Cesium carbonate → Methyl 3'-[4-(hydroxymethyl)-2-(methylsulfanyl)pyrimidin-5-yl]-4'-methoxy-2-methylbiphenyl-4-carboxylate

HRID 1508561Notes

Reaction equation

HRID 1508561 reaction equation
Br[C:2]1[C:3]([CH2:10][OH:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:21]=2[CH3:30])=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>O.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>[OH:11][CH2:10][C:3]1[C:2]([C:15]2[CH:16]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:21]=3[CH3:30])[CH:18]=[CH:19][C:14]=2[O:13][CH3:12])=[CH:7][N:6]=[C:5]([S:8][CH3:9])[N:4]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 66524860(5-Bromo-2-(methylthio)pyrimidin-4-yl)methanolHCID 67513148[2-Methoxy-5-[4-(methoxycarbonyl)-2-methylphenyl]phenyl]boronic acid2×

Product 1

HCID 67514255Methyl 3'-[4-(hydroxymethyl)-2-(methylsulfanyl)pyrimidin-5-yl]-4'-methoxy-2-methylbiphenyl-4-carboxylate

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×

Conditions

Temperature
100 °C

Procedure

Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed [5-bromo-2-(methylsulfanyl)pyrimidin-4-yl]methanol (130 g, 560 mmol, 1.00 equiv), [2-methoxy-5-[4-(methoxycarbonyl)-2-methylphenyl]phenyl]boronic acid (87.5 g, 0.5 equiv), Pd(PPh3)4 (32.3, 28 mmol, 0.05 equiv), Cs2CO3 (365.1 g, 2.00 equiv), water (300 mL), 1,4-dioxane (1200 mL). The resulting solution was stirred for 5 hour at 100° C., then added 2nd batch of [2-methoxy-5-[4-(methoxycarbonyl)-2-methylphenyl]phenyl]boronic acid (50 g, 0.3 equiv). The last batch (37 g, 0.2 equiv) was added after 2 hours. The resulting solution was stirred for 3 h at 100° C. The reaction mixture was cooled to room temperature and diluted with 1000 mL of water. The resulting solution was extracted with 2×1000 mL of ethyl acetate. The organic layers were combined, washed with 1×1000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:8). This resulted in 81 g (35.7%) of methyl 4-[3-[4-(hydroxymethyl)-2-(methylsulfanyl)pyrimidin-5-yl]-4-methoxyphenyl]-3-methylbenzoate as a yellow solid. LCMS (ES, m/z): 411 [M+H]+. 1H NMR (CDCl3, 300 MHz): δ 8.398 (1H, s), 7.976 (1H, s), 7.916 (2H, d), 7.410 (1H, d), 7.284-7.325 (1H, m), 7.066-7.114 (2H, m), 4.583 (2H, s), 3.954 (3H, s), 3.853 (3H, s), 2.663 (3H, s).

Workup

  1. customInto a 3000-mL 4-necked round-bottom flask purged
  2. temperaturemaintained with an inert atmosphere of nitrogen
  3. additionThe last batch (37 g, 0.2 equiv) was added after 2 hours
  4. stirringThe resulting solution was stirred for 3 h at 100° C
  5. temperatureThe reaction mixture was cooled to room temperature
  6. extractionThe resulting solution was extracted with 2×1000 mL of ethyl acetate
  7. washwashed with 1×1000 mL of brine
  8. dry with materialdried over anhydrous sodium sulfate
  9. concentrationconcentrated under vacuum
  10. washeluted with ethyl acetate/petroleum ether (1:8)
  11. customThis resulted in 81 g (35.7%) of methyl 4-[3-[4-(hydroxymethyl)-2-(methylsulfanyl)pyrimidin-5-yl]-4-methoxyphenyl]-3-methylbenzoate as a yellow solid

Sources & evidence

ORD record
ord-87339a454d0c48f7a54d8286c836607d
Source dataset
uspto-grants-2015_12
Patent number
US09221834B2

Reaction notes

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