Methanol → tert-Butyl (2S)-2-[(1E)-3-{4-[(3-chloro-4-fluorophenyl)amino]-5,8-dihydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-7(6H)-yl}-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate

HRID 38516Notes

Reaction equation

HRID 38516 reaction equation
C(OP([CH2:9][C:10]([N:12]1[CH2:33][CH2:32][C:15]2[C:16]3[C:21]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=4)=[N:20][CH:19]=[N:18][C:17]=3[S:31][C:14]=2[CH2:13]1)=[O:11])(=O)OCC)C.[H-].[Na+].[CH:36]([C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=O.CO>C1COCC1>[Cl:30][C:25]1[CH:24]=[C:23]([NH:22][C:21]2[C:16]3[C:15]4[CH2:32][CH2:33][N:12]([C:10](=[O:11])/[CH:9]=[CH:36]/[C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5[C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:13][C:14]=4[S:31][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:28]=[CH:27][C:26]=1[F:29]

Participants

6

Reactant 4

HCID 887MethanolHCID 24758Sodium hydrideHCID 2734674tert-butyl (2S)-2-formylpyrrolidine-1-carboxylateHCID 58116908Diethyl(2-{4-[(3-chloro-4-fluorophenyl)amino]-5,8-dihydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-7(6H)-yl}-2-oxoethyl)phosphonate

Product 1

HCID 58116987tert-Butyl (2S)-2-[(1E)-3-{4-[(3-chloro-4-fluorophenyl)amino]-5,8-dihydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-7(6H)-yl}-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of diethyl(2-{4-[(3-chloro-4-fluorophenyl)amino]-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]-pyrimidin-7(6H)-yl}-2-oxoethyl)phosphonate from Example 13A (644 mg, 1.26 mmol) in THF (2.5 mL) was cooled to −78° C. Sodium hydride (60% in mineral oil, 50 mg, 1.26 mmol) was added, and the mixture was stirred for 15 min. Subsequently, a solution of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (250 mg, 1.26 mmol) in THF (2.5 mL) was added dropwise. The mixture was slowly warmed to rt and stirred overnight. Methanol was added, and the solvent was removed in vacuo. The crude product was purified by preparative HPLC, and the title compound crystallized from PE/MTBE to yield 397 mg (56%).

Workup

  1. stirringstirred overnight
  2. customthe solvent was removed in vacuo
  3. customThe crude product was purified by preparative HPLC
  4. customthe title compound crystallized from PE/MTBE
  5. customto yield 397 mg (56%)

Sources & evidence

ORD record
ord-4b573157deaf400ab2f4ec5e8393e808
Source dataset
uspto-grants-2013_09
Patent number
US08524722B2

Reaction notes

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