CA2167406A1 - A process for the preparation of n,n'-dibenzylbispidine - Google Patents
A process for the preparation of n,n'-dibenzylbispidineInfo
- Publication number
- CA2167406A1 CA2167406A1 CA002167406A CA2167406A CA2167406A1 CA 2167406 A1 CA2167406 A1 CA 2167406A1 CA 002167406 A CA002167406 A CA 002167406A CA 2167406 A CA2167406 A CA 2167406A CA 2167406 A1 CA2167406 A1 CA 2167406A1
- Authority
- CA
- Canada
- Prior art keywords
- dibenzylbispidine
- solvent
- benzylpiperidone
- dibenzylbispidone
- reaction
- 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.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 12
- 230000008569 process Effects 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 7
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims abstract description 18
- MLEGMEBCXGDFQT-UHFFFAOYSA-N 1-benzylpiperidin-2-one Chemical compound O=C1CCCCN1CC1=CC=CC=C1 MLEGMEBCXGDFQT-UHFFFAOYSA-N 0.000 claims abstract description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 14
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000004821 distillation Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 4
- 239000006227 byproduct Substances 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 238000007792 addition Methods 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229960004279 formaldehyde Drugs 0.000 claims 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- DLNAKYFPFYUBDR-HDICACEKSA-N (4-aminophenyl)-[(1s,5r)-7-benzyl-3,7-diazabicyclo[3.3.1]nonan-3-yl]methanone Chemical compound C1=CC(N)=CC=C1C(=O)N1C[C@@H](CN(CC=2C=CC=CC=2)C2)C[C@@H]2C1 DLNAKYFPFYUBDR-HDICACEKSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229950005516 ambasilide Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 229940093932 potassium hydroxide Drugs 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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
Abstract
Described is an improved method of preparing N,N'-dibenzylbispidine by reacting N-benzylpiperidone with benzylamine and subsequent reduction.
Description
' 0050/44176 216740~
A process for the preparation of N,N'-dibenzylbispidine The present invention relates to a process for the preparation of 5 N,N'-dibenzylbispidine.
N,N'-Dibenzylbispidine is an intermediate for the preparation of ambasilide (= N-(4-aminobenzoyl)-N'-benzylbispidine, EP-A 62 119). According to DE-A 24 28 792, N,N'-dibenzylbispidine 10 can be prepared from N,N'-dibenzylbispidone by reduction with hy-drazine hydrate in triethylene glycol in the presence of potas-sium hydroxide. N,N'-Dibenzylbispidone was obtained by reacting N-benzyl-4-piperidone with benzylamine. Although in this process the intermediate and the final product were purified by distilla-15 tion, the latter has only inadequate purity, which is a disadvan-tage for further reaction to give ambasilide.
A process which provides N,N'-dibenzylbispidine in high purity has now been found.
The invention relates to a process for the preparation of N,N'-dibenzylbispidine, which comprises reacting N-benzylpiperidone with formalin and benzylamine in the presence of acetic acid in a solvent at 50 - 100 C, with the benzylamine, the acetic acid, the 25 solvent and part of the benzylpiperidone being initially introduced at 50 - 100 C, subsequently the remaining benzylpiperi-done and part of the formalin being added, and then, after addi-tion of the r~;n;ng formalin, the reaction mixture being heated to reflux, and the acetate of N,N'-dibenzylbispidone obtained in 30 this way being, after removal of the methanol by distillation, purified from byproducts by extraction and subsequently the N,N'-dibenzylbispidone being liberated and isolated, and then reacting the N,N'-dibenzylbispidone with hydrazine at 80 - 200 C in a solvent, and extracting the N,N'-dibenzylbispidine, after treat-35 ment with acid and alkali, with toluene.
For the first reaction step, the benzylamine, the acetic acid andthe solvent are introduced first with part of the benzylpiperi-done. 2 - 8 mol of acetic acid, preferably as pure substance, are 40 used per mol of benzylpiperidone. Examples of suitable solvents are methanol, ethanol, tetrahydrofuran, toluene and chlorinated hydrocarbons such as methylene chloride and chloroform. The ben-zylpiperidone is used in the reaction in a total amount of from 0.8 to 1.3 mol per mole of benzylamine, with the amount of ben-45 zylpiperidone introduced first being between 0 and 75%, prefer-ably 20 - 30%. The reaction is carried out at 50 - 100 C and, 0050/44176 ~ I B~ g ~ 6 after all the reactants have been combined, the mixture is boiled under reflux for some time.
