DE1936743C3 - Process for the preparation of bis (4-hydroxymethyl-5-hydroxy-6-methyIpyridyl-3-methyl) disulfide dichlorohydrate dihydrate - Google Patents
Process for the preparation of bis (4-hydroxymethyl-5-hydroxy-6-methyIpyridyl-3-methyl) disulfide dichlorohydrate dihydrateInfo
- Publication number
- DE1936743C3 DE1936743C3 DE1936743A DE1936743A DE1936743C3 DE 1936743 C3 DE1936743 C3 DE 1936743C3 DE 1936743 A DE1936743 A DE 1936743A DE 1936743 A DE1936743 A DE 1936743A DE 1936743 C3 DE1936743 C3 DE 1936743C3
- Authority
- DE
- Germany
- Prior art keywords
- hydroxy
- hydroxymethyl
- methyl
- disulfide
- bis
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
- C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Description
DIi Erfindung betrifft ein Verfahren zur Herstellung von Bis-(4-hydroxymethyI-5-hydroxy-6-methyIpyridyI-3-methyl)-disulfid-dichlorhydrat-dihydrat, das, auch als Pyrithioxin bekannt, eine weite Verwendung als Mittel zur Unterstützung des Gehirnmetabolismus findet. Es wird bei Zuständen der Erschöpfungsneurasthenie, Störungen der Gehirndurchblutung, Entzündung des Trigemius-Nervs, Migräne, Parkinsonismus usw. verwendet. The invention relates to a process for the preparation of bis (4-hydroxymethyI-5-hydroxy-6-methyIpyridyI-3-methyl) disulfide dichlorohydrate dihydrate, which, also known as pyrithioxin, is widely used as an agent for supporting brain metabolism finds. It is used in conditions of exhaustion neurasthenia, disorders of cerebral blood flow, inflammation of the trigeminal nerve, migraines, parkinsonism, etc.
Zahlreiche Verfahren zur Herstellung von Pyrithioxin sind bekannt (deutsche Auslegeschriften 11 35 460, 1197 455, 12 22 062, 12 27 908). Diese Verfahren, die zum Teil über S^-Dibrommethyl-S-hydroxy-ö-methylpyridin, zum Teil über entsprechende 4,5-Dihydroxymaskierte Derivate verlaufen, sind teils wegen der zudem schwer entfernbaren Schwefelverunreinigungen, teils wegen der Notwendigkeit der zusätzlichen Verfahrensstufen durch Maskierung und wieder Abspaltung der maskierenden Gruppen bei zudem ungenügender Reinheit wenig befriedigend.Numerous processes for the production of pyrithioxin are known (German Auslegeschriften 11 35 460, 1197 455, 12 22 062, 12 27 908). These procedures that partly via S ^ -dibromomethyl-S-hydroxy-ö-methylpyridine, partly via corresponding 4,5-dihydroxymasked Derivatives run, are partly because of the sulfur impurities that are difficult to remove, partly because of the need for additional procedural steps by masking and splitting off again of the masking groups with insufficient purity, not very satisfactory.
Weiter war es bereits bekannt, zur Herstellung von Pyrithioxin S-Brommethyl^-hydroxymethyl-S-hydroxy-6-methylpyridin mit Kaliumrhodamid umzusetzen und die erhaltene 3-Rhodanomethyl·Verbindung mit einem Gemisch von Wasser, Äthanol und Ammoniak zur Herstellung des Pyrithioxins zu Behandeln (Kuroda, Vitamins, 1964, Bd. 30, Nr. 6, Seite 431). Danach werden jedoeh Ausbeuten von nur etwa 40% eines zudem stark verunreinigten und nur schwierig zu reinigenden Produkts erhalten. Auch die verschiedenen anderen dort beschriebenen Verfahren sind offensichtlich wenig geeignet. Aus diesen ungünstigen Ergebnissen konnte eine Anregung für eine befriedigende Lösung nicht entnommen werden.Furthermore, it was already known for the production of pyrithioxin S-bromomethyl ^ -hydroxymethyl-S-hydroxy-6-methylpyridine to react with potassium rhodamide and the resulting 3-rhodanomethyl · compound with a Mixture of water, ethanol and ammonia for the production of pyrithioxin to treat (Kuroda, Vitamins, 1964, Vol. 30, No. 6, Page 431). After that, however Yields of only about 40% of a product that is also heavily contaminated and difficult to clean obtain. The various other methods described there are also obviously unsuitable. A suggestion for a satisfactory solution could not be drawn from these unfavorable results will.
