Journal of Medicinal Chemistry
Article
mixture was quenched with H2O, and the products were extracted with
AcOEt. The extract was dried over MgSO4, filtered, and evaporated.
The residue was purified by column chromatography (CHCl3/MeOH =
95/5 to 90/10), and the fractions were combined and evaporated.
The residue was dissolved in AcOEt, and to the mixture was added
4 M HCl−AcOEt. The precipitate was filtered and crystallized from
EtOH−AcOEt to give the title compound as a yellow powder (47 mg,
22%). 1H NMR (DMSO-d6): δ 2.09 (3H, s), 2.60−2.71 (1H, m), 2.81
(3H, s), 3.04−4.39 (14H, m), 6.95 (1H, d, J = 9.8 Hz), 7.10 (1H, d,
J = 9.8 Hz), 7.21−7.28 (2H, m), 7.32−7.39 (4H, m), 7.46−7.52 (2H,
m). MS (API-ES) m/z = 514 (M + H).
by column chromatography on silica gel (CHCl31/MeOH = 99/1 to 95/5)
to give the title compound 9i (630 mg, 51%). H NMR (DMSO-d6): δ
1.01 (9H, s), 1.73−1.90 (2H, m), 2.07 (3H, s), 3.44−3.49 (2H, m),
3.63 (1H, dd, J = 9.5, 5.5 Hz), 3.74 (1H, dd, J = 10, 3.5 Hz), 4.45−4.49
(4H, m), 7.42−7.47 (6H, m), 7.60−7.65 (4H, m), 7.86 (1H, brs), 8.73
(1H, brs). MS (ESI) m/z = 440 (M + Na).
6-[5-{[(2R)-1-{[tert-Butyl(diphenyl)silyl]oxy}-4-hydroxybu-
tan-2-yl]amino}-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-(2-
methylphenyl)pyridazin-3(2H)-one (13i). To a solution of 8 (630
mg, 1.6 mmol) in EtOH/acetic acid (1/1, 8.4 mL) was added 9i
(655.8 mg, 1.6 mmol) at room temperature, and the mixture was
stirred at 50 °C for 2 h. The mixture was quenched with NaHCO3
solution, and extraction was with ethyl acetate. The organic layer was
separated, successively washed with NaHCO3 solution and brine, dried
over MgSO4, and evaporated under reduced pressure to give the crude
product. The crude product was purified by column chromatography
on silica gel (CHCl3/MeOH = 100/0 to 90/10) to give the title
N-[(2R)-1-{[tert-Butyl(diphenyl)silyl]oxy}-4-hydroxybutan-2-yl]-
hydrazinecarbothioamide (9i). To a solution of (2R)-4-{[tert-
butyl(dimethyl)silyl]oxy}-2-(dibenzylamino)butan-1-ol (1.47 g, 3.7
mmol) in DMF (29.4 mL) were added imidazole (601 mg, 8.8
mmol) and tert-butyl(chloro)diphenylsilane (1.15 mL, 4.4 mmol) at
room temperature, and the mixture was stirred for 15 h. The mixture
was partitioned between ethyl acetate and water. The organic layer was
separated, successively washed with water and brine, dried over
MgSO4, and evaporated under reduced pressure to give the crude
product. The crude product was purified by column chromatography
on silica gel (hexane/EtOAc = 100/0 to 95/5) to give (6R)-N,N-
dibenzyl-2,2,10,10,11,11-hexamethyl-3,3-diphenyl-4,9-dioxa-3,10-disi-
1
compound (850 mg, 79%). H NMR (DMSO-d6): δ 0.80 (9H, s),
1.52−1.62 (1H, m), 1.70−1.83 (1H, m), 2.07 (3H, s), 3.46−3.86 (5H,
m), 4.46 (1H, brs), 5.53 (1H, brs), 6.92 (1H, d, J = 10 Hz), 7.03 (1H,
d, J = 10 Hz), 7.24−7.56 (18H, m), 12.27 (1H, brs). MS (API-ES)
m/z = 688 (M + H).
