Synthesis of (1-14C)butyl, (13C2-dimethyl) butyl and (2H6-dimethyl)butyl-neotame

Full text of DOI:10.1002/jlcr.1222

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Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 498–499.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1222
Short Research Article
Synthesis of [1-14C]butyl, [13C2-dimethyl]butyl
and [2H6-dimethyl]butyl-neotamey
THOMAS WINWICK and ROGER D. BARNES*
Huntingdon Life Sciences Ltd., Woolley Road, Alconbury, Huntingdon, Cambridgeshire PE28 4HS, UK
Received 31 August 2006; Revised 14 December 2006; Accepted 14 December 2006
Keywords: neotame; 14C; synthesis
Introduction
As part of the safety testing programme, neotame was
synthesized labelled with 14C at the 1-position in the
dimethylbutyl side chain and with 13C2 and separately
2H6 in the terminal methyl groups of the same side chain.
Neotame, N-[N-(3,3-dimethylbutyl)-L-a-aspartyl]-L-phe-
nylalanine 1-methyl ester is a high intensity sweetener.
*
Mg
CO2
*
(CH3)3CCH2MgCl
(CH3)3CCH2CO2H
(CH3)3CCH2Cl
BH3.Me2S
*
*
(CH3)3CCH2CH2OH
(CH3)3CCH2CHO
PCC
CO2H
H
N
CO2Me
Ph
NaBH3CN
H2N
O
CO2H
H
N
CO2Me
Ph
*
(CH3)3CCH2CH2HN
O
Scheme 1
*Correspondence to: Roger D. Barnes, Huntingdon Life Sciences Ltd.,
Woolley Road, Alconbury, Huntingdon, Cambridgeshire PE28 4HS, UK.
E-mail: barnesr@ukorg.huntingdon.com
yProceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
Copyright # 2007 John Wiley & Sons, Ltd.

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SYNTHESIS OF [1-14C]BUTYL, [13C2-DIMETHYL]BUTYL AND [2H6-DIMETHYL]BUTYL-NEOTAME 499
N
CH3
NH2
CH3CHO
Na2SO4
R
R
i)LDA
O
ii)R2CO
i) (CH3)2CuLi, Ether
ii) NaHSO3
iii) HCHO
R = CD3 or 13CH3
CO2H
H
N
CO2Me
Ph
H2N
CO2H
O
R
R
H
H3C
R
H3C
R
N
CO2Me
Ph
CHO
N
H
O
NaBH3CN
Scheme 2
acetaldeyde to form ethylidene cyclohexylamine
which was reacted with 1,3-13C2acetone to form
the labelled dimethylacrylaldehyde. Methylation
of this aldehyde by Michael-type addition using
dimethyl lithium cuprate gave the labelled dimethyl-
butyraldehyde which was reductively coupled with
Results and discussion
[1-14C]butyl-neotame synthesis
The synthesis of [1-14C]butyl-neotame was initiated by
carbonation of 2,2-dimethylpropyl magnesium chloride
with [14C]carbon dioxide to form 3,3-dimethyl-[1-14C]bu-
tyric acid. Reduction of this acid with borane-dimethyl
sulphide complex produced the alcohol which was
oxidized successfully with pyridinium chlorochromate
to the aldehyde. Reductive coupling of the 3,3-di-
methyl[1-14C]butyraldeyde with aspartame gave the
[1-14C]butyl-neotame with a specific activity of 22mCi/
mmol. The radiochemical purity was >99%. The identity
of [1-14C]neotame was confirmed by co-chromatographic
and spectrometric comparison with neotame reference
standard (Scheme 1).
aspartame to form
[
13C2-dimethyl]butyl-neotame.
Estimated isotopic purity was >98 atom % 13C. The
identity of the product was confirmed by spectro-
metric comparison with neotame reference standard
(Scheme 2).
[2H6-dimethyl]butyl-neotame synthesis
[
13C2-dimethyl]butyl-neotame
Synthesis of the [2H6dimethyl]butyl-neotame was con-
ducted by the same synthetic route except that
ethylidene cyclohexylamine was reacted with 2H6-
dimethyl-acetone (Scheme 2).
Synthesis of the [13C2-dimethyl]butyl-neotame was
initiated by reaction of cyclohexylamine with
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 498–499
DOI: 10.1002.jlcr