WO1995002599A1 - Method of preparing n,n'-dibenzylbispidine - Google Patents

Method of preparing n,n'-dibenzylbispidine Download PDF

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Publication number
WO1995002599A1
WO1995002599A1 PCT/EP1994/002101 EP9402101W WO9502599A1 WO 1995002599 A1 WO1995002599 A1 WO 1995002599A1 EP 9402101 W EP9402101 W EP 9402101W WO 9502599 A1 WO9502599 A1 WO 9502599A1
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WIPO (PCT)
Prior art keywords
benzylpiperidone
dibenzyl
solvent
bispidone
dibenzylbispidine
Prior art date
Application number
PCT/EP1994/002101
Other languages
German (de)
French (fr)
Inventor
Wolfgang Viergutz
Marco Thyes
Original Assignee
Basf Aktiengesellschaft
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to AU70733/94A priority Critical patent/AU7073394A/en
Priority to KR1019960700211A priority patent/KR960703913A/en
Priority to JP7504314A priority patent/JPH09500119A/en
Priority to PL94312609A priority patent/PL312609A1/en
Priority to EP94919667A priority patent/EP0710238A1/en
Publication of WO1995002599A1 publication Critical patent/WO1995002599A1/en

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    • 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
    • C07D471/08—Bridged systems

Definitions

  • the present invention relates to a process for the preparation of N, N'-dibenzyl bispidine.
  • N, N'-dibenzylbispi ⁇ din can be prepared from N, N'-dibenzyl bispidone by reduction with hydrazine hydrate in triethylene glycol in the presence of potassium hydroxide.
  • N, N'-dibenzylbispidone was obtained by reacting N-benzylpiperidone-4 with benzylamine.
  • the intermediate product and the end product were purified by distillation in this process, the latter has only an insufficient purity, which is disadvantageous for the further conversion to the Ambasilide.
  • the invention relates to a process for the preparation of N, N'-dibenzylbispidine, characterized in that N-benzylpiperidone is reacted with foritialin and benzylamine in the presence of acetic acid in a solvent at 50-100 ° C., the benzylamine , the acetic acid, the solvent and part of the benzylpiperidone are introduced at 50-100 ° C., then the remaining benzylpiperidone and part of the formalin are added, after which the reaction mixture is heated to reflux after addition of the remaining formalin and the acetate of the N, N'-dibenzyl bispidone obtained in this way is extracted from by-products after the methanol has been distilled off, and then the N, N'-dibenzyl bispidone is released and isolated, and then the N, N'-dibenzyl bispidone with hydrazine at 80- 200 ° C in one
  • the benzylamine, the acetic acid and the solvent with some of the benzylpiperidone are introduced. 2-8 mol of acetic acid, preferably as a pure substance, are used per mol of benzylpiperidone.
  • suitable solvents are methanol, ethanol, tetrahydrofuran, toluene and chlorinated hydrocarbons such as methylene chloride and chloroform.
  • the benzylpiperidone is used in a total amount of 0.8 to 1.3 moles per mole of benzylamine in the reaction, the amount of benzylpiperidone initially charged being between 0 and 75%, is preferably 20-30%.
  • the reaction is carried out at 50-100 ° C., after all the reactants have been brought together, the mixture is refluxed for a while.
  • the solvent is stripped off in vacuo and the residue is taken up in water.
  • the aqueous solution has been purified by extraction with a solvent such as toluene, ethers or chlorinated hydrocarbons, preferably methylene chloride
  • the N, N'-dibenzyl bispidone is released from the salt and extracted with one of the solvents mentioned.
  • the solvent preferably to n-propanol
  • the N, N'-dibenzyl bispidone crystallizes out and is washed with a solvent such as n-propanol.
  • the product obtained in this way which is over 99% pure, is reduced to N, N-dibenzylbispidine with hydrazine.
  • the reaction is carried out in an ethylene glycol such as diethylene glycol or triethylene glycol. 2-3 moles of alkali metal hydroxide solution should be added per mole of bispidone.
  • the molar ratio of bispidone: hydrazine is 1: 1 to 1: 5.
  • the reaction temperature should be 50-100 ° C. at the start of the reaction and is then slowly increased to 170-200 ° C., a hydrazine-water mixture being distilled off. The reaction is complete after 20-24 hours.
  • the product thus obtained is treated with hydrochloric acid and then with sodium hydroxide solution and extracted with toluene, an ether such as methyl tert-butyl ether or a chlorinated hydrocarbon such as methylene chloride or chlorotoluene. After removing the solvent, a very pure N, '-dibenzyl bispidine is obtained.
  • the new production process for N, N'-dibenzylbispidine has the following advantages over the process known from DE-OS 24 28 792:
  • the reaction volume can be reduced by half compared to the process known from DE-A 24 28 792. Furthermore, by using a gentle extraction process, the temperature-sensitive crude product can be freed from by-products to such an extent that a pure N, N'-dibenzyl bispidone is obtained.
  • the method also makes it possible to exploit the scale-up, which is comparable to laboratory tests, and the two high-vacuum, high-temperature distillations, which are expensive in terms of process technology and energy, are saved. The crystals thus obtained are stable on storage.
  • the purity of the .N, N'-dibenzyl bispidone is a prerequisite for its further processing into a high-purity N, N'-dibenzyl bispini, which does not require the high-vacuum distillation that was previously necessary or other cleaning processes can be directly implemented without isolation.
  • the crude product was taken up in hot n-propanol and slowly cooled to 0 ° C.
  • the crystallized material was suctioned off, washed and dried.
  • the yield was 109 g of N, N'-dibenzyl bispidone. This corresponds to a yield of 55% based on the N-benzylpiperidone used.
  • the purity was 99.8%.
  • the reaction mixture was slowly heated to reflux (125 ° C). The temperature was raised to 190-200 ° C. and the hydrazine / water mixture was distilled off. The reaction was continued at this temperature until conversion was complete. After that was on

