Manufacturing processes for Se-methyl-L-selenocysteine

Details Manufacturing processes for Se-methyl-L-selenocysteine Manufacturing processes for Se-methyl-L-selenocysteine

2002-11-07

2004-09-21

Richter, Johann (Department: 1621)

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

Organic compounds

Carboxylic acids and salts thereof

C562S899000

Reexamination Certificate

active

06794537

ABSTRACT:

BACKGROUND OF INVENTION
Selenium is an essential micronutrient for the well being of humans. Lack of adequate amounts of selenium results in various diseases and deficiencies (Rayman, M. P.; Lancet, 2000, 356, 233-241) Selenium is present naturally in several plant and animal foods. Brazil nuts, walnuts, grains, meat and sea food are good sources (Facts about dietary supplements—Selenium, NIH, 2001) . Dietary exposure from these sources varies with geographical location, depending upon the selenium content in the soil. Situations where adequate amounts of selenium cannot be obtained from natural resources warrant the use of selenium supplements. Such selenium supplements include organic forms (such as selenium yeast L-Selenomethionine) and Sodium selenite ,an inorganic form that is not well utilized (Schrauzer, G. N.; J. Med. Foods, 1998, 1, 201-206.). One important selenium supplement is L-Se-methylselenocysteine (L-Methylselenocysteine, L-Se-methylselenocysteine or L-MSC as abbreviated in this patent).
L-MSC is a selenoamino acid found naturally in vegetables such as garlic and broccoli. It is a bioavailable and safe form of supplementing the essential trace mineral nutrient, selenium. Selenium in the form of Selenocysteine is an essential component of antioxidant enzymes such as glutathione peroxidase and is also found in several proteins in the body. Antioxidant enzymes containing selenium, protect cells against oxidative damage (Cronin, J. R.; Alt. Complement. Therap. 2000, 6(6), 342-346).
Studies in animal models have shown that L-MSC is effective in cancer chemoprevention. A monomethylated selenium metabolite is reported to be essential for cancer chemoprevention (Ip, C. et al.; Cancer Res. 2001, 60(11), 2882-2886). Selenium-enriched garlic is reported to be useful as a nutritional supplement in the prevention of cancer and contains L-MSC which is a major constituent of plants grown on Selenium rich media (Ip, C. and Lisk, D.; J. Nutr. and Cancer, 2001, 28(2), 184-188). It is one of the most effective chemopreventive forms of selenium. Studies indicate that it does not get incorporated into proteins, thereby minimizing the possibility of excessive accumulation in tissues (Ip, C. et al.; Selenium In Biology and Human Health; Burk, R. F. Ed; 1994,169 180).
SCOPE OF THE INVENTION
The present patent describes efficient processes for the manufacture of L-Se-methyselenocysteine, D-Se-methylselenocysteine and DL-Se-methylselenocysteine: The structures of the referred materials are shown below;
RELATED PRIOR ART
L-Se-methylselenocysteine has been prepared from L-chloroalanine and disodiumdiselenide in a two step process (Tanaka, H; Soda, K; Selenocysteine. Methods Enzymol., 1987, 143, 240-243; Andreadou, I; Menge, W. M. P. B.; Commandeur, J. N. M.; Worthington, E. A.; Vermeulen, N. P. E.; J. Med. Chem., 1996, 39, 2040-2046). Broadly in this process chloroalanine is reacted with disodiumdiselenide to give L-selenocystine in the first step. In a subsequent step, the —Se—Se— bond in L-selenocystine is cleaved in liquid ammonia at −70° C. using small pieces of metallic sodium and subsequently alkylated with methyliodide to give L-Se-methylselenocysteine. This process utilizes very low temperature for its reaction and also metallic sodium in small pieces which is hazardous in large scale practice.
In another process (Spallholz, J. E.; Reid, T. W.; Walkup, R. D.; A method of using synthetic L-Se-methylselenocysteine as a nutraceutical and a method of its synthesis, EP 1 205 471, 2001), the synthesis is done by mixing N-(tert-butoxycarbonyl)-L-serine with a dialkyl diazodicarboxylate and at least one of a trialkylphosphine, triarylphosphine and phosphite to form a first mixture that includes N-(tert-butoxycarbonyl)-L-serine &bgr;-lactone. Methylselenol or its salt is mixed with the N-(tert-butoxycarbonyl)-L-serine &bgr;-lactone to form a second mixture that includes N-(tert-butoxycarbonyl)-Se-methylselenocysteine. The tert-butoxycarbonyl group is removed from the N-(tert-butoxycarbonyl)-Se-methylselenocysteine to form L-Se-methylselenocysteine. In this process, serine is protected with a Boc group and converted to its lactone form which is further reacted with methylselenol or its salt. The protecting group is removed to give L-Se-methylselenocysteine. The method is lengthy and involves expensive protecting groups and reagents.
Lithiated alkenylselenium compounds have been reported to be generated from Grignard reagents and disetenides followed by lithiatlon of the resultant alkenyl-alkyl selenide (Block, E.; Birringer, M.; Jiang, W.; Nakahodo, T.; Thompson, H. J.; Toscano, P. J.; Uzar, H.; Zhang, X.; Zhu, Z.; J Agri. Food Chem., 2001, 49, 458-470)
Grummon et at (U.S. Pat. No. 3,678,067) describes a process for the synthesis of selenomethionine but involves the use of liquid ammonia and sodium. As pointed out already, such processes would be cumbersome to practice routinely
Chibata et al (U.S. Pat. No. 4,401,820) teaches a process for the racemization of optically active amino acids using an aromatic aldehyde and aliphatic acid but does not teach or suggest the use of the process for selenium-containing amino acids.


REFERENCES:
patent: 3678067 (1972-07-01), Grummon et al.
patent: 4401820 (1983-08-01), Chibata et al.
Andreadou et al, Journal of Medicinal Chemistry, 1996, 39(10), pp. 2040-2046.*
Walsh et al, The Journal of Biological Chemistry, Studies on the Mechanism of D-Amino Oxidase, 1971, 246(22), pp. 6855-6866.*
Patai, The Chemistry of the Carbon-Halogen Bond, Part 1, 1973, John Wiley & Sons, New York, pp. 463-466.

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