Journal of Medicinal Chemistry
ARTICLE
and HOBt (0.16 g, 1.16 mmol) in dry dichloromethane (5 mL), N,N-
diisopropylethylamine (0.15 g, 1.16 mmol) was added. The resulting
reaction mixture was stirred for 12 h and then washed with saturated
aqueous sodium hydrogen carbonate (3 Â 5 mL), saturated aqueous
sodium chloride (2 Â 5 mL), dried (MgSO4), and concentrated under
reduced pressure to give a colorless solid. The remaining residue was
subjected to column chromatography on silica gel using dichloromethane/
methanol in a 9.9:0.1 v/v ratio (0.21 g, 54%); mp 141À143 ꢀC. 1H NMR
(300.1 MHz, CDCl3): δ = 8.54À8.20 (m, 4H, ArH), 7.22 (br s, 5H,
NH), 6.65 (s, 1H, ArH), 5.74 (s, 2H, ÀCH2Ph), 1.31 (s, 9H, t-butyl).
13C NMR (75.5 MHz, CDCl3): δ = 161.0, 158.2, 145.7, 141.6, 137.9,
134.8, 134.7, 128.6, 128.0, 127.7 (Â2), 123.9, 104.3, 54.8, 32.3, 30.7.
Anal. RP-HPLC tR = 6.82 min (method 1C, purity 97.7%). LRMS
(APCI): m/z = 335.1300 [(M + H)+] (anal. calcd for C20H23N4O+:
m/z = 335.1872).
0.35 mmol) in dichloromethane (2 mL). The reaction mixture was
stirred for 10 min, at which time 3-tert-butyl-N-(4-(aminomethyl)-
thiazol-2-yl)-1-benzyl-1H-pyrazole-5-carboxamide (52 mg, 0.14 mmol)
was added in small portions and then the mixture was stirred for an
additional 14 h at room temperature. The solution was washed with
saturated aqueous sodium hydrogen carbonate (3 Â 5 mL), saturated
aqueous sodium chloride (2 Â 5 mL), dried (MgSO4), and concentrated
under reduced pressure to give a colorless solid. The remaining residue
was subjected to column chromatography on silica gel using dichlor-
omethane/methanol in a 9.8:0.2 v/v ratio as eluent to furnish 11 as a
1
white solid (37 mg, 63%); mp 121À123 ꢀC. H NMR (300.1 MHz,
CDCl3): δ = 7.31À7.20 (m, 5H, ArH), 6.77 (s, 1H, ArH), 6.74 (s, 1H,
ArH), 6.05 (t, J = 5.7 Hz, 1H, ÀNHÀ), 5.81 (s, 2H, ÀCH2Ph), 4.37 (d,
J = 5.7 Hz, 2H, ÀCH2À), 1.99 (s, 3H, ÀCH3), 1.34 (s, 9H, t-butyl). 13
C
NMR (75.5 MHz, CDCl3): δ = 170.1, 161.5, 157.9, 156.9, 147.9, 137.6,
133.0, 128.7, 127.9, 127.8, 110.3, 104.7, 54.2, 40.0, 30.7, 29.9, 23.5. Anal.
RP-HPLC tR = 8.55 min (method 1A, purity 95.6%). LRMS (APCI): m/z=
412.1732 [(M + H)+] (anal. calcd for C21H26N5O2S+: m/z = 412.1807).
(2-Chlorothiazol-4-yl)methanamine (16). To a solution of
1,3-dichloroacetone (25.0 g, 196.9 mmol) in dry acetone (100 mL)
and thiourea (15.3 g, 200.8 mmol) in dry acetone (500 mL) was added
dropwise and stirred at room temperature for 4 h. The reaction mixture
was concentrated under vacuum, and absolute ethanol (200 mL) was
added and allowed to stir at room temperature for 3 h. The reaction
mixture was then filtered and washed with ethanol (2 Â 50 mL). The
filtrate was concentrated under vacuum, washed with dichloromethane
(2 Â 50 mL), and dried to afford 16 as a hydrochloric salt (26.0 g, 71%).