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Described is an improved method of preparing N,N'-dibenzylbispidine by reacting N-benzylpiperidone with benzylamine and subsequent reduction.

Description

Verfahren zur Herstellung von N,N'-DibenzylbispidinProcess for the preparation of N, N'-dibenzyl bispidine
Beschreibungdescription
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von N,N'-Dibenzylbispidin.The present invention relates to a process for the preparation of N, N'-dibenzyl bispidine.
N,N'-Dibenzylbispidin ist ein Zwischenprodukt für die Herstellung von Ambasilide (= N-(4-Aminobenzoyl)-N'-benzylbispidin,N, N'-Dibenzylbispidin is an intermediate for the production of Ambasilide (= N- (4-aminobenzoyl) -N'-benzylbispidin,
EP-A 62 119) . Gemäß DE-A 24 28 792 läßt sich N,N'-Dibenzylbispi¬ din aus N,N'-Dibenzylbispidon durch Reduktion mit Hydrazinhydrat in Triethylenglykol in Gegenwart von Kaliumhydroxid herstellen. N,N'-Dibenzylbispidon wurde durch Umsetzen von N-Benzylpiperi- don-4 mit Benzylamin erhalten. Obwohl bei diesem Verfahren das Zwischenprodukt und das Endprodukt destillativ gereinigt wurden, besitzt letzteres nur eine ungenügende Reinheit, die für die wei¬ tere Umsetzung zum Ambasilide nachteilig ist.EP-A 62 119). According to DE-A 24 28 792, N, N'-dibenzylbispi¬ din can be prepared from N, N'-dibenzyl bispidone by reduction with hydrazine hydrate in triethylene glycol in the presence of potassium hydroxide. N, N'-dibenzylbispidone was obtained by reacting N-benzylpiperidone-4 with benzylamine. Although the intermediate product and the end product were purified by distillation in this process, the latter has only an insufficient purity, which is disadvantageous for the further conversion to the Ambasilide.
Es wurde nun ein Verfahren gefunden, welches das N,N'-Dibenzyl- bispidin in hoher Reinheit liefert.A process has now been found which delivers the N, N'-dibenzylbispidine in high purity.
Gegenstand der Erfindung ist ein Verfahren zur Herstellung von N,N'-Dibenzylbispidin, dadurch gekennzeichnet, daß man N-Benzyl- piperidon mit Foritialin und Benzylamin in Gegenwart von Essigsäure in einem Lösungsmittel bei 50 - 100°C umsetzt, wobei das Benzyl¬ amin, die Essigsäure, das Lösungsmittel und ein Teil des Benzyl- piperidons bei 50 - 100°C vorgelegt werden, anschließend das rest¬ liche Benzylpiperidon und ein Teil des Formalins hinzugegeben werden, danach nach Zugabe des restlichen Formalins das Reakti¬ onsgemisch zum Rückfluß erhitzt wird und das so erhaltene Acetat des N,N'-Dibenzylbispidons nach Abdestillieren des Methanols ex¬ traktiv von Nebenprodukten gereinigt und anschließend das N,N'- Dibenzylbispidon freigesetzt und isoliert wird, und danach das N,N'-Dibenzylbispidon mit Hydrazin bei 80 - 200°C in einemThe invention relates to a process for the preparation of N, N'-dibenzylbispidine, characterized in that N-benzylpiperidone is reacted with foritialin and benzylamine in the presence of acetic acid in a solvent at 50-100 ° C., the benzylamine , the acetic acid, the solvent and part of the benzylpiperidone are introduced at 50-100 ° C., then the remaining benzylpiperidone and part of the formalin are added, after which the reaction mixture is heated to reflux after addition of the remaining formalin and the acetate of the N, N'-dibenzyl bispidone obtained in this way is extracted from by-products after the methanol has been distilled off, and then the N, N'-dibenzyl bispidone is released and isolated, and then the N, N'-dibenzyl bispidone with hydrazine at 80- 200 ° C in one
