US 5,962,697 A · Optically active 3-(1-(alkylamino))alkyl pyrrolidines

Abstract

This invention relates to processes for the synthesis of various optically active amino pyrrolidinyl stereoisomers, or enantiomers, that may be attached to quinolonecarboxylic acids or naphthyridones. Processes and essential intermediates are disclosed and claimed for the synthesis of compounds represented by the structure shown in figure BG.sub.4-1, below. ##STR1## where R.sup.50, R.sup.6 and R.sup.9 are defined independently and are H, --(C.sub.1 -C.sub.8)alkyl, --(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.6 -C.sub.12 aryl), --(C.sub.1 -C.sub.8) alkyl-(C.sub.6 -C.sub.12 aryl), or the aryl or alkyl is substituted with one to three of the following groups, (C.sub.6 -C.sub.12 aryl), (C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3) alkoxy, halogen, trifluoromethyl; where R.sup.2 is --(C.sub.1 -C.sub.8)alkyl, --(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.6 -C.sub.12 aryl), --(C.sub.1 -C.sub.8)alkyl-(C.sub.6 -C.sub.12 aryl), or the aryl or alkyl is substituted with one to three of the following groups, --(C.sub.6 -C.sub.12 aryl), --(C.sub.1 -C.sub.3)alkyl, --(C.sub.1 -C.sub.3) alkoxy, halogen, trifluoromethyl; depending upon the starting materials used, compounds represented by the structure shown by figure BG.sub.4-1 may have one of either of the two steriochemical arrangments shown, or, if the starting materials are a racemic mixture, the reaction may produce a 1:1 ratio of the combination of products shown in Figure BG.sub.4-1, i.e. a racemic mixture.

Claims6

Dependent claims

A compound represented by the formulas shown in formula BG.sub.4-1, shown below, where R.sup.50 is H, --(C.sub.1 -C.sub.8)alkyl, --(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.6 -C.sub.12 aryl), or --(C.sub.1 -C.sub.8)alkyl-(C.sub.6 -C.sub.12 aryl), wherein said aryl or alkyl may be substituted with one to three of the following groups, (C.sub.6 -C.sub.12 aryl), (C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3) alkoxy, halogen, or trifluoromethyl,

where R.sup.2 is --(C.sub.1 -C.sub.8)alkyl, --(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.6 -C.sub.12 aryl), or --(C.sub.1 -C.sub.8)alkyl-(C.sub.6 -C.sub.12 aryl), wherein said aryl or alkyl is substituted with one to three of the following groups, --(C.sub.6 -C.sub.12 aryl), --(C.sub.1 -C.sub.3)alkyl, --(C.sub.1 -C.sub.3) alkoxy, halogen, or trifluoromethyl;
where R.sup.6 is H, --(C.sub.1 -C.sub.8)alkyl, --(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.6 -C.sub.12 aryl), --(C.sub.1 -C.sub.8)alkyl-(C.sub.6 -C.sub.12 aryl), wherein said aryl or alkyl is substituted with one to three of the following groups, --(C.sub.6 -C.sub.12 aryl), --(C.sub.1 -C.sub.3)alkyl, --(C.sub.1 -C.sub.3) alkoxy, halogen, or trifluoromethyl;
where R.sup.9 is --CH.sub.2 --(C.sub.6)aryl, wherein said aryl may be substituted with one to three of the following groups, --(C.sub.6 aryl), --(C.sub.1 -C.sub.3)alkyl, --(C.sub.1 -C.sub.3) alkoxy, halogen, or trifluoromethyl.

