Journal of Medicinal Chemistry
ARTICLE
Synthesis of (R/S)-2-Methyl-4,6-diphenyl-3-(2-(piperidin-1-yl)ethyl)-
3,4-dihydroquinazoline (16a). Prepared according to method F from
6-bromo-2-methyl-4-phenyl-3-(2-(piperidin-1-yl)ethyl)-3,4-dihydroqui-
nazoline (15c) (41 mg, 0.1 mmol) and phenylboronic acid (18 mg, 0.15
mmol). The crude product was purified by flash column chromatography
(0.5 M NH3 (MeOH)/CH2Cl2 0:100 f 10:90) to give a brown solid (26
mg, 63%). 1H NMR (500 MHz, CDCl3): δ 7.48ꢀ4.46 (m, 2H, 2 ꢁ ArH),
7.40ꢀ7.30 (m, 7H, 7 ꢁ ArH), 7.28ꢀ7.24 (m, 2H, 2 ꢁ ArH), 7.18 (d, 1H,
J = 8.0 Hz, ArH), 7.03 (d, 1H, J = 2.5 Hz, ArH), 5.65 (s, 1H, H-4), 3.51
(ddd, 1H, J = 15.0, 9.0, 6.0 Hz, CHH), 3.23 (ddd, 1H, J = 15.0, 9.0, 6.0 Hz,
CHH), 2.57 (ddd, 1H, J = 12.5, 9.0, 5.5 Hz, CHH), 2.44ꢀ2.31 (m, 8H,
CHH, 2 ꢁ CH2, CH3), 1.59ꢀ1.54 (m, 4H, 2 ꢁ CH2), 1.46ꢀ1.41 (m, 2H,
CH2). LRMS (ES+): m/z (%) 410 (100) [M + H]+. HRMS (ES+): calcd
for C28H32N3 [M + H]+ 410.2591, found 410.2599 (ꢀ2.08 ppm).
(R/S)-3-(6-Chloro-2-methyl-4,8-diphenylquinazolin-3(4H)-yl)-N,N-
dimethylpropan-1-amine (19). Prepared according to general method
E from 3-(6-bromo-8-chloro-2-methyl-4-phenylquinazolin-3(4H)-yl)-
N,N-dimethylpropan-1-amine (18) (42 mg, 0.1 mmol) and phenyl-
boronic acid (12 mg, 0.1 mmol). The crude product was purified by
preparative HPLC to give a white solid (17 mg, 41%). 1H NMR (500
MHz, CDCl3): δ 7.64ꢀ7.62 (m, 2H, 2 ꢁ ArH), 7.41ꢀ7.37 (m, 2H, 2 ꢁ
ArH), 7.32ꢀ7.25 (m, 6H, 6 ꢁ ArH), 7.16 (d, 1H, J = 2.5 Hz, ArH), 6.79
(dd, 1H, J = 2.5, 0.5 Hz, ArH), 5.48 (s, 1H, CH), 3.46 (ddd, 1H, J = 14.5,
8.5, 6.0 Hz, CHH), 3.11 (ddd, 1H, J = 14.5, 8.5, 6.0 Hz, CHH),
2.33ꢀ2.22 (m, 5H, CH2 and CH3), 2.20 (s, 6H, 2 ꢁ NCH3), 1.82ꢀ1.65
(m, 2H, CH2). 13C NMR (125 MHz, CDCl3): δ 156.0 (C), 143.9 (C),
138.7 (C), 137.4 (C), 136.9 (C), 130.5 (CH), 129.5 (CH), 129.1 (CH),
128.3 (CH), 127.7 (CH), 127.4 (C), 127.0 (CH), 126.6 (CH), 125.1
(CH), 62.6 (CH), 56.3 (CH2), 46.8 (CH2), 45.4 (CH3), 26.3 (CH2),
22.9 (CH3). [Note: one quaternary carbon resonance is absent, possibly
due to it having an identical chemical shift to another quaternary carbon
resonance]. LRMS (ES+): m/z (%) 209.5 (42) [35Cl M + 2H]2+, 210.5
(13) [37Cl M + 2H]2+, 418 (100) [35Cl M + H]+, 420 (38) [37Cl M +
H]+. HRMS (ES+): calcd for C26H29Cl1N3 [M + H]+ 418.2045, found
418.2034 (2.54 ppm).
1.89ꢀ1.84 (m, 2H, CH2). 13C NMR (125 MHz, CDCl3): δ 171.7 (C),
169.3 (C), 139.1 (C), 138.9 (C), 132.4 (C), 132.2 (CH), 130.6 (CH),
129.6 (CH), 127.1 (CH), 126.6 (C), 124.4 (C), 121.5 (CH), 57.7
(CH2), 51.8 (CH2), 45.6 (CH3), 29.7 (CH2), 25.4 (CH3), 21.4 (CH3).
LRMS (ES+): m/z (%) 186.5 (100) [35Cl M + 2H]2+, 187.5 (32) [37Cl
M + 2H]2+, 372 (61) [35Cl M + H]+, 374 (18) [37Cl M + H]+.
