CA1105928A - Hexahydroazepine piperidine and pyrrolidine derivatives - Google Patents

Abstract

Abstract The invention concerns a novel process for preparing hexahydroazepine, piperidine and pyrrolidine derivatives of formula where n is 2,3 or 4, R3 is hydrogen, lower alkyl, aryl-(lower)alkyl, lower alkenyl or lower alkynyl, R7 is lower alkyl and R8 is hydrogen or lower alkyl from the compounds of formula

Description

~1~5928 H-257b-C

The invention relates to hexahydroazepine, piperidine and pyrrolidine derivatives. More particularly the invention relates to a novel process f~or preparing 3,3-disubstituted-hexahydroazepine, -piperidine, and -pyrrolidine derivatives.
Various 3,3-disubstituted hexahydroazepines, -piperidines and -pyrrolidines are known to have pharma-cological activity, particularly analgesic activity. For example, analgesic 2-unsubstituted-3,3-disubstituted-hexahydroazepines, such as meptazinol, are disclosed inU.K. Specification No. 1,285,025. Profadol and related 3,3-disubstituted-pyrrolidines are described in J. Med.
Chem. 1965, 8, 316 and aelgian Patent Specification No. 850,777 while myfadol and related 3,3-disubstituted-piperidines are described in 0. Med. Chem. 1965, 8, 313.The known processes for preparing the 3,3-disubstituted-hexahydroazepines, -piperidines and -pyrrolidines are expensive and it is an object of the prevent invention to provide a novel process for preparing the desired 3,3-disubstituted-hexahydroazepines~ -piperidines and pyrrolidines such that the overall process for preparing the final products is generally more economic than the known processes.
The present invention provides a process for preparing a hexahydroazepine, piperidine or pyrrolidine of general formula 7 ( C H 2 i` ~ ~ o R 8 where n is 2, 3 or 4, R3 is hydrogen, lower alkyl, phentlower)alkyl, substituted phen(lower)alkyl (wherein the substituent is halogen, alkoxy or trifluoromethyl), ' ~ ~

H-257b-C
~592~3 lower alkenyl or lower alkynyl, R7 is lower alkyl and R8 is hydrogen or lower alkyl characterised in that a compound of general formula (II) R3 ~ OR (II) [in which n and R3 are as defined above and R2 is hydrogen, lower alkyl or aryl(lower)alkyl]is C-lower alkylated and reduced and, if desired, a product in which R8 is lower alkyl is ether cleaved to give a product in which R8 is hydrogen or a product in which R3 is hydrogen is N-alkylated to give a product in which R3 is lower alkyl, phen(lower)alky~ substituted phen-(lower)alkyl (wherein the substituent is halogen, alkoxy or trifluoromethyl), alkenyl or lower alkynyl.
The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms. The radical preferably contains 1 to 4 carbon atoms. For example when R3 is lower alkyl, the radical may be, for example, methyl, ethyl, propyl or butyl.
Where R3 is lower alkenyl or lower alkynyl it is to be understood that the double or triple bond is not in the 2û 1-position of the alkenyl or alkynyl radical; examples of suitable alkenyl and alkynyl radicals are allyl, propargyl, 3,3-dimethylallyl and 1-methyl-2-propynyl.
The compounds of general formula (II) may be prepared by aromatising and optionally O-(lower)alkylating or O-aryl(lower)alkylating compounds of general formula (I) ~5928 H-257b-C

(CH2)n ~ 0 R
(I) where n is as defined above and R is hydrogen, lower alkyl, phen(lower)alkyl or substituted phen(lower)alkyl to give a compound of general formula (II) in which R3 is hydrogen, lower alkyl, phEn(lower)alkyl or substituted phen(lower)alkyl and, if desired "N-alkylating" a compound of general formula (II) in which R3 is hydrogen to give a compound of general formula (II) in which R3 is lower alkyl, phen(lower)alkyl, substituted phen(lower)-alkyl, lower alkenyl or lower alkynyl.
Oy "N-alkylating" is meant introducing onto the nitrogen atom of the heterocyclic ring a lower alkyl, phen(lower)alkyl, substituted phen(lower)alkyl, lower alkenyl or lower alkynyl radical. A compound of formula (I) may be aromatised to a compound of formula (II) in which R2 is hydrogen by treatment with cupric halide (e.g. cupric bromide or cupric chloride), in the presence or absence of lithium halide. The reaction may be carried out in a solvent such as tetrahydrofuran or, preferably, acetonitrile. Alternatively a compound of ge-eral formula (I) may be aromatised to a compound of general formula (II) by treatment with bromine, for example, in a solvent such as chloroform, methylene dichloride or carbon tetrachloride. Preferably not more than about 1 mole of bromine is used per mole of compound of general formula (I). Alternatively, a compound of formula (I) may be aromatised and 0-(lower)alkylated to a compound of formula (II) in which R2 is lower alkyl by treatment with bromine in presence of a lower alkanol (for example, in a solvent such as benzene, cyclohexane , ~5~8 H-257b-C

