R. Deprez-Poulain et al. / European Journal of Medicinal Chemistry 46 (2011) 3867e3876
3873
purified by flash chromatography with DCM to give 5a as a white
powder; purity 100%; yield 55%; mp: 134e136 ꢁC; 1H NMR:
give 5e as a white powder; purity 99%; purity 95%; yield: 79%; mp:
136e137 ꢁC; 1H NMR (300 MHz, CDCl3)
ppm 1.24 (m, 3H), 1.32
d
(300 MHz, CDCl3)
d
ppm 1.1 (t, J ¼ 6.9 Hz, 3H), 2.9 (s, 3H), 4.8
(t, J ¼ 7.2 Hz, 3H), 2.08 (s, 3H), 2.64 (q, J ¼ 7.5 Hz, 3H), 4.28
(q, J ¼ 7.2 Hz, 2H), 5.32 (d, J ¼ 18.3 Hz, 2H), 7.19 (m, 2H), 7.36
(m, 4H), 7.44e7.52 (m, 2H),7.57 (m, 2H), 7.67 (t, J ¼ 7.5 Hz, 1H), 7.80
(d, J ¼ 7.5 Hz, 1H), 7.84 (s, 0.5H), 7.96 (s, 0.5H); 13C NMR (75 MHz,
CDCl3)ppm 14.3, 15.3, 22.9, 28.5, 56.5, 60.4, 110.1, 110.9, 118.6, 126.5,
127.9, 128.8, 129.5, 130.0, 132.96, 133.8, 134.5, 135.3, 138.6, 140.þ0,
(q, J ¼ 7.2 Hz, 2H), 5.2 (d, J ¼ 16.2 Hz, 2H), 7.21 (sl, 1H), 7.38 (m, 6H),
7.44e7.52 (m, 2H), 7.58 (m, 2H), 7.66 (t, J ¼ 7.5 Hz, 1H), 7.78
(d, J ¼ 7.5 Hz, 1H), 7.83 (s, 0.5H), 7.95 (s, 0.5H) ; 13C NMR: (75 MHz,
CDCl3,) ppm 14.3, 23.0, 56.5, 60.4, 110.5, 111.2, 118.5, 126.5, 127.9,
128.3, 129.5, 130.0, 132.9, 133.8, 134.5, 135.3, 138.6, 140, 144.5, 150.5,
161.3, 170.5; LCMS (EI(þ)): m/z ¼ 465 [M þ H]þ. HRMS (EI) calcd for
C28H24N4O3 [M þ H]þ 464.19212. Found 464.19160.
142.5, 144.6, 150.5, 161.5, 171; LCMS (EI(þ)) m/z ¼ 493 [M þ H]
.
HRMS (EI) calcd for C30H28N4O3 [M þ H]þ 493.22342. Found
493.22274.
4.2.11. 3-(Acetyl-m-tolyl-amino)-1-(20-cyano-biphenyl-4-
ylmethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5b)
4.2.15. 3-[Acetyl-(4-tert-butylphenyl)-amino]-1-(20-cyano-
5b was prepared following general arylation procedure from 4
and 3-iodo-toluene. The crude product precipitated in methanol to
give 5b as a white powder; purity 100%; yield: 66%; mp:
biphenyl-4-ylmethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5f)
5f was prepared following general arylation procedure from 4
and 1-tert-butyl-4-iodo-benzene. The crude product was purified
by flash chromatography with cyclohexane/ethyle acetate (80/20)
as a white powder; purity 100%; yield : 82%; mp: 130e132 ꢁC; 1H
172e173 ꢁC; 1H NMR (300 MHz, CDCl3)
d
ppm 1.31 (t, J ¼ 6.9 Hz,
3H), 2.08 (s, 3H), 2.33 (s, 3H), 4.28 (q, J ¼ 6.9 Hz, 2H), 5.32
(d, J ¼ 14.7 Hz, 2H), 7.02e7.4 (m, 6H), 7.46 (t, J ¼ 7.5 Hz, 1H), 7.49
(d, J ¼ 7.5 Hz, 1H), 7.56 (s, 2H), 7.66 (t, J ¼ 7.5 Hz, 1H), 7.70
(d, J ¼ 7.5 Hz, 1H), 7.86 (s, 0.5H), 7.97 (s, 0.5H); 13C NMR (75 MHz,
CDCl3) ppm 14.3, 21.3, 22.7, 56.2, 60.5,110.5,111.1,118.5,123.6, 125.1,
127.3, 127.9, 128.3, 129.3, 130.0, 130.8, 132.9, 133.8, 134, 135.1, 138.6,
139.5, 142.0, 144.5, 150.8, 161.5, 171.7; LCMS (EI(þ)): m/z ¼ 479
[M þ H] þ. HRMS (EI) calcd for C29H26N4O3 [M þ H]þ 479.20777.