Der Erfindung liegt die Aufgabe zugrunde, ein Verfahren zur Verfügung zu stellen, welches frei von den Nachteilen der bislang bekannten Verfahren ist und in wirtschaftlicher Weise die Herstellung von Pyrithioxin von hoher Qualität und hoher Ausbeute ermöglicht.The invention is based on the object of providing a method which is free of the Disadvantages of the processes known to date is the production of pyrithioxine in an economical manner of high quality and high yield.
Gegenstand der Erfindung ist nun ein Verfahren zur Herstellung von Bis-(4-hydroxymethyl-5-hydroxy-6-The invention now relates to a process for the preparation of bis- (4-hydroxymethyl-5-hydroxy-6-
methylpyridyl-a-methylj-disulfid-dichlorhydrat-dihydrat, wobei zunächst ein S-HalogenmethyM-hydroxymethyl-5-hydroxy-6-methylpyridin in Gegenwart einesmethylpyridyl-a-methylj-disulfide dichlorohydrate dihydrate, initially being an S-halomethyl-hydroxymethyl-5-hydroxy-6-methylpyridine in the presence of a
ίο Verdünnungsmittels bei erhöhter Temperatur mit Kaliumrhodanid umgesetzt, das erhaltene 3-Rhodanomethyl^-hydroxymethyl-S-hydroxy-ö-methylpyridin in ammoniakhaltigem Medium gehalten und das so gebildete Bis-(4-hydroxymethyI-5-hydroxy-6-methylpyridyI-ίο Using thinner at elevated temperature Potassium rhodanide reacted, the resulting 3-rhodanomethyl ^ -hydroxymethyl-S-hydroxy-ö-methylpyridine kept in ammonia-containing medium and the bis (4-hydroxymethyl-5-hydroxy-6-methylpyridyl-
3-methyI)-disulfid mit Salzsäure in das Dichlorat überführt wird, wobei man erfindungsgemäß als 3-Halogen-3-methyl) disulfide converted into the dichlorate with hydrochloric acid is, according to the invention as 3-halogen
methyl-4-hydroxymethyl-5-hydroxy-6-methylDyridin
das S-ChlormethyM-hydroxymethyl-S-hydri-xy-e-methylpyridin
in wäßriger oder alkoholischer Suspensionmethyl-4-hydroxymethyl-5-hydroxy-6-methyldyridine
S-ChlormethyM-hydroxymethyl-S-hydri-xy-e-methylpyridine in aqueous or alcoholic suspension
bei ca. 800C umsetzt und das erhaltene 3-RhodanomethyI-4-hydroxymethyl-5-hydroxy-6-methylpyridin in wäßriger oder alkoholischer Ammoniaklösung der Einwirkung von Schwefelwasserstoff nahe bei Zimmertemperatur aussetzt und das so gebildete: Bis-(4-hydroxy-at about 80 0 C and the 3-RhodanomethyI-4-hydroxymethyl-5-hydroxy-6-methylpyridine in aqueous or alcoholic ammonia solution exposed to the action of hydrogen sulfide near room temperature and the so formed: bis- (4-hydroxy-
methyl-5-hydroxy-6-methylpyridyl-3-methyl)-disulfid
mit alkoholischer Salzsäure bei einer Temperatur von 40—500C in das Dichlorhydrat-Dihydrat überführt und
dieses isoliertmethyl-5-hydroxy-6-methylpyridyl-3-methyl) disulfide
with alcoholic hydrochloric acid at a temperature of 40-50 0 C converted into the dichlorohydrate dihydrate and this isolated
Es war zwar bereits bekannt, S-ChlormethyM-hy-Although it was already known that S-ChlormethyM-hy-
droxymethyl-S-hydroxy-e-methylpyridin mit Natriumthiosulfat umzusetzen, unter Bildung des Na-Salzes der entsprechenden 3-Thiosulfatmethyl-Verbindung und diese Verbindung dann mit Natriumhydrogensulfid in die Pyrithioxinbase zu überführen (japanische Patent-droxymethyl-S-hydroxy-e-methylpyridine with sodium thiosulphate implement, with formation of the Na salt of the corresponding 3-thiosulfate methyl compound and to convert this compound into the pyrithioxine base with sodium hydrogen sulfide (Japanese patent
schrift 41-19 067, Beispiel 7). Wie jedoch Vergleichsversuche gezeigt haben, führt diese Verfahrensweise zu nach Ausweis des Chromatogramms noch drei weitere Substanzen enthaltenden unreinen Produkten mit Schmelzpunkten von 207—212°C in zudem nur etwa 80%iger Ausbeute, während erfindungsgemäß auch chromatographisch praktisch reines Pyrithioxin eines41-19 067, example 7). However, as comparative experiments have shown, this procedure leads to According to the chromatogram, there are also impure products containing three other substances Melting points of 207-212 ° C are only about 80% yield, while, according to the invention, pyrithioxin is also practically pure chromatographically
Schmelzpunkts zwischen 219—222"C in etwa 90%iger Ausbeute erhalten wird.Melting point between 219-222 "C in about 90% Yield is obtained.