1H NMR (400.0 MHz, [D6]DMSO): δ = 9.17 (br s, 2H, NH2), 6.97 (s,
1H, ArH), 4.68 (s, 2H, ÀCH2NH2). LRMS (APCI): m/z = 149.0 [(M +
H)+] (anal. calcd for C4H6ClN2S+: m/z = 149.0).
1-Benzyl-3-tert-butyl-N-(4-chloromethylthiazol-2-yl)-1H-
pyrazole-5-carboxamide (17). EDCI (0.78 g, 4.08 mmol) was
added in small batches to a solution of 3-tert-butyl-1-methyl-1H-pyrazole-5-
carboxylic acid (0.55 g, 2.99 mmol) and HOBt (0.55 g, 4.08 mmol) in
dichloromethane (15 mL). The reaction mixture was stirred for 10 min,
at which time a solution of 4-chloromethyl thiazol-zylamine hydrochloride
(0.50 g, 2.72 mmol) and N,N-diisopropylethylamine (0.70 g, 5.44 mmol) in
dichloromethane (5 mL) was added in small portions and then the
mixture was stirred for an additional 14 h at room temperature. The
solution was washed with saturated aqueous sodium hydrogen carbo-
nate (3 Â 10 mL), saturated aqueous sodium chloride (2 Â 10 mL),
dried (MgSO4), and concentrated under reduced pressure. The remain-
ing residue was subjected to column chromatography on silica gel using
hexane/dichloromethane in a 8.5:1.5 v/v ratio as eluent to give the title
1
compound as a white solid (0.90 g, 87%); mp 94À96 ꢀC. H NMR
(400.0 MHz, CDCl3): δ = 7.27À7.20 (m, 5H, ArH), 6.86 (s, 1H, ArH),
6.49 (s, 1H, ArH), 5.78 (s, 2H, ÀCH2Ph), 4.02 (s, 2H, ÀCH2Cl), 1.27
(s, 9H, t-butyl). 13C NMR (100.6 MHz, CDCl3): δ = 161.4, 158.9,
157.4, 146.8, 137.5, 133.1, 128.7, 127.8 (Â2), 112.4, 105.2, 54.9, 40.8,
32.3, 30.6. LRMS (APCI): m/z = 388.0496 [M+] (anal. calcd for
C19H21ClN4OS+: m/z = 388.1125).
tert-Butyl (2-Aminothiazol-4-yl)methylcarbamate (33). A
solution of (2-chlorothiazol-4-yl)methanamine (15.0 g, 81.0 mmol) in
dry methanol (250 mL) was purged with ammonia gas at À15 ꢀC for
30 min in a sealed tube, at which time the reaction mixture was allowed
to stir at room temperature for 16 h. The solution was then concentrated
under vacuum to afford a yellow solid, which was used without further
purification. To a suspension of 4-(aminomethyl)thiazol-2-amine (7.3 g,
56.7 mmol) and triethylamine (17.2 g, 170.1 mmol) in N,N-dimethy-
formamide (70 mL). tert-Butyloxycarbonyl anhydride (12.4 mL, 56.7
mmol) was slowly added at 0 ꢀC. The reaction mixture was stirred at
room temperature for 16 h, at which time distilled water (140 mL) was
added. The mixture was extracted with ethyl acetate (4 Â 200 mL). The
ethyl acetate layers were combined, washed with saturated aqueous
sodium hydrogen carbonate (3 Â 25 mL), saturated aqueous sodium
chloride (2 Â 25 mL), dried (MgSO4), and concentrated under reduced
pressure to give a colorless solid. The remaining residue was subjected to
column chromatography on silica gel using petroleum ether/ethyl
acetate in a 6:4 v/v ratio as eluent to furnish 33 as a white solid (6.10 g,
47%); mp 113À115 ꢀC. 1H NMR (400.0 MHz, CDCl3): δ = 6.32 (s,
1H, ArH), 5.02 (br s, 1H, NH2), 4.18 (d, J = 5.6 Hz, 2H, ÀCH2NHÀ),
1.71 (br s, 2H, NH2), 1.45 (s, 9H, t-butyl). 13C NMR (100.6 MHz,
CDCl3): δ = 168.4, 155.5, 150.3, 100.5, 77.7, 40.6, 28.2. LRMS (ESI):
m/z = 230.2 [(M + H)+] (anal. calcd for C9H16N3O2S+: m/z = 230.1).