After the reaction is complete, the solvent is stripped off in 5 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'-dibenzylbispidone is liberated from the salt therefrom and extracted with one of said solvents. After the sol-10 vent has been changed, preferably to n-propanol, the N,N'-diben-zylbispidone crystallizes out and is washed with a solvent such as n-propanol.
The product obtained in this way, which is more than 99% pure, is 15 reduced to N,N-dibenzylbispidine [sic] with hydrazine. The reac-tion is carried out in an ethylene glycol such as diethylene gly-col or triethylene glycol. 2 - 3 mol of alkali metal hydroxide solution should be present per mole of bispidone. The bispi-done:hydrazine molar ratio is from 1:1 to 1:5. The reaction tem-20 perature should be at the start of the reaction 50 - 100 C and ïs then slowly increased to 170 - 200 C, with a hydrazine/water mix-ture dist;ll;ng out. The reaction is complete after 20 -24 hours. The product obtained in this way is then treated with hydrochloric acid and subsequently with sodium hydroxide solu-25 tion, and is extracted with toluene, an ether such as methyltert-butyl ether or a chlorinated hydrocarbon such as methylene chloride or chlorotoluene. Removal of the solvent results in very pure N,N'-dibenzylbispidine.
30 The novel process for the preparation of N,N'-dibenzylbispidine has the following advantages by comparison with the process dis-closed in DE-A 24 28 792:
The reaction volume can be reduced by one half compared with the 35 process disclosed in DE-A 24 28 792. Furthermore, by use of a mild extraction process, the temperature-sensitive crude product can be freed of byproducts to such an extent that a pure N,N'-di-benzylbispidone is obtained. Even on scale-up, the process makes it possible for yields to be comparable with those in laboratory 40 tests, and the two high vacuum/high temperature distillations which are costly in industrial and energy terms are saved. The crystals obtained in this way are stable on storage.
The purity of the N,N'-dibenzylbispidone is a precondition for 45 its further processing to a high-purity N,N'-dibenzylbispidine which can immediately be reacted further without isolation and 0050/44176 21674~6 without the high vacuum distillation or other purification pro-cesses hitherto necessary.
Example First stage: N,N'-Dibenzylbispidone 78.5 g (0.73 mol) of benzylamine, 30 g of N-benzylpiperidone and 120 ml (2.1 mol) of 99% pure acetic acid were dissolved in metha-10 nol and heated to about 70 C. To this were added, separately andslowly, 87 g of N-benzylpiperidone and 95 g of formalin (37%
strength). After the introduction of piperidone was complete, a further 30 g of formalin solution were added over the course of 15 min, and the temperature was increased to reflux for about 15 1 h. After complete conversion of the starting material, the con-tents of the flask were cooled and the methanol was removed by distillation in vacuo. Water was added to the mixture, and the phases were separated. The product-containing aqueous phase was purified several times with methylene chloride, and subsequently 20 N,N'-dibenzylbispidone was liberated with sodium hydroxide solu-tion and extracted with methylene chloride. The solvent was re-moved by distillation with vacuum assistance. The crude product was taken up in hot n-propanol and slowly cooled to 0 C. The crys-tallized material was filtered off with suction, washed and 25 dried. The yield was 109 g of N,N~-dibenzylbispidone. This corre-sponds to a yield of 55% based on N-benzylpiperidone used. The purity was 99.8%.
Second stage: N,N'-Dibenzylbispidine 50 ml of triethylene glycol and 24 g (0.075 mol) of N,N'-diben-zylbispidone were initially introduced. A mixture of 40 ml of triethylene glycol and 15 ml (0.18 mol) of 50% strength potassium hydroxide solution was added. The mixture was heated to 85 C.
35 Then, 10 ml (0.21 mol) of 100% pure hydrazine hydrate were slowly metered into the mixture in such a way that the internal tempera-ture did not rise above 80 - 90 C.