Lösungsmittel umsetzt und das N,N'-Dibenzylbispidin nach Behand¬ lung mit Säure und Lauge mit Toluol extrahiert.Reacts solvent and the N, N'-dibenzyl bispidine is extracted with toluene after treatment with acid and alkali.
Für den ersten Reaktionsschritt wird das Benzylamin, die Essig- säure und das Lösungsmittel mit einem Teil des Benzylpiperidons vorgelegt. Pro Mol Benzylpiperidon werden 2 - 8 Mol Essigsäure, vorzugsweise als Reinsubstanz, verwendet. Als Lösungsmittel eig¬ nen sich beispielsweise Methanol, Ethanol, Tetrahydrofuran, Toluol und chlorierte Kohlenwasserstoffe wie Methylenchlorid und Chloroform. Das Benzylpiperidon wird in einer Gesamtmenge von 0,8 bis 1,3 Mol pro Mol Benzylamin in die Reaktion eingesetzt, wobei die Menge des vorgelegten Benzylpiperidons zwischen 0 und 75 %, vorzugsweise 20 - 30 % beträgt. Die Reaktion wird bei 50 - 100°C durchgeführt, nach dem Zusammenführen aller Reaktionspartner wird noch eine Zeitlang unter Rückfluß gekocht.For the first reaction step, the benzylamine, the acetic acid and the solvent with some of the benzylpiperidone are introduced. 2-8 mol of acetic acid, preferably as a pure substance, are used per mol of benzylpiperidone. Examples of suitable solvents are methanol, ethanol, tetrahydrofuran, toluene and chlorinated hydrocarbons such as methylene chloride and chloroform. The benzylpiperidone is used in a total amount of 0.8 to 1.3 moles per mole of benzylamine in the reaction, the amount of benzylpiperidone initially charged being between 0 and 75%, is preferably 20-30%. The reaction is carried out at 50-100 ° C., after all the reactants have been brought together, the mixture is refluxed for a while.
Nach Ende der Umsetzung wird das Lösungsmittel im Vakuum abgezo¬ gen und der Rückstand in Wasser aufgenommen. Aus der wäßrigen Lösung wird nach deren Reinigung durch Extraktion mit einem Lösungsmittel, wie Toluol, Ethern oder chlorierten Kohlenwasser¬ stoffen, vorzugsweise Methylenchlorid das N,N'-Dibenzylbispidon aus dem Salz freigesetzt und mit einem der genannten Lösungs¬ mittel extrahiert. Nach Wechsel des Lösungsmittels, vorzugsweise auf n-Propanol kristallisiert das N,N'-Dibenzylbispidon aus und wird mit einem Lösungsmittel wie n-Propanol gewaschen.After the reaction has ended, the solvent is stripped off in vacuo and the residue is taken up in water. After the aqueous solution has been purified by extraction with a solvent such as toluene, ethers or chlorinated hydrocarbons, preferably methylene chloride, the N, N'-dibenzyl bispidone is released from the salt and extracted with one of the solvents mentioned. After changing the solvent, preferably to n-propanol, the N, N'-dibenzyl bispidone crystallizes out and is washed with a solvent such as n-propanol.
Das so erhaltene Produkt, welches zu über 99 % rein ist, wird mit Hydrazin zu N,N-Dibenzylbispidin reduziert. Die Reaktion wird in einem Ethylenglykol wie Diethylenglykol oder Triethylenglykol durchgeführt. Pro Mol Bispidon sollen 2 - 3 Mol Alkalilauge zuge¬ gen sein. Das Molverhältnis Bispidon:Hydrazin beträgt 1:1 bis 1:5. Die Reaktionstemperatur soll zu Beginn der Reaktion bei 50 - 100°C liegen und wird dann langsam auf 170 - 200°C gestei¬ gert, wobei ein Hydrazin-Wassergemisch abdestilliert wird. Nach 20 - 24 Stunden ist die Umsetzung beendet. Das so erhaltene Produkt wird noch mit Salzsäure und anschließend mit Natronlauge behandelt und mit Toluol, einem Ether wie Methyl-tert.butylether oder -einem chlorierten Kohlenwasserstoff wie Methylenchlorid oder Chlortoluol extrahiert. Nach Entfernen des Lösungsmittels erhält man ein sehr reines N, '-Dibenzylbispidin.The product obtained in this way, which is over 99% pure, is reduced to N, N-dibenzylbispidine with hydrazine. The reaction is carried out in an ethylene glycol such as diethylene glycol or triethylene glycol. 