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To a mixture of (2) (0.9 g, 3.0 mmol), triphenylphosphine
(1.311 g, 5.0 mmol), and the above 4-hydroxyquinoline (0.5 g,
3.31 mmol) in anhydrous THF (50 mL) was added DIAD
(1.036 mL, 5.0 mmol) dropwise at room temperature under
nitrogen to give a solution by the end of the addition. After
stirring for 12 h, the solution was concentrated under reduced
pressure to a yellow foam. Purification by flash chromatography
using 0–10% methanol in methylene chloride gave 0.95 g of the
product in 73% yield and 100 mg of unreacted 4-hydroxyquino-
line. LC-MS: Rt = 1.10 min, MH1 = 432.23 as the only peak.
[13C6]-5,11-dihydro-11-ethyl-5-methyl-8-{2-{(1-oxido-4-quinolinyl)-
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´
[15] C. Yoakim, P. R. Bonneau, R. Deziel, L. Doyon, J. Duan, I. Guse,
S. Landry, E. Malenfant, J. Naud, W. W. Ogilvie, J. A. O’Meara,
¨
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oxy}ethyl}-6H-dipyrido[3,2-b:20,30-e][1,4]diazepin-6-one [13C6]-(1)
To a solution of the above compound (0.75 g, 1.74 mmol) in
CH2Cl2 (25 mL) was added m-CPBA (0.5 g, 77% max.). The
resulting solution was stirred for 2 h, then treated with a solution
of Na2S2O3 (100 mL), a saturated solution of NaHCO3 (100 mL),
dried over MgSO4, filtered, and concentrated in vacuo to give
0.95 g of a yellow solid. Purification by flash chromatography
using 5% MeOH/CH2Cl2 to remove non-polar impurities and
then with 30–50% MeOH/CH2Cl2 gave the pure product in
77% yield or 0.6 g. HPLC: 1H NMR (CDCl3) d: 8.71 (dm,
JH–C = 170.35 Hz, 1H), 8.36–8.43 (m, 2H), 8.20 (dm, JH–C =
165.21 Hz, 1H), 8.19 (dd, J = 1.63, 4.68 Hz, 1H), 8.10 (d,
J = 2.45 Hz, 1H), 7.85 (dm, JH–C = 164.31 Hz, 1H), 7.71 (dm,
JH–C = 162.35 Hz, 1H), 7.48 (dd, J = 1.59, 7.93 Hz, 1H), 7.08 (dd,
J = 4.66, 7.94 Hz, 1H), 6.57 (t, J = 6.99 Hz, 1H), 4.34 (t, J = 6.31 Hz,
2H), 4.19 (q, J = 7.05 Hz, 2H), 3.51 (s, 3H), 3.22 (t, J = 6.31 Hz, 2H),
1.26 (t, J = 7.05 Hz, 3H). 13C NMR (CDCl3) d: 149.27, 142.57,
138.85–139.94 (m), 128.68–129.59 (m), 125.52–127.10 (m),
120.11–121.28 (m), 117.51–118.57 (m), 67.06, 39.30, 35.45,
29.83, 11.71. LC-MS: Rt = 1.19 min, MH1 = 448.45 as the only
peak. HPLC: 8.35 min, 99%.
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X. W. Feng, J.- Y. Kim, J. C. Lorenz, M. Sarvestani, R. Simpson, R.
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´
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F.- T. Chiu, T. Curtis, J. Kelley, Y. S. Lo, T. H. Powner, Org. Process Res.
Dev. 2008, 12, 603–613.
A potent non-nucleoside reverse transcriptase inhibitor was
prepared with the radioactive carbon atom(s) in different
locations of the molecule to perform metabolism, pharmacoki-
netics, and other studies. The specific activities ranged from 44
to 47 mCi/mmol. This inhibitor labeled with carbon-13 was also
synthesized to support analytical studies.
[18] 5,11-Dihydro-11-ethyl-8-(2-cyanoethyl)-5-methyl-6H-dipyrido[3,2-b:
20,30-e][1,4]diazepin-6-one and 5,11-dihydro-11-ethyl-8-(2-carboxy-
ethyl)-5-methyl-6H-dipyrido[3,2-b:20,30-e][1,4]diazepin-6-one: Was
isolated in 35% yield from the carboxylic acid derivative in
unlabeled run by flash chromatography using ethyl acetate to
remove the cyano-intermediate and then 10% methanol/methyl-
ene chloride was used to elute the acid. Cyano-intermediate has
Rf = 0.18 in 60% EtOAc:hexane or 0.63 in 10% MeOH/CH2Cl2; the
acid was at the base lane with 60% EtOAc:hexane and has an
Rf = 0.13 in 10% MeOH/CH2Cl2. Mꢀ (292.47). 1HNMR (CDCl3) d: 8.36
(d, J = 2.50 Hz, 1H), 8.22 (dd, J = 1.54, 4.67 Hz, 1H), 8.07 (d,
J = 2.50 Hz, 1H), 7.51 (dd, J = 1.54, 8.00 Hz, 1H), 7.13 (dd, J = 4.67,
8.00 Hz, 1H), 4.21 (q, J = 7.06 Hz, 1H), 3.71 (s, 2H), 3.52 (s, 3H), 1.27
(t, J = 7.06 Hz, 3H). 13C NMR (CDCl3) d: 166.94, 159.40, 154.31,
149.87, 144.52, 140.56, 131.46, 130.96, 120.98, 120.75, 120.06,
116.91, 41.28, 37.34, 20.21, 13.54.
Acknowledgement
We wish to thank our colleague Scott Leonard for the help with
the NMR.
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