The reaction mixture was slowly heated to reflux ~125 C). The tem-40 perature was increased to 190 - 200 C, and the hydrazine/water mixture was removed by distillation. The reaction was continued at this temperature until conversion was complete. It was then cooled to 70 C and diluted with 90 ml of water. In each case while cooling, initially 30 ml of concentrated hydrochloric acid were 45 added and, after stirring for 2 h, sufficient sodium hydroxide solution was added for the solution to have a distinct alkaline reaction. After a further 2 h, the product was extracted with 4 ~1~7~0~
toluene. The solution contained 22.1 g of N,N'-dibenzylbispidine, corresponding to a yield of 96.2%. The purity after removal of the toluene was 99.9%.
A process for the preparation of N,N'-dibenzylbispidine The present invention relates to a process for the preparation of 5 N,N'-dibenzylbispidine.
N,N'-Dibenzylbispidine is an intermediate for the preparation of ambasilide (= N-(4-aminobenzoyl)-N'-benzylbispidine, EP-A 62 119). According to DE-A 24 28 792, N,N'-dibenzylbispidine 10 can be prepared from N,N'-dibenzylbispidone by reduction with hy-drazine hydrate in triethylene glycol in the presence of potas-sium hydroxide. N,N'-Dibenzylbispidone was obtained by reacting N-benzyl-4-piperidone with benzylamine. Although in this process the intermediate and the final product were purified by distilla-15 tion, the latter has only inadequate purity, which is a disadvan-tage for further reaction to give ambasilide.
A process which provides N,N'-dibenzylbispidine in high purity has now been found.
The invention relates to a process for the preparation of N,N'-dibenzylbispidine, which comprises reacting N-benzylpiperidone with formalin and benzylamine in the presence of acetic acid in a solvent at 50 - 100 C, with the benzylamine, the acetic acid, the 25 solvent and part of the benzylpiperidone being initially introduced at 50 - 100 C, subsequently the remaining benzylpiperi-done and part of the formalin being added, and then, after addi-tion of the r~;n;ng formalin, the reaction mixture being heated to reflux, and the acetate of N,N'-dibenzylbispidone obtained in 30 this way being, after removal of the methanol by distillation, purified from byproducts by extraction and subsequently the N,N'-dibenzylbispidone being liberated and isolated, and then reacting the N,N'-dibenzylbispidone with hydrazine at 80 - 200 C in a solvent, and extracting the N,N'-dibenzylbispidine, after treat-35 ment with acid and alkali, with toluene.
For the first reaction step, the benzylamine, the acetic acid andthe solvent are introduced first with part of the benzylpiperi-done. 2 - 8 mol of acetic acid, preferably as pure substance, are 40 used per mol of benzylpiperidone. Examples of suitable solvents are methanol, ethanol, tetrahydrofuran, toluene and chlorinated hydrocarbons such as methylene chloride and chloroform. The ben-zylpiperidone is used in the reaction in a total amount of from 0.8 to 1.3 mol per mole of benzylamine, with the amount of ben-45 zylpiperidone introduced first being between 0 and 75%, prefer-ably 20 - 30%. The reaction is carried out at 50 - 100 C and, 0050/44176 ~ I B~ g ~ 6 after all the reactants have been combined, the mixture is boiled under reflux for some time.
After the reaction is complete, the solvent is stripped off in 5 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'-dibenzylbispidone is liberated from the salt therefrom and extracted with one of said solvents. After the sol-10 vent has been changed, preferably to n-propanol, the N,N'-diben-zylbispidone crystallizes out and is washed with a solvent such as n-propanol.
The product obtained in this way, which is more than 99% pure, is 15 reduced to N,N-dibenzylbispidine [sic] with hydrazine. The reac-tion is carried out in an ethylene glycol such as diethylene gly-col or triethylene glycol. 2 - 3 mol of alkali metal hydroxide solution should be present per mole of bispidone. The bispi-done:hydrazine molar ratio is from 1:1 to 1:5. The reaction tem-20 perature should be at the start of the reaction 50 - 100 C and ïs then slowly increased to 170 - 200 C, with a hydrazine/water mix-ture dist;ll;ng out. The reaction is complete after 20 -24 hours. The product obtained in this way is then treated with hydrochloric acid and subsequently with sodium hydroxide solu-25 tion, and is extracted with toluene, an ether such as methyltert-butyl ether or a chlorinated hydrocarbon such as methylene chloride or chlorotoluene. Removal of the solvent results in very pure N,N'-dibenzylbispidine.