The process for the preparation of a compound represented by the formula on the left side, or the right side of formula BG.sub.4-1, below, or, if starting materials in formula BG.sub.3-1, below, are a racemic mixture, the reaction may produce a mixed ratio of compounds represented on both sides of the formula BG.sub.4-1, below, where R.sup.50 is H, --(C.sub.1 -C.sub.8)alkyl, --(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.6 -C.sub.12 aryl), or --(C.sub.1 -C.sub.8)alkyl-(C.sub.6 -C.sub.12 aryl), wherein said aryl or alkyl may be substituted with one to three of the following groups, (C.sub.6 -C.sub.12 aryl), (C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3) alkoxy, halogen or trifluoromethyl;

where R.sup.2 is --(C.sub.1 -C.sub.8)alkyl, --(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.6 -C.sub.12 aryl), or --(C.sub.1 -C.sub.8)alkyl (C.sub.6 -C.sub.12 aryl), wherein said aryl or alkyl may be substituted with one to three of the following groups, (C.sub.6 -C.sub.12 aryl), (C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3) alkoxy, halogen or trifluoromethyl;
where R.sup.6 is H, --(C.sub.1 -C.sub.8)alkyl, --(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.6 -C.sub.12 aryl), or --(C.sub.1 -C.sub.8)alkyl-(C.sub.6 -C.sub.12 aryl), wherein said aryl or alkyl may be substituted with one to three of the following groups, --(C.sub.6 -C.sub.12 aryl), --(C.sub.1 -C.sub.3)alkyl, --(C.sub.1 -C.sub.3) alkoxy, halogen or trifluoromethyl;
where R.sup.9 is --CH.sub.2 --(C.sub.6)aryl, wherein said aryl may be substituted with one to three of the following groups, --(C.sub.6 aryl), --(C.sub.1 -C.sub.3)alkyl, --(C.sub.1 -C.sub.3) alkoxy, halogen or trifluoromethyl;
which comprises treating a compound represented by formula BG.sub.3-1 ##STR116## with a reducing agent, where R.sup.1 is H, --(C.sub.1 -C.sub.8)alkyl, --(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.6 -C.sub.12 aryl), --(C.sub.1 -C.sub.8)alkyl-(C.sub.6 -C.sub.12 aryl), --O--(C.sub.1-8 alkyl), --O--(C.sub.3-8 cycloalkyl), --O--(C.sub.1-8 alkyl)(C.sub.3-8 cycloalkyl), --O--(C.sub.6-12 aryl), or --O--(C.sub.1-8 alkyl)-aryl, wherein said aryl or alkyl may be substituted with one to three of the following groups, (C.sub.6 -C.sub.12 aryl), (C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3) alkoxy, halogen or trifluoromethyl, with the proviso that when R.sup.1 is --O--(C.sub.1-8 alkyl), --O--(C.sub.3-8 cycloalkyl), --O--(C.sub.1-8 alkyl)(C.sub.3-8 cycloalkyl), --O--(C.sub.6-12 aryl), --O--(C.sub.1-8 alkyl)-aryl, then reduction with LAH, DIBAL or Borane will always produce R.sup.50 is H.

1 more element

The process for the preparation of a compound represented by the formulas on the left side, or the right side of formula BG.sub.4-1, below, or, if starting materials are a racemic mixture, the reaction may produce a mixed ratio of compounds represented on both sides of the formula BG.sub.4-1, below, ##STR119## where R.sup.50 is H, --(C.sub.1 -C.sub.8)alkyl, --(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.6 -C.sub.12 aryl), or (C.sub.1 -C.sub.8)alkyl-(C.sub.6 -C.sub.12 aryl), wherein said aryl or alkyl may be substituted with one to three of the following groups, (C.sub.6 -C.sub.12 aryl), (C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3) alkoxy, halogen or trifluoromethyl;

