Hydrochloric Acid → HCID 57942362, compound

HRID 419157Notes

Reaction equation

HRID 419157 reaction equation
Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[C:27](=[O:29])=[O:28].CC#N.C([Mg]Cl)(C)C.[Cl:38][C:39]1[C:50](C(N(OC)C)=O)=[CH:49][CH:48]=[CH:47][C:40]=1[C:41](N(OC)C)=[O:42].[NH4+].[Cl-].Cl.O1CCOCC1>O.CCOC(C)=O.C1COCC1>[Cl:38][C:39]1[C:40]([C:41]([C:2]2[C:7]([NH:8][S:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:20])([F:22])[F:21])[CH:13]=3)(=[O:10])=[O:11])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=2)=[O:42])=[CH:47][CH:48]=[CH:49][C:50]=1[C:27]([OH:29])=[O:28]

Participants

11

Reactant 7

HCID 313Hydrochloric AcidHCID 25517Ammonium ChlorideHCID 312751,4-DioxaneHCID 57942086N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxvmethyl-3-trifluoromethyl-benzenesulfonamideHCID 57942574HCID 57942574, compoundHCID 86587134Acetonitrile dry iceHCID 178418918HCID 178418918, compound

Product 1

HCID 57942362HCID 57942362, compoundYield 12%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To an oven-dried vial containing N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl benzenesulfonamide (316 mg, 0.64 mmol) was added anhydrous THF (2 mL) under positive nitrogen pressure. The vial was cooled to −40° C. (dry ice-MeCN) and a 2.0 M solution of i-PrMgCl in THF (0.80 mL, 1.6 mmol) was added. After 5 min, the solution was warmed to 0° C. After a further 30 min, 2-chloro-N,N′-dimethoxy-N,N′-dimethyl-isophthalamide (320 mg, 1.11 mmol) was added, and the reaction mixture was warmed to room temperature over 1 h. The solution was maintained at room temperature for 24 h, after which time it was treated with saturated aqueous NH4Cl (10 mL), and poured into EtOAc (50 mL). The organic phase was washed with saturated aqueous NaCl (2×25 mL) and dried over MgSO4. The volatiles were removed in vacuo, and the residue purified by flash chromatography on 15 g of silica gel (0→75% EtOAc-Hexanes). To the resulting product were added a 4.0 N solution of HCl in dioxane (2.0 mL, 8.0 mmol) and H2O (0.5 mL). The reaction mixture was heated to 80° C. for 2 h, then cooled to room temperature. The volatiles were removed in vacuo. The product was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions lyophilized to afford the title compound (44 mg, 12% yield): HPLC retention time=2.76 minutes. MS (ES) [M−H]− expected 551.0, found 550.9. 1H NMR (400 MHz, CDCl3) δ 11.00 (s, 1H), 8.18-8.21 (m, 3H), 8.08 (dd, J=2.0, 7.6 Hz, 1H), 8.01 (dd, J=2.4, 8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.40-7.48 (m, 2H).

Workup

  1. waitAfter a further 30 min
  2. temperaturethe reaction mixture was warmed to room temperature over 1 h
  3. temperatureThe solution was maintained at room temperature for 24 h
  4. washThe organic phase was washed with saturated aqueous NaCl (2×25 mL)
  5. dry with materialdried over MgSO4
  6. customThe volatiles were removed in vacuo
  7. customthe residue purified by flash chromatography on 15 g of silica gel (0→75% EtOAc-Hexanes)
  8. temperatureThe reaction mixture was heated to 80° C. for 2 h
  9. temperaturecooled to room temperature
  10. customThe volatiles were removed in vacuo
  11. customThe product was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA)

Sources & evidence

ORD record
ord-90ce95aebce543dd8a33ca638174d622
Source dataset
uspto-grants-2012_01
Patent number
US08093247B2

Reaction notes

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