3-(6-Chloro-2-methyl-4-p-tolylquinazolin-3(4H)-yl)-N,N-dimethyl-
propan-1-amine (29a). Prepared according to general method C2 from
N-(4-chloro-2-((3-(dimethylamino)propylimino)(p-tolyl)methyl)phe-
nyl)acetamide (28a). The crude product was purified by flash column
chromatography over silica (MeOH/CH2Cl2 0:100 f 10:90) to give a
clear gum (99 mg, 28%). 1H NMR (500 MHz, CDCl3): δ 7.20ꢀ7.17
(m, 2H, AA0BB0,2 ꢁ ArH), 7.15ꢀ7.13 (m, 2H, AA0BB0, 2 ꢁ ArH), 7.09
(dd, 1H, J = 8.5, 2.5 Hz, H-7), 7.05 (d, 1H, J = 8.5 Hz, H-8), 6.77 (d, 1H.
J = 2.5 Hz, H-5), 5.46 (s, 1H, H-4), 3.46 (ddd, 1H, J = 14.5, 8.0, 6.5 Hz,
CHH), 3.11 (ddd, 1H, J = 14.5, 8.5, 6.0 Hz, CHH), 2.33 (s, 3H, CH3),
2.30 (s, 3H, CH3), 2.29ꢀ2.21 (m, 2H, CH2), 2.20 (s, 6H, 2 ꢁ NCH3),
1.81ꢀ1.64 (m, 2H, CH2). 13C NMR (125 MHz, CDCl3): δ 156.5 (C),
140.9 (C), 139.8 (C), 138.1 (C), 129.7 (CH), 128.7 (C), 128.2 (CH),
126.6 (CH), 126.5 (C), 126.0 (CH), 125.1 (CH), 62.1 (CH), 56.2
(CH2), 46.8 (CH2), 45.4 (CH3), 26.2 (CH2), 22.4 (CH3), 21.1 (CH3).
LRMS (ES+): m/z (%) 178.5 (27) [35Cl M + 2H]2+, 356 (100) [35Cl
M+H]+, 358 (31) [37Cl M + H]+. HRMS(ES+):calcdforC21H2735Cl1N3
[M + H]+ 356.1888, found 356.1881 (1.84 ppm).
(2-Amino-5-chlorophenyl)(4-tert-butylphenyl)methanone (26b).
Prepared according to general method G from 1-bromo-4-(tert-bu-
tyl)benzene (3.75 g, 17.6 mmol). The final product was purified by
flash column chromatography over silica (EtOAc/hexanes 0:100 f
1
50:50) to give a yellow solid (679 mg, 59%). H NMR (500 MHz,
CDCl3): δ 7.61ꢀ7.58 (m, 2H, AA0BB0, 2 ꢁ ArH), 7.50ꢀ7.48 (m, 2H,
AA0BB0, 2 ꢁ ArH), 7.47 (d, 1H, J = 2.5 Hz, H-6), 7.24 (dd, 1H, J = 9.0,
2.5 Hz, H-4), 6.69 (d, 1H, J = 9.0 Hz, H-3), 1.37 (s, 9H, 3 ꢁ CH3). 13
C
NMR (125 MHz, CDCl3): δ 197.8 (CO), 155.3 (C), 149.2 (C), 136.4
(C), 133.9 (CH), 133.2 (CH), 129.3 (CH), 125.3 (CH), 120.0 (C),
119.2 (C), 118.4 (CH), 35.1 (C), 31.2 (CH3). LRMS (ES+): m/z (%)
288 (100) [35Cl M + H]+, 290 (33) [37Cl M + H]+.
N-(4-Chloro-2-(4-methylbenzoyl)phenyl)acetamide (27a). p-Tolyl-
magnesium bromide (1.0 M in THF, 10 mL, 10 mmol) was slowly added
to a solution of benzoxazinone (24) (1.96 g, 10 mmol) in anhydrous
THF (40 mL) at 0 °C. The reaction mixture was allowed to warm to
25 °C over 30 min and stirred for an additional 1.5 h before the reaction
was quenched by the addition of NaCl solution (satd aq 50 mL). The
resultant biphasic mixture was separated and the aqueous layer extracted
with EtOAc (3 ꢁ 50 mL). Subsequently, the combined organic layers
were dried over MgSO4, filtered, and the solvent removed under
reduced pressure. The crude product was purified by flash column
chromatography over silica (Et2O/hexanes 0:100 f 50:50) to give a
white solid (511 mg, 18%). 1H NMR (500 MHz, CDCl3): δ 10.54 (br s,
1H, NH), 8.57 (d, 1H, J = 9.5 Hz, ArH), 7.63ꢀ7.61 (m, 2H, AA0BB0, 2 ꢁ
ArH), 7.51ꢀ7.49 (m, 2H, 2 ꢁ ArH), 7.32ꢀ7.30 (m, 2H, AA0BB0, 2 ꢁ
ArH), 2.46 (s, 3H, CH3), 2.21 (s, 3H, CH3). 13C NMR (125 MHz,
CDCl3): δ 198.0 (CO), 169.1 (C), 144.1 (C), 138.7 (C), 135.1 (C),
133.6 (CH), 132.4 (CH), 130.2 (CH), 129.3 (CH), 127.2 (C), 125.0
(C), 123.1 (CH), 25.2 (CH3), 21.7 (CH3). LRMS (ES+): m/z (%) 288
(100) [35Cl M + H]+, 290 (31) [37Cl M + H]+.
