Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
2000-02-01
2000-09-12
Ramsuer, Robert W.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D23112
Patent
active
061180092
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/ES98/00223, filed Jul. 31, 1998.
DESCRIPTION
1. Field of the Invention
This invention refers to a new procedure for obtaining the enantiomers of cyzolirtine, (.+-.)-2-[phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine, that consists of a sequential process of asymmetric reduction of a ketone followed by alkylation of the alcohol formed.
2. Background of the Invention
The racemic mixture (.+-.)-2-[phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine (cyzolirtine), of formula I, ##STR1## described in the European patent EP 289 380, shows analgesic properties and currently is in a phase of clinical trials. The two enantiomers of the compound of formula (I) have been synthesised and their analgesic properties evaluated [J. A. Hueso, J. Berrocal, B. Gutierrez, A. J. Farre and J. Frigola, Biorg. Med. Chem. Lett. 1993, 3, 269]. It was found that the dextro-rotatory enantiomer was the most active.
The enantiomers, whose formulae are (+)-I and (-)-I, were obtained by O-alkylation of the enantiomers of formulae (+)-II and (-)-II respectively, ##STR2##
The enantiomer of formula (+)-II has been obtained by synthesis with very low yields, using (-)-ethyl madelate, allowing the absolute configuration (R) to be assigned to the compound of formula (+)-II. The enantiomers of formula II have also been obtained from laborious processes of separation, by column chromatography or by fractionated crystallisation, of the diastereoisomeric esters formed by reaction of the compound of formula (+)-II with (+)-O-acetylmandelic acid. The yields obtained were 22% for the enantiomer of formula (-)-II and 25% for the enantiomer of (+)-II [J. A: Hueso, J. Berrocal, B. Gutierrez, A. J. Farre and J. Frigola, Bioorg. Med. Chem. Lett. 1993, 3, 269].
On the other hand, during the last few years, obtaining enantiomers by asymmetric synthesis has become an important synthesis method. The asymmetric or enantioselectivity synthesis methods are very abundant and have been extensively described [a) for a treatment of this topic see Morrison, Asymmetric Synthesis, 5 vols., Academic Press: New York, 1983-1985. b) For books, see Nogradi, Stereoselective Synthesis, VCH: New York, 1986; Eliel, Otsuka, Asymmetric Reactions and Processes in Chemistry, American Chemical Society: Washington, 1982; Morrison, Mosher, Asymmetric Organic Reactions, Prentice-Hall: Englewood Cliffs, N.J., 1971; Izumi, Tai, Stereo-Differentiating Reactions, Academic Press: New York, 1977. c) For reviews see Ward, Chem. Soc. Rev., 1990, 19, 1; Whitesell, Chem. Rev., 1989, 89, 1581; Fujita, Nagao, Adv. Heterocycl. Chem. 1989, 45, 1; Oppolzer, Tetrahedron, 1987, 43, 1969; Seebach, Imwinkelried, Weber, Mod. Synth. Methods, 1986, 4, 125; Mukaiyama, Asami, Top. Curr. Chem., 1985, 127, 133].
The enantioselective reduction of pro-chiral ketones to obtain alcohols with a raised enantiomeric purity is currently the topic of many studies in organic chemistry. [For reviews of the topic see: Brown, Cho, Park, Ramachandran, J Org. Chem., 1987, 52, 5406; Singh, Synthesis, 1992, 605; Brown, Ramachandran, Acc. Chem. Res., 1992, 25, 16; Midland, Morrell, in Houben-Weyl Methods of Organic Chemistry, Helmchen; Hoffmann, Mulzer, Schaumann, Eds. Thieme Verlag: Stuttgart, 1995, Vol. E21d, p4049]. In particular, during the last few years the use of oxazoborolidines as ligands has constituted a very important advance in the asymmetric reduction of ketones. [For recent reviews see: Walbaum and Martens, Tetrahedron: Asymmetry, 1992, 3, 1475; Deloux and Srebnik, Chem. Rev., 1993, 93, 763. See also: Corey, Bakshi, Shibata, Chen, Singh, J. Am. Chem. Soc., 1987, 109, 7925; Franot, Stone, Engeli, Spondlin, Waldvogel, Tetrahedron: Asymmetry, 1995, 6, 2755 and references therein; Hong, Gao, Nie, Zepp, Tetrahedron Lett., 1994, 35, 6631; Gadja, Tetrahedron: Asymmetry, 1994, 5, 1965; Willems, Dommerholt, Hammink, Vaahost, Thijs, Zwanenburg, Tetrahedron Lett., 1995, 36, 603; Dubois, Fiaud, Kagan, Tetrahedron: Asymmetry, 1995, 6, 1097; Meier, Laux, Tetrahedro
REFERENCES:
Bioorganic & Medicinal Chemistry Letters, vol. 3, N.sup.o -2, pp. 269-272, 1993. J.A. Hueso-Rodriguez etal., "Preparation of the Enantiomers Cited in the Analgesic E-3710".
Frigola-Constansa Jordi
Torrens-Jover Antoni
Laboratorios Del Dr. Esteve, S.A.
Ramsuer Robert W.
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