Labelling of GW796406X with (M+4)-methylcopper

Full text of DOI:10.1002/jlcr.1223

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 500–501.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1223
Short Research Article
Labelling of GW796406X with [M+4]-methylcoppery
ALAN H. WADSWORTH and KENNETH W. M. LAWRIE*
GlaxoSmithKline, Isotope Chemistry, Medicines Research Centre Gunnels Wood Road Stevenage SG1 2NY, UK
Received 29 August 2006; Revised 14 December 2006; Accepted 14 December 2006
Keywords: carbon-13; [13C,2H3]methyl copper; oxazolidinone; GW796406
Introduction
tic acid gave the adduct 7. Treatment with thionyl
chloride gave acid chloride 8.
A stable isotope labelled (SIL) version of GW796406X1
1 was required as a mass labelled internal standard
and a carbon-14 version 12 for ADME studies.
Compound 9 was prepared from N-Boc tyrosine
methyl ester by derivatisation of the phenolic OH group
to triflate, palladium-catalysed boronic ester forma-
tion, and periodate-assisted hydrolysis gave a boronic
acid. As 9 would eventually contain a carbon-14 label,
we optimized the coupling of the boronic acid and
pyrazole with equivalent amounts of each. Chiral HPLC
confirmed that 9 had not racemized. Condensation of 8
with amine 9 was readily carried out using Schotten-
Baumann conditions. The purified (S,S) product 10
was shown (chiral HPLC, NMR) to contain insignificant
amounts of the undesired (R,S) and (S,R) diastereoi-
somers. Alkaline hydrolysis gave the SIL-GW796406 1
after a simple work-up. The carbon-14 labelled version
12 of GW796406 was prepared similarly from N-Boc
[U-14C]tyrosine methyl ester 11.
Results and discussion
Addition of 2 equivalents of [2H3,13C]methylcopper to
the chiral N-(E)-crotonyl oxazolidinone2 3 gave clean
conversion to the required 4. The highly stereoselective
chelation-controlled aldol reaction of the titanium
enolate of imide (4) with formaldehyde trimer gave
essentially one diastereoisomer 5. Trace amounts of
the other C-2 diastereoisomer were removed during the
purification. Hydrolytic cleavage gave the acid
6
cleanly. Mitsunobu reaction of alcohol 6 with thiolace-
*Correspondence to: Kenneth W. M. Lawrie, GlaxoSmithKline, Isotope
Chemistry, Medicines Research Centre Gunnels Wood Road Stevenage
SG1 2NY, UK. E-mail: ken.w.lawrie@gsk.com
yProceedings of the Ninth Inernational Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
Copyright # 2007 John Wiley & Sons, Ltd.

LABELLING OF GW796406X WITH [M+4]-METHYLCOPPER 501
2H313C
O
O
O
O
O
HN
O
1. 13C2H3I, Li, Et2O, 5˚
2. CuI, 5˚
N
Me
n-BuLi, THF, -78˚
O
N
O
O
3. Me3SiI, THF-ether, -78˚, 4h
2
4
4. pyridine, -78˚ to 20˚
3
Me
Cl
90%
48%
2H313C
2H313C
O
O
O
1. TiCl4, CH2Cl2, 0-5˚
2. Pri2NEt, 0-5˚
3. trioxane, CH2Cl2, 0-5˚
4. TiCl4, CH2Cl2, 0-5˚
1. LiOH, H2O2, THF, H2O, 20˚
2. Na2SO3, 0-5˚
3. LiOH, H2O, 65˚
N
OH
O
HO
HO
88%
6
83%
5
2H313C
O
2H313C
O
O
DIAD, PPh3, AcSH,
THF, 20˚, 2h
SOCl2,
CH2Cl2, 20˚
H2N
OMe
Cl
OH
+
9
8
92%
S
S
100%
7
N
O
N
O
K2CO3, DCM 90%
13C2H3
13C2H3
O
O
H
H
NaOH, MeOH
n-Bu3P, H2O
S
N
HS
N
H3C
OMe
OH
O
O
O
1
10
N
N
N
N
O
H
O
H
N
O
N
HS
O
OH
*
= uniform ring [14C] label
*
O
O
11
*
N
12
OH
N
2. Bergdahl M, Iliefski T, Nillson M, Olsson T. Tetra-
hedron Lett 1995; 36: 3227–3230.
REFERENCES
1. Cooper AWJ, Mordaunt JE, Peace S, Smith PW,
Smith S. PCT International Patent WO2003104200,
Glaxo Group Ltd, UK, 2003.
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 500–501
DOI: 10.1002.jlcr