DE947163C - Process for the preparation of racemic dihydronorlysergic acid - Google Patents
Process for the preparation of racemic dihydronorlysergic acidInfo
- Publication number
- DE947163C DE947163C DES39953A DES0039953A DE947163C DE 947163 C DE947163 C DE 947163C DE S39953 A DES39953 A DE S39953A DE S0039953 A DES0039953 A DE S0039953A DE 947163 C DE947163 C DE 947163C
- Authority
- DE
- Germany
- Prior art keywords
- acid
- racemic
- dihydronorlysergic
- preparation
- sodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000002253 acid Substances 0.000 title claims description 17
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 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 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 150000004702 methyl esters Chemical class 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- GPYLCFQEKPUWLD-UHFFFAOYSA-N 1h-benzo[cd]indol-2-one Chemical group C1=CC(C(=O)N2)=C3C2=CC=CC3=C1 GPYLCFQEKPUWLD-UHFFFAOYSA-N 0.000 description 4
- HFJHUOIVZVHBBM-UHFFFAOYSA-N 1,2-dihydrobenzo[cd]indole Chemical compound C1=CC(CN2)=C3C2=CC=CC3=C1 HFJHUOIVZVHBBM-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZAGRKAFMISFKIO-QMTHXVAHSA-N lysergic acid Chemical group C1=CC(C2=C[C@H](CN([C@@H]2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-QMTHXVAHSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- DWPQZXIWONIDFV-UHFFFAOYSA-N ethyl 4,5-dihydroindolo[4,3-fg]quinoline-9-carboxylate Chemical compound C(C)OC(=O)C=1C=NC=2C=C3C4=C(C2C1)C=CC=C4NC3 DWPQZXIWONIDFV-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Verfahren zur Herstellung von racemischer Dihydronorlysergsäure Es wurde gefunden, daß man zu racemischer Dihydronorlysergsäure der Formel II gelangen kann, indem man 4, 5-Dihydro-9-carbäthoxyindolo-(4, 3-fg)-chinolin der Formel I mit Natrium und Alkohol reduziert. Die bisher veröffentlichten Synthesen (F. C. U h l e und W. A. Jacobs, J. Org. Chem., Bd. i o, 1945, S.76; A. Stoll und J. Rutschmann. Helv. Chim. Acta, Bd.33, 1950, S.67; A. .S toll, J. Rutschmann und W. Schlientz, Helv.Chim. Acta, Bd. 33, 1950, S. 375) der Dihydrolysergsäure und ihrer Derivate besitzen das gemeinsame Merkmal, daß der Ring D der Dihydrolysergsäure an das Naphthostyrilgerüst angebaut und das so entstandene tetracyclische Naphthostyrilderivat, das alle Atome des Lysergsäuregerüstes enthält, mit kräftigen Mitteln reduziert wird. Demgegenüber hat sich, wie A. S t o 11 und Th. P e t r z i 1 k a (Helv. Chim. Acta, Bd. 36, 1953, S. 1125) beschrieben haben, gezeigt, daB man zu Verbindungen mit dem Gerüst der Dihydronorlysergsäure gelangen kann, 1 indem man ein geeignetes tricyclisches Naphthostyrilderivat zuerst zum entsprechenden Benz(cd) indolin reduziert und an dieses den Ring D des Lysergsäuregerüste's anbaut. Das so gewonnene tetracyclische Benz(cd)indolinderivat der Formel I enthält ebenfalls alle Atome des Lysergsäuregerüstes und liefert bei der Reduktion nach dem vorliegenden Verfahren racemische Dihydronorlysergsäure.Process for the preparation of racemic dihydronorlysergic acid It has been found that racemic dihydronorlysergic acid of the formula II can be obtained by reducing 4,5-dihydro-9-carbethoxyindolo- (4,3-fg) -quinoline of the formula I with sodium and alcohol . The syntheses published so far (FC U hle and WA Jacobs, J. Org. Chem., Vol. Io, 1945, p.76; A. Stoll and J. Rutschmann. Helv. Chim. Acta, Vol. 33, 1950, p .67; A. .S toll, J. Rutschmann and W. Schlientz, Helv.Chim. Acta, Vol. 33, 1950, p. 375) of dihydrolysergic acid and its derivatives have the common feature that ring D of dihydrolysergic acid the naphthostyril structure is grown and the resulting tetracyclic naphthostyril derivative, which contains all the atoms of the lysergic acid structure, is reduced with vigorous means. In contrast, as A. S to 11 and Th. Petrzi 1 ka (Helv. Chim. Acta, vol. 36, 1953, p. 1125) have described, it has been shown that compounds with the structure of dihydronorlysergic acid can be obtained , 1 by first reducing a suitable tricyclic naphthostyril derivative to the corresponding benz (cd) indoline and adding ring D of the lysergic acid structure to this. The tetracyclic benz (cd) indoline derivative of the formula I obtained in this way also contains all the atoms of the lysergic acid structure and, when reduced by the present process, yields racemic dihydronorlysergic acid.