or acetonitrile) or by treatment with a brominating agent such as N-bromosuccinimide in, for example, a solvent such as chloroform, methylene dichloride or carbon tetra-chloride containing a lower alkanol.
Compounds of formula (I) and their method of preparation are described in Canadian Patent Application No. 316,048, from which the present application is divided.
The compounds of general foImula (II) in which R3 is hydrogen can be "N-alkylated" as mentioned above; it is preferable to N-alkylate a compound in which R2 is lower alkyl or aryl(lower)alkyl. Compounds of formula (II) in which R2 is hydrogen can be O-(lower)alkylated or O-aryl(lower)alkylatsd to give compounds in which R2 is lower alkyl or aryl(lower)alkyl. The compounds of formula II can be alkylated in the 3-position with, for example, a lower alkyl group to give 3,3-disubstituted compoun~ of formula ~ / 2 (CH2 ~ ~ ~ OR

where n, R2 and R3 have the meanings given above and R1 is lower alkyl. The 3,3-disubstituted compounds can be reduced to give a 2-unsubstituted-3,3-disubstituted-hexa-hydroazepine, -piperidine or -pyrrolidine derivative. An embodiment of the process of the invention for preparing

2-unsubstituted-3,3-disubstituted-hexahydroazepines is illustrated, by way of example, in the reaction scheme below:-~5~32~
H-2i7b-C

W ~R6 ~ 3 ~ I ~o (IIC) N~o (IIb) 9R6~/ /
\~ ~/
N ~ ( I ! d ) ~! DH

/~ X3 (~

1 3 ( \J I ) ' H-257b-C
~5~'~8 ln this reaction scheme R and R3 have the meanings given above, R6 is lower alkyl or aryl(lower)alkyl and R7 is lower alkyl. Compounds (Ia) can be aromatised to compounds (IIa) by the procedures described above or alternatively compounds (Ia) can be aromatised and 0-(lower)alkylated to compounds (IIc) respectively by the procedure described above. If desired compound (IIa) can be etherified to compound (IIc) by treatment with a (lower)alkylating agent, e.g. dimethyl sulphate or with an aryl(lower)alkylating agent such as benzyl chloride. Either compound IIa or compound IIc can be C-(lower)alkylated to compound IIb or IId respectively. The C-(lower)alkylation can, for example, be carried out by reacting compound IIa or IIc with an alkyl halide (e.g. an alkyl bromide) in presence of a strong base, such as sodium hydride, sodamide or a metal amide M1A (where A is as defined above and M1 is sodium, potassium or lithium). The metal amide, such as lithium diisopropylamide may be formed in situ. Under some conditions compound IIa may be both C- and 0-alkylated to a compound of formula IId. If R3 in thecompound IIa is hydrogen then the N-atom should be alkylated (using a base such as for example sodium hydride in toluene) or benzylated before carrying out the C-(lower)alkylation process. The compounds IIb and IId can be reduced to the compounds VII and VI
respectively ad disclosed in our UK Patent Specification No. 1,285,025. For example, the reduction can be carried out with a hydride. If desired compound VI can be converted to compound VII by ether cleavage, e.g. with hydrogen bromide or boron tribromide, as described in the above mentioned UK Specification No. 1,285,025.
Compounds VI and VII are disclosed in UK
Specification No. 1,285,025 as having pharmacological activity, particularly analgesic activity. A particularly important analgesic compound is that of formula VII in H-257b-C
5~

