C-14, C-13, H-2 labeling of NVP-ACQ090 - A potent and selective somastatin sst3-receptor antagonist

Full text of DOI:10.1002/jlcr.1308

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 613–615.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1308
Short Research Article
C-14, C-13, H-2 labeling of NVP-ACQ090 – a potent and
selective somastatin sst3-receptor antagonisty
THOMAS MOENIUS1,*, THOMAS TROXLER2 and ROLF MASERO1
1 Novartis Pharma, DMPK(EU)-IL, Hu¨ninger Str., CH-Basel, Switzerland
2 Novartis Pharma NIBR, Hu¨ninger Str., CH-Basel, Switzerland
Received 29 August 2006; Revised 24 January 2007; Accepted 22 February 2007
Keywords: C-14 labeling; diastereoselective synthesis; (ꢀ)-bornane-10,2-sultam moiety
Introduction
Different approaches for the synthesis of the key
intermediate 1
Somastatin is a widely distributed peptide hormone
originally isolated from the hypothalamus as an
inhibitor of growth hormone release.1 To date, five
somastatin receptor subtypes (sst1 to sst5) have been
characterized.2a,2b Data show that NVP-ACQ090 2 is a
highly potent and selective somastatin sst3-receptor
antagonist.
The research approach (Scheme 2) was not applicable,
since the labeled analogues of the pyridine derivative 3
and the chiral propionate 4 were not easily accessible.
Due to elevated reaction conditions (80 bar, 608C)
labeling by chiral hydrogenation was not feasible either
(Scheme 3).
Due to structural simplicity the chiral intermediate 1
was identified as a suitable structural component for
labeling in a metabolically stable position (Scheme 1).
Therefore, a diastereoselective approach appeared
to be most promising. The (ꢀ)-bornane-10,2-sultam
moiety is known to be an excellent auxiliary for
N
O
1,2)
O
N
H
N
N
H
N
F
F
I
O
1
2
Scheme 1 Synthesis of ACQ090. Reaction conditions: (1) amine derivative, K2CO3, DMF, 258C, 24 h, 95%; (2) fumaric acid,
2-propanol/diethyl ether.
*Correspondence to: Thomas Moenius, Novartis Pharma, DMPK(EU)-IL,
¨
Huninger Str., CH-Basel, Switzerland.
E-mail: thomas.moenius@novartis.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.

614 T. MOENIUS ET AL.
3)
4)
Br
Br
N
N
+
O
O
O
O
O
O
5
4
3
5)
N
N
H
O
O
I
O
1
6
Scheme 2 Research synthesis. Reaction conditions: (3) methyl-3-bromo-2(S)-2-methyl propionate 4, ZnEt2, MnBr2, CuCl, DMPU/
THF, Pd(dppf)Cl2, CH2Cl2, 43%; (4) LiAlH4, THF, 82%; (5) MeP(I)(OPh)3, DMF, 89%.
O
7)
8)
6)
N
H
N
N
H
H
O
O
O
O
O
O
9
8
7
5)
N
N
H
O
O
I
O
1
5
Scheme 3 Chemical development synthesis.3 Reaction conditions: (6) (EtO)2HPO/NaH, HOOCCHBrCH3, 79%; (7) LiAlH4, THF,
89%; (8) H2/[Rh(nbd)Cl2], (R)-p-DMA-MeObiphep, pðH2Þ ¼ 80 bar, 608C, 19 h, 92% ee, 97%.
O
O
13)
14)
12)
OH
N
Br
O
N
N
OH
N
O
O
O
Cl
12
13
11
14
Scheme 4 Synthesis of the intermediate 14. Reaction conditions: (12) MeOH, H2SO4, 658C, 12 h, 58%; (13) LiAlH4, diethyl ether,
308C, 1 h, 68%; (14) PBr3, CH2Cl2, 61% (unstable).
this particular approach.4 The diastereoselective
Conclusion
synthesis makes use of an a-alkylation of the pro-
The N-[14C]propionyl bornane-10,2-sultam 10 pro-
pionyl derivative 10 with the corresponding nucleo-
phile 14.
vided an excellent auxiliary for the diastereoselective
synthesis of labeled 5-((S)-3-iodo-2-methyl-propyl)-
2-methoxy-pyridine 1 – a suitable key intermediate of
labeled ACQ090 2.
Results
Labeling of NVP-ACQ090 2 (overview)
REFERENCES
Since it readily polymerized the picolyl bromide 14 was
immediately used (Schemes 4 and 5).5
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Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 613–615
DOI: 10.1002.jlcr

C-14, C-13, H-2 LABELING OF NVP-ACQ090 615
R
R
R
SO2
2C
N
10)
9)
+
Br
N
1C
2C
N 1
C
O
3C
R
R
R
O
N
O
O
SO2
14
15
10
R
R
I
R
R
2C
1C
H
R
11)
2C
1C
H
R
N
1,2)
N
H
OH
O
H
O
5
1
R
R
3C
N
2C
1C
R
O
O
N
N
H
N
F
H
F
2
1C
2C
3C
12C
13C
Name
A
B
R
14C
13C
12C
13C
1H
2H
Scheme 5 Synthesis of NVP-ACQ090 2. Reaction conditions: (9) THF, ꢀ788C, 1 M NaHMDS, HMPT, 14, N(n-Bu)4 I, ꢀ788C, 5 min,
62%; (10) THF, Et2O, 1 M LiAlH4 in Et2O, 08C, 3 h, 64%; (11) DMF, methyltriphenoxyphosphonium iodide, 08C, 1 h, 30%; (1) K2CO3,
DMF, 258C, 24 h, 56%; (2) fumaric acid, 2-propanol/diethylether. Analytical characterization of 2A/B: (R)TLC, HPLC >98% (RS),
>98%ee, MS 2.2 GBq/mmol, NMR.
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Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 613–615
DOI: 10.1002.jlcr