Neotame

Last updated
Neotame
Neotame.svg
Neotame zwitterion ball.png
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 OOjs UI icon edit-ltr-progressive.svg
E number E961 (glazing agents, ...)
PubChem CID
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 X mark.svgN
    Key: HLIAVLHNDJUHFG-HOTGVXAUSA-N X mark.svgN
  • 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
Appearancewhite 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.svgHealth 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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Neotame, also known by the trade name Newtame, [3] is a non-caloric artificial sweetener and aspartame analog by NutraSweet. [2] By mass, it is 8000 times sweeter than sucrose. [4] It has no notable off-flavors when compared to sucrose. It enhances original food flavors. It can be used alone, but is often mixed with other sweeteners to increase their individual sweetness (i.e. 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]

Contents

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, FDA approved it as a non-nutritive sweetener and flavor enhancer within United States in foods generally, except meat and poultry. [3] In 2010, it was approved for use in foods within 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 metabolism is fast and is not retained in the body. Methanol forms in its metabolism. Only trace amounts of neotame are added to foods, so the amount of methanol is insignificant for health. It is safe for 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 acceptable daily intake (ADI) of neotame for humans is 0.3 and 2 mg per kg of bodyweight (mg/kg bw), respectively. NOAEL for humans is 200 mg/kg bw per day within EU. [3] [1] Estimated possible daily intakes from foods are well below ADI levels. Ingested neotame can form phenylalanine, but in normal use of neotame, this is not significant to those with phenylketonuria. It also has no adverse effects in type 2 diabetics. It is not considered to be carcinogenic or 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 sweetness to sucrose water solutions, increase logarithmically in relative sweetness as the sucrose concentration of a comparably sweet sucrose solution increases, until a plateau is reached. Maximum sweetness is reached at neotame solution concentrations that are relatively as sweet as a water solution that is 15.1 percentage sucrose by weight, i.e. at 15.1 sucrose equivalence % (SE%). For comparison, 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 secondary amine of 3,3-dimethylbutanal and aspartame. The latter is a dipeptide of phenylalanine and aspartic acid. Neotame has 2 stereocenters and 4 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 Proton NMR Neotame.png
Proton NMR spectroscopy of neotame

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. Neotame in a jar, cropped and lightened.png
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 diketopiperazines via 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 ethyl acetate. At 25 °C the solubilities are 12.6 g/kg and 77.0 g/kg, respectively. At 40 °C the solubilities are 18.0 g/kg and 238 g/kg, respectively. At 50 °C the solubilities are 25.2 g/kg and 872 g/kg, respectively. [2] Neotame is acidic and its 0.5  wt% solution has a pH of 5.80. [1]

Manufacture

NutraSweet Neotame brand logo Neotame logo.svg
NutraSweet Neotame brand logo

Industrially neotame is made from 3,3-dimethylbutanal and aspartame via reductive amination. [2] They are dissolved in methanol, palladium on carbon catalyst is added, air is replaced with hydrogen and the reaction is carried out in room temperature under pressure for a few hours. Catalyst is filtered out. This can be aided with diatomaceous earth. Methanol is 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. NeotameMetabolism.svg
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 patent covering the neotame molecule in the US, 5,480,668, [7] was originally set to expire 7 November 2012, but was extended 973 days by the U.S. Patent and Trademark Office. The patent expired on 8 July 2015. [15]

Related Research Articles

<span class="mw-page-title-main">Aspartame</span> Artificial non-saccharide sweetener

Aspartame is an artificial non-saccharide sweetener 200 times sweeter than sucrose and is commonly used as a sugar substitute in foods and beverages. It is a methyl ester of the aspartic acid/phenylalanine dipeptide with brand names NutraSweet, Equal, and Canderel. Aspartame was approved by the US Food and Drug Administration (FDA) in 1974, and then again in 1981, after approval was revoked in 1980.

<span class="mw-page-title-main">Phenylalanine</span> Type of α-amino acid

Phenylalanine is an essential α-amino acid with the formula C
9H
11NO
2. It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino acid is classified as neutral, and nonpolar because of the inert and hydrophobic nature of the benzyl side chain. The L-isomer is used to biochemically form proteins coded for by DNA. Phenylalanine is a precursor for tyrosine, the monoamine neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), and the biological pigment melanin. It is encoded by the codons UUU and UUC.

<span class="mw-page-title-main">Sucralose</span> Non-nutritive sweetener

Sucralose is an artificial sweetener and sugar substitute. As the majority of ingested sucralose is not metabolized by the body, it adds no calories. In the European Union, it is also known under the E number E955. It is produced by chlorination of sucrose, selectively replacing three of the hydroxy groups—in the C1 and C6 positions of the fructose portion and the C4 position of the glucose portion—to give a 1,6-dichloro-1,6-dideoxyfructose–4-chloro-4-deoxygalactose disaccharide. Sucralose is about 600 times sweeter than sucrose, three times as sweet as both aspartame and acesulfame potassium, and twice as sweet as sodium saccharin.

