Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-05-16
1997-05-13
McKane, Joseph
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
544335, 544374, 544336, 546139, 546174, 5462847, 540598, 548253, 548255, 5482686, 5483154, 5483657, 549 60, C07D30726
Patent
active
056294328
DESCRIPTION:
BRIEF SUMMARY
This is a National Stage filing under 35 U.S.C. 371 of PCT/GB/93/02427, filed Nov. 25, 1993.
This invention relates to lactones, their use and a process for their preparation.
The invention is particularly concerned with the preparation of lactones of the general formula ##STR2## where R is an optionally substituted phenyl group or an optionally substituted mono- or bicyclic heteroaryl radical containing as the hetero atom or atoms one or more sulphur oxygen or nitrogen atoms, the substituents in the phenyl group or the heteroaryl radical being selected from the group consisting of lower alkyl, lower alkoxy, halogen, halogen halo (lower)alkyl, amino, (lower)alkylamino and di(lower)alkylamino.
The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4 carbon atoms. Examples of "lower alkyl" are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert.-butyl. Examples of lower alkoxy are methoxy, ethoxy, propoxy and butoxy. An example of halo(lower)alkyl is trifluoromethyl.
Preferably the heteroaryl radical contains 5 to 11 ring atoms. A monocyclic radical may, for example, contain 5 to 7 ring atoms and a bicyclic radical may contain 9 to 11 ring atoms. Preferably the hetero ring contains at least one nitrogen atom as the hetero atom.
Examples of heteroaryl are optionally substituted pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, quinolinyl, isoquinolinyl, triazolyl, tetrazolyl, thienyl and furyl.
The lactones of general formula (I) are useful as intermediates for preparing pharmacologically active compounds, for example the 5-HT.sub.1A binding agents disclosed in EP-A-0395312, EP-A-0481742 and EP-A-0481744. A particularly preferred lactone of formula I is one in which R is phenyl. This is .alpha.-phenyl-.gamma.-butyrolactone, which has the formula ##STR3##
This may be used as an intermediate in preparing the compounds described and claimed in EP-A-0481744. The compounds of EP-A-0481744 are the racemic and enantiomeric forms of 2,3,4,5,6,7-hexahydro-1-[4-[1-[4-(2-methoxyphenyl)-piperazinyl]]-2-phenylb utyryl]-1H-azepine. The compounds are 5-HT.sub.1A binding agents. They may be used, for example, as anxiolytics. The preparation of the compounds from .alpha.-phenyl-.gamma.-butyrolactone is illustrated in the reaction scheme below. The reagents and solvents for the individual steps are given for illustrative purposes only and may be replaced by other reagents and solvents known to the man skilled in the art. ##STR4##
Other compounds of formula (I) may be used in an analogous manner to prepare the compounds of EP-A-0395312 and EP-A-0481742.
Literature references (e.g. Aboul-Enein et al, Indian J. Chem., 1980, 19B, 1083 and Nilsson et al, J. Med. Chem., 1992, 35, 288) disclose the preparation of .alpha.-phenyl-.gamma.-butyrolactone by reaction of an ethylene dihalide with diethyl phenylmalonate under basic conditions followed by hydrolysis of the intermediate halo compound of formula ##STR5## where X is halo.
The process described in the literature gives poor yields of the lactone (due possibly to .beta.-elimination reactions and/or formation of dimers) and/or are unsuitable for preparation of the lactone on a large scale due to the large excess of ethylene dihalide required and/or the necessity of sequential additions of halide/NaH. These disadvantages are overcome (or substantially reduced) by the process of the present invention.
The process described by Cave et al in Eur. J. Med. Chem., 1986, 21, 487-492 for preparing the lactone is similar to the above mentioned literature references except that the intermediate 2-carbethoxy-2-phenyl-.gamma.-butyrolactone is isolated.
According to the present invention lactones of general formula II are prepared by a process which comprises reacting an anion of a malonate of formula (II) ##STR6## (where R is as defined above and R.sup.1 and R.sup.2 are each lower alkyl) with an ethylene compound of formula (III) methanesulphonyloxy) and Z is a protecting group that is removable under aq
REFERENCES:
Cave et al, European Journal of Medicinal Chemistry, Clinica Therapeutica, vol. 21, No. 6, 1986, pp. 487-492.
March, Advanced Organic Chemistry, Third Ed., Mar. 1985, John Wiley & Sons, NY pp. 210-316 (1985).
Nilsson et al., J. Med. Chem., vol. 35, No. 2, 1992, pp. 285-294.
John Wyeth & Brother Ltd.
McKane Joseph
Myers, Jr. Richard S.
Seifert Arthur G.
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