Found 479.20713.
NMR (300 MHz, CDCl3, ppm)
d
¼ 1.31 (s, 12H), 2.09 (s, 3H), 4.28
(q, J ¼ 7,8 Hz, 2H), 5.32 (d, J ¼ 18.6 Hz, 2H), 7.36e7.45 (m, 6H),
7.46e7.54 (m, 2H),7.59 (m, 2H), 7.68 (t, J ¼ 7.5 Hz, 1H), 7.79
(d, J ¼ 7.5 Hz, 1H), 7.85 (s, 0.5H), 7.98 (s, 0.5H); 13C NMR (75 MHz,
CDCl3, ppm)
d
¼ 14.3, 22.8, 31.3, 34.5, 56.5, 60.4, 110.4, 111.2, 118.5,
125.7, 126.0, 126.3, 127.6, 127.9, 128.3, 129.5, 130.0, 132.9, 133.8,
134.4, 135.3, 138.6, 142.5, 144.7, 149.2, 150.5, 161.5, 171.5; LCMS
(EI(þ)) m/z ¼ 521 [M þ H] þ. HRMS (EI) calcd for C32H32N4O3
[M þ H]þ 521.25472. Found 521.25366.
4.2.12. 3-[Acetyl-(3,5-dimethylphenyl)-amino]-1-(20-cyano-
biphenyl-4-ylmethyl)-1H-pyrazole-4-carboxylic acid ethyl ester
(5c)
5c was prepared following general arylation procedure from 4
and 1-iodo-3,5-dimethyl-benzene. The crude product was purified
by flash chromatography with cyclohexane/ethyle acetate (80/20)
to give 5c as a white powder; purity 100%; yield: 58%; mp:
4.2.16. 3-[Acetyl-(4-trifluoromethylphenyl)-amino]-1-(20-cyano-
biphenyl-4-ylmethyl)-1H-pyrazole-4-carboxylic acid ethyl ester
(5g)
5g was prepared following general arylation procedure from 4
and 1-iodo-4-trifluoromethyl-benzene. The crude product was
purified by flash chromatography with cyclohexane/ethyle acetate
(60/40) as a white powder; purity 97%; yield: 75%; mp: 141e142 ꢁC;
202e203 ꢁC; 1H NMR (300 MHz, CDCl3)
d
ppm 1.33 (t, J ¼ 7.2 Hz,
3H), 2.08 (s, 3H), 2.30 (sl, 6H), 4.29 (q, J ¼ 7.2 Hz, 2H), 5.32
(d, J ¼ 15 Hz, 2H), 6.85 (sl, 0.5H), 6.95 (sl, 0.5H), 7.05 (sl, 1H), 7.15 (sl,
1H), 7.47 (t, J ¼ 7.5 Hz, 1H), 7.5 (d, J ¼ 7.5 Hz, 2H),7.57 (sl, 2H), 7.67
(td, J1 ¼7.5 Hz, J2 ¼ 1.2 Hz, 1H), 7.77 (d, J ¼ 7.5 Hz, 1H), 7.85 (s, 0.5H),
1H NMR (300 MHz, CDCl3)
d
ppm 1.30 (t, J ¼ 7.2 Hz, 3H), 2.09 (s, 3H),
4.26 (q, J ¼ 7.2 Hz, 2H), 5.37 (s, 2H), 7.39 (d, J ¼ 7.5 Hz, 2H), 7.48
(t, J ¼ 7.5 Hz, 1H), 7.51 (d, J ¼ 7.5 Hz, 1H),7.53e7.63 (m, 6H), 7.68
(t, J ¼ 7.5 Hz, 1H), 7.79 (d, J ¼ 7.5 Hz, 1H), 7.99 (s, 1H); 13C NMR
7.97 (s, 0.5H); 13C NMR: (75 MHz, CDCl3)
d
ppm 14.3, 21.2, 22.9, 56.4,
(75 MHz, CDCl3) d ppm 14.3, 23.1, 56.6, 60.7,110.9,111.2,118.5,125.9,
60.4, 110.1, 111.2, 118.5, 124.4, 125.6, 127.9, 128.3, 129.5, 130.0, 132.9,
133.8,134.5,135.3,138.2,139.0,142,144.6,150.6,161.56 170.5; LCMS
(EI(þ)): m/z ¼ 493 [M þ H] þ. HRMS (EI) calcd for C30H28N4O3
[M þ H]þ 493.22342. Found 493.22266.
