IE54155B1 - Pyrrolidines, piperidones and hexahydroazepinones - Google Patents

Description

This invention relates to intermediates useful in the preparation of m-hydroxyphenyl substituted compounds.

Many m-hydroxyphenyl substituted compounds are known and are useful particularly as pharmaceuticals. For example analgesic 3-hydroxyphenyl-hexahydroazepines such as meptazinol are disclosed in UK Patent Specification No. 1,285,025. Profadol and related pyrrolidines are described in J. Med. Chem. 1965, !5, 316 and Belgian Patent Specification No. 850,777 while myfadol and related piperidines are described in J. Med. Chem., 1965, 8, 313.

Our Patent Specification No. , from which the present Application is divided, discloses a process for preparing m-hydroxyphenyl substituted compounds of the general formula where R is carboxymethyl, -CH2COO(lower)alkyl or a monocyclic or bicyclic heterocyclic radical containing one or more oxygen, sulphur or nitrogen atoms as heteroatoms and R^ is hydrogen or an organic radical, which process comprises dehydrohalogenating a compound of the general formula (where R and R^ are as defined above and X is chlorine or bromine) in the presence of a strong nucleophilic acid catalyst. - 3 The present invention provides certain novel intermediates of general formula (II). These novel intermediates have the formula where R and X are as defined above, n is 2, 3 or 4 3 (preferably 4), R is hydrogen or lower alkyl and R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl(lower)alkyl or aryl(lower)alkyl. R , when it is an organic radical may be an aliphatic, aromatic or heterocyclic radical. The radical may contain substituents, including functional groups. R can be, for example, (lower)alkyl, phenyl or substituted phenyl such as chlorophenyl (the substituent R^ being para to the X group in formula III)- Preferably is hydrogen. 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, a lower alkyl radical is preferably methyl, ethyl, propyl or butyl. Examples of lower alkenyl and lower alkynyl radicals are allyl, propargyl, 3,3-dimethylallyl and 1-methyl2-cyclopropylmethyl. Examples of aryl(lower) alkyl are 155 - 4 phenethyl or benzyl in which the phenyl group may be substituted by one or more substituents such as halogen, alkoxy, trifluoromethyl or other substituents common in medicinal chemistry.

The novel intermediates are useful in preparing compounds of general formula (I) where R is 3 (wherein n, R and R are as defined above) as described in Patent Specification No. ; , The compounds of general formula (III) may be 10 prepared by reacting a 2-halocyclohexenone derivative of general formula (IX) s Λ 1 5 5 ,1 (IX) where X and R1 are as defined above and Q is a hydrolysable protecting group such as lower alkoxy, benzyloxy or trialkyl-, triaryl- or triaralkyl-siloxy (e.g. trimethyl-silyloxy) with a nucleophilic reagent selected from an anion or dianion of a lactam of general formula (X) (ΓΗ ) ,CHR Λ x N 0 (X) (where n and R are as defined above and R is hydrogen, lower alkyl, aryl lower alkyl, or trialkyl-, triaryl or triaralkyl-silyl) and subjecting the product to hydrolysis. The preparation and reactions of the anion or dianion of the lactam of formula (X) is described in, for example, European Patent Application 0003253. The nucleophilic reagent may be an anion (preferably the sodium, potassium, lithium or MgHal anion) of a lactam (XX) The anion of the lactam may be prepared by reacting the lactam with e.g. lithium diisopropylamide. ? 5 ί — 6 The 2-halocyclohexanone derivatives of.general formula (XX) are known or can be prepared by the process illustrated below (XIII) The halogenation step (XI) to (XII) may be carried out by methods known in the art (by reaction with, e.g. N-bromosuccinimide or N-chlorosuccinimide in a solvent such as carbon tetrachloride, with sulphuryl chloride in a solvent such as chloroform or with chlorine or bromine), However, for superior yields, we prefer to brominate using aqueous potassium bromate in aqueous hydrobromic acid or to chlorinate with an aqueous solution of Chloramine T (N-chloro-4-methylbenzenesulphonamide sodium salt).

The halogenation step (XIII) to (IX) may also be carried out by methods known in the art. Preferably in this step X is bromine and the bromination may be carried out,e.g. with bromine in, for example, sodium acetate/acetic acid or with N-bromosuccinimide in, for example, carbon tetrachloride. However, preferably the bromination is effected with N-bromosuccinimide in a more polar solvent such as dichloroethane or acetonitrile.

The steps (XI) to (XIII) and (XII) to (IX) may be - 7 carried out by methods known in the art, for example (XI) or (XII) may be reacted with an alcohol in a solvent such as toluene in the presence of an acid with azeotropic removal of water. An alternative method of alkylation is described and claimed in our copending UK Application 2110676A. Reaction of compounds (XII) or (XIII) with silylating agents (such as trimethylsilyl chloride in the presence of an organic base) gives compounds in which Q is trialkyl-, triarylor triaralkyl-silyloxy.

