Food or edible material: processes – compositions – and products – Products per se – or processes of preparing or treating... – Noncarbohydrate sweetener or composition containing same
Patent
1997-11-21
1999-02-23
Hill, Jr., Robert J.
Food or edible material: processes, compositions, and products
Products per se, or processes of preparing or treating...
Noncarbohydrate sweetener or composition containing same
426590, 530330, C07D10352, C07D10350, C07D30722, C07C 8734
Patent
active
058741216
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of international application PCT/EP96/00393, filed Jan. 31, 1996 which was designated the U.S.
The invention is relative to a method of producing L-aspartyl-D-alanine-N-(thietane-3-yl)-amides of the general formula I ##STR2## in which
R.sup.1 stands for H or a protective group capable of being split off and
R.sup.2 -R.sup.5 signify independently of each other and equally or differently H or C.sub.1 -C.sub.4 alkyl, linear or branched.
Compounds with R.sup.1 .dbd.H are dipeptide sweeteners (U.S. Pat. No. 4,411,925; EP-A 34,876). Alitame (R.sup.1 .dbd.H, R.sup.2 -R.sup.5 .dbd.CH.sub.3) has a sweetening strength approximately 2000 times as great as that of sugar (ACS Symp. Ser. 1992, 450, 57).
The compounds of formula I are preferably produced starting from thietane amines, D-Ala and L-Asp.
These components can basically be coupled to each other in different ways. Thus, the synthesis of compounds of general formula I is described by way of example in U.S. Pat. No. 4,411,925. However, the syntheses of the three coupling partners (thietane amine and activated/protected D-Ala and L-Asp) take place in it in a rather complicated manner in accordance with methods known in the literature. This is elucidated using the example of alitame.
2,2,4,4-tetramethyl-3-thietanone is produced from diisopropylketone after dibromination by cyclization with disodium sulfide, which 2,2,4,4-tetramethyl-3-thietanone is reduced in the ammonium acetate/sodium cyanoboron hydride system in 42% yield to thietane amine. The amine can also be obtained according to EP-A 168,112 by converting 2,2,4,4-tetramethylthienanone into an oxime (<30% yield) and reduction by lithium aluminum hydride (42% yield). Furthermore, U.S. Pat. No. 4,851,548 teaches the reduction of 2,2,4,4-tetramethyl-3-thietanone to thietane amine by means of Leuckart-Wallach reaction in a max. 65% yield.
Various strategies are indicated in U.S. Pat. No. 4,411,925 for the coupling of the three reaction partners which take place according to generally current peptide coupling methods with correspondingly many protective and de-protective steps. Thus, a relatively expensive N-benzyloxycarbonyl-L-aspartic-acid-.beta.-benzylester which is difficult to synthesize and is reacted after activation with D-Ala-thietane amide is used for the selective .alpha. coupling of L-Asp. Another formula indicated there uses N-thiocarboxyanhydride as activated and at the same time protected L-Asp. This can be synthesized only with difficulty and in small yields (42% yield). In addition, materials which are critical as regards protection of labor and environmental impact such as methylene chloride, carbon disulfide and phosphorus tribromide are required for its synthesis.
In contrast thereto, the invention had the problem of indicating a method of producing compounds of general formula I, but especially of alitame, which signifies a considerable improvement in methodology as well as in yield and expenditure of time in over the known methods.
This problem is solved by reacting D-alanine-thietane amides of the general formula II ##STR3## in which
R.sup.2 -R.sup.5 have the significance indicated in formula I with oxazolidinone compounds of the general formula III ##STR4## in which
R.sup.1 has the significance indicated in formula I and
R.sup.6 and R.sup.7 stand independently of one another and equally or differently for H, C.sub.1 -C.sub.4 alkyl, linear or branched, C.sub.1 -C.sub.4 haloalkyl, linear or branched, or a preferably halogen-substituted group activating the carbonyl group in an inert organic solvent.
1,3-oxazolidin-5-ones and their fundamental suitability for peptide coupling are basically known (J. P. Greenstein, M. Winitz, Chemistry of the Amino Acids, Wiley, 1961, p. 1024; Houben-Weyl, vol. 15/I, p. 91ff).
In spite of their simple accessibility and, in the case of aspartic acid, high regioselectivity they have not been widely used previously for producing aspartic acid peptides. The reasons for this are that there was the opinion that the carbonyl
REFERENCES:
patent: 4411925 (1983-10-01), Brennan et al.
Chemical Abstracts, vol. 81, No. 19, Nov. 11, 1974, abstract No 121016u, Nagase et al: "Alpha-L-Asparaginyl-L-amino acid esters", p. 578; XP002003940 see abstract & JP,A,07 435 352, Apr. 1, 1974.
Chemical Abstracts, vol. 114, No. 3, Jan. 21, 1991, abstract No. 24570j. Burger et al: "Regiospecific reaction with omega-carboxy alpha-amino acids. A simple synthseis of aspartame", p. 765; XP002003941 see abstract & Chem. Zeitung, vol. 114, No. 7-8, 1990, pp. 249-251.
Drauz Karlheinz
Knaup Gunter
Retzow Stefan
Schwarm Michael
Weckbecker Christoph
Borin M.
Degussa - AG
Hill Jr. Robert J.
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