128.0, 128.2, 129.6, 130, 133, 133.8, 135.0, 135.2, 138.7, 144, 150.5,
161.2,170.5; LCMS (EI(þ)) : m/z ¼ 533 [M þ H] þ. HRMS (EI) calcd for
C29H23F3N4O3 [M þ H]þ 533.1795. Found 533.17813.
4.2.17. 3-(Acetyl-pyridin-3-yl-amino)-1-(20-cyano-biphenyl-4-
ylmethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5h)
4.2.13. 3-(Acetyl-p-tolyl-amino)-1-(20-cyano-biphenyl-4-
ylmethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5d)
5h was prepared following general arylation procedure from 4
and 3-iodo-pyridine. The crude product was purified by flash
chromatography with cyclohexane/ethyle acetate (60/40) as an oil;
5d was prepared following general arylation procedure from 4
and 4-iodo-toluene. The crude product was purified by flash
chromatography with cyclohexane/ethyle acetate (60/40) as
a white powder; purity 100%; yield 63%; mp: 153e154 ꢁC; 1H NMR:
purity 98%; yield: 51%; 1H NMR (300 MHz, CDCl3)
d ppm 1.23
(t, J ¼ 6.6 Hz, 3H), 2.04 (s, 3H), 4.19 (q, J ¼ 6.6 Hz, 2H), 5.32 (s, 2H),
7.20e7.59 (m, 7H), 7.62 (t, J ¼ 7.5 Hz, 1H), 7.70 (d, J ¼ 7.5 Hz, 1H),
7.80 (d, J ¼ 6.3Hz, 1H), 8.01 (s, 1H), 8.5 (sl, 2H); 13C NMR (75 MHz,
(300 MHz, CDCl3)
d
ppm 1.33 (t, J ¼ 7.2 Hz, 3H), 2.07 (s, 3H), 2.34
(s, 3H), 4.28 (q, J ¼ 7.2 Hz, 2H), 5.32 (d, J ¼ 19.5 Hz, 2H), 7.16 (m, 2H),
7.36 (m, 4H), 7.44e7.57 (m, 4H), 7.66 (t, J ¼ 7.5 Hz, 1H), 7.77
(d, J ¼ 7.5 Hz, 1H), 7.83 (s, 0.5H), 7.95 (s, 0.5H); 13C NMR: (75 MHz,
CDCl3) ppm 14.3, 21.1, 22.7, 56.4, 60.4,110.5,111.2,118.6,126.5,127.9,
128.3, 129.5, 130.0, 132.9, 133.8, 134.5, 135.3, 136.4, 138.6, 140.0,
144.6, 150.5, 161.5, 171; LCMS (EI(þ)): m/z ¼ 479 [M þ H] þ. HRMS
(EI) calcd for C29H26N4O3 [M þ H]þ 479.20777. Found 479.20692.
CDCl3)
d ppm 14.3, 22.8, 56.5, 60.6, 110.6, 111.0, 118.5, 127.9, 128.3,
129.5, 130.0, 130.4, 133.0, 133.7, 135.2, 135.4, 138.6, 142.0, 144.þ4,
147.0, 147.4, 149.7, 161.1, 170.6; LCMS (EI(þ)) m/z ¼ 466 [M þ H]
.
HRMS (EI) calcd for C27H23N5O3 [M þ H]þ 466.18737. Found
466.18683.
4.3. General procedure for the synthesis of tetrazoles
4.2.14. 3-[Acetyl-(4-ethylphenyl)-amino]-1-(20-cyano-biphenyl-4-
ylmethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5e)
5e was prepared following general arylation procedure from 4
and 1-ethyl-4-iodo-benzene. The crude product was purified by
flash chromatography with cyclohexane/ethyle acetate (70/30) to
Nitrile derivative (1eq, 0.1 M) was solubilized in toluene. Tri-
methylsilane azide (5eq) and (nBu)2SnO (0.18eq) were added to the
solution. The mixture was refluxed during 60 h. The reaction
mixture was concentrated under reduced pressure and the crude