Process for hydrolyzing optically active amides

Details Process for hydrolyzing optically active amides Process for hydrolyzing optically active amides

2001-09-11

2004-03-30

Barts, Samuel (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S386000, C564S384000, C564S374000, C562S588000

Reexamination Certificate

active

06713652

ABSTRACT:

The present invention relates to a novel process for cleaving optically active amides.
The hydrolytic cleavage of optically active amides having a center of chilarity in the amine moiety of the molecule can be carried out with retention of the center of chirality only under very elaborate conditions or not at all.
Devant and Braun (Chem. Berichte 119, 2197-2207 (1986)) describe the elimination of chiral amines from acetamides as being impossible without destruction of the center of chirality (page 2194). In addition, the authors find that numerous attempts to hydrolyze the amides to the carboxylic acid and optically active amine under alkaline or acidic conditions were unsuccessful, and that only reaction with dinitrogen tetroxide by the method of White (J. Am. Chem. Soc. 77, 6008 (1955)) gives the desired result. However, this reaction with N
2
O
4
is complicated and thus unsuitable for industrial processes.
WO 95/08636 describes an enzymatic process for the resolution of racemates of optically active amines, in which the amines are acylated enantioselectively with an ester, then the acylated amine (amide) and unreacted amine in the mixture are separated and, if required, the optically active amine is liberated from the acylated amine (amide) by amide cleavage. However, no process parameters with which the amide cleavage can be carried out are indicated.
WO 97/10201 describes a process for cleaving optically active amides with retention of the center of chirality. In this case, the amides are hydrolyzed with alkali metal or alkaline earth metal hydroxide in the presence of a polyol or amino alcohol. The amount of polyol or amino alcohol used is 10-90, preferably 30-80% of the total weight of the mixture.
It is an object of the present invention to optimize even further the process described in WO 97/10201 in terms of space-time yields, and to reduce the costs of the process.
We have found that this object is achieved by a process for hydrolyzing optically active amides to carboxylic acids and optically active amines with retention of the center of chirality, where the hydrolysis of the amides is carried out with an alkali metal or alkaline earth metal hydroxide in the presence of 5-30% by weight, based on the amide employed, of a polyol or an amino alcohol.
The process according to the invention is suitable for virtually all amides which can be prepared from optically active primary or secondary amines. It is particularly suitable for amides whose amine moiety consists of an optically active arylalkylamines.
It proceeds particularly well with primary arylalkylamines, for example those with the following structures:
where X is any conventional aromatic substituent, in particular halogen, nitro, cyano, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy and C
1
-C
4
-alkylthio.
The process according to the invention is also suitable for cleaving amides whose amine moiety consists of an amino alcohol of the formula (I)
in which the substituents have the following meaning:
R
5
, R
6
=independently of one another H, branched and unbranched C
1
-C
10
-alkyl, C
1
-C
4
-alkoxycarbonyl, phenyl, phenyl-C
1
-C
4
-alkyl, where the phenyl groups may be substituted by halogen, nitro, cyano, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy and C
1
-C
4
-alkylthio. It is also possible for R
5
and R
6
to be connected by a carbon chain which may be interrupted by oxygen, sulfur or nitrogen and in turn may be substituted to form a mono-, bi- or tricyclic system
R
7
=H, C
1
-C
10
-alkyl, C
1
-C
4
-alkoxycarbonyl
R
8
=H, C
1
-C
10
-alkyl
n=0, 1 or 2, preferably 0 or 1.
Where the carbon atoms substituted by OR
7
or NHR
8
are stereogenic centers, the process according to the invention relates both to the syn and to the anti isomers.
Examples of amino alcohols of the above structure (I) which may be mentioned are:
2-amino-1-butanol; ephedrine; pseudoephedrine; norephedrine; norpseudoephedrine; tert-leucinol; phenylglycinol; 1,2-diphenylaminoethanol; cis- and trans-2-aminocyclopentanol; cis- and trans-1-amino-2-hydroxyindan; cis- and trans-2-aminocyclohexanol, statine, 2-hydroxy-3-aminophenylpropionic acid.
Preferred amino alcohols which may be mentioned are: cis- and trans-1-amino-2-hydroxyindane.
The polyols which can be used in the process according to the invention are glycols, e.g. ethylene glycol and its monoethers e.g. monomethyl glycol.
Further suitable polyols are 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 2,3-butanediol, 2,4-pentanediol, cis- and trans-cyclohexane-1,2-diol, cis- and trans-cyclohexane-1,4-diol, 2-methyl-2,3-butanediol, 3-methyl-2,4-pentanediol, 2,2-dimethyl-1,3-propanediol, 1-phenyl-1,2-ethanediol, 3-methoxy-1,2-propanediol, 3-phenoxy-1,2-propanediol, 3-butene-1,2-diol, cis- and trans-2-butene-1,4-diol, triethanolamine, triisopropanolamine.
It is also possible to employ polyalkylene glycols, preferably dialkylene glycols and their ethers, in particular diethylene glycol and diglyme, as polyols.
Preferred polyols are ethylene glycol and diethylene glycol.
Suitable amino alcohols for the amide cleavage according to the invention are ethanolamine, diethanolamine and triethanolamine. Triethanolamine is the particularly preferred amino alcohol.
The polyols or amino alcohols should be soluble in water or homogeneously miscible with water. It is also possible to employ mixtures of polyols or amino alcohols.
The polyols are used in an amount of 5-30, preferably 5-20 and, particularly preferably 8-15% of the weight of the amide employed.
Another necessary component in the cleavage according to the invention is an alkali metal or alkaline earth metal hydroxide, in particular sodium or potassium hydroxide. This catalyzes the hydrolysis but is also neutralized by the acid produced, so that it is normally employed in an amount of 1-10 equivalents based on amide.
The hydroxides can advantageously be employed in the form of their aqueous solutions because a certain amount of water is required anyway in the cleavage according to the invention. The amount of water is usually 5-90% of the total weight of solvent. The cleavage according to the invention is preferably carried out at temperatures above 100° C. particularly preferably between 100 and 180° C.
The hydrolysis according to the invention of the amides can be carried out either batchwise or continuously.
It is possible in the continuous procedure to employ, for example, a loop reactor or else a cascade of stirred vessels.
The course of the reaction can easily be followed by conventional methods, for example by gas chromatography.
After the hydrolysis has taken place, the resulting amine is separated and isolated from the carboxylic acid which is in the form of a salt. This preferably takes place be extraction, employing as extractants ethers such as diethyl ether, methyl tert-butyl ether and dibutyl ether, halogenated hydrocarbons such as dichloromethane or trichloroethylene or hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene and xylene.
A likewise preferred embodiment of the isolation of the amine is steam distillation.
A particularly suitable embodiment of the invention consists of carrying out the cleavage at such a high temperature that the product resulting from the reaction (amine) is distilled out with steam and thus immediately removed from the reaction mixture, whereas the acid, which is in dissociated form under the alkaline conditions, remains where it was.
The process according to the invention can be employed very successfully as one step (step 3) in the process described in WO 95/08636 for resolving racemates of primary and secondary amines. This process comprises the following steps:
1. Reaction of the racemic amines with an ester whose acid component has a fluorine, nitrogen, oxygen, phosphorus or sulfur atom bonded to a carbon atom in the alpha, beta or gamma position relative to the carbonyl carbon atom with specific catalysis by a hydrolase,
2. separation of the enantioselectively acylated amine from the unreacted other enantiomer of the amine,
3. subsequent hydrolysis of the acylated ami

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