<span class="mw-page-title-main">Splenda</span> Brand of sugar substitute

Splenda is a global brand of sugar substitutes and reduced-calorie food products. While the company is known for its original formulation containing sucralose, it also manufactures items using natural sweeteners such as stevia, monk fruit and allulose. It is owned by the American company Heartland Food Products Group. The high-intensity sweetener ingredient sucralose used in Splenda Original is manufactured by the British company Tate & Lyle.

<span class="mw-page-title-main">Sugar substitute</span> Sugarless food additive intended to provide a sweet taste

A sugar substitute is a food additive that provides a sweetness like that of sugar while containing significantly less food energy than sugar-based sweeteners, making it a zero-calorie or low-calorie sweetener. Artificial sweeteners may be derived through manufacturing of plant extracts or processed by chemical synthesis. Sugar substitute products are commercially available in various forms, such as small pills, powders, and packets.

<span class="mw-page-title-main">Xylitol</span> Synthetic sweetener

Xylitol is a chemical compound with the formula C
5H
12O
5, or HO(CH2)(CHOH)3(CH2)OH; specifically, one particular stereoisomer with that structural formula. It is a colorless or white crystalline solid that is freely soluble in water. It can be classified as a polyalcohol and a sugar alcohol, specifically an alditol. The name derives from Ancient Greek: ξύλον, xyl[on] 'wood', with the suffix -itol used to denote sugar alcohols.

<span class="mw-page-title-main">Saccharin</span> Chemical compound

Saccharin, also called saccharine or benzosulfimide, or used in saccharin sodium or saccharin calcium forms, is a non-nutritive artificial sweetener. Saccharin is a benzoic sulfimide that is about 500 times sweeter than sucrose, but has a bitter or metallic aftertaste, especially at high concentrations. It is used to sweeten products, such as drinks, candies, baked goods, tobacco products, excipients, and for masking the bitter taste of some medicines. It appears as white crystals and is odorless.

<span class="mw-page-title-main">Acesulfame potassium</span> Calorie-free sugar substitute

Acesulfame potassium, also known as acesulfame K or Ace K, is a synthetic calorie-free sugar substitute often marketed under the trade names Sunett and Sweet One. In the European Union, it is known under the E number E950. It was discovered accidentally in 1967 by German chemist Karl Clauss at Hoechst AG. In chemical structure, acesulfame potassium is the potassium salt of 6-methyl-1,2,3-oxathiazine-4(3H)-one 2,2-dioxide. It is a white crystalline powder with molecular formula C
4H
4KNO
4S and a molecular weight of 201.24 g/mol.

<span class="mw-page-title-main">Diet soda</span> Type of sugar-free or artificially sweetened soda

Diet or light beverages are generally sugar-free, artificially sweetened beverages with few or no calories. They are marketed for diabetics and other people who want to reduce their sugar and/or caloric intake.

<span class="mw-page-title-main">Erythritol</span> Chemical compound

Erythritol (, ) is an organic compound, the naturally occurring achiral meso four-carbon sugar alcohol (or polyol). It is the reduced form of either D- or L-erythrose and one of the two reduced forms of erythrulose. It is used as a food additive and sugar substitute. It is synthesized from corn using enzymes and fermentation. Its formula is C
4H
10O
4, or HO(CH2)(CHOH)2(CH2)OH.

<span class="mw-page-title-main">Alitame</span> Chemical compound

Alitame is an aspartic acid-containing dipeptide sweetener. It was developed by Pfizer in the early 1980s and currently marketed in some countries under the brand name Aclame. Most dipeptides are not sweet, but the unexpected discovery of aspartame in 1965 led to a search for similar compounds that shared its sweetness. Alitame is one such second-generation dipeptide sweetener. Neotame, developed by the owners of the NutraSweet brand, is another.

<span class="mw-page-title-main">Lactisole</span> Chemical compound

Lactisole is the sodium salt and commonly supplied form of 2-(4-methoxyphenoxy)propionic acid, a natural carboxylic acid found in roasted coffee beans. Like gymnemic acid, it has the property of masking sweet flavors and is used for this purpose in the food industry.

<span class="mw-page-title-main">Sweetness</span> Basic taste

Sweetness is a basic taste most commonly perceived when eating foods rich in sugars. Sweet tastes are generally regarded as pleasurable. In addition to sugars like sucrose, many other chemical compounds are sweet, including aldehydes, ketones, and sugar alcohols. Some are sweet at very low concentrations, allowing their use as non-caloric sugar substitutes. Such non-sugar sweeteners include saccharin, aspartame, and sucralose. Other compounds, such as miraculin, may alter perception of sweetness itself.

<span class="mw-page-title-main">Brazzein</span> Protein

Brazzein is a protein found in the West African fruit of Oubli. It was first isolated by the University of Wisconsin–Madison in 1994.