30 The novel process for the preparation of N,N'-dibenzylbispidine has the following advantages by comparison with the process dis-closed in DE-A 24 28 792:
The reaction volume can be reduced by one half compared with the 35 process disclosed in DE-A 24 28 792. Furthermore, by use of a mild extraction process, the temperature-sensitive crude product can be freed of byproducts to such an extent that a pure N,N'-di-benzylbispidone is obtained. Even on scale-up, the process makes it possible for yields to be comparable with those in laboratory 40 tests, and the two high vacuum/high temperature distillations which are costly in industrial and energy terms are saved. The crystals obtained in this way are stable on storage.
The purity of the N,N'-dibenzylbispidone is a precondition for 45 its further processing to a high-purity N,N'-dibenzylbispidine which can immediately be reacted further without isolation and 0050/44176 21674~6 without the high vacuum distillation or other purification pro-cesses hitherto necessary.
Example First stage: N,N'-Dibenzylbispidone 78.5 g (0.73 mol) of benzylamine, 30 g of N-benzylpiperidone and 120 ml (2.1 mol) of 99% pure acetic acid were dissolved in metha-10 nol and heated to about 70 C. To this were added, separately andslowly, 87 g of N-benzylpiperidone and 95 g of formalin (37%
strength). After the introduction of piperidone was complete, a further 30 g of formalin solution were added over the course of 15 min, and the temperature was increased to reflux for about 15 1 h. After complete conversion of the starting material, the con-tents of the flask were cooled and the methanol was removed by distillation in vacuo. Water was added to the mixture, and the phases were separated. The product-containing aqueous phase was purified several times with methylene chloride, and subsequently 20 N,N'-dibenzylbispidone was liberated with sodium hydroxide solu-tion and extracted with methylene chloride. The solvent was re-moved by distillation with vacuum assistance. The crude product was taken up in hot n-propanol and slowly cooled to 0 C. The crys-tallized material was filtered off with suction, washed and 25 dried. The yield was 109 g of N,N~-dibenzylbispidone. This corre-sponds to a yield of 55% based on N-benzylpiperidone used. The purity was 99.8%.
Second stage: N,N'-Dibenzylbispidine 50 ml of triethylene glycol and 24 g (0.075 mol) of N,N'-diben-zylbispidone were initially introduced. A mixture of 40 ml of triethylene glycol and 15 ml (0.18 mol) of 50% strength potassium hydroxide solution was added. The mixture was heated to 85 C.
35 Then, 10 ml (0.21 mol) of 100% pure hydrazine hydrate were slowly metered into the mixture in such a way that the internal tempera-ture did not rise above 80 - 90 C.
The reaction mixture was slowly heated to reflux ~125 C). The tem-40 perature was increased to 190 - 200 C, and the hydrazine/water mixture was removed by distillation. The reaction was continued at this temperature until conversion was complete. It was then cooled to 70 C and diluted with 90 ml of water. In each case while cooling, initially 30 ml of concentrated hydrochloric acid were 45 added and, after stirring for 2 h, sufficient sodium hydroxide solution was added for the solution to have a distinct alkaline reaction. After a further 2 h, the product was extracted with 4 ~1~7~0~
toluene. The solution contained 22.1 g of N,N'-dibenzylbispidine, corresponding to a yield of 96.2%. The purity after removal of the toluene was 99.9%.