which R3 is methyl and R7 is ethyl. This compound is meptazinol. The present invention provides a novel process for preparing such compounds in good yield from readily available starting materials. For example, the starting materials of formula V in which n is 4 are readily available derivatives of caprolactam.
The processes shown in the reaction scheme can be subject to various modifications. For example, the alkyl halides used in the C-alkylation of compounds IIa 1û and IIc can be replaced by other active halogen compounds to give compounds corresponding to VI and VII in which the 3-(lower)alkyl radical is replaced by an alkyl radical containing a functional group; if this functional group is reducible it may be further modified during the subsequent reduction step. In a further modi-fication the group in the 1-position of the intermediate compounds may be removed to give a N-H-derivative which may subsequently be alkylated, as for example, described in Specification 1,285,025, to give a product having a different 1-substituent. Analogous reactions to those described above in connection with the reaction scheme and the modifications can be carried out ~ith compounds I and II in which n is 2 or 3 to give analogous 2-unsubstituted-3,3-disubstituted-piperidines and -pyrrolidines having pharmacological activity such as profadol and related pyrrolidines described in J. Med.
Chem., 1965, 8, 316 and Oelgian Patent Specification No. 850777 and myfadol and related piperidines described in J. Med. Chem. 1965, 8, 313.
Compounds of general formula II can be prepared by alternative methods. ûne method is illustrated below:-' ~ 28 H-257b-C

O ( l oLIe r ) - : k ~ : ~ ( l o we r ) a l ky l CHco2Alkyl CHC02~1kY
(CH2)n-1 (CH2)nNH2 (VIII) \ / (IX) \ / O(lower)alkyl (CH~)n ~ N '~0 H

(X) In the above formulae n has the meaning given hereinbefore. In this process a nitrile ester of general formula UIII is reduced either directly to the cyclised compound of formula X or to the open chain compound IX
~hich can be cyclised to ths compound X. The reduction can be carried out by catalytic hydrogenation, e.g. at a temperaturs up to about 80C (for example with hydrogen in presence of palladium on charcoal at about room temperature in a solvent such as methanol containing sulphuric acid and under a pressure of about 60 p.s.i.) or at a temperature above about 100C (e.g. ~ith hydrogen in the presence of Raney nickel at temperatures of about 100 to 150C in a solvent such as cyclohexane and under .; , . ~ -H-257b-C
~p~ 8 pressures of about 800 to 1200 p.s.i.). Low temperature reduction tends to give the open chain compound IX while higher temperature reduction tends to give compound X.
The open chain compound IX may be cyclised to the compound X, e.g. by heating in a solvent (e.g. refluxing xylene or toluene). The compounds X are compounds of formula II in which R3 is hydrogen. Compounds X can be convsrted into-the compounds II in which R3 is lower alkyl or aryl(lower)alkyl by sel"ctively N-alkylating (including N-arylkylating) them with alkylating agents such as alkyl halides in the presence of a base.

The follouing examples illustrate the invention:

Hexahydro-3-(3-methoxyphenyl)-2H-azepin-2-one 2-(3-Methoxyphenyl)-5-cyanopentanoic acid methyl ester (10 9) was reduced at 60 p.s.i. in methanol (100 ml) containing conc. sulphuric acid (7.2 ml) and 10%
palladium charcoal (2.2 9). Uptake ceased when 2 moles of hydrogen had been taken up. The catalyst was filtered off, methanol removed under reduced pressure affording an oil, The oil was poured into water, basified with conc.
ammonium hydroxide, extracted into ether, the combined ether washings dried over magnesium sulphate and evaporated to an oil.
The oil (11 9) was heated under reflux in xylene for six days. The xylene was removed under reduced pressure affording an oil which gave pale yellow crystals of the title product from ethyl acetate (2.72 9), m.p. 116-11-7C.
A further 8g4 mg of crystals were obtained by distilling ---the residue and crystallising the resulting oil from ethyl acetate.
Analvsis: Found: C, 71.35; H, 7.94; N, 6.7%
C13H17N02 requires: C, 71.2; H, 7.8; N, 6.4%.

