Potassium Phosphate, Tribasic → 2-(4-(difluoromethoxy)-N-(1-(4-(pyrimidin-5-yl)phenyl)cyclobutyl)phenylsulfonamido) acetic acid

HRID 1951749Notes

Reaction equation

HRID 1951749 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:12]([CH2:26][C:27]([OH:29])=[O:28])[S:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C(O)CCC.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]>[F:24][CH:23]([F:25])[O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:12]([CH2:26][C:27]([OH:29])=[O:28])[C:8]2([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:35]=[N:30][CH:31]=[N:32][CH:33]=4)=[CH:3][CH:4]=3)[CH2:11][CH2:10][CH2:9]2)(=[O:15])=[O:14])=[CH:17][CH:18]=1

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 53373333HCID 53373333, compound

Product 1

HCID 533734692-(4-(difluoromethoxy)-N-(1-(4-(pyrimidin-5-yl)phenyl)cyclobutyl)phenylsulfonamido) acetic acidYield 16%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 2631-ButanolSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 2-(N-(1-(4-bromophenyl)cyclobutyl)-4-(difluoromethoxy)phenylsulfonamido) acetic acid (20 mg, 0.041 mmol) in n-butanol (2 mL) was added pyrimidin-5-ylboronic acid (7.58 mg, 0.061 mmol), followed by potassium phosphate (17.32 mg, 0.082 mmol) and Pd2 dba3 (2.345 mg, 4.08 μmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (3.89 mg, 8.16 μmol). The mixture was degassed and flushed with argon and then shook at 100° C. for 3 h. The resultant mixture was filtered and the filtrate purified using Shimadzu prep HPLC employing an ACN/water and 0.1% TFA buffer with a Xterra column, 30 mm×100 mm, Gradient over 15 min; Starting conc: 10% B; Ending conc: 100% B. The solvent was removed in vacuo to give 3.3 mg (16% yield, 95% pure) of the title compound as a light gray solid. ESI-MS m/z 490 (MH+), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.67 (q, J=10.07 Hz, 1H), 1.78-1.92 (m, 1H), 2.63 (t, J=8.70 Hz, 2H), 2.86 (d, J=2.44 Hz, 2H), 4.21 (s, 3H), 6.58 (t, J=75.00 Hz, 1H), 7.09 (d, J=8.55 Hz, 2H), 7.54 (d, J=8.24 Hz, 2H), 7.67 (dd, J=14.80, 8.70 Hz, 4H), 9.10 (s, 2H), 9.31 (s, 1 H).

Workup

  1. customThe mixture was degassed
  2. customflushed with argon
  3. filtrationThe resultant mixture was filtered
  4. customthe filtrate purified
  5. customover 15 min
  6. customThe solvent was removed in vacuo

Sources & evidence

ORD record
ord-eaac1630d56f458e98af268a5c39d972
Source dataset
uspto-grants-2013_03
Patent number
US08404741B2

Reaction notes

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