The artificial sweetener aspartame has been the subject of several controversies since its initial approval by the U.S. Food and Drug Administration (FDA) in 1974. The FDA approval of aspartame was highly contested, beginning with suspicions of its involvement in brain cancer, alleging that the quality of the initial research supporting its safety was inadequate and flawed, and that conflicts of interest marred the 1981 approval of aspartame, previously evaluated by two FDA panels that concluded to keep the approval on hold before further investigation. In 1987, the U.S. Government Accountability Office concluded that the food additive approval process had been followed properly for aspartame. The irregularities fueled a conspiracy theory, which the "Nancy Markle" email hoax circulated, along with claims—counter to the weight of medical evidence—that numerous health conditions are caused by the consumption of aspartame in normal doses.

<span class="mw-page-title-main">Lugduname</span> Chemical compound

Lugduname is one of the most potent sweetening agents known. Lugduname has been estimated to be between 220,000 and 300,000 times as sweet as sucrose, with estimates varying between studies. It was developed at the University of Lyon, France in 1996. Lugduname is part of a family of potent sweeteners which contain acetic acid functional groups attached to guanidine.

<span class="mw-page-title-main">Steviol glycoside</span> Sweet chemicals derived from the Stevia plant

Steviol glycosides are the chemical compounds responsible for the sweet taste of the leaves of the South American plant Stevia rebaudiana (Asteraceae) and the main ingredients of many sweeteners marketed under the generic name stevia and several trade names. They also occur in the related species S. phlebophylla and in the plant Rubus chingii (Rosaceae).

<span class="mw-page-title-main">Advantame</span> Chemical compound

Advantame is a non-caloric artificial sweetener and aspartame analog by Ajinomoto. By mass, it is about 20,000 times sweeter than sucrose and about 110 times sweeter than aspartame. It has no notable off-flavors when compared to sucrose and tastes sweet a bit longer than aspartame and is chemically more stable. It can be blended with many other natural and artificial sweeteners.

<span class="mw-page-title-main">Carrelame</span> Chemical compound

Carrelame is an extremely high potency artificial sweetener of the guanidine class, closely related to lugduname. While Carrelame is roughly 200,000 times as sweet as sucrose, lugduname is still somewhat sweeter. It appears safe in pigs.

<span class="mw-page-title-main">Prothioconazole</span> Chemical compound

Prothioconazole is a synthetic chemical produced primarily for its fungicidal properties. It is a member of the class of compounds triazoles, and possesses a unique toxophore in this class of fungicides. Its effective fungicidal properties can be attributed to its ability to inhibit CYP51A1. This enzyme is required to biosynthesize ergosterol, a key component in the cell membrane of fungi.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 "Neotame as a sweetener and flavour enhancer - Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food". EFSA Journal. 5 (11): 581. 2007. doi: 10.2903/j.efsa.2007.581 . ISSN   1831-4732.
  2. 1 2 3 4 5 6 7 8 9 10 11 Nabors 2012, p. 134–149
  3. 1 2 3 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. 1 2 "Food additives permitted for direct addition to food for human consumption; neotame" (PDF). Federal Register. 67 (131): 45300–45310. 2002.
  7. 1 2 "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. ↑ Assadi-Porter FM, et al. (2018). "Multimodal Ligand Binding Studies of Human and Mouse G-Coupled Taste Receptors to Correlate Their Species-Specific Sweetness Tasting Properties". Molecules. 23 (10): 2531. doi: 10.3390/molecules23102531 . ISSN   1420-3049. PMC   6214618 . PMID   30282936.
  10. ↑ Nofre, C; Tinti, Jean-Marie (15 May 2000). "Neotame: discovery, properties, utility". Food Chemistry. 69 (3): 245–257. doi:10.1016/S0308-8146(99)00254-X . Retrieved 12 November 2021.
  11. ↑ Bathinapatla A, et al. (2014). "Determination of Neotame by High-Performance Capillary Electrophoresis Using β-cyclodextrin as a Chiral Selector". Analytical Letters. 47 (17): 2795–2812. doi:10.1080/00032719.2014.924008. ISSN   0003-2719. S2CID   93160173.
  12. 1 2 Garbow, Joel R.; Likos, John J.; Schroeder, Stephen A. (1 April 2001). "Structure, dynamics, and stability of β-cyclodextrin inclusion complexes of aspartame and neotame". Journal of Agricultural and Food Chemistry. 49 (4): 2053–2060. doi:10.1021/jf001122d. PMID   11308366 . Retrieved 12 November 2021.
  13. 1 2 Prakash, Indra; Bishay, Ihab; Schroeder, Steve (1 December 1999). "Neotame: Synthesis, Stereochemistry and Sweetness". Synthetic Communications. 29 (24): 4461-4467. doi:10.1080/00397919908086610 . Retrieved 12 November 2021.
  14. ↑ Nofre, C; Tinti, Jean-Marie (15 May 2000). "Neotame: discovery, properties, utility". Food Chemistry. 69 (3): 245–257. doi:10.1016/S0308-8146(99)00254-X . Retrieved 12 November 2021.
  15. ↑ "USPTO extension of 5,480,668" . Retrieved 2012-09-21.

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