View source for Neotame

{{Short description|Artificial sweetener}}
{{chembox
| ImageFile = Neotame.svg
| ImageFile1 = Neotame zwitterion ball.png
| ImageAlt1 = Ball-and-stick model of the neotame molecule
| SystematicName = (3''S'')-3-[(3,3-Dimethylbutyl)amino]-4-{[(2''S'')-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino}-4-oxobutanoic acid
| OtherNames = E961; ''N''-(''N''-(3,3-Dimethylbutyl)-<small>L</small>-α-aspartyl)-<small>L</small>-phenylalanine 1-methyl ester
| Section1 = {{Chembox Identifiers
| CASNo_Ref = {{cascite|correct|??}}
| CASNo=165450-17-9
| PubChem=9810996
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = VJ597D52EX
| SMILES=CC(C)(C)CCN[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)OC
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 7986751
| ChEBI_Ref = {{ebicite|changed|EBI}} 
| ChEBI = 83503
| 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
| InChIKey = HLIAVLHNDJUHFG-HOTGVXAUBG
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = HLIAVLHNDJUHFG-HOTGVXAUSA-N
  }}
| Section2 = {{Chembox Properties
| C=20 | H=30 | N=2 | O=5
| Appearance=white powder<ref name=":0"/>
| Density=
| MeltingPtC=80.9–83.4
| MeltingPt_ref=<ref name=":0"/>
| BoilingPt=
| Solubility=12.6 g/kg at 25 °C<ref name=":n"/>
  }}
| Section3 = {{Chembox Hazards
| NFPA-H = 0
| NFPA-F = 1
| NFPA-R = 0
| MainHazards=
| FlashPt=
| AutoignitionPt =
  }}
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 455127090
}}

'''Neotame''', also known by the [[brand|brand name]] '''Newtame''',<ref name="fda">{{Cite web|date=14 July 2023|title=Aspartame and Other Sweeteners in Food|url=https://www.fda.gov/food/food-additives-petitions/aspartame-and-other-sweeteners-food|archive-url=https://web.archive.org/web/20230601065858/https://www.fda.gov/food/food-additives-petitions/aspartame-and-other-sweeteners-food|url-status=dead|archive-date=June 1, 2023|publisher=US Food and Drug Administration|accessdate=30 June 2024}}</ref> is a non-caloric [[artificial sweetener]] and [[aspartame]] [[Structural analog|analog]].<ref name=":n">{{Cite book|url=https://books.google.com/books?id=coDPwzFX7rAC|title=Alternative sweeteners|vauthors=Nabors LO|publisher=CRC Press|year=2011|pages=133–150|isbn=978-1439846155|edition=4th|oclc=760056415}}</ref> By [[mass]], it is 7,000 to 13,000 times sweeter than [[sucrose]].<ref name=fda/> It has no notable off-flavors when compared to sucrose. It [[Flavor enhancer|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.<ref name=":n"/>

It is suitable for use in [[carbonated]] [[soft drink]]s, [[yogurt]]s, [[cake]]s, drink powders, and [[bubble gum]]s among other foods. It can be used as a table top sweetener for [[hot drink]]s like [[coffee]]. It covers bitter tastes (e.g. [[caffeine]]).<ref name=":n"/>

In 2002, [[FDA]] approved it as a non-nutritive sweetener and flavor enhancer within the [[United States]] in foods generally, except meat and poultry.<ref name=fda/> In 2010, it was approved for use in foods within the [[European Union]] with the [[E number]] '''E961'''.<ref>{{Cite web|url=https://www.foodnavigator.com/Article/2010/01/08/Neotame-wins-approval-in-Europe|title=Neotame wins approval in Europe|last=Halliday|first=Jess|website=foodnavigator.com|date=8 January 2010 |access-date=2019-09-15}}</ref> It has also been approved as an additive in many other countries outside US and EU.<ref name=":n"/>

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]].<ref name=":4"/><ref name=":0"/>

French scientists Claude Nofre and Jean-Marie Tinti invented neotame.<ref name=":n"/> In 1992, they filed a United States [[patent]], which was granted in 1996.<ref name=":2">{{Cite web|title=US 5,480,668|url=http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=5480668.PN.&OS=PN/5480668&RS=PN/5480668|access-date=2019-09-15|archive-date=2017-05-10|archive-url=https://web.archive.org/web/20170510072311/http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=5480668.PN.&OS=PN/5480668&RS=PN/5480668|url-status=dead}}</ref>

