Journal of Medicinal Chemistry
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racemate in >98% ee purity, retention time 7.50 min, Chiral cell OD
column (4.6 mm × 250 mm) elution with 2% IPA in heptane. HPLC:
purity 98%, retention time 12.17 min, method B; purity 98%, retention
time 10.30 min, method C. LCMS: [M + 1] 452.0, [M + 3] 454.0. 1H
NMR (400 MHz, MeOD) δ 7.44 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 2.1
Hz, 1H), 7.13 (dd, J = 8.4, 2.2 Hz, 1H), 6.30 (s, 1H), 6.11 (s, 1H),
3.80 (s, 3H), 2.58 (s, 3H), 2.21 (s, 3H), 1.58 (s,9H). 13C NMR (101
MHz, MeOD) δ 166.47, 151.20, 150.95, 149.09, 141.20, 138.56,
133.85, 133.44, 132.15, 129.35, 127.57, 116.52, 97.42, 86.46, 59.36,
52.80, 28.28, 21.42, 13.92.
7.30 (d, J = 2.1 Hz, 1H), 7.14 (dd, J = 8.3, 2.2 Hz, 1H), 6.51 (s, 1H),
6.47 (s, 1H), 2.66 (s, 3H), 1.59 (s, 9H). 13C NMR (101 MHz, MeOD)
δ 167.30, 150.66, 148.79, 141.14, 140.15, 139.06, 136.23, 135.00,
134.15, 133.99, 133.81, 132.34, 129.36, 127.62, 117.59, 113.60,
86.98, 80.66, 60.48, 40.98, 28.17, 22.00, 21.21. LCMS: [M + 1]
491.8.
((R)-7-(3,4-Dichlorophenyl)-5-methyl-2-(trifluoromethyl)-
4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(4-
fluorophenyl)pyrrolidin-1-yl)methanone (13b). Compound 11b
and (S)-2-(4-fluorophenyl)pyrrolidine were coupled under the
conditions described for the preparation of example 13a to yield inter-
mediate tert-butyl 7-(3,4-dichlorophenyl)-6-((S)-2-(4-fluorophenyl)-
pyrrolidine-1-carbonyl)-5-methyl-2-(trifluoromethyl)pyrazolo[1,5-a]-
pyrimidine-4(7H)-carboxylate (0.53 g, 0.82 mmol) which was dis-
solved in 1:1 TFA:DCM (20 mL) and the reaction mixture stirred
at room temperature for 3 h. The reaction mixture was concentrated
and the residue azeotroped with toluene and then purified by silica
gel chromatography elution with 1:3:7 IPA:EtOAc:hexane to yield
((R)-7-(3,4-dichlorophenyl)-5-methyl-2-(trifluoromethyl)-4,7-
dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(4-fluorophenyl)-
pyrrolidin-1-yl)methanone as the less polar diastereomer and
((S)-7-(3,4-dichlorophenyl)-5-methyl-2-(trifluoromethyl)-4,7-
dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(4-fluorophenyl)-
pyrrolidin-1-yl)methanone as the more polar diastereomer as white
solids in yields of 29% and 17%, respectively. HPLC: purity 97%,
LiOH (10N aqueous solution, 5 mL) was added to a solution of
(R)-4-tert-butyl-6-methyl-7-(3,4-dichlorophenyl)-2,5-
dimethylpyrazolo[1,5-a]pyrimidine-4,6(7H)-dicarboxylate (0.53 g,
1.2 mmol) in THF (5 mL). The reaction mixture was stirred at RT
for 15 h and then diluted with HCl (1N aqueous solution, 20 mL) and
extracted with DCM. The combined organic portions were dried over
Na2SO4, decanted, and concentrated to yield (R)-4-(tert-butoxycar-
bonyl)-7-(3,4-dichlorophenyl)-2,5-dimethyl-4,7-dihydropyrazolo[1,5-
a]pyrimidine-6-carboxylic acid (11a) as an off-white powder (0.44 g,
yield 87%, purity 92%, retention time 4.03 min, method A). LCMS
[M + 1] 438.18. To a solution of 11a (1.2 g, 2.7 mmol) in DCM (40 mL)
was added EDCI (0.71 g, 3.7 mmol), HOBt (0.50 g, 3.7 mmol), and
(S)-2-(4-fluorophenyl)pyrrolidine (0.61 g, 3.7 mmol). The reaction
mixture was stirred at room temperature for 14 h and then diluted
further with DCM (50 mL) and the solution washed successively with
saturated NaHCO3 and satd NaCl. The organic portion was dried over
Na2SO4, decanted, and concentrated to yield intermediate (R)-tert-
butyl-7-(3,4-dichlorophenyl)-6-((S)-2-(4-fluorophenyl)pyrrolidine-1-
carbonyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine-4(7H)-carboxylate
as a tan solid (1.2 g, 75% yield, 95% purity at retention time 4.18 min).
