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H. H. SELTZMAN ET AL.
7.31 (dd, 1H, J=8.0, 21 Hz, Ar-6-H), 7.04 (s, 1H, pyrazole 4-H), 2.41 (s, 3H,
Ar-Me).
N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methyl-
phenyl)-1-H-pyrazole-3-carboxamide ð4Þ
5-(4-Chloro-3-methylphenyl)-1-H-pyrazole-3-carboxylic acid
3
(3.18 g,
13.5 mmol) was suspended in 200 ml dry toluene under dry nitrogen and
treated dropwise with distilled thionyl chloride (3.21 g, 27.0 mmol) with
stirring at ambient temperature. The reaction was heated at reflux for 1.25 h
and the volatiles removed in vacuo to afford 3.15 g (92%) of the acid chloride
as a yellow solid which was used directly in the next step.
The acid chloride (3.15 g, 12.4 mmol) suspended in 400 ml dry CH2Cl2 was
treated with (-)-fenchylamine7,9 (2.85 g, 18.6 mmol) in 5 ml dry CH2Cl2
followed by triethylamine (3.76 g, 37.2 mmol) added dropwise over 2 min with
stirring under a nitrogen atmosphere. At 1 h TLC (SiO2, 25% EtOAc:hexanes,
UV, phosphomolybdic acid/ceric sulfate detection) showed the reaction to be
complete. The reaction was extracted with saturated aqueous Na2CO3
(2 ꢀ 200 ml), 1 N HCl (2 ꢀ 200 ml), and saturated aqueous Na2CO3
(2 ꢀ 200 ml). Drying over Na2SO4, filtration and evaporation in vacuo yielded
3.48 g (76%) of the title compound as a tan solid that was 97% pure by HPLC
1
(Waters C18, 75% CH3CN:H2O, 280 nm detection). H-NMR (250 MHz,
MeOD) d 7.71 (br d, 1H, J=21 Hz, Ar-5-H), 7.53 (d, 1H, J=8.2 Hz, Ar-2-H),
7.40 (dd, 1H, J=8.2, 14.0 Hz, Ar-6-H), 7.06 (br s, 1H, pyrazole 4-H), 3.78
(s, 1H, aH), 2.42 (s, 3H, Ar-Me), 1.80–1.23 (m, 7H, fenchyl CH2 and CH), 1.16
(s, 3H, fenchyl Me), 1.09 (s, 3H, fenchyl Me0), 0.88 (s, 3H, fenchyl Me00).
[C3H2OH]-4-methylbenzyl Alcohol ð6Þ
To LiAlT4 (prepared from 0.15 mmol carrier free tritium gas, 0.24 mmol
n-BuLi, 0.24 mol TMEDA, and 0.06 mmol ALBr3 as reported10), an excess of
methyl 4-methylbenzoate 5 in dry benzene (36 mg/ml) (0.5 ml, 0.12 mmol) was
added and the reaction mixture was stirred for 1 h. Anhydrous ether (0.5 ml)
was added affording a homogeneous solution and stirred for 15 min. The
reaction was quenched with 0.1 ml water, 0.1 ml 15% NaOH, and 0.1 ml water
and stored in 2 ml ethanol at ꢁ708C overnight. Evaporation of the ethanol
(2 ꢀ ) in vacuo without going to dryness and partitioning the concentrate
between water and ether (3 ꢀ ) was followed by drying the combined organic
layers over Na2SO4. This was concentrated and stored in toluene to afford
485 mCi (9%) of product that coelutes with authentic unlabeled 4-
methylbenzyl alcohol on TLC radioscan (SiO2, 25% ether-hexane). Significant
product losses that were experienced were likely due to volatility and
incomplete extraction that can be addressed by dilution of the quenched
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 589–596