Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1998-02-05
2001-03-27
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S151000
Reexamination Certificate
active
06207862
ABSTRACT:
INTRODUCTION
1. Field of the Invention
2. Background and Description of the Prior Art
Chiral 1,3-aminoalcohols are important intermediates in the synthesis of various pharmaceutical products and product candidates, yet the preparation of these compounds remains a significant synthetic challenge to chemists. Gaining control over the stereochemistry of chiral centers at both the alcohol and amine (or in the cases in which only the alcohol- or amine- bearing carbon is chiral, a single chiral center) is the key to the production of these important chemical intermediates.
Chiral 1,3-aminoalcohols have potential applications both as pharmaceutically active compounds, agricultural chemicals, chiral intermediates, and chiral auxiliary agents. For example, U.S. Pat. No. 3,668,199 describes novel 1,3-aminoalcohols having potential applications as anti-diabetic agents and diuretics. In the preparation of these compounds according to the method described in U.S. Pat. 3,668,199, a diketone is first converted into a keto-enamine, followed by catalytic hydrogenation of the keto-enamine using a platinum catalyst or similar. This method has the limitation that the 1,3-aminoalcohols are not produced in optically-pure form and the amino group must be a dialkylamine. U.S. Pat. No. 5,200,561 describes a process for producing optically active amines, including aminoalcohols. This method reacts an oxime with a metal borohydride compound complexed to a different optically-active amine. This method is costly, and further, requires that another optically active amine be used to form the borohydride complex in order to produce the desired optically active amine. Classical methods involving the formation of diastereomeric salts may also be employed to produce optically active 1,3-aminoalcohols; these resolution procedures require the use of an optically active acid to form the diastereomeric salt. The maximum theoretical yield in this method is only 50%, and in actual practice the yield is significantly lower. Thus, previously-described methods for the production of 1,3-aminoalcohols have limitations in scope, efficiency, chiral purity, and yield. An efficient method for the production of 1,3-aminoalcohols of high optical purity would facilitate the production of a number of pharmaceutical intermediates and chiral auxiliaries, and would be greatly desired.
U.S. patent application Ser. No. 08/994,163 describes an efficient method for the production of chiral 1,3-aminoalcohols. Central to the practice of this method is the production of novel intermediates which are precursors of chiral 1,3-aminoalcohols. The present invention, which is a continuation-in-part of U.S. patent application Ser. No. 08/994,163, describes novel precursors useful for the production of chiral 1,3-aminoalcohols.
DETAILED DESCRIPTION OF THE INVENTION
This invention describes key precursors for the production of chiral 1,3-aminoalcohols and methods for their synthesis. These precursors are chiral 4-hydroxycarboxamides, 4-hydroxyhydroxamic acids, or 4-hydroxyhydrazides produced from chiral gamma-lactones, which in turn are derived from 1,4-diols by stereoselective oxidation. The importance of these precursors as intermediates for the production of chiral 1,3-aminoalcohols lies in their ability to be converted via stereospecific rearrangement into chiral 1,3-aminoalcohols with retention of configuration at the carbon ultimately bearing the amine through either the Hofmann Rearrangement (in the case of chiral 4hydroxycarboxamides); the Lossen
Rearrangement (in the case of chiral 4-hydroxyhydroxamic acids); or the Curtius Rearrangement (in the case of chiral 4-hydroxyhydrazides). An important aspect of this invention is the broad scope with which the compounds described herein may be employed to produce a broad range of chiral 1,3-aminoalcohols, both cyclic and acyclic, substituted or unsubstituted, bearing aromatic, aliphatic, or heterocyclic groups, in high stereochemical purity. The compounds of the present invention may be used to produce 1,3-aminoalcohols in which both the carbon atom bearing the amino group and the carbon atom bearing the hydroxy group are chiral, or alternatively, 1,3-aminoalcohols in which only the carbon bearing the amino group or the carbon bearing the hydroxy group is chiral.
