GB2145089A - Pyrrolidones, piperidones and hexahydroazepinones - Google Patents
Pyrrolidones, piperidones and hexahydroazepinones Download PDFInfo
- Publication number
- GB2145089A GB2145089A GB08424826A GB8424826A GB2145089A GB 2145089 A GB2145089 A GB 2145089A GB 08424826 A GB08424826 A GB 08424826A GB 8424826 A GB8424826 A GB 8424826A GB 2145089 A GB2145089 A GB 2145089A
- Authority
- GB
- United Kingdom
- Prior art keywords
- hydrogen
- alkyl
- enyl
- compound
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D223/08—Oxygen atoms
- C07D223/10—Oxygen atoms attached in position 2
Abstract
Novel compounds of the formula <IMAGE> [where R<1> is hydrogen or an organic radical, X is chlorine or bromine, n is 2, 3 or 4, R<2> is hydrogen or lower alkyl and R<3> is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl(lower)alkyl or aryl(lower)alkyl] are useful as intermediates for preparing m-hydroxyphenyl substituted compounds of formula <IMAGE> (where n, R<1>, R<2> and R<3> have the meanings given above).
Description
SPECIFICATION
Pyrrolidones, piperidones and hexahydroazepinones
This invention relates to intermediates useful in the preparation of m-hydroxyphenyl substituted compounds.
Many m-hydroxphenyl substituted compounds are known and are useful particularly as pharmaceuticals. For example analgesic 3-hydroxphenyl-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, 8, 316 and Belgian Patent Specification No. 850,777 while myfadol and related piperidines are described in J. Med. Chem., 1965, 8, 313.
Our UK Application No. 8232536 (Publication No. 2113676A), from which the present application is-divided, discloses a process for preparing m-hydroxyphenyl substituted compounds of the general formula
where R is an organic radical and R' is hydrogen or an organic radical, which process comprises dehydrohalogenating a compound of the general formula
(where R is an organic radical, R' is hydrogen or an organic radical and X is chlorine or bromine) in the presence of a strong nucleophilic acid catalyst.
According to UK Application 8232536 the organic radical R, and also R' when it is an organic radical, may be an aliphatic, aromatic or heterocyclic radical. The radicals may contain substituents, including functional groups. R' can be, for example (lower)alkyl, phenyl or substituted phenyl such as chlorophenyl (the substituent R1 being meta to both the R group and the hydroxy group in formula 1). Preferably R' is hydrogen.
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 (preferably 4), R2 is hydrogen or lower alkyl and R3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl(lower)alkyl or aryl(lower)alkyl. 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-methyl-2-cyclopropylmethyl. Examples of aryl(lower)alkyl are 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
(wherein n, R2 and R3 are as defined above) as described in UK Application 8232536.
The compounds of general formula (III) may be prepared by reacting a 2-halocylohexenone derivative of general formula (IX)
where X and R1 are as defined above and Q is a hydrolysable protecting group such as lower alkoxy, benzyloxy or trialkyi-, 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)
(where n and R2 are as defined above and R5 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 of general formula (Xl)
The anion of the lactam may be prepared by reacting the lactam with e.g. lithium diisopropylamide.
The 2-halocyclohexanone derivatives of general formula (IX) are known or can be prepared by the process illustrated below
The halogenation step (Xl) 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 (Xl) to (XIII) and (XII) to (IX) may be 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-, triaryl- or triaralkyl-silyloxy.
The foilowing Examples illustrate the invention:
EXAMPLE 1 3-(2-Chloro-3-oxocylohex- 1 -en yl)-hexahydro- 1-methylazepin-2-one Lithium diisopropylamide was prepared from n-butyllithium (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 (1.279) 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.
118-120"C. (Found: C, 61.4; H, 7.3; N, 5.3%. C,3H8CINO2 requires C, 61.1; H, 7.1; N, 5.5%).
EXAMPLE 2 3-(2-Bromo-3-oxocylohex- 1-en yl)-hexahydro- 1 -meth ylazepin-2-one Lithium diisopropylamide was made from n-butyl lithium (1.55M in hexane, 12.9 ml) and diisopropylamine (2.8 ml) in THF (13 ml). The mixture was treated with 1-methyl-caprolactam (2.459) and then with 2-bromo-3-methoxycyclohexenone (4.1 9) in THF (15 ml). After 1 min.
the reaction mixture was poured onto 5NHCI (8 ml) and cold paper (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 (4.9 g), m.p. 112-115 C (d). (Found: C, 51.7; H, 6.2; N, 4.7%. CI3H18BrNO2 requires: 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-methylhexahydroazepin-2-one, the following compounds were prepared: (a) 3-(2-bromo-3-oxocylohex- 1 -enyl)-3-ethyl-hexahydro-1 -methylazepin-2-one, m.p. 106-7"C (Found: C, 54.7; H, 6.8; N, 4.2%. C'5H22BrNO2 requires: C, 54.9; H, 6.8; N, 4.3%) (b) 3-(2-chloro-3-oxocylohex- 1 -enyl)-3-ethylhexahydro- 1 -methylazepin-2-one, m.p. 115-116 C (Found: C, 63.7; H, 7.9; N, 4.85%. C15H22CINO2 requires C, 63.5; H, 7.8; N, 4.9%).
