Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-25
2002-08-13
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S965000, C564S080000, C564S084000, C564S092000
Reexamination Certificate
active
06433172
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to new methods for stereospecifically preparing [(1-optionally substituted aryl)- or (1-optionally substituted heteroaryl)]-2-substituted ethyl-2-amines, having chirality at the 2-position.
The invention is directed also to new intermediates that are useful for preparing substituted ethyl-2-amines.
The substituted ethyl-2-amines, and intermediate compounds therefor, are useful as intermediates in the synthesis of cardiovascular agents, including antihypertensive agents, anti-ischemic agents, cardioprotective agents which ameliorate ischemic injury or myocardial infarct size consequent to myocardial ischemia, and antilipolytic agents which reduce plasma lipid levels, serum triglyceride levels, and plasma cholesterol levels.
For example, the substituted ethyl-2-amines are useful as intermediates in the preparation of antihypertensive and anti-ischemic heterocyclyl adenosine derivatives and analogues as disclosed in U.S. Pat. No. 5,364,862. They are useful also in the preparation of N
9
-cyclopentyl-substituted adenine derivatives reported to be adenosine receptor ligands, and to be useful in treating cardiovascular conditions such as hypertension, thrombosis and atherosclerosis, and also in treating central nervous system conditions comprising psychotic conditions such as schizophrenia, and convulsive disorders such as epilepsy, as disclosed in U.S. Pat. No. 4,954,504. They are useful also in the preparation of N-6 and 5′-N substituted carboxamidoadenosine derivatives which have beneficial cardiovascular and antihypertensive activity as reported in U.S. Pat. No. 5,310,731.
REPORTED DEVELOPMENTS
Stereospecific preparation of chiral optionally substituted heteroaryl-2-substituted ethyl 2-amines by reaction of heteroaryl anions with 2-substituted ethylene oxides, and subsequent stereospecific conversion of the resulting chiral ethyl alcohol to the amine has been reported by Spada et al., in U.S. Pat. No. 5,364,862.
Facilitation of acidolytic cleavage reactions, for example the removal of various protecting groups, in the presence of electrophilic scavengers has been reported. Deprotection of N
G
-mesitylene-2-sulfonylarginine is reported by Yajima et al.,
Chem. Pharm. Bull
. 26 (12) 3752-3757 (1978). Removal of the protecting group of O-benzyl serine, threonine, and tyrosine, and deprotection of N
e
-benzyloxycarbonyllysine is reported by Kiso et al.,
Chem. Pharm. Bull
. 28 (2) 673-676 (1980). Deprotection procedures for the p-toluenesulfonyl and p-methoxybenzenesulfonyl groups from the N
im
function of histidine is reported by Kitagawa et al.,
Chem. Pharm. Bull
. 28 (3) 926-931 (1980).
SUMMARY OF THE INVENTION
The present invention is directed to methods for stereospecifically preparing [(1-optionally substituted aryl)- or (1-optionally substituted heteroaryl)]-2-substituted ethyl-2-amines, having chirality at the 2-position, comprising reacting a 2-amino-2-substituted ethyl alcohol, having chirality at the 2-position, with an [(optionally substituted aryl)- or (trihalomethyl) sulfonyl]-halide or anhydride in the presence of a base to form an [(N-arylsulfonyl)- or (N-trihalomethylsulfonyl)]-2-substituted aziridine having chirality at the 2-position.
DETAILED DESCRIPTION
As used above, and throughout the description of this invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
“Aryl” means phenyl or naphthyl.
“Optionally substituted aryl” means an aryl group which may be substituted with one or more aryl group substituents. Examples of aryl group substituents include alkyl, alkoxy, amino, aryl, heteroaryl, trihalomethyl, nitro, carboxy, carboalkoxy, carboxyalkyl, cyano, alkylamino, halo, hydroxy, hydroxyalkyl, mercaptyl, alkylmercaptyl, and carbamoyl. Preferred aryl group substituents include halo, hydroxy, alkyl, aryl, alkoxy, trihalomethyl, cyano, nitro, and alkylmercaptyl.
“Heteroaryl” means about a 4 to about a 10 membered aromatic ring structure in which one or more of the atoms in the ring is an element other than carbon, e.g., N, O or S. Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, isoquinolinyl, quinolinyl, quinazolinyl, imidazolyl, pyrrolyl, furanyl, thienyl, thiazolyl, and benzothiazolyl. A preferred heteroaryl group is thienyl.