Bei dem erfindungsgemäßen Verfahren wird dabei das S-Rhodanmethyl^-hydroxymethyl-S-hydroxy-emethylpyridin beim Erwärmen von 3-Chlormethyl-4-hydroxymethyl-5-hydroxy-6-methylpyridin mit Kaliumrhodanid in wäßriger Suspension am Rückflußkühler mit 96%iger Ausbeute, dargestellt. Die so erhaltene Rhodanverbindung wird dann durch ünwirkung von Schwefelwasserstoff in Bis-(4-hydroxymethyl-5-hydrox/-6-methylpyridyl-3-methyI)-disulfid überführt.In the process according to the invention, S-Rhodanmethyl ^ -hydroxymethyl-S-hydroxy-emethylpyridine is used on heating 3-chloromethyl-4-hydroxymethyl-5-hydroxy-6-methylpyridine with potassium rhodanide in aqueous suspension on the reflux condenser with a 96% yield. The thus obtained The rhodan compound is then converted into bis (4-hydroxymethyl-5-hydrox / -6-methylpyridyl-3-methyl) disulfide by the action of hydrogen sulfide convicted.
Dazu wird im einzelnen das 3-Rhodanmethyl-4-hydroxymethyI-5-hydroxy-6-methylpyridin in Ammoniak-3-Rhodanmethyl-4-hydroxymethyl-5-hydroxy-6-methylpyridine is used for this in detail in ammonia
> > lösung in Wasser oder Äthanol suspendiert und der Einwirkung von Schwefelwasserstoffgas bei Zimmertemperatur 1,5—2 Stunden lang ausgesetzt. Danach wird der Niederschlag filtriert und mit Wasser gewaschen, wodurch reines, von Schwefelverunreinigung freies Bis- ^-hydroxymethyl-S-hydroxy-e-methylpyridyl-S-methyl)-disulfid gewonnen wird. Schließlich wird es in Dichlorhydrat übergeführt, indem es in alkoholischer Salzsäurelösung bei einer Temperatur von 40—50"C gelöst und in bekannter Weise abgeschieden wird.>> solution suspended in water or ethanol and exposed to the action exposed to hydrogen sulfide gas at room temperature for 1.5-2 hours. After that, will the precipitate is filtered and washed with water, producing pure bis- ^ -hydroxymethyl-S-hydroxy-e-methylpyridyl-S-methyl) disulfide is won. Finally it is converted into dichlorohydrate by placing it in alcoholic hydrochloric acid solution is dissolved at a temperature of 40-50 "C and deposited in a known manner.
20 g S-Chlormethyl^-hydroxymethyl-S-hydroxy-ömethylpyridin und 13,6 g Kaliumrhodanid werden in20 g of S-chloromethyl ^ -hydroxymethyl-S-hydroxy-o-methylpyridine and 13.6 g of potassium rhodanide are in
HO rnl Wasser suspendiert und unter Rückfluß 2,5 Stunden erwärmt, wobei eine Temperatur von 80—82°C gehalten wird. Nach Abkühlung wird die gewonnene Krisiallabscheidung abfiltriert und mit ca. 70 ml Wasser durchgewaschen. Es wird 21,6g 3-Rhodanmethyl-4-hydroxymethyl-5-hydroxy-6-methylpyridin von 143 bis 144° C Schmelzpunkt gewonnen. Es werden 96,3% der theoretischen Ausbeute erlangt.HO suspended in water and refluxed for 2.5 hours heated, with a temperature of 80-82 ° C kept will. After cooling, the crystalline deposit obtained is used filtered off and washed through with about 70 ml of water. It becomes 21.6 g of 3-rhodanemethyl-4-hydroxymethyl-5-hydroxy-6-methylpyridine obtained from 143 to 144 ° C melting point. 96.3% of the theoretical yield are obtained.
