Process for the preparation of lactam derivatives

Details Process for the preparation of lactam derivatives Process for the preparation of lactam derivatives

1993-10-18

2001-01-16

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S085000, C546S086000, C546S087000, C548S335500, C548S429000

Reexamination Certificate

active

06175014

ABSTRACT:

This invention relates to a process for the preparation of heterocyclic compounds.
In British patent application no. 2209335A, which was unpublished at the priority date of the present application, a group of lactam derivatives are described which may be represented by the general formula (I):
wherein Im represents an imidazolyl group of the formula:
and R
1
represents a hydrogen atom or a group selected from C
1-6
alkyl, C
3-6
alkenyl, C
3-10
alkynyl, C
3-7
cycloalkyl, C
3-7
cycloalkyl C
1-4
alkyl, phenyl, phenyl C
1-3
alkyl, phenylmethoxymethyl, phenoxyethyl, phenoxymethyl, —CO
2
R
5
, —COR
5
, —CONR
5
R
6
or —SO
2
R
5
(wherein R
5
and R
6
, which may be the same or different, each represents a hydrogen atom, a C
1-6
alkyl or C
3-7
cycloalkyl group, or a phenyl or phenyl C
1-4
alkyl group, in which the phenyl group is optionally substituted by one or more C
1-4
alkyl, C
1-4
alkoxy or hydroxy groups or halogen atoms, with the proviso that R
5
does not represent a hydrogen atom when R
1
represents a group —CO
2
R
5
or —SO
2
R
5
);
one of the groups represented by R
2
, R
3
and R
4
is a hydrogen atom or a C
1-6
alkyl, C
3-7
cycloalkyl, C
3-6
alkenyl, phenyl or phenyl C
1-3
alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C
1-6
alkyl group;
n represents 2 or 3;
and physiologically acceptable salts and solvates thereof.
Several processes for the preparation of these compounds are described in the abovementioned British patent application.
As described in British patent application no. 2209335A, the compounds of formula (I) are potent and selective antagonists of 5-hydroxytryptamine (5-HT) at 5-HT
3
receptors. They are useful in the treatment of conditions such as psychotic disorders (e.g. schizophrenia and mania); anxiety; and nausea and vomiting, particularly that associated with cancer chemotherapy and radiotherapy.
The present invention provides a process for the preparation of a compound of general formula (I) which comprises reacting a compound of formula (II):
or a protected derivative thereof, with a compound of formula (III):
HOCH
2
-Im  (III)
or a salt thereof, in the presence of an acid at an elevated temperature, followed where necessary by removal of any protecting groups.
The acid may be, for example, a strong mineral acid (e.g. hydrochloric acid), a hydrocarbylsulphonic acid (e.g. p-toluenesulphonic or methanesulphonic acid), or a carboxylic acid (e.g. maleic or acetic acid).
The reaction may conveniently be effected in a high boiling polar solvent such as N-methylpyrrolidinone or dimethylacetamide, at an elevated temperature, for example in the range 100 to 200° C. Alternatively the reaction may be conveniently effected in water, an alcohol (e.g. isopropanol or n-butanol), xylene or acetic acid at the reflux temperature of the solvent.
According to one aspect of the invention, the acid may be, for example, a strong mineral acid (e.g. hydrochloric acid) or a hydrocarbylsulphonic acid (e.g. p-toluenesulphonic acid). According to another aspect of the invention, the reaction may be effected in water or an alcohol (e.g. isopropanol) at the reflux temperature of the solvent.
Most preferably, the reaction is effected in the presence of a hydrocarbylsulphonic acid (e.g. p-toluenesulphonic or methanesulphonic acid) or hydrochloric acid, in N-methylpyrrolidinone or dimethylacetamide at a temperature in the range 100 to 200° C., more preferably 100 to 150° C. The use of a hydrocarbylsulphonic acid (e.g. p-toluenesulophonic acid) is particularly preferred.
The compound of formula (III) is preferably used in the form of a salt, more particularly the hydrochloride salt. When the reaction is effected with the hydrochloride salt of a compound of formula (III), the addition of an acid is optional, since the hydrogen chloride associated with the compound of formula (III) provides sufficiently acidic conditions.
