Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1987-06-04
1990-02-20
Hollrah, Glennon H.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
544365, 544379, 546 18, 546206, 564341, 564349, C07D40106
Patent
active
049027999
DESCRIPTION:
BRIEF SUMMARY
This invention is concerned with new pharmacologically active compounds. More particularly, the compounds with which this invention is concerned are bicyclic alkoxy- and alkylthio-substituted amino alcohols of the formula: ##STR1## wherein R represents a lower straight or branched alkyl group, X represents --O-- or --S--, n is an integer from 1 to 3, R.sub.1 represents hydrogen or a lower alkyl group; R.sub.2 represents hydrogen or benzyl; R.sub.3 represents an alkyl group; or alternatively R.sub.2 and R.sub.3 taken together represents a divalent group selected from:
(a) ##STR2## wherein Y represents hydrogen or halogen;
(b) ##STR3## wherein A is a group selected from ##STR4## wherein R.sub.4 represents a lower alkyl group;
(c) ##STR5## and
(d) ##STR6## wherein W represents hydrogen, phenyl, benzyl, alkoxyphenyl, methylphenyl, 2-furoyl, nicotinoyl or a radical halogen, lower alkyl or alkoxy groups: and their salts with inorganic acids, organic acids, cationic exchange resins and complexes with cyclodextrins.
As apparent to all those skilled in organic chemistry, the compounds in which R.sub.1 does not represent hydrogen, having two structural asymmetry centers, may exist both in the erythro and threo configuration.
In most cases, by the manufacturing process which will be hereinafter described, a mixture of the two steric isomers is obtained, and an appropriate separation may occasionally be necessary. In other instances, however, formation of one single isomer is so prevailing as to approach 100 per cent, and a separation is not required unless the product is desired in an analytically pure condition for purposes of study.
The configuration of the erythro and threo isomers was assigned through .sup.1 H.NMR (Nuclear Magnetic Resonance) spectra by determining the characteristic coupling constants (J.sub.C-1,C-2) of the compounds.
The chemical process for the preparation of the invention compounds consists in contacting a bromo ketone of the partial formula II with an amine to give the amino ketone of the partial formula III.
The amino ketone is then hydrogenated to give the desired amino alcohol ##STR7## Depending on the circumstances, the amino ketone III may be isolated from the reaction mixture before it is hydrogenated. On the other hand, if the intermediate III shows a low degree of stability, it is preferable to hydrogenate it directly in the reaction mixture in which it is formed by reaction of the bromo ketone with the amine.
The first step of the process is carried out in the presence of a proton acceptor, such as an alkali metal or earth alkali carbonate or bicarbonate or a tertiary amine.
In some instances, an excess over the molecular amount of the same amine which if being contacted with the bromo ketone may be used with satisfactory results. Usually this first step is carried out in a solvent inert to the instant reaction such as a lower alkanol, for instance methanol or ethanol, or a ketone, such as a di-lower alkyl ketone, for instance acetone or methyl ethyl ketone. It is immaterial whether the amine is added to the bromo ketone, both or only one of them being dissolved in the solvent, or vice versa the bromo ketone is added to the amine, still both in solution or only one of them.
The appropriate way of conducting the first step will be selected considering the properties of the reactants and their reactivity. The reaction temperature is also adjusted depending on the reactivity of the two reactants, although normally the boiling temperature of the solvent is generally preferred. The second step of the process, i.e. the hydrogenation, may be carried out by any conventional hydrogenation procedures apt to convert a ketone into an alcohol. However, we have found that the hydrogenation is best performed by using a metal hydride, preferably a double hydride, such as NaBH.sub.4, LiAlH.sub.4 etc., by conventional procedures in a solvent inert to the hydrogenation reaction, which in the case of NaBH.sub.4 may be water, or a lower alkanol, such as methanol or ethanol, both in the presence of vario
REFERENCES:
patent: 4246268 (1981-01-01), Carr
patent: 4338323 (1982-07-01), Regnier et al.
patent: 4552965 (1985-11-01), Parsons
Chemical Abstracts, vol. 103, No. 15, Oct. 14, 1985, (Columbus, Ohio, U.S.), see p. 698, abstract 123196w, & JP, A. 60100542, (Otsuka Pharmaceutical Factory, Inc.), Jun. 1985.
Gentili Piergiorgio
Picciola Giampaolo
Ravenna Franco
Riva Mario
Hollrah Glennon H.
Maggioni-Winthrop S.P.A.
Turnipseed James H.
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