Process for ring cleavage of thiazolidine derivatives

Details Process for ring cleavage of thiazolidine derivatives Process for ring cleavage of thiazolidine derivatives

2000-04-05

2002-04-16

Shah, Mukund J. (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S200000, C548S201000, C560S147000, C562S557000, C562S558000, C564S198000

Reexamination Certificate

active

06372912

ABSTRACT:

TECHNICAL FIELD
The invention relates to a process for the hydrolytic ring cleavage of thiazolidine derivatives.
BACKGROUND ART
The acid- or base-catalyzed hydrolysis of thiazolidine derivatives to give the corresponding (substituted) 2-aminomercaptan derivatives and (substituted) aldehydes or ketones is known.
Depending on the degree of substitution at the 2 position, thiazolidine derivatives have highly differing hydrolytic stabilities. Whereas 2,2-disubstituted thiazolidine derivatives derived from the corresponding ketones are, in most cases, quite susceptible to hydrolysis, 2-monosubstituted thiazolidine derivatives, derived from the corresponding aldehydes, are relatively stable to hydrolytic ring cleavage. Electron-withdrawing groups in the &agr; position in 2,2-disubstituted thiazolidines also render these derivatives relatively stable to hydrolysis.
In order to cleave thiazolidine derivatives which are not very susceptible to hydrolysis, in general, one of the hydrolysis products is removed from the equilibrium mixture. In the case of thiazolidine derivatives which release a volatile carbonyl compound during hydrolysis, this compound can be removed from the equilibrium, for example, by distillation. In DE-A 1795297, isobutyraldehyde is removed from 2-isopropyl-5,5-dimethylthiazolidine-4-carboxylic acid (hydrochloride) by steam distillation, to obtain DL-penicillamine (hydrochloride). In this process, approximately 25 l of water have to be evaporated per mole of thiazolidine derivative. The long reaction time at high temperatures under acidic or alkaline conditions is a considerable disadvantage. In the case of sensitive compounds, this may lead to decomposition or, for example in the case of optically active compounds, to racemization.
A further process for cleaving thiazolidine derivatives which are not very susceptible to hydrolysis is reaction of the carbonyl compound that is liberated during hydrolysis with a “carbonyl reagent” such as hydroxylamine, which reacts with the carbonyl groups with high efficiency under the reaction conditions. DE-A 2142336 describes the ring cleavage of 2-isopropyl-5,5-dimethylthiazolidine compounds by reaction with a carbonyl reagent. Suitable carbonyl reagents are, for example, hydrazine, phenylhydrazine, 2,4-dinitrophenylhydrazine, semicarbazide, thiosemicarbazide and, in particular, hydroxylamine. Disadvantageous here is the fact that it is often difficult or even impossible to regenerate the carbonyl compound afterwards.
Alternatively, the acidic hydrolysis can be carried out at temperatures above 100° C., i.e. in an autoclave under pressure. This is described, for example, in DE-A 3607167. However, relatively long reaction times under drastic conditions are harmful in the case of temperature-sensitive compounds or, for example in the case of optically active compounds, lead to racemization.
A further possibility of cleaving thiazolidine derivatives which are not very susceptible to hydrolysis consists in the oxidative removal of the liberated aminomercaptan derivative from the equilibrium by conversion into the corresponding disulfide. However, if the mercaptan is the desired target compound, this has to be recovered subsequently in a further reductive reaction step. EP 213785 A1 describes the reaction of (4R)-thiazolidine-4-carboxylic acid with hydrogen peroxide to give L-cystine, which is subsequently reduced electrolytically to L-cysteine.
DISCLOSURE OF INVENTION
It is the object of the present invention to provide a process for the hydrolytic cleavage of thiazolidine derivatives, in particular of thiazolidine-4-carboxylic acids and thiazolidine-4-carboxylic acid derivatives, which avoids the disadvantages of the prior art and yields, in particular, both the 2-aminomercaptan derivative and the carbonyl compound in high yield and purity. Furthermore, the percent invention provides a process which is simple, and cost-effective to carry out on an industrial scale. The process is amenable not only to difficulty cleavable thiazolidines, but can be used to advantage even for thiazolidines which are considered readily susceptible to hydrolysis.