LCMS [M + 1] 585.16. To (R)-tert-butyl-7-(3,4-dichlorophenyl)-6-
((S)-2-(4-fluorophenyl)pyrrolidine-1-carbonyl)-2,5-dimethylpyrazolo-
[1,5-a]pyrimidine-4(7H)-carboxylate (1.2 g, 2.0 mmol) was added
1:1 DCM:TFA solution (3 mL). The solution was stirred at room
temperature for 3 h and then diluted with DCM, and the organic
portion was washed with satd NaHCO3, dried over Na2SO4, decanted,
and concentrated. The residue was purified by silica gel chromatog-
raphy elution with 1:1:0.1 hexane:EtOAc:IPA to yield compound 13a
as a white powder (0.22 g, 23% yield, 99% purity, retention time 6.83
min, method B); Rf 0.30 10% IPA in 1:1 hexane:EtOAc. 13C NMR
(101 MHz, MeOD) δ 164.0, 162.5, 152.0, 145.0, 142.0, 141.0, 133.8,
133.7, 133.6, 132.0, 130.0, 128.3, 116.0, 102.8, 87.58, 62.0, 28.0, 17.0,
13.6. Due to rotomers, the proton spectra for this diastereomer had
1
retention time 3.86 min, method A. H NMR (400 MHz,) δ 7.44
(s, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.09 (s, 1H), 7.02 (s, 2H), 6.88 (t,
J = 8.5 Hz, 2H), 6.78 (d, J = 10.4 Hz, 2H), 6.23 (s, 1H), 5.56 (s, 1H),
4.86 (t, J = 7.7 Hz, 1H), 4.05−3.82 (m, 1H), 3.32 (s, 1H), 3.13 (s, 1H),
2.19 (m, 2H), 1.74 (s, 3H). 19F NMR (376 MHz) δ −62.53, −114.61.
13C NMR (101 MHz,) δ 167.43, 160.08, 138.57, 132.89, 130.77, 128.30,
127.50, 125.78, 115.45, 115.24, 103.29, 85.29, 77.32, 77.01, 76.69, 64.48,
60.62, 49.31, 34.85, 32.25, 25.32, 16.81, 0.99, −10.63. HRMS [M + 1]
obsd 539.1028, calcd 539.1029.
((R)-7-(3,4-Dichlorophenyl)-5-methyl-4,7-dihydropyrazolo-
[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-
1-yl)methanone (13c). (R)-4-(tert-Butoxycarbonyl)-7-(3,4-dichlor-
ophenyl)-5-methyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylic
acid (11c) was coupled to (S)-3-methyl-5-(pyrrolidin-2-yl)isoxazole
(12) using the conditions and subsequent deprotection described for
example 13a to yield ((R)-7-(3,4-dichlorophenyl)-5-methyl-4,7-dihydro-
pyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-
1-yl)methanone in 26% yield. HPLC: purity 95%, retention time 7.88
1
min, method B; purity 96%, retention time 7.59 min, method C. H
1
broad peaks as noted. H NMR (400 MHz, MeOD) δ 7.15 (s, 1H),
NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 1.9
Hz, 1H), 7.25 (d, J = 4.4 Hz, 1H), 7.24 (d, J = 1.9 Hz, 1H), 7.01 (dd,
J = 8.3, 1.8 Hz, 1H), 6.50 (s, 1H), 6.07 (s, 1H), 5.53 (d, J = 1.9 Hz,
1H), 5.52 (s, 1H), 3.52 (s, 1H), 3.19 (s, 1H), 2.24 (s, 3H), 2.02−1.84
(m, 5H), 2.04 (s, 2H). 13C NMR (101 MHz, MeOD) δ 173.58,
161.88, 151.20, 143.56, 141.76, 133.45, 132.88, 131.93, 130.13, 127.99,
103.10, 102.44, 87.74, 61.17, 16.88, 13.64, 11.32. LCMS: [M + 1]
458.1, [M + 3] 460.1
7.32 (s, 1H), 6.95 (t, J = 8.0 Hz, 2H), 6.73 (s, 1H), 5.95 (s, 1H), 5.41
(s, 2H), 5.05 (s, 1H), 3.69 (s, 2H), 3.47 (m, 1H), 3.30 (s, 1H), 3.19
(s, 1H), 2.30 (s, 1H), 2.06 (s, 3H), 2.00−1.61 (m, 2H). HRMS [M + 1]
obsd 485.1309, calcd 485.1311.
