Potassium Phosphate, Tribasic → Methyl 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxylate

HRID 1499534Notes

Reaction equation

HRID 1499534 reaction equation
Br[C:2]1[S:3][C:4]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[F:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([F:28])[C:21]=1B(O)O.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.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[C:15]([O:14][C:12]([NH:11][C:4]1[S:3][C:2]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:20]=2[F:19])=[N:6][C:5]=1[C:7]([O:9][CH3:10])=[O:8])=[O:13])([CH3:18])([CH3:17])[CH3:16]

Participants

5

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27831312,6-Difluoro-3-methoxybenzeneboronic acid2×HCID 86726650Methyl 2-bromo-5-{[(tert-butoxy)carbonyl]amino}-1,3-thiazole-4-carboxylate

Product 1

HCID 86726766Methyl 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxylateYield 39.2%

Reagents, catalysts & solvents 1

HCID 178439015HCID 178439015, compoundCatalyst2×

Conditions

Temperature
40 °C

Procedure

To a vial, methyl 2-bromo-5-[(tert-butoxycarbonyl)amino]-1,3-thiazole-4-carboxylate (from Example 1 step 3, 104 mg, 0.309 mmol), (2,6-difluoro-3-methoxyphenyl)boronic acid (from Aldrich, 207 mg, 1.10 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (37.5 mg, 0.0477 mmol), and potassium phosphate (276 mg, 1.30 mmol) were added. The vial was sealed with a PTFE screw-cap then purged with nitrogen three times. 1,4-Dioxane (4.0 mL) was added, followed by deoxygenated water (2.0 mL). The mixture was heated at 40° C. for 1 h. The reaction mixture was allowed to cool to room temperature. Additional (2,6-difluoro-3-methoxyphenyl)boronic acid (262 mg, 1.39 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (40.2 mg, 0.0511 mmol) were added. The mixture was stirred at room temperature for 15 h. The mixture was filtered through a pad of diatomaceous earth (eluted with EtOAc) and concentrated. The residue was purified on silica gel (eluting with 0-50% EtOAc in hexanes) to give the sub-title compound as a white solid (48.5 mg, 39%). LCMS calc. for C17H19F2N2O5S (M+H)+: m/z 401.1. Found: 401.1.

Workup

  1. customscrew-cap
  2. customthen purged with nitrogen three times
  3. addition1,4-Dioxane (4.0 mL) was added
  4. customby deoxygenated water (2.0 mL)
  5. temperatureto cool to room temperature
  6. filtrationThe mixture was filtered through a pad of diatomaceous earth (eluted with EtOAc)
  7. concentrationconcentrated
  8. customThe residue was purified on silica gel (eluting with 0-50% EtOAc in hexanes)

Sources & evidence

ORD record
ord-d1deb165980e4be589f0c632552cb42f
Source dataset
uspto-grants-2015_12
Patent number
US09200004B2

Reaction notes

Loading…