EXAMPLE 4 3-(2-Bromo-3-oxocylohex- 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), diisopropylamine (7 ml, 50 mM) and THF (33 ml)l. A solution of 2-bromo-3-methoxy-cyclohex-2en-1-one (10.259, 50 nM) 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 9).
Claims (7)
1. A compound of general formula
wherein R' is hydrogen or an organic radical, X is chlorine or bromine, n is 2, 3, or 4, R2 is hydrogen or lower alkyl and R3 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 -enyl)-hexahydro- 1 -methylazepin-2-one or 3-(2-bromo-3-oxocy lohex-l -enyl)-hexahydro-l -methylazepin-2-one or 3-(2-bromo-3-oxocyclohex-1 -enyl)-3-ethyl-hex ahydro- 1 -methylazepin-2-one or 3-(2-chloro-3-oxocyclohex- 1 -enyl)-3-ethyl-hexahydro-l -methyla- zepin-2-one.
4. 3-(2-Bromo-3-oxocylohex-1 -enyl)-1 -propyl-2-piperidone.
5. A process for preparing a compound claimed in Claim 1 which comprises reacting a 2halocyclo-hexenone derivative of general formula
where X and R' 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, R2 is hydrogen or lower alkyl and R5 is hydrogen, lower alkyl, aryl(lower)alkyl or tiralkyl-, 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 with reference to any one of Examples 1, 2, 3a, 3b and 4.
7. A compound whenever prepared by the process claimed in Claim 5 or 6.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB08424826A GB2145089B (en) | 1981-12-02 | 1984-10-02 | Pyrrolidines, piperidones and hexahydroazepinones |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8136364 | 1981-12-02 | ||
GB8220721 | 1982-07-16 | ||
GB08232536A GB2113676B (en) | 1981-12-02 | 1982-11-15 | M-hydroxypheny1 substituted compounds |
GB08424826A GB2145089B (en) | 1981-12-02 | 1984-10-02 | Pyrrolidines, piperidones and hexahydroazepinones |
Publications (3)
Publication Number | Publication Date |
---|---|
GB8424826D0 GB8424826D0 (en) | 1984-11-07 |
GB2145089A true GB2145089A (en) | 1985-03-20 |
GB2145089B GB2145089B (en) | 1985-10-16 |
Family
ID=27449299
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08424826A Expired GB2145089B (en) | 1981-12-02 | 1984-10-02 | Pyrrolidines, piperidones and hexahydroazepinones |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2145089B (en) |
-
1984
- 1984-10-02 GB GB08424826A patent/GB2145089B/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
GB8424826D0 (en) | 1984-11-07 |
GB2145089B (en) | 1985-10-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6197976B1 (en) | Preparation of ketorolac | |
JP4538114B2 (en) | Novel process for the preparation of derivatives of 4-phenyl-1,2,3,6-tetrahydropyridine and intermediates used | |
EP0060120B1 (en) | Process for preparing 4-haloazetidin-2-ones | |
GB2145089A (en) | Pyrrolidones, piperidones and hexahydroazepinones | |
US4463177A (en) | Process for making m-hydroxyphenyl substituted compounds | |
IE54155B1 (en) | Pyrrolidines, piperidones and hexahydroazepinones | |
US4197239A (en) | Hexahydroazepine, piperidine and pyrrolidine derivatives | |
EP0021772B1 (en) | Method of preparing 2-oxo- and 2-unsubstituted-hexahydroazepine derivatives | |
US6153755A (en) | Process for preparing pharmaceutically active compounds and intermediates thereof | |
EP0536512B1 (en) | A method and intermediates for the preparation of 6-fluorobenzisothiazoles | |
GB2113676A (en) | m-Hydroxyphenyl substituted compounds | |
US5908961A (en) | Production of aminophenols | |
NO179903B (en) | Process for the preparation of a haloacetamide derivative and a pyrrolidinylacetamide derivative | |
US4545934A (en) | Process for the producton of 4-substituted acetoacetic acid derivatives | |
JP4663105B2 (en) | Method for producing 2-sulfonyl-4-oxypyridine derivative | |
Azzena et al. | Application of the anionic homologous Fries‐rearrangement to the synthesis of 3‐alkylbenzofuran‐2 (3H)‐ones | |
US3347866A (en) | 4-(indol-3-yl)-hexahydro-1h-azepines and their method of preparation | |
EP0131921A2 (en) | Ortho-(mono-substituted amino)phenylimines and production thereof | |
JPH07103098B2 (en) | Efficient Stereoconservative Synthesis of 1-Substituted (S)-and (R) -2-Aminomethylpyrrolidines and Intermediates Thereof | |
JPH051259B2 (en) | ||
JPH07121949B2 (en) | 2β-N-Substituted triazolylmethylpenam derivative, its salt and its ester, and their production method | |
JPS6024187B2 (en) | Method for producing β-lactam derivatives | |
JPH09227556A (en) | Isoxazolidine compound and its production | |
EP0017264A1 (en) | Bicyclic lactams and a process for their preparation | |
JPS60255762A (en) | Manufacture of 1-substituted azetidine-3-ol derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20001115 |