General Procedure 2 for the Synthesis of 3-tert-Butyl-
N-[4-(aminomethyl)thiazol-2-yl]-1-methyl-1H-pyrazole-5-
carboxamide (18). EDCI (0.63 g, 3.27 mmol) was added in small
batches to a solution of 3-(tert-butyl)-1-methyl-1H-pyrazole-5-carboxylic
acid (0.44 g, 2.40 mmol) and HOBt (0.44 g, 3.27 mmol) in dry dichloro-
methane (10 mL). The reaction mixture was stirred for 10 min, at which
time a solution of tert-butyl (2-aminothiazol-4-yl)methylcarbamate (0.50 g,
2.18 mmol) and N,N-diisopropylethylamine (0.56 g, 4.36 mmol) in dry
dichloromethane (5 mL) was added in small portions and then the
mixture was stirred for an additional 14 h at room temperature. The solu-
tion was washed with saturated aqueous sodium hydrogen carbonate
3-tert-Butyl-N-(4-(aminomethyl)thiazol-2-yl)-1-benzyl-1H-
pyrazole-5-carboxamide (3). NaN3 (1.34 g, 20.62 mmol) was slowly
added to a solution of 1-benzyl-3-tert-butyl-N-(4-chloromethyl thiazol-
2-yl)-1H-pyrazole-5-carboxamide (0.40 g, 1.03 mmol) in DMF (5 mL).
The reaction mixture was stirred at 80 ꢀC for 24 h and was then
concentrated under reduced pressure to give 3-tert-butyl-N-(4-(azido-
methyl)thiazol-2-yl)-1-benzyl-1H-pyrazole-5-carboxamide, which was
used without further purification. To a solution of 3-tert-butyl-N-(4-
(azidomethyl)thiazol-2-yl)-1-benzyl-1H-pyrazole-5-carboxamide (322 mg,
0.82 mmol) in THF (3 mL) was added distilled water (15 mg, 0.82 mmol),
followed by triphenylphosphine (235 mg, 0.90 mmol). The reaction
mixture was stirred for 24 h and then washed with saturated aqueous
sodium hydrogen carbonate (3 Â 5 mL), saturated aqueous sodium
chloride (2 Â 5 mL), dried (MgSO4), and concentrated under reduced
pressure to give a colorless solid. The remaining residue was subjected to
column chromatography on silica gel using hexane/ethyl acetate in a 8:2 v/v
ratio as eluent to furnish 3 as a light-yellow solid (202 mg, 67%); mp
163À165 ꢀC. 1H NMR (400.0 MHz, CDCl3): δ = 7.24À7.15 (m, 5H,
ArH), 6.82 (s, 1H, ArH), 6.61 (s, 1H, ArH), 5.76 (s, 2H, ÀCH2Ph), 3.79
(s, 2H, ÀCH2NH2), 1.29 (s, 9H, t-butyl). 13C NMR (100.6 MHz,
CDCl3): δ = 161.3, 158.5, 157.4, 152.8, 137.7, 133.4, 128.6, 127.9, 127.7,
108.2, 105.1, 54.8, 42.4, 32.3, 30.6. Anal. RP-HPLC tR = 7.86 min
(method 1A, purity 98. 2%). LRMS (APCI): m/z = 370.1404 [(M +
H)+] (anal. calcd for C19H24N5OS+: m/z = 370.1702).
General Procedure 2 for the Synthesis of 3-tert-Butyl-
N-(4-(acetamidomethyl)thiazol-2-yl)-1-benzyl-1H-pyrazole-
5-carboxamide (11). EDCI (68 mg, 0.35 mmol) was added in small
batches to a solution of acetic acid (9 mg, 0.16 mmol) and DMAP (43 mg,
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dx.doi.org/10.1021/jm201108k |J. Med. Chem. 2011, 54, 7713–7719