2-3 moles of alkali metal hydroxide solution should be added per mole of bispidone. The molar ratio of bispidone: hydrazine is 1: 1 to 1: 5. The reaction temperature should be 50-100 ° C. at the start of the reaction and is then slowly increased to 170-200 ° C., a hydrazine-water mixture being distilled off. The reaction is complete after 20-24 hours. The product thus obtained is treated with hydrochloric acid and then with sodium hydroxide solution and extracted with toluene, an ether such as methyl tert-butyl ether or a chlorinated hydrocarbon such as methylene chloride or chlorotoluene. After removing the solvent, a very pure N, '-dibenzyl bispidine is obtained.
Das neue Herstellverfahren für N,N'-Dibenzylbispidin besitzt ge¬ genüber dem aus der DE-OS 24 28 792 bekannten Verfahren folgende Vorteile:The new production process for N, N'-dibenzylbispidine has the following advantages over the process known from DE-OS 24 28 792:
Das Reaktionsvolumen kann im Vergleich zu dem aus der DE-A 24 28 792 bekannten Verfahren auf die Hälfte reduziert wer¬ den. Weiter kann durch Anwendung eines schonenden Extraktionsver¬ fahrens das temperaturempfindliche Rohprodukt so weit von Neben¬ produkten befreit werden, daß ein reines N,N'-Dibenzylbispidon erhalten wird. Das Verfahren ermöglicht auch beim scale-up Aus- beuten, die mit den Laborversuchen vergleichbar sind, und es wer¬ den die beiden verfahrenstechnisch und energetisch aufwendigen Hochvakuum-Hochtemperaturdestillationen eingespart. Das so erhaltene Kristallisat ist lagerstabil.The reaction volume can be reduced by half compared to the process known from DE-A 24 28 792. Furthermore, by using a gentle extraction process, the temperature-sensitive crude product can be freed from by-products to such an extent that a pure N, N'-dibenzyl bispidone is obtained. The method also makes it possible to exploit the scale-up, which is comparable to laboratory tests, and the two high-vacuum, high-temperature distillations, which are expensive in terms of process technology and energy, are saved. The crystals thus obtained are stable on storage.
Die Reinheit des. N,N'-Dibenzylbispidons ist Voraussetzung für dessen Weiterverarbeitung zu einem hochreinen N,N'-Dibenzylbispi¬ din, welches ohne die bisher notwendige Hochvakuumdestillation oder andere Reinigungsverfahren ohne Isolierung direkt weiter um¬ gesetzt werden kann.The purity of the .N, N'-dibenzyl bispidone is a prerequisite for its further processing into a high-purity N, N'-dibenzyl bispini, which does not require the high-vacuum distillation that was previously necessary or other cleaning processes can be directly implemented without isolation.
Beispiel 5Example 5
Erste Stufe: N,N'-DibenzylbispidonFirst stage: N, N'-dibenzyl bispidone
78,5 g (0,73 mol) Benzylamin, 30 g N-Benzylpiperidon und 120 ml (2,1 mol) 99 %ige Essigsäure wurden in Methanol gelöst und auf78.5 g (0.73 mol) of benzylamine, 30 g of N-benzylpiperidone and 120 ml (2.1 mol) of 99% acetic acid were dissolved in methanol and dissolved
10 etwa 70°C erwärmt. Dazu wurden getrennt 87 g N-Benzylpiperidon und 95 g Formalin (37 %ig) langsam zugegeben. Nach beendetem Zulauf vom Piperidon wurden weitere 30 g Formalin-Lösung in 15 min zuge¬ führt und die Temperatur für etwa 1 h auf Rückfluß erhöht. Nach vollständigem Umsatz des Ausgangsmaterials wurde der Kolbeninhalt 5 gekühlt und das Methanol im Vakuum abdestilliert. Der Ansatz wurde mit Wasser versetzt und die Phasen getrennt. Die produkt- haltige Wasserphase wurde mehrfach mit Methylenchlorid gereinigt, anschließend wurde N,N'-Dibenzylbispidon durch