Process and intermediates for production of donepezil and...

Details Process and intermediates for production of donepezil and... Process and intermediates for production of donepezil and...

2001-05-24

2002-12-10

Chang, Ceila (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S205000, C546S238000, C546S342000, C558S179000

Reexamination Certificate

active

06492522

ABSTRACT:

REFERENCE TO RELATED APPLICATIONS
The present application is the national stage under 35 U.S.C. 371 of international application PCT/IL99/00436, filed Aug. 11, 1999 which designated the United States, which international application was published under PCT Article 21 (2) in English.
FIELD OF THE INVENTION
The present invention relates to a new process for the preparation of acetylcholinesterase inhibitors (anti-AchE) such as Donepezil, to some novel intermediates used in this process and to their preparation.
BACKGROUND OF THE INVENTION
Dementia is a chronic progressive organic mental disorder in which there is disturbance of multiple higher cortical functions including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgement. Alzheimer's Disease is the commonest cause of dementia and is characterized by degeneration of specific nerve cells, presence of neurotic plaques, and neurofibrillary tangles. Definitive diagnosis of Alzheimer's Disease requires demonstration of these characteristic pathological features in brain tissue, although in the vast majority of cases diagnosis is made on clinical grounds alone, where it is more correctly called Senile Dementia of the Alzheimer Type (SDAT).
Various attempts have been made to treat the senile dementia with a drug. It was found that compounds of formula [X] (Scheme 1) possess a high acetylcholinesterase inhibitory activity (Sugimoto, H., et al.,
J. Med. Chem.,
v. 38, 481 (1995). One of the most potent acetylcholinesterase inhibitors (anti-AChE) of this class is Donepezil (E2020) [VII].
Donepezil is a new drug treatment for use in mild to moderate dementia due to SDAT. Donepezil acts by inhibiting acetylcholine esterase, the enzyme responsible for metabolising acetylcholine, thereby enhancing neurotransmitter levels.
The general synthetic route to compounds [X] comprises the condensation of cyclic aromatic ketones [XI] with 1-substituted-4-(&ohgr;-formylalkyl)piperidines [XII] followed by reduction of the obtained compounds [XIII] (Scheme 1) (Sugimoto, H., et al.,
J. Med. Chem.,
v. 38, 481 (1995); Eisai Co., U.S. Pat. No. 5,100,901).
SUMMARY OF INVENTION
The present invention relates to a process for preparing a compound of formula [I] or a salt thereof:
wherein:
R
1
is N-acyl-4-piperidyl; N-alkoxycarbonyl-4-piperidyl; 4-piperidyl; N-alkyl-4-piperidyl; N-benzyl-4-piperidyl; N-(&ohgr;-aralkyl)-4-piperidyl; 4-pyridyl;
R
4
, R
5
, R
6
and R
7
are identical or different and each represents hydrogen, straight-chain or branched alkyl, aryl, hydroxy, alkoxy, aryloxy, benzyloxy, acyloxy, alkylthio, arylthio, benzylthio, acylamino, phthalimido or halogen;
n is 1, 2 or 3;
m is 1, 2, 3, 4 or 5;
which process comprises cyclisation of a compound of formula [II] or salts thereof
wherein
R
1
, R
4
, R
5
, R
6
and R
7
, m and n are as defined above;
R
2
is selected from a derivatised or non-derivatised carboxyl, cyano, N-substituted aminocarbonyl groups or hydrogen;
R
3
is selected from a derivatised or non-derivatised carboxyl, cyano or N-substituted aminocarbonyl groups, optionally in the presence of acids and/or solvents.
According to the present invention, enantiomerically enriched compounds of formula [I] or salts thereof are prepared by cyclisation of optically pure compounds of formula [II], wherein R
2
and R
3
are different.
The present invention also relates to new compounds of formula [II]:
wherein
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
, m and n are as defined above, including salts thereof and the optically active enantiomers thereof, with the proviso that when R
1
is 4-pyridyl, and n=m=1, then at least one of R
4
, R
5
, R
6
and R
7
does not represent hydrogen or lower alkyl.
The present invention further relates to a process for preparing a compound [II] by the hydrogenation of a compound of formula [VIII] or [IX] or mixtures thereof
wherein
R
1
, R
3
, R
4
, R
5
, R
6
, R
7
, n and m are as defined above.
Alternatively, a compound of the formula [II] can be prepared by reaction of a compound of formula [V]
with a compound of the formula [VI]
in the presence of a strong base,
wherein in all the above formulae, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, X, m and n are as defined above.
Alternatively, a compound of the formula [II] can be prepared by reacting of compound of formula [III]
wherein
X is a facile leaving group,
with a compound of the formula [IV]
in the presence of a strong base as it was shown in one example by Miyoshi, Hideto et. al. (
J. Biol. Chem.,
(1998), 273 (28).
DETAILED DESCRIPTION OF THE INVENTION
The compounds of formula [I] and formula [II] can be prepared as described in the following reaction schemes and discussion. Unless otherwise indicated, the meanings R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, X, n and m in compounds of the formulae [I], [Ia], [II], [IIa], [III], [IIIa], [IV], [IVa], [V], [V], [VI], [VII], [IX], [XX], [XX], [VIIa], [IXa], [XVIIIa], [XIXa] which are shown or mentioned in the reaction schemes and discussion tat follow, are as defined above.
Scheme 2 below refers to a process for the preparation of a compound of formula [I] or salts thereof by cyclisation of a compound of formula [II] or salts thereof:
When the above process is carried out with an optically pure compound of formula [II], (R
2
and R
3
are different), the obtained product is an enantiomically enriched compound of formula [I] or salts thereof.
According to the present invention ester, amido, cyano or ether protecting groups can be hydrolyzed under the conditions of the cyclisation reaction either in the starting compound [II] or in the desired compound [I].
Preferably, the cyclisation is carried out with a previously hydrolysed compound [II], wherein R
2
is hydrogen or a carboxyl group and to R
3
is a carboxyl group. Compound [II] wherein R
2
and R
3
are carboxyl groups, are decarboxylated in the course of the intramolecular acylatin.
More preferably, said cyclisation of compound [II] (R
2
=H, R
3
=COOH) is carried out under Friedel-Crafts reaction conditions, optionally with previous derivatisation of the R
3
carboxylic group to a halocarbonyl group.
Preferably, the cyclisation of the present invention is carried out in the presence of protic acids or Lewis acids or a mixture thereof. Examples of such acids are trifluoromethanesulfonic acid, methanesulfonic acid, polyphosphoric acid, fluoro- or chlorosulfonic acid, sulfuric acid, hydrogen fluoride, hydrogen chloride, zinc chloride, zinc bromide, aluminium chloride, aluminium bromide, titanium chloride, boron fluoride, phosphorus pentoxide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thyonyl chloride and sulfuryl chloride.
The cyclisaton of the present invention can be carried out in the presence of a solvent. Preferably, the solvent is selected from dichloromethane, chloroform, dichloroethane, tetrachloroethane, chlorobenzene, dichlorobenzene, nitromethane, nitroethane, nitrobenzene, ether or mixtures thereof.
Pharmaceutically important compounds of formula [Ia] are obtained according to Scheme 3:
Acids of formula [XV] or [XVI], which are obtained by hydrolysis of the corresponding esters [XIV] and [XVII], undergo cyclisation to yield Donepezil [VII] in high yield and purity (Scheme 4).
According to another aspect, the present invention relates to new compounds of formula [II] including the optically active enantiomers thereof (R
2
≠R
3
) which are used in the cyclisati

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