Process for the electrochemical synthesis of N-acetylcysteine fr

Details Process for the electrochemical synthesis of N-acetylcysteine fr Process for the electrochemical synthesis of N-acetylcysteine fr

1999-01-12

2000-12-12

Phasge, Arun S.

Chemistry: electrical and wave energy

Processes and products

Electrophoresis or electro-osmosis processes and electrolyte...

204541, 205435, C25B 304

Patent

active

061593524

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD OF THE INVENTION

The present invention is within the technical field of processes for producing N-acetyl-cysteine, which is a product with important applications in the pharmaceutical sector.
More specifically, the present invention provides a new process for the electrochemical synthesis of N-acetyl-cysteine which has clear advantages over conventional processes, especially, as far as the quality of the product is concerned, as well as the environmental impact.


PRIOR ART OF THE INVENTION

N-acyl-cysteine derivatives, in which the acyl group can come from a mono or dicarboxylic acid and, in particular, monoacyl derivatives among which is N-acetyl-cysteine, have therapeutic applications as a mucolytic (U.S. Pat. No. 3,184,505 (1965)), in the treatment of cornea lesions (Bull. Mem. Soc. Fr. Ophthalmol. 94,425 (1982)), as an antidote in aminoketophen overdose (Review Pharmacological and Biochemical Properties of Drug Substances, vol. 2. M. E. Goldberg Ed. (An. Pharm. Assoc. Washington, D.C., 1979), pp. 479-488).
More recently, its use in the prevention of apoptotic death of neuron cells has been described (Journal of Neuroscience, 15, 4, (1995)), the inhibition by N-acetyl-cysteine of the interleucine 6 RNA messenger (Febbs Letter. 353, 1 (1994)), the suppression of antiproliferous effects of the tumoral necrosis factor (ibid.), and the regulation of nitric acid cytochina synthetase in rat retina pigments (Experimental Eye Research. 59, 2 (1994)).
N-acetyl-L-cysteine of formula (I) ##STR1## is obtained conventionally by monoacetylation of L-cysteine hydrochloride of formula (II): ##STR2## in a suitable aqueous-organic solvent. The nature of this solvent makes the yield of the reaction vary between 60 and 95%. However, compound (II) is not a raw material available commercially, but rather it must be obtained by reduction of L-cystine of formula (III): ##STR3## either using conventional reducing agents or using electrochemical reduction.
In this process, separation of (I) from the solution coming from acetylation of (II) implies handling solutions with very high salt contents in acetate that may influence the quality of the product, if its application is centered within the pharmaceutical field. On the other hand, in order to obtain (I) from (II) it is necessary that the latter product (II) is perfectly separated from product (III) used as a starting material in the synthesis thereof since traces of (III) could harm the following step of the process.
On the other hand, there is the possibility of obtaining N-acetyl-L-cysteine (I) by reduction of bis-acetyl-L-cystine of formula (IV): ##STR4## by means of using conventional reducing agents such as zinc. In turn, compound (IV) would be obtained previously by acetylation of (III).
The problem of this second alternative process mainly lies on the reduction phase. When the reducing agent, normally metallic zinc, has acted it converts into Zn.sup.+2, whereby the desired compound (I) must be isolated in a medium that has a high salt content in Zn.sup.+2 which involves problems of separation and of quality of the obtained final product. On the other hand, residual water, that has a high salt content in Zn.sup.+2 ions, constitutes an important environmental problem.
Another aspect of this reduction to be considered is that significant volumes of hydrogen gas are produced which, as known, is a dangerous gas to handle due to its potential explosion capacity.
On the other hand, the excess of unconverted zinc metal has to be eliminated by forming the corresponding lead mercaptan, followed by isolation, treatment with hydrogen sulfide, elimination of the lead sulfide formed, lyophilization of the solution and subsequent recrystallizations with solvents, in order to achieve a final yield of approximately 48% (M. W. Pirie et al. Biochemical Journal 2, 614 (1931); M. W. Pirle et al. Ibid., 27, 1716 (1933); Smith, Gorin. J. Org. Chem. 26, (1961); and Greenstein. Chemistry of the Amino Acids. Vol. 3. Ed Krieger. Florida (1984).
U.S. Pat. No. 3,184,505 describes

REFERENCES:
Patent Abstract of Japan, 1988, 12:358 & JP 63 112546 no month available.
Patent Abstract of Japan, 1977, 1:45 & JP 52003021 no month available.

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