Natronlauge frei¬ gesetzt und mit Methylenchlorid extrahiert. Das Lösungsmittel 0 wurde mit Vakuumunterstützung abdestilliert. Das Rohprodukt wurde in heißem n-Propanol aufgenommen und langsam auf 0°C gekühlt. Das kristallisierte Material wurde abgesaugt, gewaschen und getrock¬ net. Die Ausbeute betrug 109 g N,N'-Dibenzylbispidon. Das ent¬ spricht einer Ausbeute von 55 % bezogen auf eingesetztes N-Ben- 5 zylpiperidon. Die Reinheit betrug 99,8 %.10 heated to about 70 ° C. For this purpose, 87 g of N-benzylpiperidone and 95 g of formalin (37%) were slowly added separately. After the feed of piperidone had ended, a further 30 g of formalin solution were fed in in 15 min and the temperature was raised to reflux for about 1 h. After complete conversion of the starting material, the contents of the flask 5 were cooled and the methanol was distilled off in vacuo. Water was added to the mixture and the phases were separated. The product-containing water phase was purified several times with methylene chloride, then N, N'-dibenzyl bispidone was released by sodium hydroxide solution and extracted with methylene chloride. The solvent 0 was distilled off with vacuum support. The crude product was taken up in hot n-propanol and slowly cooled to 0 ° C. The crystallized material was suctioned off, washed and dried. The yield was 109 g of N, N'-dibenzyl bispidone. This corresponds to a yield of 55% based on the N-benzylpiperidone used. The purity was 99.8%.
Zweite Stufe: N,N'-DibenzylbispidinSecond stage: N, N'-dibenzyl bispidine
Vorgelegt wurden 50 ml Triethylenglykol und 24 g (0,075 mol) 0 N,N'-Dibenzylbispidon. Eine Mischung aus 40 ml Triethylenglykol und 15 ml (0,18 mol) 50 %iger Kalilauge wurde hinzugegeben. Es wurde auf 85°C erhitzt. Danach wurden zum Gemisch 10 ml (0,21 mol) 100 %iges Hydrazinhydrat langsam so hinzudosiert, daß die Innen¬ temperatur nicht über 80 - 90°C stieg.50 ml of triethylene glycol and 24 g (0.075 mol) of 0N, N'-dibenzylbispidone were initially charged. A mixture of 40 ml triethylene glycol and 15 ml (0.18 mol) 50% potassium hydroxide was added. It was heated to 85 ° C. Then 10 ml (0.21 mol) of 100% hydrazine hydrate were slowly metered into the mixture in such a way that the internal temperature did not exceed 80-90 ° C.
3535
Die Reaktionsmischung wurde langsam auf Rückfluß (125°C) erhitzt. Die Temperatur wurde auf 190 - 200°C erhöht und das Hydrazin-Was- ser-Gemisch abdestilliert. Die Reaktion wurde bis zum vollständi¬ gen Umsatz bei dieser Temperatur fortgesetzt. Danach wurde aufThe reaction mixture was slowly heated to reflux (125 ° C). The temperature was raised to 190-200 ° C. and the hydrazine / water mixture was distilled off. The reaction was continued at this temperature until conversion was complete. After that was on
40 70°C gekühlt und mit 90 ml Wasser verdünnt. Jeweils unter Kühlung wurden zunächst 30 ml konzentrierte Salzsäure und nach 2 h Rühr¬ zeit so viel Natronlauge zugegeben bis die Lösung deutlich alka¬ lisch reagierte. Nach weiteren 2 h wurde das Produkt mit Toluol extrahiert. Die Lösung enthielt 22,1 g N,N'-Dibenzylbispidin,40 70 ° C cooled and diluted with 90 ml of water. In each case with cooling, initially 30 ml of concentrated hydrochloric acid and, after a stirring time of 2 h, as much sodium hydroxide solution were added until the solution reacted clearly alkaline. After a further 2 h the product was extracted with toluene. The solution contained 22.1 g of N, N'-dibenzyl bispidine,
45 entsprechend einer Ausbeute von 96,2 %. Die Reinheit betrug nach Entfernen des Toluols 99,9 %. 45 corresponds to a yield of 96.2%. The purity was 99.9% after removal of the toluene.

