Hydrogen Peroxide → dibenzyl 1-((4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutyl phosphate

HRID 1668308Notes

Reaction equation

HRID 1668308 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]5([OH:32])[CH2:29][C:28]([F:31])([F:30])[CH2:27]5)=[C:20]([O:33][CH3:34])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)[P:39]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(C)C.N1C=NC=N1.[OH:64]O>ClCCCl.C(Cl)Cl>[P:39]([O:32][C:26]1([CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([N:13]3[C:14](=[O:17])[C:15]4[S:16][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)=[CH:9][C:10]=4[N:11]=[CH:12]3)=[CH:19][C:20]=2[O:33][CH3:34])[CH2:27][C:28]([F:30])([F:31])[CH2:29]1)([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([O:48][CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)=[O:64]

Participants

7

Reactant 4

HCID 784Hydrogen PeroxideHCID 92571H-1,2,4-TriazoleHCID 196621Bis(benzyloxy)(diisopropylamino)phosphineHCID 57988809HCID 57988809, compound

Product 1

HCID 44539264dibenzyl 1-((4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutyl phosphateYield 85%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 6-(4-chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphen-yl)thieno[3,2-d]pyrimidin-4(3H)-one (1.01 g, 2.000 mmol) described in Example 2, dibenzyl diisopropylphosphoramidite (2.073 g, 6.00 mmol) and 1H-1,2,4-triazole (0.414 g, 6.00 mmol) in 1,2-dichloroethane (30 mL) was heated at reflux temperature. After 1 h, the mixture was cooled to RT; whereupon, 2 mL 50% H2O2 was added. After stirring for 15 minutes at RT, the mixture was diluted with CH2Cl2, washed sequentially with water, 5% aq. sodium thiosulfate and water. The organic layer was dried over MgSO4, concentrated and the crude product was subjected to flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient) to afford dibenzyl 1-((4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutyl phosphate (1.3 g, 1.699 mmol, 85% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 8.10 (1 H, s), 7.66 (2 H, d, J=8.56 Hz), 7.54 (1 H, s), 7.45 (2H, d, J=8.56 Hz), 7.28-7.40 (10 H, m), 6.95 (1 H, d, J=8.56 Hz), 6.92 (1 H, d, J=2.27 Hz), 6.87 (1 H, dd, J=8.31, 2.27 Hz), 5.08 (4 H, dd, J=7.81, 1.26 Hz), 4.32 (2 H, s), 3.76 (3 H, s), 2.89-3.30 (4 H, m).

Workup

  1. temperaturewas heated
  2. temperatureat reflux temperature
  3. washwashed sequentially with water, 5% aq. sodium thiosulfate and water
  4. dry with materialThe organic layer was dried over MgSO4
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-7086e753444f4f58bf0814abd34bad1d
Source dataset
uspto-grants-2011_08
Patent number
US07989433B2

Reaction notes

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