Compounds of formula (II) may be prepared, for example, by the method described in British patent application no. 2209335A. Compounds of formula (II) may be obtained by a Beckmann rearrangement of an oxime of formula (IV):
wherein m represents 1 or 2, or a protected derivative thereof. The Beckmann rearrangement may be effected using conventional methods, for example by using an acid (e.g. polyphosphoric or sulphuric acid, or a mixture of hydrochloric acid, acetic anhydride and acetic acid) in an inert solvent such as an ether (e.g. dioxan), an amide (e.g. dimethylformamide) or a hydrocarbon (e.g. toluene or cyclohexane), at an elevated temperature of, for example, 50 to 120° C. Alternatively, the hydroxy group of the oxime of formula (IV), may be converted into a leaving group such as a chloride (using, for example, phosphorus pentachloride) or a hydrocarbylsulphonate (e.g. a mesylate or a tosylate) or a trifluoroacetate group (using conventional acylation methods). Subsequent heating at a temperature of, for example, 20 to 150° C., in an inert solvent as described above, gives a compound of formula (II).
Compounds of formula (III) are either known, or may be prepared from known compounds by conventional procedures.
Where a protected derivative of a compound of formula (II) is used in the above process, it may be a derivative in which the indole nitrogen atom is protected. The N-protecting group may be, for example, an arylmethoxymethyl (e.g. phenylmethoxymethyl) group. This group may be cleaved from a protected derivative of a compound of formula (I) by hydrogenolysis in the presence of a catalyst (e.g. palladium on charcoal).
Where it is desired to isolate a compound of formula (I) as a salt, for example a physiologically acceptable salt, e.g. a hydrochloride, this may be achieved by reacting the compound of formula (I) in the form of the free base with an appropriate acid, preferably with an equivalent amount, in a suitable solvent such as an alcohol (e.g. ethanol or methanol), an aqueous alcohol (e.g. aqueous ethanol), a halogenated hydrocarbon (e.g. dichloromethane), an ester (e.g. ethyl acetate), an ether (e.g. tetrahydrofuran) or a ketone (e.g. acetone). Alternatively, salt formation may take place in situ and the compound of formula (I) may be isolated directly from the reaction mixture in the form of a salt.
Physiologically acceptable salts may also be prepared from other salts, including other physiologically acceptable salts, of the compound of formula (I) using conventional methods.
Individual enantiomers of the compounds of the invention may be obtained by resolution of a mixture of enantiomers (e.g a racemic mixture) using conventional means, such as an optically active resolving acid; see for example ‘Stereochemistry of Carbon Compounds’ by E. L. Eliel (McGraw Hill, 1962) and ‘Tables of Resolving Agents’ by S. H. Wilen.
According to a preferred embodiment, the process of the invention may be used for the preparation of compounds of formula (I) in which R
1
represents a hydrogen atom or a C
1-3
alkyl (e.g. methyl, ethyl, n-propyl or isopropyl) group, R
2
and R
3
represent hydrogen atoms, R
4
represents a methyl group and n represents 2.
More particularly the process of the present invention may be used to prepare 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one and its physiologically acceptable salts (e.g. hydrochloride) and solvates.
The invention is illustrated by the following Examples which all describe the preparation of 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one (Compound X). All temperatures are in 0° C. Thin layer chromatography (t.l.c.) was carried out on silica. Solvent System A as used for t.l.c. denotes dichloromethane: ethanol: 0.88 ammonia solution.
1
H-N.m.r. spectra were obtained at 250 MHz for dilute solutions in d
6
-dimethyl sulphoxide. Intermediate 1 denotes 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one and Intermediate 2 denotes 4-hydroxymethyl-5-methylimidazole hydrochloride.


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