==Safety==
In US and EU, the [[acceptable daily intake]] (ADI) of neotame for humans is 0.3 and 2&nbsp;mg per kg of bodyweight (mg/kg&nbsp;bw), respectively. [[NOAEL]] for humans is 200&nbsp;mg/kg&nbsp;bw per day within EU.<ref name=fda/><ref name=":0"/> 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]].<ref name=":4">{{Cite journal|date=2002|title=Food additives permitted for direct addition to food for human consumption; neotame|url=https://www.govinfo.gov/content/pkg/FR-2002-07-09/pdf/02-17202.pdf|journal=Federal Register|volume=67|issue=131|pages=45300–45310}}</ref><ref name=":0"/> The [[Center for Science in the Public Interest]] has ranked neotame as safe.<ref>{{Cite web|url=https://cspinet.org/eating-healthy/chemical-cuisine|title=Chemical Cuisine {{!}} Center for Science in the Public Interest|website=cspinet.org|date=25 February 2016|access-date=2019-09-15}}</ref>

==Sweetness==

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&nbsp;SE%, 11.3&nbsp;SE% and 9&nbsp;SE%, respectively.<ref name=":n"/>

Neotame is a high-potency sweetener, and it is 7,000 to 13,000 times sweeter than table sugar.<ref name=fda/> Neotame contains flavor-enhancing properties, and compared to sucrose or aspartame, it has a relatively lower cost per sweetness factor.<ref>{{cite journal |last1=Nofre |first1=C |last2=Tinti |first2=Jean-Marie |title=Neotame: discovery, properties, utility |journal=Food Chemistry |date=15 May 2000 |volume=69 |issue=3 |pages=245–257 |doi=10.1016/S0308-8146(99)00254-X |url=https://reader.elsevier.com/reader/sd/pii/S030881469900254X?token=94BD3C2662EF3EFCFB126841D82A6ED5DDDADEFA522206B4B4A9C8F64B58CFE6A9CCF4D8A3D20891264742DB94F07CE1&originRegion=us-east-1&originCreation=20211112232110 |access-date=12 November 2021|url-access=subscription }}</ref>

==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 [[stereocenter]]s and 4 [[stereoisomers]]. Sweetness is due to the (2''S''),(3''S'')-stereoisomer.<ref name=":3">{{Cite journal|vauthors=Bathinapatla A|date=2014|title=Determination of Neotame by High-Performance Capillary Electrophoresis Using β-cyclodextrin as a Chiral Selector|url=https://www.researchgate.net/publication/265390621|journal=Analytical Letters|volume=47|issue=17|pages=2795–2812|doi=10.1080/00032719.2014.924008|s2cid=93160173|issn=0003-2719|display-authors=etal}}</ref>

===Spectroscopy===
Neotame [[Nuclear magnetic resonance spectroscopy|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.<ref name="garbow">{{cite journal |last1=Garbow |first1=Joel R. |last2=Likos |first2=John J. |last3=Schroeder |first3=Stephen A. |title=Structure, dynamics, and stability of β-cyclodextrin inclusion complexes of aspartame and neotame |journal=Journal of Agricultural and Food Chemistry |date=1 April 2001 |volume=49 |issue=4 |pages=2053–2060 |doi=10.1021/jf001122d |pmid=11308366 |bibcode=2001JAFC...49.2053G |url=https://pubs.acs.org/doi/pdf/10.1021/jf001122d |access-date=12 November 2021|url-access=subscription }}</ref>
[[File:Proton NMR Neotame.png|thumb|Proton NMR spectroscopy of neotame<ref name=garbow/>]]

===Synthesis===
Neotame is synthesized from aspartame through a reductive [[alkylation]] with [[3,3-dimethylbutyraldehyde]] in a [[palladium]] catalyst with methanol.<ref name="prakash">{{cite journal |last1=Prakash |first1=Indra |last2=Bishay |first2=Ihab |last3=Schroeder |first3=Steve |title=Neotame: Synthesis, Stereochemistry and Sweetness |journal=Synthetic Communications |date=1 December 1999 |volume=29 |issue=24 |page=4461-4467 |doi=10.1080/00397919908086610 |access-date=12 November 2021 |url=https://www.tandfonline.com/doi/pdf/10.1080/00397919908086610|url-access=subscription }}</ref> The stereochemistry of aspartame is conserved during the synthesis and therefore, neotame and aspartame have the same stereochemistry. (2''S''),(3''S'')-stereoisomer of aspartame is needed to synthesize the (2''S''),(3''S'')-stereoisomer of neotame.<ref name=prakash/>

