Neotame

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Neotame
Ball-and-stick model of the neotame molecule
Names
Systematic IUPAC name
(3S)-3-[(3,3-Dimethylbutyl)amino]-4-{[(2S)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino}-4-oxobutanoic acid
Other names
E961; N-(N-(3,3-Dimethylbutyl)-L-α-aspartyl)-L-phenylalanine 1-methyl ester
Identifiers
3D model (
JSmol
)
ChEBI
ChemSpider
ECHA InfoCard
 100.109.344 Edit this at Wikidata
E number E961 (glazing agents, ...)
UNII
  • InChI=1S/C20H30N2O5/c1-20(2,3)10-11-21-15(13-17(23)24)18(25)22-16(19(26)27-4)12-14-8-6-5-7-9-14/h5-9,15-16,21H,10-13H2,1-4H3,(H,22,25)(H,23,24)/t15-,16-/m0/s1 ☒N
    Key: HLIAVLHNDJUHFG-HOTGVXAUSA-N ☒N
  • InChI=1/C20H30N2O5/c1-20(2,3)10-11-21-15(13-17(23)24)18(25)22-16(19(26)27-4)12-14-8-6-5-7-9-14/h5-9,15-16,21H,10-13H2,1-4H3,(H,22,25)(H,23,24)/t15-,16-/m0/s1
    Key: HLIAVLHNDJUHFG-HOTGVXAUBG
  • CC(C)(C)CCN[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)OC
Properties
C20H30N2O5
Molar mass 378.469 g·mol−1
Appearance white powder[1]
Melting point 80.9–83.4 °C (177.6–182.1 °F; 354.0–356.5 K)[1]
12.6 g/kg at 25 °C[2]
Hazards
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 0: Exposure under fire conditions would offer no hazard beyond that of ordinary combustible material. E.g. sodium chlorideFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
0
1
0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Neotame, also known by the

synergistic effect) and decrease their off-flavors (e.g. saccharin). It is chemically somewhat more stable than aspartame. Its use can be cost effective in comparison to other sweeteners as smaller amounts of neotame are needed.[2]

It is suitable for use in

carbonated soft drinks, yogurts, cakes, drink powders, and bubble gums among other foods. It can be used as a table top sweetener for hot drinks like coffee. It covers bitter tastes (e.g. caffeine).[2]

In 2002,

EU with the E number E961.[5] It has also been approved as an additive in many other countries outside US and EU.[2]

Its

type 2 diabetics and those with phenylketonuria.[6][1]

French scientists Claude Nofre and Jean-Marie Tinti invented neotame.[2] In 1992 they filed a patent for neotame within US, which was granted in 1996.[7]

Safety

In US and EU, the

mutagenic.[6][1]

The Center for Science in the Public Interest ranks neotame as safe.[8]

Sweetness

Neotame is

sweet because it binds to TAS1R2 receptors in the mouth as an agonist. Aspartame binds to the same receptor.[9]

Water solutions of neotame, that are equivalent in

acesulfame K, cyclamate and saccharin reach their maximum sweetness at 11.6 SE%, 11.3 SE% and 9 SE%, respectively.[2]

Neotame is a high-potency sweetener, and it is 6,000 to 10,000 times sweeter than sugar (sucrose), and even around 30 to 60 times sweeter than aspartame. Neotame contains flavor-enhancing properties and compared to sucrose or aspartame it has a relatively lower cost per sweetness factor. [10]

Chemistry

Structure

Neotame is formally a

stereoisomers. Sweetness is due to the (2S),(3S)-stereoisomer.[11]

Spectroscopy

Neotame NMR spectroscopy identifies its structure with a peak at 0.84 ppm indicating the three methyl groups on the carbon chain bonded to the nitrogen.[12]

Proton NMR spectroscopy of neotame[12]

Synthesis

Neotame is synthesized from aspartame through a reductive alkylation with 3,3-dimethyl-butylaldehyde in a palladium catalyst with methanol.[13] The stereochemistry of aspartame is conserved during the synthesis and therefore, neotame and aspartame have the same stereochemistry. (2S),(3S)-stereoisomer of aspartame is needed to synthesize the (2S),(3S)-stereoisomer of neotame.[13]

Properties and reactivity

Neotame, a fine white powder, in a jar
Neotame.

