Hydrochloric Acid → HCID 71711176, compound

HRID 528529Notes

Reaction equation

HRID 528529 reaction equation
Br[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[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.[CH3:31][N:32]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=[N:33]1.C([O-])([O-])=O.[K+].[K+].Cl>O1CCOCC1.O.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>[CH3:31][N:32]1[C:36]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=2[N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[C:19]([S:22]([NH:25][C:26]4[S:30][N:29]=[CH:28][N:27]=4)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]2=3)=[CH:35][CH:34]=[N:33]1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 49129081-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 71711761HCID 71711761, compound

Product 1

HCID 71711176HCID 71711176, compoundYield 17.7%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

A microwave vial was charged with INTERMEDIATE D (0.100 g, 0.192 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Sigma Aldrich, St. Louis, Mo., 0.060 g, 0.288 mmol), tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol), and K2CO3 (0.133 g, 0.959 mmol). The solids were diluted with dioxane (1.279 mL) and water (0.639 mL), and the reaction was heated under microwave irradiation at 100° C. for 60 minutes (starting material remained, but the reaction was moved forward). The reaction mixture was diluted with water, and washed with DCM. Equal partitioning between both layers was observed, so the organic and aqueous layers were combined and concentrated. The material was taken up in methanol, and acidified with HCl (1N) (3.84 mL, 3.84 mmol), and then re-concentrated under a vacuum. The solids were taken up in DCM, and washed with water. The organic layer was then dried using a phase separator, concentrated under a vacuum and purified by reverse-phase preparative HPLC (Column: Phenomenex 150×30 mm, 5 micron, C18 column; 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 20 min (Phenomenex, Torrance, Calif.)) to provide 4-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.018 g, 0.034 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.66 (s, 3 H) 4.14 (br. s., 2 H) 6.31 (d, J=1.66 Hz, 1 H) 6.68 (d, J=8.51 Hz, 1 H) 7.07-7.16 (m, 2 H) 7.42 (d, J=1.76 Hz, 1 H) 7.72 (d, J=8.41 Hz, 1 H) 7.86 (s, 1 H) 7.90 (d, J=8.61 Hz, 1 H) 8.44 (s, 1 H). m/z (ESI) 523.0 (M+H)+.

Workup

  1. washwashed with DCM
  2. customEqual partitioning between both layers
  3. concentrationconcentrated
  4. concentrationre-concentrated under a vacuum
  5. washwashed with water
  6. customThe organic layer was then dried
  7. concentrationconcentrated under a vacuum
  8. custompurified by reverse-phase preparative HPLC (Column: Phenomenex 150×30 mm, 5 micron, C18 column; 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 20 min (Phenomenex, Torrance, Calif.))

Sources & evidence

ORD record
ord-acc5ccad0a8c495785d1c367e24f5155
Source dataset
uspto-grants-2016_05
Patent number
US09346798B2

Reaction notes

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