Während die Reduktion tetracyclischer Naphthostyrilderivate zu racemischer Dihydronortysergsäure nach A. Stop und J. Rutschmann (Helv. Chim. Acta, Bd. 33, 195o, S. 67) nur durch Natrium in 990/aigem n-Butanol zu erreichen war, hat sich überraschenderweise herausgestellt, daB das tetracyclische Benz(cd)indolinderivat der Formel I durch Natrium in Äthanol, das zur Verhinderung der Reduktion der Carbäthoxygruppe kleine Mengen Wasser enthält, zur racemischen Dihydronorlysergsäure der Formel TI reduziert wird. Die rohe racemische Dihydronorlysergsäure wird mit Methylalkohol und trockenem Chlorwasserstoff in ein Gemisch von Methylestern verwandelt, aus dem durch Chromatographie reiner racemischer Dihydronorlysergsäuremethylester erhalten wird, der in .,allen Eigenschaften mit dem nach den früheren Methoden (A. Stoll und J. Rutschmann, Helv. Chim. Acta, Bd. 33, 1950, S. 67) dargestellten übereinstimmt.While the reduction of tetracyclic naphthostyril derivatives to racemic Dihydronortysergic acid according to A. Stop and J. Rutschmann (Helv. Chim. Acta, Vol. 33, 195o, p. 67) could only be achieved with sodium in 990% n-butanol, has become It was surprisingly found that the tetracyclic benz (cd) indoline derivative of formula I by sodium in ethanol, which is used to prevent the reduction of the carbethoxy group Contains small amounts of water, to the racemic dihydronorlysergic acid of the formula TI is reduced. The crude racemic dihydronorlysergic acid is made with methyl alcohol and dry hydrogen chloride converted into a mixture of methyl esters, from the pure racemic dihydronorlysergic acid methyl ester obtained by chromatography becomes, which in., all properties with that according to the earlier methods (A. Stoll and J. Rutschmann, Helv. Chim. Acta, Vol. 33, 1950, p. 67).
