Diisopropylcarbodiimide → tert-Butyl 1-(4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-2-methylpropan-2-yl Malonate

HRID 1916372

Reaction equation

HRID 1916372 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])=[C:20]([O:30][CH3:31])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[C:32]([O:36][C:37](=[O:42])[CH2:38][C:39](O)=[O:40])([CH3:35])([CH3:34])[CH3:33].C(N=C=NC(C)C)(C)C>C(Cl)Cl>[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:42])[CH2:38][C:39]([O:29][C:26]([CH3:28])([CH3:27])[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([N:13]2[C:14](=[O:17])[C:15]3[S:16][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:9][C:10]=3[N:11]=[CH:12]2)=[CH:19][C:20]=1[O:30][CH3:31])=[O:40]

Participants

5

Reactant 3

HCID 12734Diisopropylcarbodiimide2×HCID 5458533-(Tert-butoxy)-3-oxopropanoic acid2×HCID 167186196-(4-chlorophenyl)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one

Product 1

HCID 58858121tert-Butyl 1-(4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-2-methylpropan-2-yl MalonateYield 79.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A suspension of 6-(4-chlorophenyl)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxy-phenyl)-thieno[3,2-d]pyrimidin-4(3H)-one (100 mg; 0.219 mmol) (Example 82), 3-tert-butoxy-3-oxopropanoic acid (83 uL; 0.538 mmol), diisopropylcarbodiimide (83 uL; 0.538 mmol) and 4-N,N-dimethylaminopyridine (27 mg; 0.219 mmol) in 1 mL of CH2Cl2 was stirred at rt for 17 h. Additional 3-tert-butoxy-3-oxopropanoic acid (83 uL; 0.538 mmol) and diisopropylcarbodiimide (83 uL; 0.538 mmol) were added and the suspension stirred at rt for 3 h. The suspension was diluted with CH2Cl2, filtered and the filtrate washed with 1N HCl, saturated aq. NaHCO3 and brine, dried over anhydrous MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, Hexanes/EtOAc; 100:0 to 1:1 gradient) to afford 104 mg (79%) of the title compound as a beige foam. 1H NMR (CDCl3) δ 1.47 (s, 9H), 1.64 (s, 6H), 3.23 (s, 2H), 3.87 (s, 3H), 4.20 (s, 2H), 6.91 (dd, J=8.24 Hz, 2.20 Hz, 1H), 6.95 (d, J=2.20 Hz, 1H), 7.02 (d, J=8.24 Hz, 1H), 7.44 (d, J=8.24 Hz, 2H), 7.53 (s, 1H), 7.66 (d, J=8.80 Hz, 2H), 8.13 (s, 1H); 13C NMR (CDCl3) δ 23.37, 27.92, 44.04, 56.23, 74.44, 81.83, 82.01, 111.53, 114.75, 119.20, 120.87, 123.22, 127.65, 129.47, 130.51, 131.54, 135.67, 148.19, 149.30, 150.49, 151.63, 156.79, 157.40, 165.85, 166.20; HPLC (Method #1) 4.46 min retention time, (97%); MS (ES): m/z 599 [M+H]+.

Workup

  1. stirringthe suspension stirred at rt for 3 h
  2. filtrationfiltered
  3. washthe filtrate washed with 1N HCl, saturated aq. NaHCO3 and brine
  4. dry with materialdried over anhydrous MgSO4
  5. filtrationfiltered
  6. concentrationthe filtrate concentrated under reduced pressure
  7. customThe residue was purified by flash chromatography (silica gel, Hexanes/EtOAc; 100:0 to 1:1 gradient)

Sources & evidence

ORD record
ord-01b0403561e8421b83480f373dbbb5c2
Source dataset
uspto-grants-2013_12
Patent number
US08618115B2

Linked notes

Loading…