Sodium Carbonate → 2-Cyclopropyl-5-(2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl)phenyl)-4H-thieno[3,2-c]pyrrol-6(5H)-one

HRID 1772126Notes

Reaction equation

HRID 1772126 reaction equation
C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:16][C:15]3[CH:17]=[C:18]([CH:20]4[CH2:22][CH2:21]4)[S:19][C:14]=3[C:13]2=[O:23])=[CH:10][CH:9]=[CH:8][C:7]=1Br)(=O)C.[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][N:45]=[CH:44][N:43]=2)[C:27]1=[O:48].C(=O)([O-])[O-].[Na+].[Na+].O.[OH-].[Li+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CO.O1CCOCC1.CN(C=O)C>[CH:20]1([C:18]2[S:19][C:14]3[C:13](=[O:23])[N:12]([C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:30]5[CH:29]=[C:28]([NH:41][C:42]6[CH:47]=[CH:46][N:45]=[CH:44][N:43]=6)[C:27](=[O:48])[N:26]([CH3:25])[CH:31]=5)[C:6]=4[CH2:5][OH:4])[CH2:16][C:15]=3[CH:17]=2)[CH2:22][CH2:21]1

Participants

10

Reactant 4

HCID 10340Sodium CarbonateHCID 168937Lithium hydroxide, monohydrateHCID 580438621-methyl-3-(pyrimidin-4-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneHCID 666358662-Bromo-6-(2-cyclopropyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)benzyl Acetate

Product 1

HCID 569286572-Cyclopropyl-5-(2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl)phenyl)-4H-thieno[3,2-c]pyrrol-6(5H)-oneYield 22%

Reagents, catalysts & solvents 5

HCID 178418397HCID 178418397, compoundCatalystHCID 887MethanolSolventHCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Procedure

A 50-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 116h (124 mg, 0.300 mmol), 116a (100 mg, 0.300 mmol), sodium carbonate (95 mg, 0.900 mmol), DMF (2.5 mL), water (1.2 mL) and 1,4-dioxane (4 mL). After bubbling nitrogen through the resulting suspension for 30 min, tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.003 mmol) was added, and the reaction mixture was heated at reflux for 14 h. After this time, the mixture was cooled to room temperature, and methanol (2 mL), water (2 mL) and lithium hydroxide monohydrate (42 mg, 1.00 mmol) were added. The mixture was stirred for 4 h at room temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate (150 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with a 20% (v/v) solution of methanol in methylene chloride (3×150 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 10% methanol/methylene chloride) to afford a 22% yield (32 mg) of 116 as an off-white solid: mp 140-141° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.70 (d, 1H, J=1.1 Hz), 8.64 (s, 1H), 8.29 (d, 1H, J=5.8 Hz), 7.52 (d, 1H, J=2.5 Hz), 7.48 (m, 1H), 7.43 (m, 1H), 7.38 (m, 1H), 7.31 (dd, 1H, J=5.9, 1.1 Hz), 7.04 (s, 1H), 4.91 (t, 1H, J=5.0 Hz), 4.83 (s, 2H), 4.34 (d, 2H, J=5.0 Hz), 3.60 (s, 3H), 2.29 (m, 1H), 1.12 (m, 2H), 0.82 (m, 2H); MS (ESI+) m/z 486.2 (M+H).

Workup

  1. customA 50-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet
  2. customAfter bubbling nitrogen through the resulting suspension for 30 min
  3. temperaturethe reaction mixture was heated
  4. temperatureat reflux for 14 h
  5. concentrationconcentrated in vacuo
  6. customThe residue was partitioned between ethyl acetate (150 mL) and water (30 mL)
  7. customThe organic layer was separated
  8. extractionthe aqueous layer was extracted with a 20% (v/v) solution of methanol in methylene chloride (3×150 mL)
  9. dry with materialThe combined organic layers were dried over sodium sulfate
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified by column chromatography (silica, 0% to 10% methanol/methylene chloride)

Sources & evidence

ORD record
ord-02725c6af92f4aa6a0583fb191047617
Source dataset
uspto-grants-2016_02
Patent number
US09249123B2

Reaction notes

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