H-257b-C

Hexahydro-3-(3-methoxyphenyl)-1-methyl-2H-azepin-2-one Hexahydro-3-(3-methoxyphenyl)-2H-azepin-2-one (2.2 9) in dry toluene (40 ml) was added dropwise to a stirred suspension of sodium hydride (0.62 9, 0.015 mole of 50%
dispension in oil, pre-washed with dry light petroleum (b.p. 40-60). After stirring and heating at 60 for 1 hour the reaction was cooled to 5C and methyl iodide (1.9 ml, 2.5 9, 0.02 mole) was acded rapidly. After stirring at ambient temperature for 20 hours acetic acid and water were added. The aqueous layer was separated and washed with toluene. Toluene extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated to an oil. Oil was recrystallised from ethyl-acetate light petroleum (b.p. 60-80) affording 1.95 9 (83%) of hexahydro-3-(3-methoxyphenyl)-1-methyl-2H-azepin-2-one, in several crops, m.p. 74-5C.
Analysis: C, 72.4; H, 8.5; N, 5.7%
C14H19N02 requires: C, 72.1; H, 8.2; N, 6.0%

Hexahydro-3-(3-hydro~yphenyl)-1-methyl-2H-azepin-2-one Hexahydro-1-methyl-3-(oxocyclohexen-1-yl)-2H-azepin-2-one (11.1 9) in acetonitrile (250 ml) was stirred overnight with a mixture of copper (II) bromide (22.3 9) and lithium bromide (4.3 9). The acetonitrile was removed under reduced pressure and the dark residue suspended in sodium hydroxide solution (2N, 200 ml). The solution was filtered, the precipitate washed with water and the filtrate acidified with conc. hydrochloric acid. The precipitated title phenol was filtered and washed with water affording 8.62 9 of off-white powder m.p. 185-187C.
A second crop of 900 mg, m.p. 188-191C was obtained by extracting the mother liquors with chloroform. The H-257b-C
~l~S~Z8 product was purified by recrystallising from ethyl acetate or ethyl acetate/methanol to give pure product, m.p. 192-193C.
Analvsis: Found: C, 71.1; H, 8.û; N, 6.4%
C13H17N02 requires C, 71.2; H, 7.8; N, 6.4%

Hexahydro-3-(3-methoxyphenyl)-1-methyl-2H-azepin-2-one Hexahydro-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one (21.9 9) was dissolved in 2M sodium hydroxide solution (100 ml) and dimethyl sulphate (18.3 9, 14.5 ml) added. The reaction mixture was stirred at room temperature for 10 minutes then seeded. The product crystallised after leaving at 0C for 3 hours. The product was filtered, washed with water and dried affording 16.99 9 of title compound as off-white powder m.p. 73-74C, identical to that obtained in Example 2.
A further 1.69 9 of the required material was obtained by treating the aqueous mother liquors with 2M sodium hydroxide (50 ml) and dimethyl sulphate (7.25 ml).

3-Ethyl-hexahydro-3-(3-methoxyphenyl)-1-methyl-2H-azepin-2-one Hexahydro-3-(3-methoxyphenyl)-1-methyl-2H-azepin-2-one (4.66 9) in dry toluene (25 ml) was added propwise to a stirred suspension of sodium amide (1.0 9) in dry toluene (50 ml). The reaction mixture was heated to reflux, ammonia was evolved and the reaction mixture became red. After refluxing for 2 hours dry tetrahydro-furan (20 ml) was added, the mixture cooled and ethyl iodide (3.7 9) added. A white precipitate was formed and the red colour rapidly disappeared. The reaction mixture ~5~8 H-257b-C

was heated under reflux for 2 hours, cooled and decomposed by the addition of water. The aqueous phase was separated and the organic layer ~ashed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated affording an oil which crystallised from diisopropyl ether to give the title compound (3.29 9), m.p. 62-64C.
AnalYsis: Found: C, 73.5; H, 9.0; N, 5.15%
C16H23N02 requires C, 73.5; H, 8.9; N, 5.4%

3-Ethyl-hexahydro-3-(3-methoxyphenyl)-1-methyl-1H-azepine 3-Ethyl-hexahydro-3-(3-methoxyphenyl-1-methyl-2H-azepin-2-one (5.52 9) in anhydrous ether (100 ml) was added dropwise to a stirred suspension of aluminium lithium hydride (1.5 9) in anhydrous ether (50 ml).
The reaction was heated under reflux for 3 hours.
A further portion of aluminium lithium hydride (1.0 9) was added and heating continued for a further 2 hours.
After cooling, the reaction mixture was decomposed by the successive addition of water (3 ml), 15% sodium hydroxide (3 ml) and water (6 ml). The granular precipitate was filtered and the precipitate washed with ether. The combined filtrate and ether washings were extracted with 2M hydrochloric acid (3 x 25 ml)~
The combined acid washings were basified with 15 M
aqueous ammonium hydroxide and extracted with ether.
After drying over anhydrous magnesium sulphate the solvent was removed to leave 3.98 9 of title compound as a colourless oil 98% pure by gas/liquid chromato-graphy and identical to the material prepared by analternative route. [The product is converted to 3-ethyl-hexahydro-3-(3-hydroxyphenyl)-1-methyl-1H-azepine by treatment with hydrobromic acid according to the procedure described in U.K. Specification No. 1,285,025].

