PREPARATION OF 1-BUTYL-4-PIPERIDINYLMETHYLAMINE

Abstract: A process for the preparation of 1-butyl-4-piperidinylmethylamine, which process comprises: i) the reaction of isonipecotamide and 1-bromobutane to give the N-butyl derivative of isonipecotamide; followed by ii) reduction with LiAlH4, characterised in that the reactions i) and ii) are carried out in toluene as solvent.

Description: PREPARATION OF l-BUTYL-4-PIPERroiNYLMETHYLA INE This invention relates to a new synthetic process to an intermediate which is useful for the preparation of compounds having pharmacological activity WO 93/03725, WO 93/05038, WO 93/08187, WO 93/16072, WO 93/18027 , WO 93/18036, WO 94/07859, WO 94/08965, WO 94/08994, WO 94/08995, WO 94/08998, WO 94/17071 (SmithKline Beecham pic) describe compounds having 5-HT4 receptor antagonist activity. WO 93/18036 , Example 3 describes N-[(l- n butyl-4-piperidyi)methyl]-3,4- dihydro-2H-[l,3]oxazino[3,2-a]indole-10-carboxamide SB 207266, (the hydrochloride salt is SB 207266-A) which is being developed by SmithKline Beecham pic as the active ingredient in a medicament for treatment of irritable bowel syndrome. WO 93/18036 describes a method of preparation of SB 207266-A from N-[( l- n butyl-4-piperidyl)methyl]indole-3-carboxamide (i.e. the compound corresponding to SB 207266, without the oxazino moiety), by reacting with N-chlorosuccinimide and 3- bromo-1-propanol, followed by treatment with sodium carbonate. N-[(l- n butyl-4- piperidyI)methyl]indole-3-carboxamide is prepared by coupling l-butyl-4- piperidinylmethylamine with indole-3-carboxylic acid. The l-butyl-4- piperidinylmethylamine is prepared as in Description 7 of WO 93/05038 and Description 1 of WO 93/18036, in a three stage process from isonipecotamide and 1 -bromobutane, by alkylation in ethanol, to give the N-butyl derivative of isonipecotamide which is dehydrated to the corresponding nitrile and then reduced with LiAlH.4 in ether. An alternative process for preparing l-butyl-4-piperidinylmethylamine has now been discovered which involves the use of a common solvent, allowing the two stages to be run without isolation of the N-butyl derivative of isonipecotamide. Accordingly, the present invention provides a process for the preparation of l-butyl-4-piperidinylmethylamine, which process comprises: i) the reaction of isonipecotamide and 1 -bromobutane to give the N-butyl derivative of isonipecotamide; followed by ii) reduction with LiAlH.4, characterised in that the reactions i) and ii) are carried out in toluene as solvent The advantages of this process as compared with that previously described are as follows 1 Toluene does not contain any additives, whereas THF contains a stabiliser (di- .-butylcresol) which can only be removed from l-butyl-4-pιperidinyimethylamine by fractional distillation 2 The overall process does not involve the preparation/isolation of the intermediate nitrile, and is therefore one step shorter 3 The process does not involve the isolation of the N-butyl derivative of isonipecotamide 4 The process uses a single solvent and eliminates the use of ethanol, chloroform and THF 5 the special extractive work-up of the LiAlH-j reaction reduces the usage of solvent and loss of product on solid alumina residues The following Examples illustrate the invention Example I 4-Pιperidinecarboxamide (wo-nipecotamide) and potassium carbonate (2 equivs ) were stirred in toluene and treated with 1 -bromobutane (1 equiv ) The reaction mixture was heated at reflux (107-110°C) for 2 hours After cooling to 80- 85°C the mixture was washed with hot water followed by hot aqueous potassium carbonate solution The resulting toluene solution of 1 -butyl-/.ro-nιpecotamide was dried by azeotropic distillation, maintaining the reaction volume by addition of fresh toluene The toluene solution was cooled to 0-5°C, under nitrogen A solution of Li A1H 4 2THF in toluene ( 1 0 molar solution, 2 0 equivs ) was added over 1 hour, keeping the temperature <10°C The mixture was allowed to warm to room temperature and was then heated to reflux for 1 hour After cooling to 0-5°C, 32% w/w sodium hydroxide solution (1 5 equivs wit substrate) was added cautiously over 1 hour, keeping the temperature <10°C The mixture was stirred for 30 minutes at ambient temperature and the precipitate filtered through celite, washing the bed thoroughly with toluene The filtrate was evaporated in vacuo to give l-butyl-4- piperidinylmethylamine as a pale yellow oil, containing -13% by weight toluene, in 72% yield (after adjusting for toluene content) Example 2 Alternatively the first part of the preparation may be carried out as follows 4-Piperidinecarboxamide (wo-nipecotamide) and 5M aqueous potassium carbonate solution (2 equivs.) were stirred in toluene and treated with 1 -bromobutane ( 1 equiv.) The reaction mixture was heated at reflux ( 107- 110°C) for 2 hours After cooling to 70-80°C the mixture was washed with hot water followed by hot aqueous potassium carbonate solution The resulting toluene solution of 1-butyl-wo- nipecotamide was dried by azeotropic distillation, maintaining the reaction volume by addition of fresh toluene Example 3 A 3L vessel was purged with nitrogen and charged with iso- nipecotamide (112 lg 0.87mol) and dry toluene (785ml). The suspension was warmed to 50°C and potassium carbonate (248g, I 79mol) and butyl bromide (1 19 8g, 0 87mol) were added in one portion The resulting mixture was heated at reflux under Dean-Stark conditions for three hours and then cooled to 65°C and quenched by addition of water (875ml) The aqueous phase was separated at about 80°C and the organic layer dried by azeotropic distillation of toluene (200ml) Fresh toluene (200ml) was added to maintain a constant volume The reaction mixture was cooled to about 5°C and treated, dropwise, with a solution of lithium aluminium hydπde 2THF in toluene (500ml, 3 5M, 1 75moi) The mixture was stirred at ambient temperature for one hour and then at about 55°C for a further two hours The reaction was then quenched by cautious addition of sodium hydroxide solution (1200ml, 10 8M) and heated to about 70°C The aqueous phase was separated and washed twice with toluene (300ml each wash) The combined organic washes were concentrated under reduced pressure and the product 1 -butyl-4- piperidinylmethylamine (SB-211156) (127g) was isolated as a pale yellow oil in 85% yield by vacuum distillation (bp 106°C at 20mm Hg approx )

