Process for the preparation of azabicyclic derivatives

Details Process for the preparation of azabicyclic derivatives Process for the preparation of azabicyclic derivatives

1996-11-12

1998-09-15

Ford, John M.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D45302

Patent

active

058080759

DESCRIPTION:

BRIEF SUMMARY
This is a 371 of PCT/EP95/01757 filed May 9, 1995.
This invention relates to a process for the preparation of compounds having pharmaceutical activity.
EP-A-0392803 (Beecham Group p.l.c.) discloses certain azabicyclic compounds which enhance acetylcholine function via an action at muscarinic receptors within the central nervous system.
These compounds are therefore of potential use in the treatment and/or prophylaxis of dementia in mammals. Various preparative methods are also disclosed.
WO93/17018 and WO 92/03433 disclose certain routes to intermediates useful in the preparation of certain compounds disclosed in EP-A-0392803.
We have now developed an improved process for the preparation of one class of the compounds disclosed in EP-A-0392803.
The present invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR2## wherein R.sub.1 represents ##STR3## r represents an integer of 2 to 4, s represents 1 or 2 and t represents 0 or 1; alkenyl or C.sub.2-4 alkynyl or a group OCOR.sub.5 where R.sub.5 is hydrogen or R.sub.4 ; and ##STR4## wherein R.sub.1 ' is R.sub.1 or a group convertible thereto, and R.sub.3 ' is an electron withdrawing group, with a source of nitrous acid and thereafter converting the resulting .dbd.NOH group to .dbd.NR.sub.2 wherein R.sub.2 is as defined in formula (I), converting R.sub.1 ' and R.sub.3 ' when other than R.sub.1 and R.sub.3 to R.sub.1 and R.sub.3, and thereafter optionally forming a pharmaceutically acceptable salt.
Compounds of formula (I) are capable of existing in a number of stereoisomeric forms including geometric isomers such as E and Z and, for certain compounds, enantiomers. The different stereoisomeric forms may be separated one from the other by the usual methods.
If desired, the compounds of formula (I) can be formed into acid addition salts with acids, such as the conventional pharmaceutically acceptable acids, for example hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tararic, oxalic and methanesulphonic.
The term pharmaceutically acceptable salt encompasses solvates and hydrates. Thus where compounds of formula (I) or pharmaceutically acceptable salts thereof form solvates or hydrates, these also form an aspect of the invention.
Preferred combinations of (r,s,t) include (2,2,0), (2,1,1), (3,1,1), (2,1,0) and (3,1,0), most preferably (2,2,0).
The groups R.sub.4 and R.sub.5 in R.sub.2 are preferably selected from methyl, ethyl, allyl and propargyl. Suitable values for R.sub.2 include methoxy, ethoxy, allyloxy, propargyloxy and acetoxy, preferably methoxy.
Examples of suitable electron withdrawing groups include CN, CO.sub.2 R and CON(R).sub.2 in which each R is independently H, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl C.sub.1-4 alkyl or aryl C.sub.1-4 alkyl, wherein aryl groups are selected from optionally substituted phenyl and naphthyl. Suitable examples of substituents on phenyl and naphthyl include one or more, for example 1 to 3, substituents selected from halo, hydroxy, C.sub.1-4 alkoxy and C.sub.1-4 alkyl. R.sub.3 ' is preferably CN.
The compound of formula (II) may be provided in the form of an ester hydrolysed to the free acid prior to reaction with the source of nitrous acid.
The reaction of the compound of formula (II) with the source of nitrous acid, for example an alkali metal nitrite such as sodium nitrite may be carried out in aqueous acid such as hydrochloric acid for example at 0.degree. C. to 50.degree. C.
After basification, the reaction results in a compound of formula (III): ##STR5## When R.sub.1 ' is R.sub.1 where (r, s, t) is (2, 2, 0) and R.sub.3 ' is CN, the Z isomer of the compound of formula (III) may be crystallised out from the reaction mixture in the zwitterionic form. Compounds of formula (III) in zwitterionic form are novel and as such form part of the invention.
The .dbd.NOH group of the oxime of formula (III) may be converted to .dbd.NR.sub.2 by conventional ro

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