Danach wird der Niederschlag in 220 ml Ammoniaklösung (10—12%) in Wasser oder Alkohol suspendiert und der Einwirkung von Schwefelwasserstoffgas in Zimmertemperatur ausgesetzt Es werden 16,7 g Bis- ^-hydroxymethyl-S-hydroxy-e-methylpyridyi-S-methyl)-dtsulftd mit einem Schmelzpunkt von 220—223° C gewonnen; 84,2% der theoretischen Ausbeute. Diese Verbindung wird in Dichlorhydrat übergeführt, indem sie in einer Lösung von 13,5 g Salzsäure in 80 g absolutem Äthanol bei einer Temperatur von 40—5O0C aufgelöst wird. Nach Abkühlung auf —7°C wird die Kxistallabscheidung abfiltriert und mit einer kleinen Menge Isopropanol durchgewaschen. Es werden 19,3 g liis-The precipitate is then suspended in 220 ml of ammonia solution (10-12%) in water or alcohol and exposed to hydrogen sulfide gas at room temperature. 16.7 g of bis- ^ -hydroxymethyl-S-hydroxy-e-methylpyridyi-S-methyl are then added ) -dtsulftd obtained with a melting point of 220-223 ° C; 84.2% of the theoretical yield. This compound is converted into dihydrochloride by dissolving it in a solution of 13.5 g of hydrochloric acid in 80 g of absolute ethanol at a temperature of 40-5O 0 C. After cooling to −7 ° C., the crystal deposit is filtered off and washed through with a small amount of isopropanol. There are 19.3 g liis-
in ^-hydroxymethyl-S-hydroxy-e-methyl-pyridyl-S-methyl)-disulfid-dichlorhydrat-dihydrat mit einem Schmelzpunkt von 135—136°C gewonnen.in ^ -hydroxymethyl-S-hydroxy-e-methyl-pyridyl-S-methyl) disulfide dichlorohydrate dihydrate obtained with a melting point of 135-136 ° C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL128504A PL63264B1 (en) | 1968-08-05 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1936743A1 DE1936743A1 (en) | 1970-02-12 |
| DE1936743B2 DE1936743B2 (en) | 1980-05-08 |
| DE1936743C3 true DE1936743C3 (en) | 1981-01-29 |
Family
ID=19950110
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1936743A Expired DE1936743C3 (en) | 1968-08-05 | 1969-07-18 | Process for the preparation of bis (4-hydroxymethyl-5-hydroxy-6-methyIpyridyl-3-methyl) disulfide dichlorohydrate dihydrate |
Country Status (9)
| Country | Link |
|---|---|
| BE (1) | BE736599A (en) |
| BG (1) | BG16033A3 (en) |
| CH (1) | CH498115A (en) |
| CS (1) | CS165971B2 (en) |
| DE (1) | DE1936743C3 (en) |
| HU (1) | HU177719B (en) |
| NL (1) | NL166017C (en) |
| SU (1) | SU437282A3 (en) |
| YU (1) | YU32728B (en) |
-
1969
- 1969-07-18 DE DE1936743A patent/DE1936743C3/en not_active Expired
- 1969-07-21 CH CH1113769A patent/CH498115A/en not_active IP Right Cessation
- 1969-07-25 BE BE736599D patent/BE736599A/xx unknown
- 1969-07-30 CS CS5314A patent/CS165971B2/cs unknown
- 1969-08-01 BG BG012796A patent/BG16033A3/en unknown
- 1969-08-01 YU YU2005/69A patent/YU32728B/en unknown
- 1969-08-04 NL NL6911840.A patent/NL166017C/en not_active IP Right Cessation
- 1969-08-04 SU SU1354389A patent/SU437282A3/en active
- 1969-08-05 HU HU69PO454A patent/HU177719B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BG16033A3 (en) | 1972-05-20 |
| CH498115A (en) | 1970-10-31 |
| YU32728B (en) | 1975-06-30 |
| BE736599A (en) | 1969-12-31 |
| NL166017C (en) | 1981-06-15 |
| CS165971B2 (en) | 1975-12-22 |
| DE1936743A1 (en) | 1970-02-12 |
| NL166017B (en) | 1981-01-15 |
| HU177719B (en) | 1981-12-28 |
| YU200569A (en) | 1974-12-31 |
| DE1936743B2 (en) | 1980-05-08 |
| SU437282A3 (en) | 1974-07-25 |
| NL6911840A (en) | 1970-02-09 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| SH | Request for examination between 03.10.1968 and 22.04.1971 | ||
| C3 | Grant after two publication steps (3rd publication) | ||
| 8339 | Ceased/non-payment of the annual fee |