....

~5~28 H-257b_C

3-Ethylhexahydro-3-(3-hydroxyphenyl).1-methyl-2H-azepin-2-one -Butyl lithium (77 ml of a 1.4 molar solution in hexane) was added to a solution of diisopropylamine (14.8 ml) in dry tetrahydrofuran (20 ml) at -10C under nitrogen. The mixture was stirred at -10C for ten minutes and finely powdered hexahydro-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one (11 9) was added. Tetrahydro-furan (500 ml) was added and the mixture heated underreflux for 3 hours. After cooling, ethyl iodide (8.2 9) was added and the mixture again heated under reflux for 3 hours. ~ater (20 ml) was then cautiously added to the cooled solution and the mixture evaporated to a brown residue. After dissolving in water the mixture was extracted with dichloromethane and the dichloromethane extracted in turn with 2M sodium hydroxide. The aqueous and sodium hydroxide washings were combined and acidified with concentrated hydrochloric acid. The precipitated solid was filtered, washed with water, dried and recrystallised from ethyl acetate, affording 8.72 9 of the title compound as white crystals, m.p. 178-180C. .
Analysis: Found: C, 72.55; H, 8.6; N, 5.3%.
C15H21N02 requires C, 72.8; H, 8.6; N, 5.7%.

3-Ethyl-hexahydro-3-(3-hydroxyphenyl)-1-methyl-2H-azepine A solution of 3-ethylhexahydro-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one (1.5 9) in dry tetrahydrofuran was added to a sti~-red suspension of aluminium lithium 30 hydride (0.48 9) and heated under reflux for 5 hours.
The reaction mixture was cooled and decomposed by the addition of water and the precipitate filtered. The ~ 5~8 H-257b-C

precipitate was washed with tetrahydrofuran and the combined filtrate and washings evaporated to a solid.
The solid was dissolved in water and ammonium chloride added. The precipitated oil was extracted with dichloro-methane, dried over anhydrous magnesium sulphate andevaporated to leave a solid which was recrystallised from acetonitrile to give 0.91 9 of the title compound, m.p. 127.5-133C., identical with material prepared by an alternative route described in U.K. Specification No.
1,285,025.

3-(3-Hydroxyphenyl)-1-methyl-2-piperidone 1-Methyl-3-(3-oxocyclohexene-1-yl)-2-piperidone (3.5 9) was refluxed in acetonitrile (100 ml) in the presence of lithium bromide (1.4 9) and cupric bromide (7.6 9) for 0.5 hours. The acetonitrile was evaporated to give a gum, to which 2N sodium hydroxide (100 ml) was added, the solution filtered, conc. HCl (30 ml) added to the filtrate, the aqueous extracted with chloroform, dried (MgS04) and evaporated to give an oil, which on standing overnight, at 0C, in hexane gave a yellow solid. This was collected, washed with ether then acetone to give the title compound as the quater hydrate, a colourless solid (0.50 9) m.p. 111-114C.
Analysis: Found: C, 69.1; H, 7.27; N, 7.11%
C12H15N02 H20 requires C, 68.7; H, 7.45; N, 6.68%.

3-(3-Hydroxyphenyl)-1-methyl-2-pyrrolidone 1-Methyl-3-(3-oxocyclohexen-1-yl)-2-pyrrolidone (9.24 9), cupric bromide (21.39 9) and lithium bromide (4.16 9) were heated to reflux in acetonitrile (50 ml) ~lQ~2.~ H-257b-C

for 1 hour. The resulting dark solution was evaporated to dryness and the residue was treated with 2N sodium hydroxide solution (100 ml). The resulting orange precipitate was removed by filtration and washed with 2N sodium hydroxide (10 ml) and water (25 ml). The alkaline filtrate and washings were combined and extracted with dichloromethane (3 x 50 ml) to remove unreacted starting material. The dark aqueous phase was then acidified with conc. hydrochloric acid (25 ml) and extracted with chloroform (4 x 50 ml). The combined, dried (MgS04) extracts were evaporated, leaving a dark gum (8 85 9) which crystallised on seeding and dilution with a little ethyl acetate to a brown crystalline mass (7.8 9, 86.1%), m.p. 95-115C. This material was crystallised from ethyl acetate/BO-100 petrol, giving the title compound as pale buff crystals (5.12 9), m.p. 123-124C (decomp.).

