DE4324086A1 - Process for the preparation of N, N`-dibenzylbispidine - Google Patents

Description

The present invention relates to a method for manufacturing of N, N′-dibenzyl bispidine.

N, N'-Dibenzylbispidin is an intermediate for the production of Ambasilide (= N- (4-aminobenzoyl) -N'-benzylbispidine, EP-A 62 119). According to DE-A 24 28 792, N, N'-dibenzylbispi din 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-benzylpiperi don-4 obtained with benzylamine. Although with this procedure Intermediate and the end product were purified by distillation, the latter has an insufficient purity, which for the white tere implementation to Ambasilide is disadvantageous.

A method has now been found which is the N, N′-dibenzyl bispidine provides high purity.

The invention relates to a method for producing N, N'-Dibenzylbispidin, characterized in that one N-benzyl piperidone with formalin and benzylamine in the presence of acetic acid reacted in a solvent at 50-100 ° C, the benzyl amine, acetic acid, the solvent and part of the benzyl piperidons are submitted at 50-100 ° C, then the rest Liche benzylpiperidone and part of the formalin added then, after adding the remaining formalin, the reacti is heated to reflux and the acetate thus obtained of the N, N'-dibenzyl bispidone after distilling off the methanol ex tractively cleaned of by-products and then the N, N'- Dibenzylbispidon is released and isolated, and then that N, N'-Dibenzylbispidon with hydrazine at 80-200 ° C in one Reacts solvent and the N, N'-dibenzyl bispidine after treatment tion extracted with acid and alkali with toluene.

For the first reaction step, the benzylamine, the vinegar acid and the solvent with part of the benzylpiperidone submitted. Per mole of benzylpiperidone, 2-8 moles of acetic acid, preferably used as a pure substance. As a solvent For example, methanol, ethanol, tetrahydrofuran, Toluene and chlorinated hydrocarbons such as methylene chloride and Chloroform. The benzylpiperidone is in a total amount of 0.8 up to 1.3 moles per mole of benzylamine used in the reaction, wherein the amount of benzylpiperidone presented between 0 and 75%,  is preferably 20-30%. The reaction is carried out at 50-100 ° C is carried out after all reaction partners have been brought together cooked under reflux for a while.

After the reaction has ended, the solvent is stripped off in vacuo gene and the residue taken up in water. From the watery After cleaning, the solution is extracted by extraction with a Solvents such as toluene, ethers or chlorinated hydrocarbons substances, preferably methylene chloride, the N, N'-dibenzyl bispidone released from the salt and with one of the solutions mentioned medium extracted. After changing the solvent, preferably the n, N′-dibenzyl bispidone crystallizes out on n-propanol and is washed with a solvent such as n-propanol.

The product thus obtained, which is over 99% pure, is with Hydrazine reduced to N, N-dibenzyl bispidine. The reaction is in an ethylene glycol such as diethylene glycol or triethylene glycol carried out. Per mole of bispidone, 2-3 moles of alkali solution should be added be. The molar ratio bispidone: hydrazine is 1: 1 to 1: 5. The reaction temperature should be at the beginning of the reaction 50-100 ° C and is then slowly increased to 170-200 ° C device, a hydrazine / water mixture being distilled off. To The implementation is completed in 20-24 hours. The so obtained Product is still with hydrochloric acid and then with sodium hydroxide solution treated and with toluene, an ether such as methyl tert-butyl ether or a chlorinated hydrocarbon such as methylene chloride or Chlorotoluene extracted. After removing the solvent a very pure N, N′-dibenzyl bispidine.

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 to half that of 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 the extent that a pure N, N'-dibenzyl bispidone is obtained. The process also enables yields that are comparable to laboratory tests to be used for scale-up, and it saves the two high-vacuum high-temperature distillations, which are expensive in terms of process engineering and energy. The crystals thus obtained are stable on storage.

The purity of the N, N′-dibenzyl bispidone is a prerequisite for its further processing to a high-purity N, N'-dibenzylbispi din, which without the previously necessary high vacuum distillation  or other cleaning processes without insulation can be set.

example First stage: N, N′-dibenzyl bispidone

78.5 g (0.73 mol) of benzylamine, 30 g of N-benzylpiperidone and 120 ml (2.1 mol) 99% acetic acid was dissolved in methanol and dissolved heated to about 70 ° C. For this purpose, 87 g of N-benzylpiperidone and 95 g of formalin (37%) slowly added. After the feed has ended A further 30 g of formalin solution were added from the piperidone in 15 minutes leads and the temperature is raised to reflux for about 1 h. To complete conversion of the starting material became the contents of the flask cooled and the methanol distilled off in vacuo. The approach water was added and the phases were separated. The product containing water phase was cleaned several times with methylene chloride, then N, N'-dibenzylbispidon was released by sodium hydroxide solution set and extracted with methylene chloride. The solvent was distilled off with vacuum support. The raw product was taken up in hot n-propanol and slowly cooled to 0 ° C. The crystallized material was suctioned off, washed and dried net. The yield was 109 g of N, N′-dibenzyl bispidone. That ent speaks a yield of 55% based on the N-Ben used zylpiperidone. The purity was 99.8%.

Second stage: N, N′-dibenzyl bispidine

50 ml of triethylene glycol and 24 g (0.075 mol) were introduced N, N′-dibenzyl bispidone. A mixture of 40 ml triethylene glycol and 15 ml (0.18 mol) of 50% potassium hydroxide solution was added. It was heated to 85 ° C. 10 ml (0.21 mol) were then added to the mixture. 100% hydrazine hydrate slowly added so that the inside temperature did not rise above 80-90 ° C.

The reaction mixture was slowly heated to reflux (125 ° C). The temperature was raised to 190-200 ° C and the hydrazine was distilled water mixture. The reaction was complete continued sales at this temperature. After that was on Chilled 70 ° C and diluted with 90 ml of water. Each with cooling were first 30 ml of concentrated hydrochloric acid and after 2 h of stirring Add as much sodium hydroxide solution until the solution becomes clearly alkaline reacted cally. After a further 2 h the product was treated with toluene extracted. The solution contained 22.1 g of N, N′-dibenzyl bispidine, corresponding to a yield of 96.2%. The purity was after Remove the toluene 99.9%.

Claims (1)

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, acetic acid, solvent and a part of the benzylpiperidone are placed at 50-100 ° C, then the remaining benzylpiperidone and part of the formalin are added, then after the addition of the remaining formalin the reaction mixture is heated to reflux and the resulting acetate of N, N'- After distilling off the methanol, dibenzylbispidons are extracted 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 the N, N '- Dibenzylbispidin extracted with toluene after treatment with acid and alkali.