6-[(5R)-2-(4-Fluorophenyl)-5-(hydroxymethyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)-
pyridazin-3(2H)-one (3i). To a solution of 13i (850 mg, 1.2 mmol)
in acetonitrile (17 mL) were added methanesulfonyl chloride
(143.5 μL, 1.8 mmol) and triethylamine (516.7 μL, 3.7 mmol), and
the mixture was stirred at 80 °C for 2 h. The mixture was partitioned
between ethyl acetate and water. The organic layer was separated,
successively washed with 10% citric acid solution and brine, dried over
MgSO4, and evaporated under reduced pressure to give the crude
product, which was purified by column chromatography on silica gel
(CHCl3/MeOH = 99/1 to 95/5) to give 6-[(5R)-5-({[tert-butyl-
(diphenyl)silyl]oxy}methyl)-2-(4-fluorophenyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)-
1
ladodecan-6-amine (1.97 g, 84%). H NMR (400 MHz, CDCl3): δ
−0.04 (6H, s), 0.82 (9H, s), 1.07 (9H, s), 1.63−1.72 (1H, m), 1.80−
1.89 (1H, m), 2.87−2.94 (1H, m), 3.50−3.58 (1H, m), 3.60−3.82
(7H, m), 7.16−7.21 (2H, m), 7.23−7.28 (4H, m), 7.31−7.44 (10H,
m), 7.64−7.69 (4H, m). MS (API-ES) m/z = 639 (M + H).
To a solution of (6R)-N,N-dibenzyl-2,2,10,10,11,11-hexamethyl-3,3-
diphenyl-4,9-dioxa-3,10-disiladodecan-6-amine (1.97 g, 3.0 mmol) in
dioxane (19.7 mL) was added 4 N HCl (3.94 mL) at room tem-
perature, and the mixture was stirred for 1 h. The mixture was parti-
tioned between ethyl acetate and water. The organic layer was
separated, successively washed with NaHCO3 solution and brine, dried
over MgSO4, and evaporated under reduced pressure to give the crude
product. The crude product was purified by column chromatography
on silica gel (hexane/EtOAc = 9/1 to 4/1) to give (3R)-4-{[tert-
butyl(diphenyl)silyl]oxy}-3-(dibenzylamino)butan-1-ol (1.53 g, 95%).
1H NMR (400 MHz, CDCl3): δ 1.10 (9H, s), 1.47−1.56 (1H, m),
1.86−1.99 (1H, m), 3.02−3.11 (1H, m), 3.56 (2H, d, J = 13 Hz),
3.69−3.80 (2H, m), 3.83−3.88 (2H, m), 3.93 (2H, d, J = 13 Hz),
7.20−7.33 (10H, m), 7.38−7.47 (6H, m), 7.66−7.71 (4H, m). MS
(API-ES) m/z = 524 (M + H).
1
pyridazin-3(2H)-one (495.6 mg, 60%). H NMR (DMSO-d6): δ 0.90
(9H, s), 1.97−2.00 (1H, m), 2.03 (3H, s), 2.15−2.23 (1H, m), 3.52−
3.68 (3H, m), 4.00−4.05 (2H, m), 6.03 (1H, brs), 6.92 (1H, d, J =
10 Hz), 7.07 (1H, d, J = 10 Hz), 7.19−7.57 (18H, m). MS (ESI)
m/z = 692 (M + Na).