3-(3-i~ydroxyphenyl)-1-methyl-3-(1-propyl)-2-pyrrolidone Lithium diisopropylamide was prepared under nitrogen at room temperature from n-butyllithium (1.4 M in hexane, 16 ml) and diisopropylamine (2.8 ml, 2.02 9). A solution of 3-(3-hydroxyphenyl)-1-methyl-2-pyrrolidone (1.71 9) in THF (50 ml) was added and the resulting suspension was stirred for 1 hour at room temperature. 1-Iodopropane (0.95 ml, 1.63 9) was then added in one lot, when the solid immediately dissolved. The mixture was warmed over 2 hours to reflux, held at reflux for 30 minutes, cooled, and treated with water (20 ml). Organic solvents were removed under reduced pressure and the residual aqueous phase was diluted with water (20 ml), and extracted with dichloromethane (2 x 50 ml). The lower emulsion phases were separated, combined, and back-extracted with water (3 x 10 ml). The dichloromethane - H-257b-C
~1~5~ZB

phase was dried (MgS04) and evaporated, leaving impure title compound as a brown gum which partially crystallised (0.3 9). The aqueous phases were combined with the original aqusous phase (pH>12) and acidified with conc.
hydrochloric acid to pH<1. The precipitated yellow gum was extracted into dichloromethane (4 x 25 ml) and the combined extracts were dried (MgS04) and evaporated, leaving a brown gum which crystallised on trituration with a little ethyl acetate treatment in ethyl acetate and removal of the solvent, from cyclohexane-toluene (about 1:1 v/v) to give 3-(3-hydroxyphenyl)-1-methyl-3-(1-propyl)-2-pyrrolidone as ochre crystals (0.91 9), m.p. 75.5-76.5C.
Analysis: Found: C, 72.2; H, 8.4; N, 6.2%
C14H19N02 requires C, 72.1; H, 8.2; N, 6.0%.

3-(3-Hydroxyphenyl)hexahydro-2H-azepin-2-one A mixture of hexahydro-3-(3-oxocyclohexen-1-yl)-2H-azepin-2-one (20.73 9), cupric bromide (44.9 9) and lithium bromide (8.8 9) was refluxed in acetonitrile (1000 ml) for 1 hour. Evaporation of the solvent left a black gum which was triturated with an excess of 2N
sodium hydroxide solution. The resulting orange suspension was filtered through Kieselguhr, and the filtrate acidified (conc. HCl). The white suspension was extracted several times with chloroform, and the residue left on evaporation of the organic layers was crystallised from ethyl acetate to give 3-(3-hydroxy-phenyl)hexahydro-2H-azepin-2 one (11.18 9) m.p. 175-178C.
Analysis: Found: C, 70.1; H, 7.6; N, 6.6%
C12H15N02 requires C, 70.22; H, 7.37; N, 6.82%.

H-257b-C
~1~35~3~8 3-(3-Benzyloxyphenyl)hexahydro-2H-azepin-2-one A solution of 3-(3-hydroxyphenyl)hexahydro-2H-azepin-2-one (2.05 9) in dry DMF was added dropwise to a suspension of sodium hydride (0.3 9). After 30 minutes at ambient temperature, benzyl chloride (1.3 9) was added.
The mixture was stirred for a further 2 hours and then cooled, and treated with water. The resulting solution was extracted several times with toluene, and the combined toluene layers washed thoroughly with water. The solvent was evaporated to give an oil that crystallised fron ethyl acetate to give the title compound as a white solid (1.4 9) m.p. 119-122C.
Analysis: Found: C, 77.42; H, 7.37; N, 4.64%
15 C19H21N02 requires C, 77.26; H,7.17; N, 4.74%. ~^;

3-Ethyl-hexahydro-3-(methoxyphenyl)-2H-azepin-2-one Lithium diisopropylamide, prepared by adding 15%
butyl lithium in hexane (15.7 ml) to diisopropylamine (3.15 ml) at -10C under nitrogen, was treated with a solution of hexahydro-3-t3-methoxyphenyl)-1-methyl-2H-azepin-2-one in THF. After 30 minutes, ethyl bromide (1.0 ml) was added. The mixture was allowed to warm to ambient temperature. After a further 2 hours the reaction was quenched with water. The organic layer was evaporated to give an oil that crystallised on scratching. The solid was recrystallised from ethyl acetate to give the title compound (1.68 9) m.p. 85-87C.
Analysis: Found: C, 72.88; H, 8.91; N, 5.39%
C15H21N02 requires C, 72.84; H, 8.56; N, 5.66%.