Claims
We claim:
A process for the preparation of N,N'-dibenzylbispidine, which comprises reacting N-benzylpiperidone with formalin and benzyl-amine in the presence of acetic acid in a solvent at 60 - 100°C, with the benzylamine, the acetic acid, the solvent and part of the benzylpiperidone being initially introduced at 50 - 100°C, subsequently the remaining benzylpiperidone and part of the for-malin being added, and then, after addition of the remaining for-malin, the reaction mixture being heated to reflux, and the acetate of N,N'-dibenzylbispidone obtained in this way being, after removal of the methanol by distillation, purified from byproducts by extraction and subsequently the N,N'-dibenzylbispi-done being liberated and isolated, and then reacting the N,N'-dibenzylbispidone with hydrazine at 80 - 200°C in a solvent, and extracting the N,N'-dibenzylbispidine, after treatment with acid and alkali, with toluene.
A process for the preparation of N,N'-dibenzylbispidine, which comprises reacting N-benzylpiperidone with formalin and benzyl-amine in the presence of acetic acid in a solvent at 60 - 100°C, with the benzylamine, the acetic acid, the solvent and part of the benzylpiperidone being initially introduced at 50 - 100°C, subsequently the remaining benzylpiperidone and part of the for-malin being added, and then, after addition of the remaining for-malin, the reaction mixture being heated to reflux, and the acetate of N,N'-dibenzylbispidone obtained in this way being, after removal of the methanol by distillation, purified from byproducts by extraction and subsequently the N,N'-dibenzylbispi-done being liberated and isolated, and then reacting the N,N'-dibenzylbispidone with hydrazine at 80 - 200°C in a solvent, and extracting the N,N'-dibenzylbispidine, after treatment with acid and alkali, with toluene.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4324086.0 | 1993-07-17 | ||
| DE4324086A DE4324086A1 (en) | 1993-07-17 | 1993-07-17 | Process for the preparation of N, N`-dibenzylbispidine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2167406A1 true CA2167406A1 (en) | 1995-01-26 |
Family
ID=6493125
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002167406A Abandoned CA2167406A1 (en) | 1993-07-17 | 1994-06-28 | A process for the preparation of n,n'-dibenzylbispidine |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0710238A1 (en) |
| JP (1) | JPH09500119A (en) |
| KR (1) | KR960703913A (en) |
| AU (1) | AU7073394A (en) |
| CA (1) | CA2167406A1 (en) |
| CZ (1) | CZ5296A3 (en) |
| DE (1) | DE4324086A1 (en) |
| HU (1) | HU9503859D0 (en) |
| MX (1) | MX9405030A (en) |
| PL (1) | PL312609A1 (en) |
| WO (1) | WO1995002599A1 (en) |
Families Citing this family (1)
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2428792A1 (en) * | 1974-06-14 | 1976-01-02 | Knoll Ag | NEW ANTIARRHYTHMICS |
-
1993
- 1993-07-17 DE DE4324086A patent/DE4324086A1/en not_active Withdrawn
-
1994
- 1994-06-28 CA CA002167406A patent/CA2167406A1/en not_active Abandoned
- 1994-06-28 EP EP94919667A patent/EP0710238A1/en not_active Withdrawn
- 1994-06-28 HU HU9503859A patent/HU9503859D0/en unknown
- 1994-06-28 WO PCT/EP1994/002101 patent/WO1995002599A1/en not_active Application Discontinuation
- 1994-06-28 KR KR1019960700211A patent/KR960703913A/en not_active Application Discontinuation
- 1994-06-28 CZ CZ9652A patent/CZ5296A3/en unknown
- 1994-06-28 PL PL94312609A patent/PL312609A1/en unknown
- 1994-06-28 JP JP7504314A patent/JPH09500119A/en active Pending
- 1994-06-28 AU AU70733/94A patent/AU7073394A/en not_active Abandoned
- 1994-07-01 MX MX9405030A patent/MX9405030A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PL312609A1 (en) | 1996-04-29 |
| CZ5296A3 (en) | 1996-04-17 |
| KR960703913A (en) | 1996-08-31 |
| DE4324086A1 (en) | 1995-01-19 |
| HU9503859D0 (en) | 1996-02-28 |
| WO1995002599A1 (en) | 1995-01-26 |
| MX9405030A (en) | 1995-01-31 |
| JPH09500119A (en) | 1997-01-07 |
| AU7073394A (en) | 1995-02-13 |
| EP0710238A1 (en) | 1996-05-08 |
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