4-(4-tert-Butylphenyl)-6-chloro-2-methyl-3-(2-(piperidin-1-yl)ethyl)-
3,4-dihydroquinazoline (29b). Prepared in three steps from 26b, acetyl
chloride, and 1-(2-aminoethyl)piperidine following general methods A, B,
andC2. Thefinalproductwas purified byreversephasepreparative HPLC
1
to give a white solid (40 mg, 6% over 3 steps). H NMR (500 MHz,
CDCl3): δ 7.33ꢀ7.31 (m, 2H, AA0BB0), 7.21ꢀ7.19 (m, 2H, AA0BB0),
7.07 (dd, 1H, J = 8.5, 2.0 Hz, H-7), 7.01 (d, 1H, J = 8.5 Hz, H-8), 6.77 (d,
1H, J =2.0 Hz, H-5), 5.51(s, 1H, H-4), 3.45 (ddd, 1H, J= 14.5, 8.5, 6.0Hz,
CHH), 3.20 (ddd, 1H, J = 14.5, 8.5, 6.0 Hz, CHH), 2.52 (ddd, 1H, J =
13.0, 8.5, 6.0 Hz, CHH), 2.40ꢀ2.31 (m, 5H, CHH and 2 ꢁ CH2), 2.28 (s,
3H, CH3), 1.58ꢀ1.53 (m, 4H, 2 ꢁ CH2), 1.45ꢀ1.40 (m, 2H, CH2), 1.29
(s, 9H, 3 ꢁ CH3). 13C NMR (125 MHz, CDCl3): δ 156.4 (C), 151.2 (C),
140.9 (C), 139.9 (C), 128.6 (C), 128.2 (CH), 126.5 (C), 126.3 (CH),
126.00 (CH), 125.95 (CH), 125.0 (CH), 62.8 (CH), 57.4 (CH2), 55.1
(CH2), 46.9 (CH2), 34.6 (C), 31.3 (CH3), 26.0 (CH2), 24.2 (CH2), 22.5
(CH3). LRMS (ES+): m/z (%) 424 (100) [35Cl M + H]+, 426 (34) [37Cl
M + H]+. HRMS (ES+): calcd for C26H3535Cl1N3 [M + H]+ 424.2514,
found 424.2520 (ꢀ1.52 ppm).
N-(4-Chloro-2-((3-(dimethylamino)propylimino)(p-tolyl)methyl)-
phenyl)acetamide (28a). Prepared according to general method B from
N-(4-chloro-2-(4-methylbenzoyl)phenyl)acetamide (27a) and 3-(di-
methylamino)-1-propylamine. The crude product was purified by flash
column chromatography over silica (0.5 M NH3 in MeOH/CHCl3 1:99
6-Chloro-4-(4-chlorophenyl)-2-methyl-3-(2-(piperidin-1-yl)ethyl)-
3,4-dihydroquinazolin-4-ol (31a). Prepared according to general meth-
od H using 4-chlorophenylmagnesium bromide (1.0 M solution in Et2O,
8 mL, 8 mmol). The final product was purified by recrystallization from
1
MeCN to give a white solid (339 mg, 41%). H NMR (500 MHz,
1
f 4:96) to give a white solid (485 mg, 65%). H NMR (500 MHz,
CDCl3): δ 9.48 (br s, 1H, OH), 7.49ꢀ7.46 (m, 2H, AA0BB0, 2 ꢁ ArH),
7.35ꢀ7.32 (m, 2H, AA0BB0, 2 ꢁ ArH), 7.14 (dd, 1H, J = 8.5, 2.5 Hz,
H-7), 7.11 (d, 1H, J = 8.5 Hz, H-8), 6.79 (d, 1H, J = 2.5 Hz, H-5),
3.51ꢀ3.47 (m, 1H, CHH), 3.10ꢀ3.05 (m, 1H, CHH), 2.60ꢀ2.55 (m,
1H, CHH), 2.50ꢀ2.45 (m, 2H, 2 ꢁ CHH), 2.35ꢀ2.31 (m, 3 ꢁ CHH
CDCl3): δ 13.66 (s, 1H, NH), 8.71 (d, 1H, J = 9.0 Hz, H-6), 7.29ꢀ7.25
(m, 3H, AA0BB0 and H-5), 6.99ꢀ6.97 (m, 2H, AA0BB0), 6.86 (d, 1H, J =
2.5 Hz, H-3), 3.33 (t, 2H, J = 7.0 Hz, CH2), 2.42 (s, 3H, CH3), 2.30 (t,
2H, J = 7.5 Hz, CH2), 2.21 (s, 3H, CH3), 2.19 (s, 6H, 2 ꢁ CH3),
6527
dx.doi.org/10.1021/jm200312v |J. Med. Chem. 2011, 54, 6514–6530