Potassium Phosphate, Tribasic → tert-butyl 4-(2-(7-(N-(pyrimidin-4-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2 H)-carboxylate

HRID 528544Notes

Reaction equation

HRID 528544 reaction equation
Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.B1([C:41]2[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH:42]=2)OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[N:29]1[CH:30]=[CH:31][C:26]([NH:25][S:22]([C:19]2[CH:20]=[CH:21][C:13]3[N:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=4[C:41]4[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH:42]=4)[CH2:17][CH2:16][O:15][C:14]=3[CH:18]=2)(=[O:24])=[O:23])=[N:27][CH:28]=1

Participants

5

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 4642098Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylateHCID 717121864-(2-chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide

Product 1

HCID 89761945tert-butyl 4-(2-(7-(N-(pyrimidin-4-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2 H)-carboxylate

Reagents, catalysts & solvents 1

HCID 178482226HCID 178482226, compoundCatalyst

Conditions

Temperature
115 °C

Procedure

A 5-mL glass microwave reaction vessel was charged with 4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.075 g, 0.159 mmol), (N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.123 mL, 0.398 mmol), 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (0.017 g, 0.024 mmol), potassium phosphate (0.053 mL, 0.637 mmol) and sealed with a septa cap. The reaction head space was flushed with nitrogen and dioxane (0.6 mL) and water (0.2 mL) were added. The mixture was sparged with nitrogen for 5 min. The reaction mixture was stirred and heated in a microwave reactor at 115° C. for 3 h. The reaction mixture was diluted with EtOAc and the organic layer was decanted from the aqueous layer at the bottom of the vial by pipet. The organic layer was concentrated and absorbed onto a 5 g loading cartridge and passed through a silica gel column (12 g) using a gradient from 0% to 70% EtOAc in Heptanes to provide tert-butyl 4-(2-(7-(N-(pyrimidin-4-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2 H)-carboxylate. This product was taken up in 0.5 mL DCM and 0.5 mL of trifluoroacetic acid was added and the solution was maintained at rt for 10 min. The solution was concentrated to dryness and then triturated with ether and IPA to give N-(pyrimidin-4-yl)-4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide 2,2,2-trifluoroacetate (0.005 g, 7.92 μmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.13-3.25 (m, 3 H) 3.57-3.64 (m, 3 H) 3.65-3.72 (m, 3 H) 4.24-4.40 (m, 2 H) 5.82-5.94 (m, 1 H) 6.42-6.55 (m, 1 H) 7.01-7.14 (m, 1 H) 7.24-7.38 (m, 2 H) 7.53-7.67 (m, 2 H) 7.72-7.82 (m, 1 H) 8.32-8.47 (m, 1 H) 8.63-8.72 (m, 1 H) 8.73-8.86 (m, 2 H).

Workup

  1. customThe reaction head space was flushed with nitrogen and dioxane (0.6 mL) and water (0.2 mL)
  2. additionwere added
  3. customThe mixture was sparged with nitrogen for 5 min
  4. additionThe reaction mixture was diluted with EtOAc
  5. customthe organic layer was decanted from the aqueous layer at the bottom of the vial by pipet
  6. concentrationThe organic layer was concentrated
  7. customabsorbed onto a 5 g loading cartridge

Sources & evidence

ORD record
ord-77f50a05b6a346e2aa74fcf2066687cc
Source dataset
uspto-grants-2016_05
Patent number
US09346798B2

Reaction notes

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