Neotame has similar stability as aspartame, but has greater stability especially in heated and dairy foods. Increased temperature, moisture or pH increase losses, and are the main relevant properties of a food when considering the stability of neotame. For example, about 90% of original neotame remains after 8 weeks of storage in pH 3.2 beverages. Neotame is especially stable as a dry powder at room temperature and humidity even if mixed with e.g. glucose or maltodextrin, and is relatively inert in foods with reducing sugars like fructose.[2]

Unlike aspartame, neotame doesn't form

intra-molecular cyclization due to its N-alkyl substitution with 3,3-dimethylbutyl. This increases its heat stability.[2]

Over 1000 g of neotame dissolves in 1 kg of ethanol at 15 °C. At 15 °C the solubility of neotame is 10.6 g/kg in water and 43.6 g/kg in

wt% solution has a pH of 5.80.[1]

Manufacture

NutraSweet Neotame brand logo

Industrially neotame is made from 3,3-dimethylbutanal and aspartame via

distilled followed by addition of water. The mixture is cooled for a few hours, neotame is isolated via centrifugation, washed with water and vacuum dried. Neotame is milled to suitable size.[1]

Metabolism

Neotame de-esterification via hydrolysis. CH3OH is methanol.

In humans and many other animals like dogs, rats and rabbits, neotame is rapidly, but incompletely absorbed. Its

metabolites are not retained or concentrated in specific tissues.[1]

In humans at oral doses of about 0.25 mg per kg of bodyweight (mg/kg bw), about 34% is absorbed into blood. Pharmacokinetics of oral doses of 0.1–0.5 mg/kg bw are somewhat linear, and at such doses, maximum neotame concentration in blood plasma is reached after about 0.5 hours with a half-life of about 0.75 hours. In blood and in body in general, non-specific esterases degrade neotame to de-esterified neotame and methanol, which is the main metabolic pathway in humans. De-esterified neotame has a plasma half-life of about 2 hours, and is the main metabolite in plasma.[1]

In humans, over 80% of the original oral dose is excreted in feces and urine within 48 hours and the rest later. About 64% of the original dose is excreted in feces mostly as metabolites. Major metabolite in feces is the de-esterified neotame. Over 1% of the original dose is excreted in feces as N-(3,3-dimethylbutyl)-L-aspartyl - L - phenylalanine. Over 1% is excreted in urine as carnitine conjugate of 3,3-dimethylbutyric acid. Other minor metabolites form.[1]

The major metabolic pathway leads to N-(3,3-dimethylbutyl)-L-aspartyl - L - phenylalanine with a side product of methanol, and the minor pathway happens when the N-(3,3-dimethylbutyl)-L-aspartyl - L - phenylalanine is oxidized into 3,3-dimethylbutyric acid. The side products for the minor pathway is methanol, aspartic acid and phenylalanine.[14]

Methanol from neotame metabolism is insignificant at regulated levels used in foods and in comparison to methanol naturally found in foods.[1]

Patent

The

U.S. Patent and Trademark Office. The patent expired on 8 July 2015.[15]

References

  1. ^
    ISSN 1831-4732
    .
  2. ^ a b c d e f g h i j k Nabors 2012, p. 134–149
  3. ^ a b c Nutrition (2019-02-09). "Additional Information about High-Intensity Sweeteners Permitted for Use in Food in the United States". FDA.
  4. ^ Nabors 2012, p. 2–3
  5. ^ Halliday, Jess. "Neotame wins approval in Europe". foodnavigator.com. Retrieved 2019-09-15.
  6. ^ a b "Food additives permitted for direct addition to food for human consumption; neotame" (PDF). Federal Register. 67 (131): 45300–45310. 2002.
  7. ^ a b "US 5,480,668". Retrieved 2019-09-15.
  8. ^ "Chemical Cuisine | Center for Science in the Public Interest". cspinet.org. 25 February 2016. Retrieved 2019-09-15.
  9. PMID 30282936
    .
  10. doi:10.1016/S0308-8146(99)00254-X
    . Retrieved 12 November 2021.
  11. S2CID 93160173
    .
  12. ^
    PMID 11308366
    . Retrieved 12 November 2021.
  13. ^
    doi:10.1080/00397919908086610
    . Retrieved 12 November 2021.
  14. doi:10.1016/S0308-8146(99)00254-X
    . Retrieved 12 November 2021.
  15. ^ "USPTO extension of 5,480,668". Retrieved 2012-09-21.

Further reading

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Neotame&oldid=1213189166"