To a solution of 6-[(5R)-5-({[tert-butyl(diphenyl)silyl]oxy}-
methyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]-
pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one (450 mg,
0.67 mmol) in THF (4.5 mL) was added a solution of 1 M
tetrabutylammonium fluoride in THF (0.67 mL, 0.67 mmol) at room
temperature. After being stirred for 30 min, the mixture was parti-
tioned between EtOAc and H2O. The organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (CHCl3/MeOH = 98/2 to
95/5). The obtained oil was crystallized from iPrOH−Hex to give the
To a solution of (3R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-
(dibenzylamino)butan-1-ol (1.57 g, 3.0 mmol) in ethanol (24 mL)
were added ammonium formate (2.84 g, 45.0 mmol) and palladium on
carbon (628 mg, 10% wt on carbon) at room temperature, and the
mixture was refluxed for 4 h. After cooling to room temperature, the
mixture was filtered through a funnel. The filtrate was evaporated
under reduced pressure to give (3R)-3-amino-4-{[tert-butyl(diphenyl)-
1
1
title compound (269 mg, 93%). H NMR (DMSO-d6): δ 1.71−1.84
silyl]oxy}butan-1-ol (1 g, 97%). H NMR (400 MHz, CDCl3): δ 1.06
(1H, m), 2.05−2.09 (1H, m), 2.11 (3H, s), 3.26−3.33 (1H, m), 3.40
(1H, m), 3.48−3.52 (1H, m), 3.98−4.14 (2H, m), 4.89 (1H, t, 5 Hz),
6.11 (1H, brs), 6.92 (1H, d, J = 10 Hz), 7.03 (1H, d, J = 10 Hz), 7.26
(2H, t, J = 9 Hz), 7.31−7.37 (4H, m), 7.49 (2H, dd, J = 9, 5 Hz). MS
(ESI) m/z = 454 (M + Na).
N-[(2S)-1-{[tert-Butyl(diphenyl)silyl]oxy}-4-hydroxybutan-2-yl]-
hydrazinecarbothioamide (9j). (6S)-N,N-Dibenzyl-2,2,10,10,11,
11-hexamethyl-3,3-diphenyl-4,9-dioxa-3,10-disiladodecan-6-amine
was synthesized from (2S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-
(dibenzylamino)butan-1-ol according to the procedure for the R-
isomer ((6R)-N,N-dibenzyl-2,2,10,10,11,11-hexamethyl-3,3-diphenyl-
4,9-dioxa-3,10-disiladodecan-6-amine) (99%). 1H NMR (400 MHz,
CDCl3): δ 0.03 (6H, s), 0.85 (9H, s), 1.05 (9H, s), 1.63−1.73
(1H, m), 1.81−1.90 (1H, m), 2.86−2.94 (1H, m), 3.51−3.58 (1H, m),
3.59−3.82 (7H, m), 7.18−7.23 (2H, m), 7.25−7.30 (4H, m),
7.31−7.46 (10H, m), 7.65−7.68 (4H, m). MS (API-ES) m/z = 639
(M + H).
(9H, s), 1.53−1.60 (2H, m), 3.01−3.05 (1H, m), 3.44 (1H, dd, J = 6,
10 Hz), 3.56 (1H, dd, J = 4, 10 Hz), 3.79−3.82 (2H, m), 7.34−7.46
(6H, m), 7.62−7.68 (4H, m). MS (API-ES) m/z = 344 (M + H).
To a solution of (3R)-3-amino-4-{[tert-butyl(diphenyl)silyl]oxy}-
butan-1-ol (1.0 g, 2.9 mmol) in CH2Cl2/H2O (1/1, 30 mL) were
added O-phenyl carbonochloridothioate (471 μL, 3.5 mmol) and
NaHCO3 (489.1 mg, 5.8 mmol) at 0 °C followed by stirring at room
temperature for 30 min. The mixture was partitioned between ethyl
acetate and water. The organic layer was separated, successively
washed with water and brine, dried over MgSO4, and evaporated
under reduced pressure to give 1.42 g of O-phenyl [(2R)-1-{[tert-
butyl(diphenyl)silyl]oxy}-4-hydroxybutan-2-yl]carbamothioate. MS
(ESI) m/z = 502 (M + Na). To a solution of the above product
(1.42 g, 3.0 mmol) in isopropyl alcohol (8.0 mL) was added hydrazine
hydrate (1.4 mL, 29.6 mmol) at room temperature, and the mixture
was stirred for 2 h. The mixture was partitioned between ethyl acetate
and water. The organic layer was separated, washed successively with
1 N NaOH solution and brine, dried over MgSO4, and evaporated
under reduced pressure to give the crude product, which was purified
(3S)-4-{[tert-Butyl(diphenyl)silyl]oxy}-3-(dibenzylamino)butan-1-ol
was synthesized from (6S)-N,N-dibenzyl-2,2,10,10,11,11-hexamethyl-3,
K
dx.doi.org/10.1021/jm3008008 | J. Med. Chem. XXXX, XXX, XXX−XXX