4-(tert-Butoxycarbonyl)-7-(3,4-dichlorophenyl)-5-methyl-2-
(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-car-
boxylic Acid (11b). Methyl 7-(3,4-dichlorophenyl)-5-methyl-2-
(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate
was prepared as described for example 11a from the condensation of
3-(trifluoromethyl)-1H-pyrazol-5-amine, 3,4-dichlorobenzaldehyde,
and methyl 3-oxobutanoate to yield intermediate methyl 7-(3,4-dichloro-
phenyl)-5-methyl-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]-
pyrimidine-6-carboxylate as an orange solid in 52% yield, 96% purity,
((R)-7-(3,4-Dichlorophenyl)-2,5-dimethyl-4,7-dihydropyra-
zolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)-
pyrrolidin-1-yl)methanone (13d). Compound 11a was coupled to
(S)-3-methyl-5-(pyrrolidin-2-yl)isoxazole (12) using the conditions
and subsequent deprotection described for example 13a to yield ((R)-
7-(3,4-dichlorophenyl)-2,5-dimethyl-4,7-dihydropyrazolo[1,5-a]-
pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)-
methanone in 64% yield. HPLC: purity 94%, retention time 7.22 min,
1
retention time 2.90 min. H NMR (400 MHz,) δ 7.35 (d, J = 8.0 Hz,
1H), 7.31 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 8.3, 2.1 Hz, 1H), 6.63
(s, 1H), 6.38 (s, 1H), 5.87 (s, 1H), 3.61 (s, 3H), 2.52 (s, 3H). LCMS
[M + 1] 405.95, [M + 3] 407.91. Methyl 7-(3,4-dichlorophenyl)-5-methyl-
2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate
was converted to 4-tert-butyl-6-methyl-7-(3,4-dichlorophenyl)-5-methyl-
2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-4,6(7H)-dicarboxylate
and subsequently hydrolyzed as described to 4-(tert-butoxycarbonyl)-
7-(3,4-dichlorophenyl)-5-methyl-2-(trifluoromethyl)-4,7-dihydro-
pyrazolo[1,5-a]pyrimidine-6-carboxylic acid using the procedure
described in example 13a in 94% yield. HPLC: purity 96%, reten-
tion time 11.85 min, method B; purity 93%, retention time 10.28 min,
method C. 1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 8.3 Hz, 1H),
1
method B; purity 96%, retention time 7.32 min, method C. H NMR
(400 MHz, MeOD) δ 7.50 (d, J = 8.3 Hz, 1H), 7.22 (d, J = 1.7 Hz,
1H), 7.02 (dd, J = 8.3, 1.9 Hz, 1H), 5.92 (s, 1H), 5.72 (s, 1H), 5.48
(s, 1H), 5.11 (s, 1H), 3.62 (dt, J = 10.8, 7.1 Hz, 1H), 3.21 (s, 1H), 2.26
(s, 3H), 2.12 (s, 3H), 1.98 (m, 4H). 13C NMR (101 MHz, MeOD)
δ 173.58, 161.41, 151.20, 143.56, 141.76, 133.45, 132.88, 131.93, 130.13,
127.99, 103.10, 102.44, 87.74, 61.17, 16.88, 13.64, 11.32. LCMS:
[M + 1] 472.1, [M + 3] 474.1
((R)-7-(3,4-Dichlorophenyl)-5-methyl-2-(trifluoromethyl)-
4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisox-
azol-5-yl)pyrrolidin-1-yl)methanone (13e). Compound 11b was
3044
dx.doi.org/10.1021/jm201386u | J. Med. Chem. 2012, 55, 3036−3048