WO1995002599A1 - Procede de preparation de la n,n'-dibenzylbispidine - Google Patents

Procede de preparation de la 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
Authority
WO
WIPO (PCT)
Prior art keywords
benzylpiperidone
dibenzyl
solvent
bispidone
dibenzylbispidine
Prior art date
Application number
PCT/EP1994/002101
Other languages
German (de)
English (en)
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 EP94919667A priority Critical patent/EP0710238A1/fr
Priority to JP7504314A priority patent/JPH09500119A/ja
Priority to KR1019960700211A priority patent/KR960703913A/ko
Priority to AU70733/94A priority patent/AU7073394A/en
Priority to PL94312609A priority patent/PL312609A1/xx
Publication of WO1995002599A1 publication Critical patent/WO1995002599A1/fr

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Classifications

    • 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

On décrit un procédé amélioré pour la préparation de la N,N'-dibenzylbispidine par réaction de la N-benzylpipéridone avec la benzylamine et réduction consécutive.
PCT/EP1994/002101 1993-07-17 1994-06-28 Procede de preparation de la n,n'-dibenzylbispidine WO1995002599A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP94919667A EP0710238A1 (fr) 1993-07-17 1994-06-28 Procede de preparation de la n,n'-dibenzylbispidine
JP7504314A JPH09500119A (ja) 1993-07-17 1994-06-28 Ｎ，ｎ’−ジベンジルビスピジンの製法
KR1019960700211A KR960703913A (ko) 1993-07-17 1994-06-28 N,N'-디벤질비스피딘의 제조 방법(Method of Preparing N,N'-Dibenzybispidine)
AU70733/94A AU7073394A (en) 1993-07-17 1994-06-28 Method of preparing n,n'-dibenzylbispidine
PL94312609A PL312609A1 (en) 1993-07-17 1994-06-28 Method of manufacturing n,n'-dibenzylbispydine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4324086A DE4324086A1 (de) 1993-07-17 1993-07-17 Verfahren zur Herstellung von N,N`-Dibenzylbispidin
DEP4324086.0 1993-07-17

Publications (1)

Publication Number Publication Date
WO1995002599A1 true WO1995002599A1 (fr) 1995-01-26

Family

ID=6493125

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1994/002101 WO1995002599A1 (fr) 1993-07-17 1994-06-28 Procede de preparation de la n,n'-dibenzylbispidine

Country Status (11)

Country Link
EP (1) EP0710238A1 (fr)
JP (1) JPH09500119A (fr)
KR (1) KR960703913A (fr)
AU (1) AU7073394A (fr)
CA (1) CA2167406A1 (fr)
CZ (1) CZ5296A3 (fr)
DE (1) DE4324086A1 (fr)
HU (1) HU9503859D0 (fr)
MX (1) MX9405030A (fr)
PL (1) PL312609A1 (fr)
WO (1) WO1995002599A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115626925A (zh) * 2022-12-08 2023-01-20 山东汇海医药化工有限公司 一种双哌啶的合成方法

Citations (1)

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

Patent Citations (1)

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

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115626925A (zh) * 2022-12-08 2023-01-20 山东汇海医药化工有限公司 一种双哌啶的合成方法

Also Published As

Publication number Publication date
AU7073394A (en) 1995-02-13
HU9503859D0 (en) 1996-02-28
CA2167406A1 (fr) 1995-01-26
KR960703913A (ko) 1996-08-31
MX9405030A (es) 1995-01-31
JPH09500119A (ja) 1997-01-07
CZ5296A3 (en) 1996-04-17
PL312609A1 (en) 1996-04-29
DE4324086A1 (de) 1995-01-19
EP0710238A1 (fr) 1996-05-08

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