Central to the synthesis of chiral 1,3-aminoalcohols by the method described in U.S. patent application Ser. No. 08/994163 is the novel combination of three steps, each of which proceeds with a well-defined and controllable stereochemical outcome. The first step is the stereoselective oxidation of a 1,4-diol to the corresponding chiral gamma-lactone using an alcohol dehydrogenase. The 1,4-diol used in the practice of the present invention is preferably substituted at the 2-position or at both the 2- and 3-positions as shown in Figure 1.
Figure 1: Structures of 1,4-Diols
The substitution is represented in the figure by R
1
and R
2
, which may be selected independently from the substituent groups alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkyl, alkynyl, aryl, aralkyl, and heterocyclic ring system. R
1
and R
2
may also together form a cycloalkyl, cycloalkenyl, or heterocyclic ring system, for example, as in the compound 1,2-cyclohexane dimethanol or 1,2-cyclopentane dimethanol. In cases where R
1
and R
2
are identical and the diol is a meso compound, the yield of the resulting 1,3-aminoalcohol produced by the method of the present invention can approach 100% of theoretical.
As utilized herein, the term “alkyl,” alone or in combination, means a straight-chain or branched-chain alkyl group containing from 1 to about 12 carbon atoms. Any of the carbon atoms may be substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, acylamido, halogen, nitro, sulfhydryl, sulfide, carboxyl, oxo, seleno, phosphate, phosphonate, phosphine, and the like. Examples of such alkyl groups include methyl, ethyl, chloroethyl, propyl, isopropyl, butyl, isobutyl, tertiary-butyl, 3-fluorobutyl, 4-nitrobutyl, 2,4-dibromobutyl, pentyl, isopentyl, neopentyl, 3-ketopentyl, hexyl, 4-acetamidohexyl, 3-phosphonoisohexyl, 4-fluoro-5,5-dimethylpentyl, 5-phosphinoheptyl, octyl, nonyl dodecyl, and the like.
As utilized herein, the term “alkenyl,” alone or in combination, means a straight-chain or branched-chain hydrocarbon group containing one or more carbon-carbon double bonds and containing from 2 to about 18 carbon atoms. Any of the carbon atoms may be substituted with one or more substituents selected from alkoxy, acyloxy, acylamido, halogen, nitro, sulfhydryl, sulfide, carboxyl, oxo, seleno, phosphate, phosphonate, phosphine, and the like. Examples of such alkenyl groups include ethenyl, propenyl, allyl, 1,4-butadienyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2,6-decadienyl, 2-fluoropropenyl, 2-methoxypropenyl, 2-carboxypropenyl, 3-chlorobutadienyl, and the like.
As utilized herein, the term “cycloalkyl,” alone or in combination, means an alkyl group which contains from about 3 to about 12 carbon atoms and is cyclic. Any of the carbon atoms may be substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, acylamido, halogen, nitro, sulfhydryl, sulfide, carboxyl, oxo, seleno, phosphate, phosphonate, phosphine, and the like. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopentyl, 3-methylcyclohexyl, various substituted derivatives, and the like.
As utilized herein, the term “cycloalkenyl,” alone or in combination, means an alkenyl group which contains from about 3 to about 12 carbon atoms and is cyclic.
Any of the carbon atoms may be substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, acylamido, halogen, nitro, sulfhydryl, sulfide, carboxyl, oxo, seleno, phosphate, phosphonate, phosphine, and the like. Examples of cycloalkyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cydoheptenyl, 2-methylcyclopentenyl, 3-methylcycloh
Barts Samuel
BioCatalytics, Inc.
Christie Parker & Hale LLP
LandOfFree
Precursors for the production of chiral 1,3-aminoalcohols does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Precursors for the production of chiral 1,3-aminoalcohols, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Precursors for the production of chiral 1,3-aminoalcohols will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2488522