Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1993-03-01
1994-02-01
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
549372, 549350, 562463, 564177, 564169, 564355, 564363, 568 6, C07C 6976, C07F 502
Patent
active
052833593
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the preparation of arylethanolamines, and in particular to the synthesis of albuterol (salbutamol) and other arylethanolamines of the type disclosed in British Patent Specifications Nos. 1,200,886, 1,214,012 and 1,266,058. Furthermore, the present invention also relates to the preparation of certain novel boron-complexes and of certain acetals, hemi-acetals and hydrates of arylglyoxals useful as intermediates in preparing said arylethanolamines, particularly albuterol.
BACKGROUND
British Patent Specification No. 1,200,886 discloses certain arylethanolamines, which are theraputically active compounds useful as antihypertensive and bronchodilating agents, and two methods for their preparation.
British Patent Specification 1,200,886, "Pharmazeutische Wirkstoffe (Synthesen, Patente, Anwendungen)", Vol. 5, by Kleeman and Engel (2nd Edition, New York and Stuttgart), p. 813, 1982 and "Pharmaceutical Manufacturing Encyclopedia", Second Edition, Vol. 1, by Marshall Sittig, Noyes Publications, Park Ridge, N.J., U.S.A., 1988, pp. 31-33, teach the preparation of albuterol by condensation of a haloacetophenone with a benzyl protected t-butyl amine. These processes have the disadvantage of producing albuterol in low yields with a significant generation of waste or undesirable by-products. Part of this inefficiency is due to the requisite use of multiple reducing agents, i.e. lithium aluminum hydride, sodium borohydride and hydrogenation with palladium/carbon catalysts, accompanied by multiple clean-up procedures. Another reason for the inefficiency is the requisite use of a benzyl-protecting group on the amine to prevent dialkylation of the amine, necessitating further deprotection and clean-up procedures.
British Patent Specification 1,247,370 teaches the preparation of albuterol by condensation of t-butylamine with arylglyoxal, followed by multiple reductions using lithium aluminum hydride and sodium borohydride. This patent also teaches a process for preparing arylglyoxals requiring multiple steps using low temperatures (e.g. room temperature) and long reaction periods (e.g. up to one week) to minimize undesirable polymerization of the labile arylglyoxal. This process has the disadvantage of producing albuterol in low yields with significant generation of undesirable by-products.
Arylglyoxals are compounds useful as intermediates for preparing pharmaceutical compounds. Conventional processes for preparing arylglyoxal compounds are known in the art. N. Kornblum, J. W. Powers, G. J. Anderson, W. J. Jones, H. O. Larson, O. Levand and W. M. Weaver, JACS, Vol. 79, (1957) page 6562, J. March, Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, Third Edition, John Wiley & Sons, New York, N.Y., (1985) pp. 1081-1083 and British Patent Specification 1247370 teach the oxidation of primary halides and esters of primary alcohols to aldehydes with dimethyl sulfoxide. M. B. Floyd, M. T. Du, P. F. Fabio, L. A. Jacob and Bernard D. Johnson, J. Org. Chem. Vol. 50, (1985), pp. 5022-5027 and R. Desmond, S. Mills, R. P. Volante and I. Shinkai, Synthetic Comm. Vol. 19 (3 and 4), (1989) pp. 379-385 disclose the reaction of acetophenones with aqueous hydrobromic acid (HBr) in DMSO leading to the formation of arylglyoxals. G. Cardillo, M. Orena and S. Sandri, J.C.S. Chem. Comm. (1976) pp. 190 disclose the preparation of aldehydes by reacting alkyl halides with potassium chromate in hexamethylphosphoramide in the presence of crown ethers. K. R. Henery-Logan and T. L. Fridinger, Chemical Communications, (1968) pp. 130-131 disclose the conversion of .alpha.,.alpha.-dichloroacetophenone with sodium methoxide in methyl alcohol to phenylglyoxals. V. E. Gunn and J. P. Anselme, J. Org. Chem., Vol. 42, No. 4, (1977) pp. 754-755 disclose the conversion of phenacylbromides to phenylglyoxals with N,N-diethyl and N,N-dibenzylhydroxylamines. H. A. Riley and A. R. Gray, Organic Synth. Coll. Vol. 2, pp. 509-511 disclose the conversion of acetophenone to phenylglyoxal with selenium dio
REFERENCES:
Collin, D. T. et al J. Med. Chem. 13(4) 674-80 1970.
Chiu John
Colon Cesar
Green Michael
Lee Junning
McAllister Timothy L.
Dicker Eric S.
Killos Paul J.
Majka Joseph T.
Mazer Edward H.
Schering Corp.
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