where R.sup.2 is --(C.sub.1 -C.sub.8)alkyl, --(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.6 -C.sub.12 aryl), or --(C.sub.1 -C.sub.8)alkyl-(C.sub.6 -C.sub.12 aryl), wherein said aryl or alkyl may be substituted with one to three of the following groups, (C.sub.6 -C.sub.12 aryl), (C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3) alkoxy, halogen or trifluoromethyl;
where R.sup.6 is H, --(C.sub.1 -C.sub.8)alkyl, --(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.6 -C.sub.12 aryl), or --(C.sub.1 -C.sub.8)alkyl-(C.sub.6 -C.sub.12 aryl), wherein said aryl or alkyl may be substituted with one to three of the following groups, --(C.sub.6 -C.sub.12 aryl), --(C.sub.1 -C.sub.3)alkyl, --(C.sub.1 -C.sub.3) alkoxy, halogen or trifluoromethyl;
where R.sup.9 is --CH.sub.2 --(C.sub.6)aryl, wherein said aryl may be substituted with one to three of the following groups, --(C.sub.6 aryl), --(C.sub.1 -C.sub.3)alkyl, --(C.sub.1 -C.sub.3) alkoxy, halogen or trifluoromethyl;
comprising a process for preparing a compound represented by formula BG.sub.3-1 ##STR120## where R.sup.1 is H, --(C.sub.1 -C.sub.8)alkyl, --(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.6 -C.sub.12 aryl), --(C.sub.1 -C.sub.8)alkyl-(C.sub.6 -C.sub.12 aryl), --O--(C.sub.1-8 alkyl), --O--(C.sub.3-8 cycloalkyl), --O--(C.sub.1-8 alkyl)(C.sub.3-8 cycloalkyl), --O--(C.sub.6-12 aryl), --O--(C.sub.1-8 alkyl)-aryl, wherein said aryl or alkyl may be substituted with one to three of the following groups, (C.sub.6 -C.sub.12 aryl), (C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3) alkoxy, halogen or trifluoromethyl, with the proviso that when R.sup.1 is --O--(C.sub.1-8 alkyl), --O--(C.sub.3-8 cycloalkyl), --O--(C.sub.1-8 alkyl)(C.sub.3-8 cycloalkyl), --O--(C.sub.6-12 aryl), or --O--(C.sub.1-8 alkyl)-aryl, then reduction with LAH, DIBAL or Borane will always produce R.sup.50 is H;
where R.sup.2, R.sup.6 and R.sup.9 are defined above;
which comprises subjecting to ozonolysis a compound represented by formula ##STR121## where R.sup.3 is --(C.sub.1 -C.sub.8)alkyl, --(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.6 -C.sub.12 aryl), or --(C.sub.1 -C.sub.8)alkyl-(C.sub.6 -C.sub.12 aryl), wherein said aryl or alkyl may be substituted with one to three of the following groups, --(C.sub.6 -C.sub.12 aryl), --(C.sub.1 -C.sub.3)alkyl, --(C.sub.1 -C.sub.8) alkoxy, halogen, or trifluoromethyl;
where, R.sup.4, R.sup.5 and R.sup.6 independently are H, (C.sub.1 -C.sub.8)alkyl, or (C.sub.1 -C.sub.8)alkyl (C.sub.6 -C.sub.12)aryl, wherein said aryl may be substituted with one to three of any of the following groups:
(C.sub.6 -C.sub.12) aryl, C.sub.1 -C.sub.3 alkoxy, C.sub.1 -C.sub.3 alkyl, trifluoromethyl, fluoro, chloro, or bromo;
X is O, NH, or S,
followed by reaction with R.sup.9 --NH.sub.2, under reducing conditions, such as with sodium cyano borohydride, sodium triacetoxy borohydride or sodium borohydride, (in order of preference) at about 0.degree. to 50.degree. C., to produce a compound represented by formula BG.sub.3-1 ##STR122## and then treating the compounds of BG.sub.3-1 with a reducing agent to produce the desired compounds, where R.sup.1 is as defined above;
to produce the compounds of BG.sub.4-l.

8 more elements

Dependencies are inferred from the claim text.

Optically active 3-(1-(alkylamino))alkyl pyrrolidines

Life of this patent

Optically active 3-(1-(alkylamino))alkyl pyrrolidines

Life of this patent

Abstract

Claims6