Potassium Carbonate → N-(6-((R)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)ethoxy)-2-(4-fluorobenzyl-thio)pyrimidin-4-yl)-3-methylazetidine-1-sulfonamide

HRID 1027862Notes

Reaction equation

HRID 1027862 reaction equation
Cl[C:2]1[CH:7]=[C:6]([O:8][C@@H:9]([C@@H:11]2[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]2)[CH3:10])[N:5]=[C:4]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:3]=1.[CH3:27][CH:28]1[CH2:31][N:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH2:29]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:16][C:13]1([CH3:17])[O:12][C@H:11]([C@H:9]([O:8][C:6]2[N:5]=[C:4]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:3]=[C:2]([NH:35][S:32]([N:30]3[CH2:31][CH:28]([CH3:27])[CH2:29]3)(=[O:34])=[O:33])[CH:7]=2)[CH3:10])[CH2:15][O:14]1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 714875803-Methylazetidine-1-sulfonamide2×HCID 866766774-Chloro-6-((R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)-2-(4-fluorobenzylthio)pyrimidine

Product 1

HCID 71231083N-(6-((R)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)ethoxy)-2-(4-fluorobenzyl-thio)pyrimidin-4-yl)-3-methylazetidine-1-sulfonamideYield 81.1%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of the sub-title product of step (iii) (94 g) dissolved in dioxane (700 mL) was treated with 3-methylazetidine-1-sulfonamide (Intermediate B) (42.5 g), potassium carbonate (65.1 g), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (11.2 g) and tris(dibenzylideneacetone)dipalladium(0) (10.8 g) under nitrogen. The resulting mixture was stirred at 100° C. for 60 minutes. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL). The organics were dried over magnesium sulfate, filtered and evaporated in vacuo to afford crude product. The crude product was purified by flash silica chromatography with elution 30% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the sub-title product (98 g) as a red oil.

Workup

  1. extractionextracted with ethyl acetate (500 mL)
  2. dry with materialThe organics were dried over magnesium sulfate
  3. filtrationfiltered
  4. customevaporated in vacuo
  5. customto afford crude product
  6. customThe crude product was purified by flash silica chromatography with elution 30% ethyl acetate in isohexane
  7. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-04fc41c38b27445b8f8bad0b8c8a43d2
Source dataset
uspto-grants-2014_05
Patent number
US08735413B2

Reaction notes

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