Claims

PatentanspruchClaim
Verfahren zur Herstellung von N,N'-Dibenzylbispidin, dadurch ge- kennzeichnet, daß man N-Benzylpiperidon mit Formalin und Benzyl¬ amin in Gegenwart von Essigsäure in einem Lösungsmittel bei 60 - 100°C umsetzt, wobei das Benzylamin, die Essigsäure, das Lösungsmittel und ein Teil des Benzylpiperidons bei 50 - 100°C vorgelegt werden, anschließend das restliche Benzylpiperidon und ein Teil des Formalins hinzugegeben werden, danach nach Zugabe des restlichen Formalins das Reaktionsgemisch zum Rückfluß er¬ hitzt wird und das so erhaltene Acetat des N,N'-Dibenzylbispidons nach Abdestillieren des Methanols extraktiv von Nebenprodukten gereinigt und anschließend das N,N'-Dibenzylbispidon freigesetzt und isoliert wird, und danach das N,N'-Dibenzylbispidon mit Hy¬ drazin bei 80 - 200°C in einem Lösungsmittel umsetzt und das N,N'- Dibenzylbispidin nach Behandlung mit Säure und Lauge mit Toluol extrahiert. Process for the preparation of N, N'-dibenzylbispidine, characterized in that N-benzylpiperidone is reacted with formalin and benzylamine in the presence of acetic acid in a solvent at 60-100 ° C., the benzylamine, the acetic acid, which Solvent and part of the benzylpiperidone are initially introduced at 50-100 ° C., then the remaining benzylpiperidone and part of the formalin are added, after the remaining formalin has been added the reaction mixture is heated to reflux and the acetate of N, N thus obtained '-Dibenzylbispidons after the methanol has been distilled off, extracts from by-products and then the N, N'-dibenzylbispidon is released and isolated, and then the N, N'-dibenzylbispidon is reacted with hydrazine at 80-200 ° C. in a solvent and that N, N'-Dibenzylbispidin extracted with toluene after treatment with acid and alkali.
PCT/EP1994/002101 1993-07-17 1994-06-28 Method of preparing n,n'-dibenzylbispidine WO1995002599A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU70733/94A AU7073394A (en) 1993-07-17 1994-06-28 Method of preparing n,n'-dibenzylbispidine
KR1019960700211A KR960703913A (en) 1993-07-17 1994-06-28 Method of Preparing N, N'-Dibenzybispidine
JP7504314A JPH09500119A (en) 1993-07-17 1994-06-28 Process for producing N, N'-dibenzylbispidine
PL94312609A PL312609A1 (en) 1993-07-17 1994-06-28 Method of manufacturing n,n'-dibenzylbispydine
EP94919667A EP0710238A1 (en) 1993-07-17 1994-06-28 Method of preparing n,n'-dibenzylbispidine

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DE4324086A DE4324086A1 (en) 1993-07-17 1993-07-17 Process for the preparation of N, N`-dibenzylbispidine
DEP4324086.0 1993-07-17

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JP (1) JPH09500119A (en)
KR (1) KR960703913A (en)
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CA (1) CA2167406A1 (en)
CZ (1) CZ5296A3 (en)
DE (1) DE4324086A1 (en)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115626925A (en) * 2022-12-08 2023-01-20 山东汇海医药化工有限公司 Synthesis method of bispidine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2428792A1 (en) * 1974-06-14 1976-01-02 Knoll Ag NEW ANTIARRHYTHMICS

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2428792A1 (en) * 1974-06-14 1976-01-02 Knoll Ag NEW ANTIARRHYTHMICS

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115626925A (en) * 2022-12-08 2023-01-20 山东汇海医药化工有限公司 Synthesis method of bispidine

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HU9503859D0 (en) 1996-02-28
MX9405030A (en) 1995-01-31
JPH09500119A (en) 1997-01-07
EP0710238A1 (en) 1996-05-08
KR960703913A (en) 1996-08-31
CA2167406A1 (en) 1995-01-26
CZ5296A3 (en) 1996-04-17
DE4324086A1 (en) 1995-01-19
AU7073394A (en) 1995-02-13

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