~ S~28 H-257b-C

Hexahydro-3-(3-hydroxyphenyl)-1-phsnylmethyl-2H-azepin-2-one A solution of hexahydro-1-phenylmethyl-2H-azepin-2-one (5.68 9) in dry THF was added at -1ûC to lithium diisopropylamide (0.032 m) prepared from diisopropylamine (4.4 ml) and butyl lithium (22.9 ml of 1.4M solution in hexane). The mixture was stirred for 30 minutes and then treated with a solution of 3-methoxy-2-cyclohexenone (2.53 9) in THF. After 5 hours at ambient temperature the mixture was poured onto ice-cold concentrated hydrochloric acid (1ûû ml). After vigorously stirring for 12 hours the solution was shaken with several portions of chloroform.
The combined chloroform layers were evaporated to gi~e an orange oil. This was refluxed with cupric bromide (B.95 9) and lithium bromide (1.74 9; 0.02 m) in acetonitrile for 1 hour. Removal of the solvent left a black oil that was triturated with excess 2N sodium hydroxide solution. The filtrate, after removal of the orange precipitate, was extracted wlth methylene chloride. The organic layer was acidified (conc. HCl) and the white suspension shaken with several portions of chloroform and were evaporated to leave a dark red oil (1.2 9) that crystallised from ethyl acetate to give the title compound (û.35 9) m.p. 160-166C.
AnalYsis: Found: C, 75.31; H, 7.48; N, 4.36%.
C19H21N02~H20 requires C, 74.97; H, 7.28; N, 4.6%.

Hexahydro-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one A solution of hexahydro-1-methyl-3-(3-oxocyclohexene-1-yl)-2H-azepin-2-one (150 9) in dichloromethane (750 ml) was warmed to 25C. Bromine (97.5) was added over 40 minutes at 25-32C (occasional water cooling being applied) and the mixture stirred for 2 hours at about 25C.

.
~: :

~1~5928 H-257b-C

Water (200 ml) was added and the dichloromethane layer washed with water (100 ml). The aqueous phasss were combined and extracted into dichloromethane (2 x 100 ml).
The dichloromethane extracts were combined and the solvent distilled off and replaced with ethyl acetate to keep temperature of 72C (750 ml ethyl acetate added; 900 ml distillate collected). The mixture was cooled to room temperature and filtered. The product was washed with 100 ml ethyl acetate and dried to give the title compound (134.3 9) as a crystalline fawn powder, m.p. 184-1C9C.
Identical to product of Example 3.

Hexahydro-3-(3-methoxyphenyl)-2H-azepin-2-one _ A suspension of hexahydro-3-(3-hydroxyphenyl)-2H-azepin-2-one (4.1 9), anhydrous potassium carbonate (5.6 9) and dimethyl sulphate (2.52 9) was heated under reflux with stirring in acetone (50 ml). After cooling the solution was filtered and evaporated to dryness under reduced pressure. The product was recrystallised from 2û diisopropyl ether/ethyl acetate affording the title compound, identical to that obtained by the method of Example 1.

3-Ethylhexahydro-3-(3-methoxyphenyl)-2H-azepin-2-one -Hexahydro-3-(3-methoxyphenyl)-2H-azepin-2-one (2.19 9) in dry tetrahydrofuran was added to a stirred solution of lithium diisopropylamide (from butyllithium 1.4 molar 15.7 ml, and diisopropylamine 3.15 ml) under nitrogen at 0C.
Ethyl bromide (1 ml) was added in one portion and the reaction allowed to warm up to room temperature. After two hours the reaction was poured into 2M HCl, the organic ~ ~ ~ Sc~ 8 H-257b-C

layer separated and the aqueous layer extractsd with chloroform. The combined organic layers were dried over magnesium sulphate, filtered and svaporated to an oil which was crystallised from ethyl acetate giving 1.68 9 of the title compound m.p. 85-7C.
Analysis: Found: C, 72.0; H, B.9; N, 5.4%
C15H21N02 requires C, 72.8; H, 8.6; N, 5.7%

