80863-62-3

Basic information

• Product Name: Alitame
• Synonyms: (3s)-3-amino-4-oxo-4-[[(2r)-1-oxo-1-[(2,2,4,4-tetramethylthietan-3-yl)amino]propan-2-yl]amino]butanoic acid;Alitame;l-alpha-aspartyl-n-(2,2,4,4-tetramethyl-3-thietanyl)-d-alaninamide;l-α-aspartyl-N-(2，2，4，4-tetramethyl-3-thietanyl)-D-alaninamide;CP 54802;(S)-3-AMino-4-oxo-4-(((R)-1-oxo-1-((2,2,4,4-tetraMethylthietan-3-yl)aMino)propan-2-yl)aMino)butanoic acid;(S)-3-Amino-4-oxo-4-(((R)-1-oxo-1-((2,2,4,4-tetramethylthietan-3-yl)amino)propan-2-yl)amino)butan;(S)-3-amino-4-(((R)-1-amino-1-oxopropan-2-yl)(2,2,4,4-tetramethylthietan-3-yl)amino)-4-oxobutanoic acid
• CAS NO: 80863-62-3
• Molecular Formula: C₁₄H₂₅N₃O₄S
• Molecular Weight: 331.43
• EINECS: 1312995-182-4
• Product Categories: Amino Acids & Derivatives;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 80863-62-3.mol
• Article Data: 1

Chemical Properties

• Melting Point: 136-147°
• Boiling Point: 608.5oC at 760 mmHg
• Flash Point: 321.8oC
• Appearance: /
• Density: 1.25g/cm3
• Vapor Pressure: 2.25E-16mmHg at 25°C
• Refractive Index: 1.559
• PKA: 3.71±0.10(Predicted)
• CAS DataBase Reference: Alitame(CAS DataBase Reference)
• NIST Chemistry Reference: Alitame(80863-62-3)
• EPA Substance Registry System: Alitame(80863-62-3)

Safety Data

• Hazardous Substances Data: 80863-62-3(Hazardous Substances Data)

Usage

Chemical Properties

Different sources of media describe the Chemical Properties of 80863-62-3 differently. You can refer to the following data:
1. White Solid
2. Alitame is a white nonhygroscopic crystalline powder; odorless or having a slight characteristic odor.

Physical properties

Alitame [L-a-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide] is a sweetener based on an amino acid. It is a very intense sweetener, possessing a sweetening power of about 2000 times that of sucrose. It also exhibits a clean sweet taste similar to sucrose. Although it is metabolized, so little is needed that its caloric contribution is insignificant. Alitame is prepared from the amino acids, L-aspartic acid, D-alamine, and a novel amine.

Characteristics

Alitame is an amino acidbased sweetener developed by Pfizer Central Research from l-aspartic acid, d-alanine, and 2,2,4,4-tetraethylthioethanyl amine. A terminal amide group instead of the methyl ester constituent of ASP was used to improve the hydrolytic stability. The incorporation of d-alanine as a second amino acid in place of l-phenylalanine has resulted in optimum sweetness. The increased steric and lipophilic bulk on a small ring with a sulfur derivative has provided a very sweet product and good taste qualities. Alitame offers several benefits such as stability at high temperatures and a broader pH range. For instance, it is stable for over a year at pH 6–8 and room temperature and withstands pasteurization. However, prolonged storage of acidic solutions at high temperatures or in combination with certain ingredients (hydrogen peroxide or sodium bisulfite) may produce off-flavors. In the presence of high levels of reducing sugars, alitame can undergo Maillard reactions.

History

Alitame, L-α-aspartyl-D-alanine N-(2,2,4,4-tetra methylthietan-3-yl)amide (5), was developed by Pfizer, but is owned by Danisco now. In 1986, Pfizer filed a food additive petition with the FDA. As of 2006, it was still pending. Alitame was approved for use as a sweetener by Australia in 1993, by China, Mexico, and New Zealand in 1994, by Indonesia in 1995, and by Colombia in 1996.

Uses

Different sources of media describe the Uses of 80863-62-3 differently. You can refer to the following data:
1. Alitame [L-a-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide] is a sweetener based on an amino acid. It is a very intense sweetener, possessing a sweetening power of about 2000 times that of sucrose. It also exhibits a clean sweet taste similar to sucrose. Although it is metabolized, so little is needed that its caloric contribution is insignificant. Alitame is prepared from the amino acids, L-aspartic acid, D-alamine, and a novel amine.
2. Alitame is a dipeptide amide derivative of aspartic acid used as an artificial sweetener. Alitame is about ten times sweeter than Aspartame (A790015) with a half life about twice as long.

