Potassium Carbonate → tert-butyl 4-(5-chloro-2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

HRID 528549Notes

Reaction equation

HRID 528549 reaction equation
Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][O:12][C:11]2[CH:15]=[C:16]([S:19]([N:22]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:23]3[S:24][CH:25]=[CH:26][N:27]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:10]1=2.B1([C:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH:47]=2)OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[CH2:14][CH2:13][O:12][C:11]3[CH:15]=[C:16]([S:19](=[O:21])(=[O:20])[N:22]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)[C:23]4[S:24][CH:25]=[CH:26][N:27]=4)[CH:17]=[CH:18][C:10]2=3)=[C:2]([C:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH:47]=2)[CH:7]=1

Participants

8

Reactant 3

HCID 11430Potassium CarbonateHCID 4642098Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylateHCID 897613564-(2-bromo-4-chlorophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide

Product 1

HCID 89762066tert-butyl 4-(5-chloro-2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A microwave vial was charged with 4-(2-bromo-4-chlorophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.576 g, 0.949 mmol), (N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.293 g, 0.949 mmol), tetrakis(triphenylphosphine)palladium(0) (0.110 g, 0.095 mmol), and K2CO3 (0.656 g, 4.75 mmol). The solids were diluted with dioxane (6.33 mL) and water (3.16 mL), and the reaction was heated under microwave irradiation at 100° C. for 30 minutes. The reaction was diluted with water and DCM, and the layers separated. The aqueous was washed once more with DCM, and the organics were combined and dried using a phase separator to yield material. The material was then further purified via silica gel MPLC eluting with 0 to 100% ethyl acetate in heptane to yield tert-butyl 4-(5-chloro-2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3 H)-yl)phenyl)-5,6-dihydropyridine-1(2 H)-carboxylate as a red oil. A portion of material (117 mg) was diluted with 1.00 mL of DCM, and TFA (1.00 mL) and the reaction was stirred at RT for 5 minutes. The material was concentrated under a vacuum and purified via HPLC to yield 4-(4-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide 2,2,2-trifluoroacetate (0.073 g, 0.121 mmol, 12.76% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30-2.43 (m, 1 H) 2.54 (m, J=0.60 Hz, 1 H) 3.15-3.23 (m, 2 H) 3.52 (m, J=3.30 Hz, 2 H) 3.63-3.70 (m, 2 H) 4.25-4.32 (m, 2 H) 5.82 (br. s., 1 H) 6.33 (d, J=8.31 Hz, 1 H) 6.79 (d, J=4.50 Hz, 1 H) 7.09-7.15 (m, 2 H) 7.23 (d, J=4.60 Hz, 1 H) 7.36-7.41 (m, 2 H) 7.45-7.50 (m, 1 H) 8.79 (br. s., 2 H) 12.55 (br. s., 1H). m/z (ESI) 489.0 (M+H)+.

Workup

  1. customthe layers separated
  2. washThe aqueous was washed once more with DCM
  3. customdried
  4. customto yield material
  5. customThe material was then further purified via silica gel MPLC
  6. washeluting with 0 to 100% ethyl acetate in heptane

Sources & evidence

ORD record
ord-187055433e5944029d4d5ab6017973fd
Source dataset
uspto-grants-2016_05
Patent number
US09346798B2

Reaction notes

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