Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1998-04-23
1999-10-26
Geist, Gary
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
564336, 564372, 564373, 564374, 564397, C07C20900
Patent
active
059732059
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a novel process, to certain novel compounds prepared by such process, to pharmaceutical compositions comprising such compounds and to the use of such compounds in medicine.
European Patent Application, Publication Number 233762 discloses certain compounds of formula (A): ##STR4## wherein
R.sub.a and R.sub.d are independently phenyl optionally substituted by one, two or three of halogen, trifluoromethyl, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, cyano, hydroxy, nitro, NR.sub.e R.sub.f or O.sub.2 SNR.sub.e R.sub.f wherein R.sub.e and R.sub.f are independently hydrogen or C.sub.1-6 alkyl or together are C.sub.3-6 polymethylene, or disubstituted at adjacent carbon atoms by C.sub.1-2 alkylenedioxy and optionally further substituted by one of the above groups;
R.sub.b is selected from (CH.sub.2).sub.z CN where z is 0 or an integer from 1 to 4, C.sub.1-12 alkyl C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-4 alkyl, phenyl C.sub.1-4 alkyl, pyridyl, pyridyl C.sub.1-4 alkyl, COR.sub.g, COCH.sub.2 COR.sub.g, SO.sub.2 R.sub.g, CO.sub.2 R.sub.g, CONHR.sub.g and CSNHR.sub.g, where R.sub.g is selected from C.sub.3-12 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-4 alkyl, phenyl and phenyl C.sub.1-4 alkyl, any alkyl moiety in R.sub.g optionally substituted by hydroxy or C.sub.1-4 alkanoyloxy, any pyridyl or phenyl moiety in R.sub.b optionally substituted as defined for R.sub.a and R.sub.d and any cycloalkyl moiety in R.sub.b optionally substituted by one or two C.sub.1-4 alkyl groups;
R.sub.c is hydrogen or C.sub.1-4 alkyl;
A represents C.sub.2-5 alkylene; and
B represents C.sub.1-4 alkylene; which compounds are stated to possess cardiovascular activity, in particular anti-angina activity.
EP233762 also discloses intermediates for the preparation of the compound of formula (A) of formula (B): ##STR5## in which R.sub.a, R.sub.c, R.sub.d, A, and B are as defined with respect to formula (A) or are groups convertible thereto.
One particular compound from EP 233762 is the compound of Example 50 which is N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4dimethoxyphenyl)ethyl]methylamino]pro pyl]-4-nitrobenzamide hydrochloride (hereinafter Compound I).
EP233762 discloses a range of alternative methods of preparing the compound of formula (B).
Synthetic Communications 20, 3167-3180, (1990) discloses the preparation of .beta.-aminoaldehydes. These compounds are stated to be unstable but they are demonstrated to react in situ with a range of different reagents to provide various aminated products.
We have now found that in addition to the reagents disclosed in Synthetic Communications, a .beta.-aminoaldehyde reacts with certain arylamines to provide arylimines which are readily reduced to a compound of formula (B) wherein variable A represents C.sub.3 alkylene. The reactions are high yielding and are readily carried out in the same reaction vessel providing a useful `one pot` synthesis of the intermediate compounds (B) wherein variable A represents C.sub.3 alkylene and in particular the intermediate to Compound I.
Accordingly, in its most preferred aspect the present invention provides a process for preparing a compound of formula (I) or an addition salt thereof and/or a solvate thereof: ##STR6## wherein R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are each independently C.sub.1-4 alkoxy and R.sup.3 is C.sub.1-6 alkyl, ##STR7## wherein R.sup.4 and R.sup.5 are as defined in relation to formula (I) with a .beta.-aminoaldehyde of formula (III): ##STR8## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in relation to formula (I); and thereafter reducing the intermediate so formed and, optionally, forming an addition salt of the compound of formula (I) and/or a solvate thereof.
Generally, the intermediate is an imine. The reaction is suitably carried out in an aprotic solvent, preferably tetrahydrofuran at any temperature providing a suitable rate of formation of the final product including temperatures up to room temperature, but usually at a temperature below room temperature such as a temperature in the range of -1
REFERENCES:
patent: 3707563 (1972-12-01), Piki
patent: 5442120 (1995-08-01), Van Der Meji
patent: 5494933 (1996-02-01), Maschler
Chesney, et al., Synth. Commun; vol. 20, No. 20; 1990, pp. 3167-3180.
Boor, et al., Chemical Abstracts; vol. 112, No. 17; 1990, Abstract No. 153201.
Oki, et al., Chemical Abstracts; vol. 70, No. 5; 1969, Abstract No. 18601.
Attrill Robin Patrick
Ramsay Thomas Weir
Geist Gary
Kinzig Charles M.
McCarthy Mary E.
SmithKline Beecham Plc
Venetianer Stephen
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