===Properties and reactivity===
[[File:Neotame in a jar, cropped and lightened.png|alt=Neotame, a fine white powder, in a jar|left|thumb|190px|Neotame.]]
Neotame has similar stability as aspartame, but has greater stability especially in heated and dairy foods.<ref name=fda/> 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&nbsp;weeks of storage in pH&nbsp;3.2 beverages. Neotame is especially stable as a dry powder at room temperature and [[humidity]] even if mixed with [[glucose]] or [[maltodextrin]], and is relatively inert in foods with [[reducing sugar]]s like [[fructose]].<ref name=":n"/>

Unlike aspartame, neotame doesn't form [[diketopiperazine]]s via [[intra-molecular]] cyclization due to its N-alkyl substitution with 3,3-dimethylbutyl. This increases its heat stability.<ref name=fda/>

Over 1000&nbsp;g of neotame dissolves in 1&nbsp;kg of ethanol at 15&nbsp;°C. At 15&nbsp;°C the solubility of neotame is 10.6&nbsp;g/kg in water and 43.6&nbsp;g/kg in [[ethyl acetate]]. At 25&nbsp;°C the solubilities are 12.6&nbsp;g/kg and 77.0&nbsp;g/kg, respectively. At 40&nbsp;°C the solubilities are 18.0&nbsp;g/kg and 238&nbsp;g/kg, respectively. At 50&nbsp;°C the solubilities are 25.2&nbsp;g/kg and 872&nbsp;g/kg, respectively.<ref name=":n"/> Neotame is [[acidic]] and its 0.5&nbsp;[[wt%]] solution has a pH of 5.80.<ref name=":0"/>

===Manufacture===
Industrially neotame is made from 3,3-dimethylbutanal and aspartame via [[reductive amination]].<ref name=":n"/> 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 drying|vacuum dried]]. Neotame is milled to suitable size.<ref name=":0"/>

==Metabolism==
[[File:NeotameMetabolism.svg|thumb|440px|Neotame de-esterification via [[hydrolysis]]. CH<sub>3</sub>OH 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.<ref name=":0">{{Cite journal|date=2007|title=Neotame as a sweetener and flavour enhancer - Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food|journal=EFSA Journal|volume=5|issue=11|pages=581|doi=10.2903/j.efsa.2007.581|issn=1831-4732|doi-access=free}}</ref>

In humans at oral doses of about 0.25&nbsp;mg per kg of bodyweight (mg/kg&nbsp;bw), about 34% is absorbed into blood. [[Pharmacokinetics]] of oral doses of 0.1–0.5&nbsp;mg/kg&nbsp;bw are somewhat linear, and at such doses, maximum neotame concentration in [[blood plasma]] is reached after about 0.5&nbsp;hours with a [[half-life]] of about 0.75&nbsp;hours. In blood and in body in general, non-specific [[esterase]]s 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&nbsp;hours, and is the main metabolite in plasma.<ref name=":0"/>

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.<ref name=":0"/>

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.<ref>{{cite journal |last1=Nofre |first1=C |last2=Tinti |first2=Jean-Marie |title=Neotame: discovery, properties, utility |journal=Food Chemistry |date=15 May 2000 |volume=69 |issue=3 |pages=245–257 |doi=10.1016/S0308-8146(99)00254-X |url=https://reader.elsevier.com/reader/sd/pii/S030881469900254X?token=94BD3C2662EF3EFCFB126841D82A6ED5DDDADEFA522206B4B4A9C8F64B58CFE6A9CCF4D8A3D20891264742DB94F07CE1&originRegion=us-east-1&originCreation=20211112232110 |access-date=12 November 2021|url-access=subscription }}</ref>

Methanol from neotame metabolism is insignificant at regulated levels used in foods and in comparison to methanol naturally found in foods.<ref name=":0"/>

==Patent==
The [[patent]] covering the neotame molecule in the US, 5,480,668,<ref name=":2"/> was originally set to expire 7 November 2012, but was extended for 973 days by the [[U.S. Patent and Trademark Office]]. The patent expired on 8 July 2015.<ref>{{cite web|url=http://www.uspto.gov/patents/resources/terms/156.jsp|title=USPTO extension of 5,480,668|access-date=2012-09-21}}</ref>

==References==
{{Reflist}}

==External links==
*{{Commons category-inline}}

{{E number infobox 950-969}}
{{Food Substitutes}}

[[Category:Sugar substitutes]]
[[Category:Dipeptides]]
[[Category:E-number additives]]
[[Category:Carboxylic acids]]
[[Category:Methyl esters]]
[[Category:Food additives]]