Hydrochloric Acid → HCID 71711177, compound

HRID 528530Notes

Reaction equation

HRID 528530 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.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][N:42](C(OC(C)(C)C)=O)[CH:43]=2)O1.C([O-])([O-])=O.[K+].[K+].Cl>O1CCOCC1.O.CO.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>[NH:41]1[CH:40]=[C:39]([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:43]=[N:42]1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 16217654tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylateHCID 71711761HCID 71711761, compound

Product 1

HCID 71711177HCID 71711177, compoundYield 22.4%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A microwave vial was charged with INTERMEDIATE D (0.100 g, 0.192 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (Sigma-Aldrich, St. Louis, Mo., 0.113 g, 0.384 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 30 minutes. The reaction mixture was lyophilized overnight and the material was then taken up in methanol, and acidified with HCl (1N) (3.84 mL, 3.84 mmol). The mixture was concentrated onto silica gel, and purified via silica gwel MPLC (Biotage Isolera One; PuriFlash HP, 15μ, 25 g), eluting with 0 to 100% ethyl acetate in heptane to yield slightly impure material. The material was loaded onto a 500 mg SCX column and the product was eluted (with impurity) in the ammonia wash. The resulting material was then 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) to provide 4-(2-(1H-pyrazol-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.022 g, 0.043 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.47 (m, J=12.80 Hz, 2H) 4.28-4.37 (m, 2H) 6.25 (d, J=8.51 Hz, 1 H) 7.08 (dd, J=8.56, 2.20 Hz, 1 H) 7.14 (d, J=2.15 Hz, 1 H) 7.59-7.64 (m, 1 H) 7.65-7.70 (m, 1 H) 7.96 (s, 2 H) 8.02 (d, J=1.37 Hz, 1 H) 8.43 (s, 1 H). m/z (ESI) 509.0 (M+H)+.

Workup

  1. concentrationThe mixture was concentrated onto silica gel
  2. custompurified via silica gwel MPLC (Biotage Isolera One; PuriFlash HP, 15μ, 25 g)
  3. washeluting with 0 to 100% ethyl acetate in heptane
  4. customto yield slightly impure material
  5. washthe product was eluted (with impurity) in the ammonia
  6. washwash
  7. customThe resulting material was then 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)

Sources & evidence

ORD record
ord-adb17ce406d144acae7e5d83aa3b5a17
Source dataset
uspto-grants-2016_05
Patent number
US09346798B2

Reaction notes

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