Preparation of N-substituted-hydroxycycloalkylamine derivatives

Details Preparation of N-substituted-hydroxycycloalkylamine derivatives Preparation of N-substituted-hydroxycycloalkylamine derivatives

2001-04-07

2003-05-20

Chang, Ceila (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S541000, C549S034000, C549S040000, C546S280700

Reexamination Certificate

active

06566525

ABSTRACT:

BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to a process for a preparation of N-substituted-hydroxycycloalkylamine derivatives and more particularly, to the process for the preparation of N-substituted-hydroxycycloalkylamine derivatives represented in the following formula (1), regioselectively in high yield via 1,2-cyclosulfinylalkyl halide as an intermediate from the 1,2-dihydroxyalkyl alcohol as a starting material. Moreover, the synthetic method in this invention effectively provides optically active N-substituted-hydroxycycloalkylamine derivatives in high purity with regioselectivity and stereoselectivity, as well as racemic compounds, when optically active 1,2-dihydroxyalkyl alcohol is used as a starting material.
wherein,
* represents an asymmetric carbon;
R
1
is hydrogen or typical amino-protecting groups such as linear alkyl, branched alkyl, or cycloalkyl containing 1~10 carbon atoms or aromatic hydrocarbons;
R
2
is hydrogen or hydroxyl group;
R
3
is hydrogen or hydroxymethyl group; and
n is 1 or 2.
N-substituted-hydroxycycloalkylamine derivatives are widely used as the intermediates for the synthesis of various organic compounds as well as pharmaceutical and agrochemical compounds. Especially, the optically active (R)- or (S)-N-substituted-3-hydroxypyrrolidine is generally known as the key intermediate in the preparation of pharmaceutical and agrochemical compounds. For example, the optically active N-substituted-3-hydroxypyrrolidine is used as the essential intermediate for the preparation of various pharmaceuticals such as carbapenem antibiotic (Panipenem), vasodilatin (Barnidipine), or antihypertensive in developing (Darifenacine, Lirequilli Clinafloxacine) [EP No. 483,580, No. 330,469, No. 304,087; U.S. Pat. Nos. 5,463,064, 5,364,872, 5,281,711, 5,109,008, 4,916,141; International Patent WO 91/09013].
Several methods for the preparation of optically active 3-hydroxypyrrolidine derivatives have been reported as introduced hereinafter.
One of the most general methods for the preparation of N-substituted-3-hydroxypyrrolidine is the reduction of N-benzyl-3-hydroxysuccinimide using the reducing agent, lithium aluminum hydride (LAH), which is prepared by the reaction of d- or l-malic acid and benzyl amine [
Synthetic Communications,
1983, 13(13), 1171~1123;
Synthetic Communications,
1985, 15(7), 587~598; U.S. Pat. Nos. 5,109,008, 4,705,853].
Another method for the synthesis of N-substituted-3-hydroxypyrrolidine is the decarboxylation of (2S, 4R)-(−)-4-hydroxy-2-pyrrolidine carboxylic acid [International Patent WO 91/09013, U.S. Pat. No. 5,233,053].
Another method is the preparation of (S)-3-hydroxypyrrolidine by reduction of (S)-3-hydroxypyrrolidine derivatives developed by Eugene J. Trybulsky [U.S. Pat. No. 4,937,235].
However, the above conventional methods are not adequate to be introduced to industrial process, because of the delicate synthetic process, low yield, and expensive raw materials and reagents.
The preparation of (S)-3-hydroxypyrrolidine with hydroxybutyronitrile compounds has been reported [EP No. 269,258]. This method is effective on the preparation of 3-hydroxypyrrolidine as a racemic mixture. However, it can be hardly applied to industrial process, because the optically active 3-hydroxybutyro-4-nitrile, a key intermediate in the synthetic process of optically pure 3-hydroxypyrrolidine, is not easily prepared.
Inou and coworkers reported the preparation of 3-hydroxypyrolidine from 4-chloro-3-hydroxybutyronitrile [EP No. 347,818]. According to this method, 3-hydroxypyrrolidine is prepared from (R)-2-acetoxy-3-chloropropyltosylate which is obtained by enzyme-mediated stereoselective hydrolysis of racemic epichlorohydrine. But, it has many problems to be utilized in industry because of the multi-step procedures and low yield.
