反応 #1755492

反応方程式

HCl

(S)-1-((4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutyl 2-(tert-butoxycarbonylamino)-propanoate

HCl

MeOH

→

(S)-1-((4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutyl 2-aminopropanoate

収率 83.0%

溶媒

CH2Cl2

TFA CH2Cl2

反応条件

後処理

1. 1
   その他After removal of the volatiles under vacuum
2. 2
   その他the crude product was purified by prep-HPLC (PHENOMENEX® Axia, Luna 5 micron 30×100 mm, flow rate=40 ml/min., gradient 0% A to 100% B in 10 min.
3. 3
   濃縮The desired fractions were concentrated
4. 4
   その他dried under high vacao
5. 5
   workup.ADDITIONto addition of aq. saturated NaHCO3 (6 ml) and extraction with CH2Cl2 (2×10 ml)
6. 6
   乾燥The combined CH2Cl2 layers were dried over Na2SO4
7. 7
   濃縮concentrated
8. 8
   濃縮The HCl salt was then concentrated
9. 9
   その他was dried under high vacuum

実験手順

A mixture of (S)-1-((4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutyl 2-(tert-butoxycarbonylamino)-propanoate from Part A (59 mg, 0.087 mmol) in 25% TFA/CH2Cl2 (4 mL) was stirred at RT for 30 min. After removal of the volatiles under vacuum, the crude product was purified by prep-HPLC (PHENOMENEX® Axia, Luna 5 micron 30×100 mm, flow rate=40 ml/min., gradient 0% A to 100% B in 10 min., A=90% H2O/10% MeOH/0.1% TFA, B=10% H2O/90% MeOH/0.1% TFA). The desired fractions were concentrated and dried under high vacao prior to addition of aq. saturated NaHCO3 (6 ml) and extraction with CH2Cl2 (2×10 ml). The combined CH2Cl2 layers were dried over Na2SO4 and concentrated prior to conversion of the free base (42 mg, 0.073 mmol) to the HCl salt by dissolution in CH2Cl2 (2 ml) and addition of 1.0 M HCl (0.079 mL, 0.079 mmol)/MeOH (2 ml) at −30° C. The HCl salt was then concentrated and was dried under high vacuum to yield (S)-1-((4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutyl 2-aminopropanoate (41.94 mg, 0.073 mmol, 83% yield) as white solid. 1H NMR (400 MHz, MeOD) δ ppm 8.27 (1H, s), 7.73 (2 H, d)3 7.63 (1 H, s), 7.43 (2 H, d), 7.02-7.15 (2 H, m), 6.94 (1 H, dd, J=8.56, 2.52 Hz), 4.41 (2 H, d, J=3.02 Hz), 3.91-4.02 (1 H, m), 3.78 (3 H, s), 2.87-3.18 (4 H, m), 1.44 (3 H, d, J=7.30 Hz). LC-MS: 2.33 min 576 (M+H). Luna 5 u C18 30×4.6 mm ID, flow rate=4 ml/min., gradient=0% A to 100% B in 2 min., A=90% H2O/10% MeOH/0.1% TFA, B=10% H2O/90% MeOH/0.1% TFA).

出典