - or the addition of a large amount of base such as tertiary amine or alkali carbonate. This is esterified under Acid chloride prepared under these conditions with methanol gives the expected methyl ester with a yield of at least 95% of theory The acid chloride is suitable as a starting material for subsequent reactions for further structural conversion of the side chain substituent in the 17-position of the steroid ring structure.
The starting product can be produced according to EP-OS 0033439.
The compound produced according to the invention is an important intermediate for the partial synthesis of pharmaceutically active steroids. A particular advantage over the compounds which have no double bond in the A 17 (20) position is that substituents in the 17 position can easily be introduced into the first-mentioned compound.
Example: 17 g (50 mmol) of A'-BNC in 100 ml of absolute CH2Cl2 are mixed with 4.0 ml (55 mmol) of freshly distilled squalene thionyl chloride at OOC and stirred at OOC for 20 min.
The solvent and excess thionyl chloride are then removed in vacuo at the same temperature. The residue is taken up again in methylene chloride and the solution is again evaporated to dryness. The backlog is to be used for further implementations. To obtain an acid chloride suitable for analysis, the crude acid chloride is digested with absolute ether and, after the ether has been stripped off, carefully dried on an oil pump.
Elemental analysis:
EMI1.2
<tb>
<tb> here. <SEP>: <SEP> C <SEP> 73, <SEP> 2, <SEP> H <SEP> 8.10, <SEP> Cl <SEP> 9.82; <SEP>
<tb> found <SEP>: <SEP> C <SEP> 72, <SEP> 85, <SEP> H <SEP> 8.22, <SEP> Cl10.1 <SEP>. <SEP>
<tb>
H-NMR spectrum of A'R-BNC chloride, measured in CDC1 ,, at 80 MHz. a values: 1.01 (18 - CH2, s); 1.24 (19 - CH3, s); 2.07 (21 - CH3, s); 6.07; 6.15; 6.17; 6.26; 6.26; 7, 00: 7, 11 (olefinic protons at C (1), C (2) and C (4).
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0078481A AT374205B (en) | 1980-02-04 | 1980-02-04 | METHOD FOR PRODUCING A NEW DELTA 1,4,17-BISNOVCHOLANIC ACID DERIVATE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0078481A AT374205B (en) | 1980-02-04 | 1980-02-04 | METHOD FOR PRODUCING A NEW DELTA 1,4,17-BISNOVCHOLANIC ACID DERIVATE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AT374205B true AT374205B (en) | 1984-03-26 |
Family
ID=3680905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AT0078481A AT374205B (en) | 1980-02-04 | 1980-02-04 | METHOD FOR PRODUCING A NEW DELTA 1,4,17-BISNOVCHOLANIC ACID DERIVATE |
Country Status (1)
| Country | Link |
|---|---|
| AT (1) | AT374205B (en) |
-
1980
- 1980-02-04 AT AT0078481A patent/AT374205B/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| ELJ | Ceased due to non-payment of the annual fee |