Besides, several biochemical methods have been reported [JP Pyung 5-227991, Pyung 6-141876]: For example, the preparation of optically active N-substituted-3-hydroxypyrrolidine by selective deacetylation of racemic 3-acetoxy-N-benzylpyrrolidine using Lipase PS [
Bull. Chem. Soc. Jpn.,
1996, 69, 207~215], and the preparation of optically active N-substituted-3-hydroxypyrrolidine by enzyme-mediated stereoselective hydrolysis of N-substituted-3-acyloxypyrrolidine [International Patent WO 95/03421]. However, the application of the aforesaid biochemical synthetic process to industry needs to improve the process for the recovery of enzyme and separation/purification of reaction mixtures.
Also, the preparation of N-substituted-3-hydroxypyrrolidine from 1,2,4-butanetriol or its derivatives is reported, as described hereinafter [
Heterocycles,
1987, 26 (8), 2247~2265].
Initially, 1,4-dibromo-2-butanol is prepared by the reaction of 1,2,4-butanetriol with hydrogen bromide via selective bromination of only primary alcohol at the position of C1 and C4, then reacted with benzyl amine and cyclized to yield N-benzyl-3-hydroxypyrrolidine [
J. Med. Pharm. Chem.,
1959, 1, 76]. But, the aforesaid bromination is not controlled easily, with very low yield of 31% and use of expensive bromination reagents.
The optically active 3-hydroxypyrrolidine is prepared from the optically active 4-halo-3-hydroxybutanol [EP No. 452,143, U.S. Pat. No. 5,144,042]. According to this method, the reduction of the ester of (S)-4-chloro-3-hydroxybutylic acid with calcium borohydride provides (S)-4-chloro-1,3-butanediol, and the subsequent selective sulfonylation of the only primary alcohol using methanesulfonyl chloride followed by the reaction with benzyl amine gives (S)-N-benzyl-3-hydroxypyrrolidine. In this process, it can't be considered as an economical method because the selective sulfonylation of only primary alcohol is difficult to result in good yield.
Moreover, the method for the preparation of the optically active N-benzyl-3-hydroxypyrolidine by optical resolution is reported [JP Pyung 9-263578, Pyung 5-336992]. But, this process may not be recommended to prepare optically active compounds in high purity at the viewpoint of economics and efficiency.
Besides, other methods have been reported [EP No. 431,521].
Even though there are various methods for the preparation of optically active N-substituted-3-hydroxypyrrolidine derivatives as described above, it has been urgent to develop the method for the efficient preparation of cycloamine derivatives via cyclization of alkyltriol with higher yield and purity than those in the conventional methods.
SUMMARY OF THE INVENTION
The inventors in this invention have investigated for a long time that an efficient synthetic method for N-substituted-hydroxycycloalkylamine derivatives from 1,2-dihydroxyalkyl alcohol and eventually realized that the three hydroxyl groups, of the starting material, 1,2-dihydroxyalkyl alcohol, should be distinguished each other from the reactivity in the nucleophilic substitution.
To fit this requirement, both of the hydroxyl groups at C1, C2 positions of 1,2-dihydroxyalkyl alcohol were converted to a cyclic sulfite group by the reaction of 1,2-dihydroxyalkyl alcohol with thionyl chloride. The subsequent conversion of terminal hydroxyl group to halide provided 1,2-cyclosulfinylalkyl halide of which the functional groups showed different reactivities. Eventually, N-substituted-hydroxycycloalkylamine derivatives were prepared by the cyclosubstitution of the aforesaid alkyl halide with nucleophile such as amine compounds. Especially, optically active N-substituted-hydroxycycloalkylamine could be prepared in high purity with regioselectivity and stereoselectivity, if the optically pure 1,2-dihydroxyalkyl alcohol was used as a starting material.
Therefore, the purpose of this invention is to provide the synthetic method of racemic or optically active N-substituted-hydroxycycloalkylamine, as the target product, in maximum yield as well as high purity simultaneously inhibiting the side-reaction, racemization or

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