“Optionally substituted heteroaryl” means that the heteroaryl group may be substituted by one or more heteroaryl group substituents. Examples of heteroaryl group substituents include alkyl alkoxy, alkylamino, aryl, carbalkoxy, carbamoyl, cyano, halo, heteroaryl, trihalomethyl, hydroxy, mercaptyl, alkylmercaptyl and nitro. Preferred heteroaryl group substituents include halo, hydroxy, alkyl, aryl, alkoxy, trihalomethyl, cyano, nitro, and alkylmercaptyl.
“Halogen” (“halo”, “halide”) means chlorine (chloro, chloride), fluorine (fluoro, fluoride), bromine (bromo, bromide) or iodine (iodo, iodide). “Alkyl” means a saturated aliphatic hydrocarbon group which may be straight or branched and have about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups may be straight or branched and have about 1 to about 10 carbon atoms in the chain. Lower alkyl means an alkyl group which may be straight or branched having about 1 to about 6 carbon atoms, such as methyl, ethyl, propyl or tert-butyl. Branched means that a lower alkyl group is attached to a linear alkyl chain.
“Aralkyl” means an alkyl group substituted by an aryl group. “Optionally substituted aralkyl” means that the aryl group of the aralkyl group may be substituted with one or more aryl group substituents.
“Heteroaralkyl” means an alkyl group substituted by a heteroaryl group. “Optionally substituted heteroaralkyl” means that the heteroaryl group or the heteroaralkyl group may be substituted with one or more aryl group substituents.
“Electrophilic scavenger” means an agent that can have a promoting effect on acidolytic cleavage reactions, for example, as described by Yajima et al.,
Chem. Pharm. Bull
. 26 (12) 3752-3757 (1978), Kiso et al.,
Chem. Pharm. Bull
. 28 (2) 673-676 (1980), and Kitagawa et al.,
Chem. Pharm. Bull
. 28(3)926-931 (1980).
An embodiment according to the invention is directed to the reaction of a 2-amino-2-substituted ethyl alcohol with a sulfonyl halide or anhydride, preferably in the presence of an aprotic organic solvent. Aprotic organic solvents which are suitable for the reaction include aprotic organic ethers, aromatic hydrocarbons, heteroaromatic hydrocarbons, aliphatic hydrocarbons, and aprotic organic amides. More particularly, examples of suitable aprotic organic solvents include diethyl ether, tert-butyl methyl ether, isopropyl methyl ether, diisopropyl ether, tetrahydrofuran, tetrahydropyran, and dioxan. In a special embodiment of methods according to the invention, the preferred aprotic organic solvent is tert-butyl methyl ether.
The reaction with the sulfonyl halide or anhydride takes place preferably at a temperature in the range of from about 25° C. to about 90° C.; more preferably from about 25° C. to about 40° C.
Suitable sulfonyl halides and anhydrides include phenyl-, tol-4-yl-, 2,4,6-trimethylphenyl-, 2,4-dimethylphenyl-, 4-methoxyphenyl-, 4-nitrophenyl-, 4-bromophenyl-, naphth-1-yl-, naphth-2-yl-, and trifluoromethyl-sulfonyl chloride and anhydride. In a special embodiment of methods according to the invention, a preferred sulfonyl chloride is p-toluenesulfonyl chloride (i.e., tol-4-yl sulfonyl chloride).
According to the invention, the reaction of the 2-amino-2-substituted ethyl alcohol with the sulfonyl halide or anhydride takes place in the presence of a base. Bases which are suitable for the reaction include aqueous alkali metal hydroxides, aqueous alkali metal carbonates, and aprotic organic amines. More particularly, examples of suitable alkali metal hydroxides include sodium hydroxide, potassium hydroxide, and lithium hydroxide; examples of suitable alkali metal carbonates include potassium carbonate, sodium carbonate, and cesium carbonate; and examples of s
Casimir Jean-Paul
Grondard Luc
Leon Patrick
O'Brien Michael K.
Powers Matthew R.
Aventis Pharmaceuticals Inc.
Coppola William C.
Darkes Paul R.
Lambkin Deborah C.
Oehler Ross J.
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