Production Methods

Alitame may be synthesized by a number of routes.For example, 3-(D-alaninamido)-2,2,4,4-tetramethylthietane is dissolved in water and L-aspartic acid N-thiocarboxyanhydride is then added in portions with vigorous stirring, maintaining the pH of 8.5–9.5. The pH is then adjusted to 5.5 and p-toluenesulfonic acid monohydrate is added over a period of one hour. The precipitated crystalline p-toluenesulfonate salt is collected by filtration. To obtain alitame from its salt, a mixture of Amberlite LA-1 (liquid anion exchange resin), dichloromethane, deionized water, and the salt is stirred for one hour, resulting in two clear layers. The aqueous layer is treated with carbon, clarified by filtration, and cooled to crystallize alitame. Alternatively, tetramethylthietane amine is condensed with anNprotected form of D-alanine to give alanyl amide. This is then coupled to a protected analogue of L-aspartic acid to give a crude form of alitame. The crude product is then purified.

Pharmaceutical Applications

Alitame is an intense sweetening agent developed in the early 1980s and is approximately 2000 times sweeter than sucrose. It has an insignificant energy contribution of 6 kJ (1.4 kcal) per gram of alitame. Alitame is currently primarily used in a wide range of foods and beverages at a maximum level of 40–300 mg/kg.

Safety Profile

The Joint Expert Committee on Food Additives (JECFA) concluded that alitame was not carcinogenic and did not show reproductive toxicity. In 1996, an ADI of 0–1 mg/kg of body weight was allocated. It is approved for use in Australia, New Zealand, Mexico, and China. A food additive petition was submitted to the FDA in 1986, and approval is awaited. In the petition, the estimated daily intake is 0.34 mg/kg of body weight, which represents the amount if alitame is the only sweetener in the diet. The level at which no observed adverse effects occur in animals is 100 mg/ kg. Potential uses include baked goods, baking mixes, hot and cold beverages, dry beverage mixes, tabletop sweeteners, chewing gum, candies, frozen desserts, and pharmaceuticals. Alitame has been approved for use in some countries such as Australia, Mexico, New Zealand, and China, but not in the United States or the EU.

Safety

Alitame is a relatively new intense sweetening agent used primarily in foods and confectionary. It is generally regarded as a relatively nontoxic and nonirritant material. Chronic animal studies in mice, rats, and dogs carried out for a minimum of 18 months at concentrations >100 mg/kg per day exhibited no toxic or carcinogenic effects. In people, no evidence of untoward effects were observed following ingestion of 15 mg/kg per day for two weeks. Following oral administration 7–22% of alitame is unabsorbed and excreted in the feces. The remaining amount is hydrolyzed to aspartic acid and alanine amide. The aspartic acid is metabolized normally and the alanine amide excreted in the urine as a sulfoxide isomer, as the sulfone, or conjugated with glucuronic acid. The WHO has set an acceptable daily intake of alitame at up to 0.1 mg/kg body-weight. LD50 (mouse, oral): >5 g/kg LD50 (rabbit, skin): >2 g/kg LD50 (rat, oral): >5 g/kg

Metabolism

Alitame is noncariogenic. From an oral intake, 7%–22% is unabsorbed and excreted in the feces. The remainder is hydrolyzed to aspartic acid and alanine amide. The aspartic acid is normally metabolized, and the alanine amide is excreted in the urine as a sulfoxide isomer, sulfone, or conjugated with glucuronic acid. The incomplete absorption and metabolism result in a core value of 1.4 kcal g?1.

storage

Alitame is stable in dry, room temperature conditions but undergoes degradation at elevated temperatures or when in solution at low pH. Alitame can degrade in a one-stage process to aspartic acid and alanine amide (under harsh conditions) or in a slow two-stage process by first degrading to its β-aspartic isomer and then to aspartic acid and alanine amide. At pH 5–8, alitame solutions at 238℃ have a half-life of approximately 4 years. At pH 2 and 238℃ the half-life is 1 year. Alitame should be stored in a well-closed container in a cool, dry place.

Incompatibilities

Alitame may be incompatible with oxidizing and reducing substances or strong acids and bases.

Regulatory Status

Alitame is approved for use in food applications in a number of countries worldwide including Australia, Chile, China, Mexico, and New Zealand.

InChI:InChI=1/C14H25N3O4S/c1-7(16-11(21)8(15)6-9(18)19)10(20)17-12-13(2,3)22-14(12,4)5/h7-8,12H,6,15H2,1-5H3,(H,16,21)(H,17,20)(H,18,19)/t7-,8+/m1/s1

Synthetic route

3-(L-Aspartyl-D-alaninamido)-2,2,4,4-tetramethylthietane (80863-62-3) + toluene-4-sulfonic acid (104-15-4) → 3-L-α-aspartyl-D-alanylamido-2,2,4,4-tetramethylthietanylamine p-toluenesulfonate

Conditions	Yield
Stage #1: 3-(L-Aspartyl-D-alaninamido)-2,2,4,4-tetramethylthietane With hydrogenchloride In water for 18h; pH=3.0; Stage #2: toluene-4-sulfonic acid In water Product distribution / selectivity;

Relevant articles and documents

Processes for preparation, isolation and purification of dipeptide sweeteners

Aromatic sulfonic acid salts of certain dipeptide sweeteners which are L-aspartyl-D-alaninamides or L-aspartyl-D-serinamides, each substituted on amide nitrogen with an organic radical having a highly branched carbon skeleton; the process for preparing said salts by crystallization; and utilization of this crystallization process in processes for the preparation, isolation and purification of said amides.