Die nach dem beanspruchten Verfahren hergestellte racemische Dihydronorlysergsäure dient als Zwischenprodukt, z. B. für die Darstellung von d,1-Dihydronorlysergylglycinamid nach. der schweizerischen Patentschrift 302 316, das als uteruswirksames Mittel therapeutisch zu verwenden ist. Beispiel Man versetzt eine siedende Lösung von 1,47 g 4, 5-Dihydro-9-carbäthoxyindolo-(4, 3-fg) -chinolin in 74 ccm Alkohol und 0,37 ccm Wasser unter kräftigem Rühren innerhalb von io Minuten mit 5,9 g Natrium. Die abgekühlte Lösung wird mit 75 ccm Wasser verdünnt und zweimal mit Benzol ausgeschüttelt. Die Benzolauszüge wäscht man zweimal mit wenig Wasser nach. Die vereinigten wäBrigen Extrakte werden mit Kohlensäure gesättigt 'und mit dem doppelten Volumen' Alkohol verdünnt, wobei die Hauptmenge des Natriumhydrogencarbonats ausfällt. Nach dem Abfiltrieren vom ausgefallenen Salz dampft man das Filtrat im Vakuum zur Trockne ein, löst den Eindampfrückstand in 30 ccm trockenem Methanol, sättigt die Lösung bei o° mit trockenem Chlorwasserstoff, läßt sie i Stunde bei Zimmertemperatur stehen und dampft hierauf die Hauptmenge des Lösungsmittels im Vakuum bei einer Badtemperatur von 3o° ab. Der dickflüssige Rückstand wird in Chloroform aufgenommen und unter Eiskühlung mit verdünntem Ammoniak ausgeschüttelt. Die getrocknete Chloroformlösung liefert o;87 g rohes Estergemisch, das an einer Säule von 8o g Aluminiumoxyd (B r o c k m a n n) chromatographiert wird.The racemic dihydronorlysergic acid prepared by the claimed process serves as an intermediate product, e.g. B. for the representation of d, 1-Dihydronorlysergylglycinamid after. the Swiss patent specification 302 316, which is to be used therapeutically as an agent effective in the uterus. EXAMPLE A boiling solution of 1.47 g of 4,5-dihydro-9-carbäthoxyindolo- (4,3-fg) -quinoline in 74 cc of alcohol and 0.37 cc of water is added within 10 minutes while stirring vigorously with 5, 9 g sodium. The cooled solution is diluted with 75 ccm of water and extracted twice with benzene. The benzene extracts are washed twice with a little water. The combined aqueous extracts are saturated with carbonic acid and diluted with twice the volume of alcohol, most of the sodium hydrogen carbonate being precipitated. After the precipitated salt has been filtered off, the filtrate is evaporated to dryness in vacuo, the evaporation residue is dissolved in 30 ccm of dry methanol, the solution is saturated with dry hydrogen chloride at 0 °, left to stand for 1 hour at room temperature and most of the solvent is then evaporated in Vacuum at a bath temperature of 30 °. The viscous residue is taken up in chloroform and extracted with dilute ammonia while cooling with ice. The dried chloroform solution yields 87 g of crude ester mixture, which is chromatographed on a column of 80 g of aluminum oxide (Rockmann).
Die ersten mit reinem Chloroform ausgewaschenen Fraktionen liefern aus Benzol eine kleine Menge eines Kristallisates vom F. = 95 bis 96°. Die folgenden, ebenfalls mit reinem Chloroform ausgewaschenen Fraktionen liefern aus Essigester ö;o65 g Nadeln vom F: = Zoo bis 2o2°, die in der Mischprobe- mit reinem racemischen Dihydronorlysergsäuremethylester keine Erniedrigung des Schmelzpunktes zeigen und mit dieser Verbindung auch in allen übrigen Eigenschaften übereinstimmen. Der Ester läßt sich -in bekannter Weise zur racemischen Dihydronorlysergsäure verseifen.Deliver the first fractions washed out with pure chloroform from benzene a small amount of crystals with a temperature of 95 to 96 °. The following, Fractions that have also been washed out with pure chloroform are produced from ethyl acetate ö; o65 g needles from F: = zoo to 2o2 °, those in the mixed sample with pure racemic Dihydronorlysergsäuremethylester show no lowering of the melting point and agree with this connection in all other properties. The ester can be saponified in a known manner to give racemic dihydronorlysergic acid.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH947163X | 1953-07-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE947163C true DE947163C (en) | 1956-08-09 |
Family
ID=4549802
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DES39953A Expired DE947163C (en) | 1953-07-27 | 1954-07-11 | Process for the preparation of racemic dihydronorlysergic acid |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE947163C (en) |
-
1954
- 1954-07-11 DE DES39953A patent/DE947163C/en not_active Expired
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