Process for preparing hydroxypyrrolidinyl ethylamine...

Details Process for preparing hydroxypyrrolidinyl ethylamine... Process for preparing hydroxypyrrolidinyl ethylamine...

2002-04-26

2003-09-23

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06624313

ABSTRACT:

This invention relates to a novel process for preparing hydroxypyrrolidinyl ethylamine compounds and their pharmaceutically acceptable salts. The pharmaceutically active compounds prepared by the process of this invention can be used as selective kappa-receptor agonists.
BACKGROUND ART
Opioid analgesics such as morphine are therapeutically useful, but their usage is strictly limited because of their side effects such as drug dependency and abuse. Thus, analgesics with high usefulness and reduced tendency to cause drug dependency are desired. Considerable pharmacological and biochemical studies have been carried out to discover the opioid peptides and opioid receptors, and the discovery of the subtype of opioid receptor such as mu (&mgr;), delta (&dgr;), kappa (&kgr;) in a variety of species, including human, has made a beginning towards creating new analgesics. As it is thought that opioid analgesics such as morphine act as a mu-receptor agonist, separating the action based on a kappa-receptor agonist from the action based on mu-receptor agonist has been investigated. Recently kappa-selective agonists (kappa-agonists) have been reported from the above viewpoint for example, EMD-61753: A. Barber et al.,
Br. J. Pharmacol.,
Vol. 113, pp. 1317-1327, 1994. Some of them actually have been studied in clinical trials (
Med. Res. Rev.,
Vol. 12, p. 525, 1992).
WO 98/12177, published Mar. 26, 1998, and U.S. Pat. No. 6,031,114 refer to a method for preparing pyrrolidinyl hydroxamic acid derivatives related to the compounds prepared by the present invention, which are useful as analgesic, antiinflammatory or neuroprotective agents. Each of the foregoing United States patent and PCT international application are incorporated herein by reference in its entirety.
European Patent No. EP 0254545 B1 discloses a variety of ethylenediamine compounds which are related to the compounds prepared by the present method. European Patent No. EP 0483580 B1 discloses a variety of pyrrolidine compounds as analgesics. International Patent Publication WO 96/30339, published Oct. 3, 1996, refers to a wide variety of pyrrolidinyl hydroxamic acid compounds as selective kappa-receptor agonists.
The present invention provides several enhancements over the methods set forth in WO98/12177 and U.S. Pat. No. 6,031,114 for preparing hydroxypyrrolidinyl ethylamine compounds. These enhancements include (1) better control of epimerization at labile optical centers in the conversion steps from benzoic acid pyrrolidiny-3-yl ester to benzoic acid 1-(2-chloro-2-phenylethyl)pyrrolidin-3-yl ester and (2) the avoidance of methyl ether impurities in the conversion steps to the end-stage benzoic acid hydrolysis. These two deficiencies of the above methods significantly diminish the selectivity and the efficiency of the conversion to the desired hydroxypyrrolidinyl ethylamine compounds.
SUMMARY OF THE INVENTION
The present invention provides a process of preparing a compound having the formula I:
or an optical isomer or racemic or optically active mixture of two or more stereoisomers thereof, wherein Ar
1
is phenyl optionally substituted by one or more substituents, preferably from one to two substituents, independently independently selected from halo, hydroxy, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkoxy-C
1
-C
4
alkoxy, CF
3
, carboxy-C
1
-C
4
alkoxy and C
1
-C
4
alkoxy-carbonyl-C
1
-C
4
alkoxy;
Ar
2
is aryl selected from phenyl and naphthyl, or heteroaryl selected from pyridyl, thienyl, furyl, pyrrolyl and pyrimidyl, the aryl or heteroaryl being optionally substituted by one or more substituents, preferably from one to two substituents, independently selected from halo, hydroxy, amino, nitro, carboxy, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, halo C
1
-C
4
alkyl, C
1
-C
4
alkylthio and sulfonyl methyl;
R
1
is hydrogen, hydroxy, C
1
-C
4
alkyl, C
1
-C
4
alkoxy or OY wherein Y is a hydroxy protecting group; and
R
2
and R
3
are independently selected from hydrogen; hydroxy; C
1
-C
7
alkyl optionally substituted by one or more substituents, preferably one, two or three substituents, independently selected from hydroxy and halo; C
3
-C
6
cycloalkyl; C
2
-C
6
alkenyl; C
2
-C
6
alkynyl; C
1
-C
7
alkoxy; and phenyl optionally substituted by one or more substituents, preferably one, two or three substituents, selected from halo, phenyl C
1
-C
7
alkyl, halo substituted phenyl C
1
-C
7
alkyl, and (CH
2
)
n
X—R
0
wherein n is one or two;
X is O, NH or S; and
R
0
is C
1
-C
3
alkyl, or when Ar
2
is phenyl, —Ar
2
—C(═O)—N(R
2
)— is a phthalimide group and R
3
is C
1
-C
7
alkyl; or
R
2
and R
3
, together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine or morpholine ring, optionally substituted by one, two or three substituents independently selected from C
1
-C
3
alkyl or halo;
which comprises (a) treating a compound having the formula II:
wherein Ar
1
, Ar
2
, R
1
, R
2
, and R
3
are as defined above and R
4
is C
1
-C
4
alkyl(C═O)—, aryl(C═O)—, NH
2
(C═O)—, tri(C
1
-C
4
alkyl)silyl, or triarylsilyl, and having the same stereochemical configuration at corresponding chiral centers as the desired compound of formula I, with a base in the presence of an alkyl alcohol and (b) isolating in crystalline form the compound of formula I. In one embodiment of said process of preparing the compound of formula I, the base is an aqueous hydroxide base and the alkyl alcohol is methanol or ethanol. Preferably, R
4
is Bz, and the compound of formula II is treated with aqueous sodium hydroxide in the presence of methanol. More preferably, the reaction mixture of the compound of formula II and an aqueous hydroxide base is subsequently treated with benzoic acid prior to isolation of the compound of formula I.
In a further aspect of the present invention, the above process further comprises forming a pharmaceutically acceptable salt of the compound having the formula:
or an optical isomer or racemic or optically active mixture of two or more stereoisomers thereof, wherein Ar
1
, A
2
, R
1
, R
2
, and R
3
are as defined above. Examples of such pharmaceutically acceptable salts are those selected from the group consisting of, but not limited to, hydrochloride, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, p-toluenesulfonate, oxalate and pamoate (1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The salt is preferably a benzoate salt.
Compounds that may be prepared by the process of present invention include:
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-N′-propylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-2-methoxy-N′-propylbenzamide;
6-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-N′-propylnicotinamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-N′-(2-(S)-hydroxypropyl)benzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-N′-isopropylbenzamide;
3-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-N′-propylbenzamide;
2-chloro-4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-N′-propylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-3-methoxy-N′-propylbenzamide;
3-chloro-4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-N′-propylbenzamide;
4-{N-{1-(S)-(3-hydroxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl}-N-methylamino}-N′-propylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-(3-methoxyphenyl)-ethyl}-N-methylamino}-N′-propylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrr

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