The following Examples illustrate the invention: EXAMPLE 1 3-(2-Chloro-3-oxocyclohex-1-enyl)-hexahydro-1methylazepin-2-one Lithium diisopropylamide was prepared from nbutyllithium (1.55M in hexane, 6.45 ml) and diisopropylamine (1.4 ml) in tetrahydrofuran (10 ml). It was treated at 0°C with 1-methylcaprolactam (1.27 g) and then with 2-chloro-3-methoxycyclohexenone (1.61 g) in THF (5 ml). The reaction mixture was stirred for 5 minutes and then poured on to cold 2N hydrochloric acid. After % hour toluene was added and the layers separated. The organic phase was washed with aqueous NaOH and water, dried and evaporated to give the crystalline product (1.9 g) m.p. T18-120°C. (Found: C, 61.4? H, 7.3; N, 5.3%. C^H^CltK^ requires C, 61.1; H, 7.1; N, 5.5%). 4 155 ~ 8 EXAMPLE 2 3-(2-Bromo-3-oxocyclohex-l-enyl)-hexahydro-l-methylazepin 2-one Lithium diisopropylamide was made from n-butyl lithium (1.55M in hexane, 12.9 ml) and diisopropylamine(2.8ml) in THF (13 ml). The mixture was treated with 1-methyl-caprolactam.(2.54g)and then with 2-bromo-3-methoxycyclohexenone (4.1 g) in THF (15 ml). After 1 min. the reaction mixture was poured onto 5NHC1 (8 ml) and cold water (100 ml).

After 0.5 h ether was added and the organic phase separated, dried and evaporated. Recrystallisation of the residue from ethyl acetate gave the title compound 14.9 g), m.p. 112-115°C (d). (Found; C, 51.7; H, 6.2; N,4.7%. C13H18BrNO2 squires; C, 52.0; H, 6.0; 4.7%).

EXAMPLE 3 Following the procedures of Examples 1 and 2 but using the appropriate halomagnesium anion of 3-ethyl-1-methylhexahydroa2epin-2-one, the following compounds were prepared: (a) 3-(2-bromo-3-oxocyclohex-l-enyl)-3-ethyl-hexahydro20 l-methylazepin-2-one, m.p. 106-7°C (Found: C, 54.7; H, 6.8; N, 4.2%. C15H22BrNO2 requires: C, 54.9; H, 6.8; N, 4.3%) (b) 3-(2-chloro-3-oxocyclohex-l-enyl)-3-ethylhexahydrol-methylazepin-2-one, m.p. 115-116°C (Found: C, 63.7; H, 7.9; N, 4.85%. C15H22C1NO2 requires C, 63.5; H, 7.8; N, 4.9%). 415 · - 9 EXAMPLE 4 3-(2-Bromo-3-oxocyclohex-1-enyl)-1 -propyl-2-piperidone A solution of 1-propyl-2-piperidone (50mM) in benzene (40 ml) was added dropwise to a solution of lithium di-isopropylamide [ex n-butyl lithium in hexane (32.3 ml, 50 mM), di-isopropylamine (7 ml, 50 mM) and THF (33 ml)]. A solution of 2-bromo-3-methoxycyclohex-2 -en-1-one (10.25g, 50 mM) in THF (40 ml) was added, and after 5 minutes the mixture was quenched by pouring on to excess aqueous hydrochloric acid. Ether extraction followed by passage through a short silica pad using ethyl acetate as eluant gave the title compound as a colourless oil (10.75 g).

Claims (7)

1. A compound of general formula wherein Is hydrogen or an organic radical, . . 2 X is chlorine or bromine, n is 2, 3 or 4, R is 3 hydrogen or lower alkyl and R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl(lower)alkyl or aryl(lower)alkyl.

2. A compound as claimed in Claim 1 wherein R^ is hydrogen.

3. 3-(2-Chloro-3-oxocyclohex-1-eny1)-hexahydro-1methylazepin-2-one or 3-(2-bromo-3-oxocyclohex-1enyl)-hexahydro-1-methylazepin-2-one or 3-(2-bromo3-oxocyclohex-1-enyl)-3-ethyl-hexahydro-1methylazepin-2-one or 3-(2-chloro-3-oxocyclohex-1-enyl) 3-ethyl-hexahydro-1-methylazepin-2-one.

4. 3-(2-Bromo-3-oxocyclohex-l-enyl)-1-propy1-2piperidone.

5. A process for preparing a compound claimed in Claim 1 which comprises reacting a 2-halocyclohexenone derivative of general formula 5 415? where X and are as defined in Claim 1 and Q is a hydrolysable protecting group with an anion or dianion of a lactam of general formula (X) where n is 2, 3 or 4, R is hydrogen or lower alkyl 5 and R 3 is hydrogen, lower alkyl, aryl (lower) alkyl or trialkyl-, triaryl- or trialkyl-silyl, and subjecting the product to hydrolysis.

6. A process for preparing a compound as claimed in Claim 1 substantially as hereinbefore described 10 with reference to any one of Examples 1, 2, 3a, 3b and 4.

7. A compound as claimed in Claim 1 whenever prepared by the process claimed in Claim 5 or 6.