Claims: Ciaims 1. A process for the preparation of 1 -butyl-4-piperidinylmethylamine, which process comprises: i) the reaction of isonipecotamide and 1 -bromobutane to give the N-butyl derivative of isonipecotamide; followed by ii) reduction with LiAlH characterised in that the reactions i) and ii) are carried out in toluene as solvent. 2. A process according to Claim 1 in which the reaction mixture after the reduction is treated with hot sodium hydroxide solution and the mixture is extracted with an organic solvent. 3. A process for the preparation of SB 207266, or a pharmaceutically acceptable salt thereof, which process comprises preparing l-butyl-4-piperidinylmethylamine according to the process of claim 1, followed by coupling with an appropriate indole 3- carboxylic acid derivative, and thereafter as necessary converting the indole and/or substituents, including cyclisation to 3,4-dihydro-2H-[l,3]oxazino[3,2-a]indole. 4. SB 207266 whenever prepared by the process of Claim 3.

Inventors: FEDOULOFF MICHAEL, GUEST DAVID WILLIAM, SMITH GILLIAN ELIZABETH, FEDOULOFF, MICHAEL, GUEST, DAVID, WILLIAM, SMITH, GILLIAN, ELIZABETH
Applicants: FEDOULOFF MICHAEL, GUEST DAVID WILLIAM, SMITH GILLIAN ELIZABETH, SMITHKLINE BEECHAM PLC, FEDOULOFF, MICHAEL, GUEST, DAVID, WILLIAM, SMITH, GILLIAN, ELIZABETH, SMITHKLINE BEECHAM P.L.C.
Application year: 1997
Main classification: C07D211
IPC codes: A61K31, A61P1, A61P43, C07D211, C07D498