BEST MODE FOR CARRYING OUT THE INVENTION
The invention provides a process for the hydrolytic ring cleavage of thiazolidine derivatives to give 2-aminomercaptan derivatives and carbonyl compounds, which comprises
a) contacting an aqueous solution of the thiazolidine derivative with an acidic cation exchanger in the H
+
form, giving a solution L
1
which contains the carbonyl compound and
b) eluting the cation exchanger with a suitable eluent, giving a solution L
2
which contains the 2-aminomercaptan derivative.
The thiazolidine derivatives used are preferably compounds of the formula 1:
where
A is CN, COOR
4
or CONR
5
R
6
;
R
4
is selected from the group consisting of H, and linear or branched C
1
- to C
12
-alkyl radicals;
R
5
and R
6
are identical or different and are H or a linear or branched C
1
- to C
12
-alkyl radical;
R
1
and R
2
are identical or different and are selected from the group consisting of H, a linear or branched C
1
- to C
12
-alkyl, a C
1
- to C
6
-alkyl mono- or polysubstituted by alkoxy or hydroxyl, (CH
2
)
n
COOR
4
, where n is an integer from 0 to 12 and R
4
is as defined above, phenyl mono- or poly-(C
1
, to C
6
alkyl) substituted 1-naphthyl, 2-naphthyl, 9-phenanthrenyl, and 5- or 6-membered heteroaryl having 1 to 3 identical or different heteroatoms from the group consisting of O, N and S, and where the radicals R
1
and R
2
together comprise a C
2
- to C
9
-cycloalkyl radical and R
3
is H or methyl. Particular preference is given to using thiazolidine derivatives which have a solubility in water of at least 1 g/l at 25° C. and atmospheric pressure.
Most preferably, the process is employed for cleaving thiazolidine derivatives which, after the reaction, give a compound selected from the group consisting of cysteine, cysteine methyl ester, cysteine ethyl ester, penicillamine, penicillamine methyl ester, penicilamine ethyl ester and/or the hydrochlorides of these compounds.
Prior to eluting the solution L
2
, the cation exchanger is preferably washed with a wash solution, preferably water.
In the hydrolysis of a thiazolidine derivative according to the invention by means of an acidic cation exchanger in the H
+
form, the 2-aminomercaptan derivative which is formed binds (in the protonated form) to the cation exchanger. It is thus removed from the equilibrium. The carbonyl compound which is also formed and which is not present in cationic form does not bind to the cation exchanger and can easily be removed.
All acidic cation exchangers are suitable for the process according to the invention. Acidic cation exchangers are known and commercially available. A selection of different materials is compiled in Ullmann's Encyclopedia of Industrial Chemistry, Vol. A14, p. 451. As active ion-exchanging groups they contain, for example but not by limitation, carboxylic acid groups (weakly acidic cation exchangers), or sulfonic acid or phosphonic acid groups (strongly acidic cation exchangers). These acidic groups are capable of immobilizing the protonated aminomercaptan derivative.
In the process according to the invention, preference is given to using strongly acidic cation exchangers. Particular preference is given to using strongly acidic cation exchangers having sulfonic acid groups or phosphonic acid groups.
The reaction temperature in the process according to the invention can be varied within a wide range of preferably from +5 to +120° C., depending on the hydrolytic stability of the thiazolidine derivative used. Thiazolidine derivatives which are susceptible to hydrolysis, such as 2,2-dialkylthiazolidine derivatives, are preferably reacted at from +5 to +60° C., more preferably at from +5 to +40° C., whereas thiazolidine derivatives which are stable to hydrolysis, such as 2-monoalkylthiazolidine derivatives, or thiazolidine derivatives substituted by electron-withdrawing groups at the 2-position, are preferably reac

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