Preparation of 1-butyl-4-piperidinylmethylamine

Details Preparation of 1-butyl-4-piperidinylmethylamine Preparation of 1-butyl-4-piperidinylmethylamine

2000-08-22

2001-12-18

Shah, Mukund J. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S205000

Reexamination Certificate

active

06331631

ABSTRACT:

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 plc) describe compounds having 5-HT
4
receptor antagonist activity.
WO 93/18036, Example 3 describes N-[(1-
n
butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide SB 207266, (the hydrochloride salt is SB 207266-A) which is being developed by SmithKline Beecham plc 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-[(1-
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-[(1-
n
butyl-4-piperidyl)methyl]indole-3-carboxamide is prepared by coupling 1-butyl-4-piperidinylmethylamine with indole-3-carboxylic acid. The 1-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 1-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 1-butyl-4-piperidinylmethylamine, which process comprises:
i) the reaction of 4-piperidinecarboxamide (“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-t-butylcresol) which can only be removed from 1-butyl-4-piperidinylmethylamine 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
4
reaction reduces the usage of solvent and loss of product on solid alumina residues.


REFERENCES:
patent: 0 829 474 (1998-03-01), None
patent: WO 93/05038 (1993-03-01), None
patent: 93/05038 (1993-03-01), None
patent: WO 93/18036 (1993-09-01), None
patent: 93/18036 (1993-09-01), None
patent: WO 94/08965 (1994-04-01), None
patent: WO 96/38420 (1996-05-01), None
B. Gutkowska and M. Krawczynska,Roczniki Chemii, 1976, 50(10), pp. 1791-1794.

Affiliated with

Also associated with

Rating

Preparation of 1-butyl-4-piperidinylmethylamine does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Preparation of 1-butyl-4-piperidinylmethylamine, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Preparation of 1-butyl-4-piperidinylmethylamine will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2601261