3-n-Butyl-hexahydro-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one 3-(3-Hydroxyphenyl)-1-methyl-hexahydro-2H-azepin-2-one (11 9) as a finely powdered solid was added portionwise to a solution of lithium diisopropylamide (from diisopropylamine 14.8 ml, and 77 ml of 1.4M
butyllithium) in dry tetrahydrofuran(500 ml) under nitrogen. The suspension was heated under reflux for 3 hours, and n-bromobutane (5.6 ml, 7.14 9) added. The reaction was heated under reflux for a further 6 hours, cooled to 0C and an excess of 5M hydrochloric acid added slowly dropwise. The organic layer was separated and the aqueous layer extracted with chloroform. The combined organic extracts were washed with saturated sodium chloride, dried with magnesium sulphate and evaporated to an oil. The oil was crystallised and recrystallised from ethylacetate, affording 9.5 9 of colourless crystals, m.p. 138-142C.
Analysis: Found: C, 74.05; H, 9.52; N, 4.58%
C17H25N02 requires C, 74.1; H, 9.5; N, 5.1%.

Claims (5)

H-257b-C

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a hexahydroazepine, piperidine or pyrrolidine of general formula where n is 2, 3 or 4, R3 is hydrogen, lower alkyl, phen(lower)alkyl, substituted phen(lower)alkyl (wherein the substituent is halogen, alkoxy or trifluoromethyl), lower alkenyl or lower alkynyl, R7 is lower alkyl and R8 is hydrogen or lower alkyl characterised in that a compound of general formula (II) (II) [in which n and R3 are as defined above and R2 is hydrogen, lower alkyl or aryl(lower)alkyl] is C-lower alkylated and reduced and, if desired, a product in which R8 is lower alkyl is ether cleaved to give a product in which R8 is hydrogen or a product in which R3 is hydrogen is N-alkylated to give a product in which R3 is lower alkyl, phen(lower)alkyl, substituted phen(lower)alkyl (wherein the substituent is halogen, alkoxy or trifluoromethyl), alkenyl or lower alkynyl.

H-257b-C

2. A process as claimed in Claim 1 in which n is 4.

3. A process as claimed in Claim 1 in which the compound of formula II is prepared by a process which comprises (a) aromatising and optionally O-(lower)alkylating or O-aryl(lower)alkylating a compound of general formula (I) (I) where n is as defined in Claim 1 and R is hydrogen, lower alkyl, phen(lower)alkyl or substituted phen(lower) alkyl (wherein the substituent is halogen, alkoxy or trifluoromethyl) to give a compound of general formula (II) in which R3 is hydrogen, lower alkyl, phen(lower) alkyl or substituted phen(lower)alkyl (wherein the substituent is halogen, alkoxy or trifluoromethyl) and, if desired, N-alkylating a compound of general formula (II) in which R3 is hydrogen to give a compound of general formula (II) in which R3 is lower alkyl, phenyl(lower)alkyl, substituted phen(lower)alkyl (wherein the substituent is halogen, alkoxy or trifluoro-methyl), lower alkenyl or lower alkynyl, or (b) reducing and cyclising a compound of general formula (VIII) (VIII) H-257b-C

or (c) cyclising a compound of general formula (IX) (IX) and, if desired, N-alkylating a product in which R3 is hydrogen to give a compound in which R3 is lower alkyl, phen(lower)alkyl or substituted phen(lower)alkyl (where the substituent is halogen, alkoxy or trifluoro-methyl).

4. A process for preparing 3-ethyl-hexahydro-3-(3-methoxyphenyl)-1-methyl-1H-azepine which comprises ethylating hexahydro-3-(3-methoxyphenyl)-1-methyl-2H-azepin-2-one to give 3-ethyl-hexahydro-3-(3-methoxyphenyl)-1-methyl-2H-azepin-2-one and reducing the azepin-2-one product.

5. A process for preparing 3-ethyl-hexahydro-3-(3-hydroxyphenyl)-1-methyl-1H-azepine which comprises ethylating hexahydro-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one to give 3-ethylhexahydro-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one and reducing the azepin-2-one product.