Nitrosation process

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C546S112000, C548S452000, C544S171000

Reexamination Certificate

active

06596869

ABSTRACT:

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.
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 process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein R
1
represents
r represents an integer of 2 to 4, s represents 1 or 2 and t represents 0 or 1;
R
2
is a group OR
4
, where R
4
is C
1-4
alkyl C
2-4
alkenyl or C
2-4
alkynyl or a group OCOR
5
where R
5
is hydrogen or R
4
; and
R
3
is CN;
said process comprising nitrosating a compound of formula (II):
 wherein R
1
′ is R
1
or a group convertible thereto, and R
3
′ is an electron withdrawing group, and thereafter converting the resulting ═NOH group to ═NR
2
wherein R
2
is as defined in formula (I), converting R
1
′ and R
3
′ when other than R
1
and R
3
to R
1
and R
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 syn and anti and, for certain compounds, enantiomers. The different stereoisomeric forms may be separated one from the other by the usual methods.
Compounds of formula (I) having two asymetric centres which have the stereochemical configuration in which the group —C(R
3
)═NR
2
and the (CH
2
)
s
bridge are on the same side of the plane of the molecule which contains both bridgehead atoms and the ring carbon atom bonded to the aforesaid group will hereinafter be referred to as having the exo configuration.
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, tartaric, 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
4
and R
5
in R
2
are preferably selected from methyl, ethyl, allyl and propargyl. Suitable values for R
2
include methoxy, ethoxy, allyloxy, propargyloxy and acetoxy, preferably methoxy.
Examples of suitable electron withdrawing groups include CN, CO
2
R and CON(R)
2
in which each R is independently H, C
1-8
alkyl, C
2-8
alkenyl, C
2-8
alkynyl, C
3-8
cycloalkyl, C
3-8
cycloalkyl C
1-4
alkyl or aryl C
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
1-4
alkoxy and C
1-4
alkyl. R
3
′ is preferably CN.
The nitrosation of the compound of formula (II) may be carried out using a nitrosating agent such as an alkylnitrite, preferably a C
1-8
alkylnitrite such as t-butyl nitrite or, more preferably, iso-amyl nitrite and a base such as sodium ethoxide or, more preferably, potassium t-butoxide. Dimethylsulphoxide (DMSO) and tetrahydrofuran (THF) are suitable examples of solvents for the nitrosation.
The nitrosation results in a compound of formula (III):
The ═NOH group of the oxime of formula (III) may be converted to ═NR
2
by conventional routes, for example compounds where R
2
is OCOR
5
can be made by acylation with an acylating agent such as an acyl halide, for example acetyl chloride. Compounds where R
2
is OR
4
can be made by alkylation with an alkylating agent such as methyltosylate (methyl p-toluene sulphonate) or an alkyl halide, for example methyl iodide. The alkylation is preferably carried out at a temperature of −20° C.-40° C., more preferably 0° C.-40° C., for example 18° C.-36° C., most preferably below 35° C.
R
3
′ groups other than CN may be converted thereto conventionally, for example conversion, if necessary, to the primary amide followed by dehydration.
Examples of R
1
′ groups other than R
1
include suitable azacyclic precursors which may be cyclised as described in, for example, EP 0392803.
The different steroisomeric forms of compounds of formula (I) may be separated one from the other by the usual methods, for example chromatographic methods. Enantiomers may be separated using chiral resolving agents such as (S)-(+)- and (R)-(−)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate, or chiral chromatography.
The invention also provides a process for preparing a compound of formula (III) which process comprises nitrosating a compound of formula (II) and thereafter converting R
1
′ and R
3
′ when other than R
1
and R
3
to R
1
and R
3
and thereafter optionally forming a salt.
Compounds of formula (II) can be prepared from compounds of formula (IV):
by hydrogenation according to standard procedures.
The reduction of compounds of formula (IV) is preferably carried out by treating a methanolic solution of a compound of formula (IV) with hydrogen under pressure in the presence of Palladium on carbon as a catalyst.
Compounds of formula (IV) may be prepared conventionally, for example as described in EP 0414394, for example by reacting a compound of formula (V).
with a phosphorus ylide of formula (VI) or (VII):
in which Ra, Rb and Rc are independently C
1-6
alkyl, aryl or aralkyl and R
3
′ is as defined above, to give a compound of formula (IVa):
in which R
3
′ is defined as for formulae (VI) and (VII) and thereafter, where necessary, converting R
3
′ to CN.
The reaction of a compound of formula (V) with a phosphorus ylide of formula (VI) or (VII) which is equivalent to the conversion of a ketone to an olefin is known as a Wittig Reaction and may be carried out under conditions generally used for such reactions, in particular in the presence of a suitable base such as potassium t-butoxide or, more preferably, potassium hydroxide. Preferably a compound of formula (V) is reacted with a compound of formula (VII) in a Wadsworth Emmonds reaction in which Ra and Rb are each C
1-6
alkyl, for example ethyl, and Z is cyano.
Where the R
3
′ group is a carboxy derivative such as an alkoxycarbonyl group, it may be converted to a cyano group by conventional methods as described above, but preferably before hydrogenation or before nitrosation.
However, as stated above, R
3
′ is preferably cyano and no conversion is necessary.
Alternatively, compounds of formula (IV) may be prepared by a Knoevenagel condensation (Zh. Obshch. Khim. 1962 32 2935, DE 2323303, CA 1014958 and U.S. Pat. No. 3,857,848).
Intermediates of formula (V) are known compounds (e.g. as described in Thill et al., J. Org. Chem., 1968, 33, 4376) or may be prepared analogously.
Intermediates of formula (VII) are known compounds or may be prepared by the standard Arbuzov reaction (Pure Appl. Chem. 9, 307-335 (1964)) or certain compounds of formula (VII) may be obtained commercially.
Intermediates of formula (VI) are known compounds or may be prepared by analogous methods. Certain compounds of formula (VI) may be obtained commercially.
The compounds of formula (I) are useful in therapy as described in EP-0392803.
The following Examples 1 and 2 illustrates the invention. Reference Examples 1 to 5 illustrate the preparation of intermediates.
Reference Example 1
To a stirred solution of 3-quinuclidinone (50 g; 0.309 mol) in water (250 ml) was added potassium hydroxide (17.35 g; 0.309

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