Acetyl chloride → HCID 86693826, compound

HRID 516638Notes

Reaction equation

HRID 516638 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[C:26]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:25][N:24]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[N:23]=2)[C:17]=1[F:39])[CH2:13][O:14][CH3:15])(=[O:11])=[O:10].[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([N:36]1[CH2:35][CH2:34][CH:33]([N:24]2[CH:25]=[C:26]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[C:22]([C:18]3[C:17]([F:39])=[C:16]([N:12]([CH2:13][O:14][CH3:15])[S:9]([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])(=[O:11])=[O:10])[CH:21]=[CH:20][CH:19]=3)=[N:23]2)[CH2:38][CH2:37]1)(=[O:42])[CH3:41]

Participants

4

Reactant 2

HCID 6367Acetyl chlorideHCID 66729652HCID 66729652, compound

Product 1

HCID 86693826HCID 86693826, compoundYield 56%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 2,5-difluoro-N-[2-fluoro-3-(1-piperidin-4-yl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-N-methoxymethyl-benzenesulfonamide (135 mg, 0.242 mmol) (prepared as described in Example 2) in DCM (2 mL) triethylamine (0.040 mL, 0.290 mmol, 1.2 eq) was added, followed by acetylchloride (0.019 mL, 0.266 mmol, 1.1 eq) and the solution was stirred at r.t. for 2 h. The reaction mixture was then diluted with DCM and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography (DCM/MeOH 97:3) affording 81 mg (56%) of N-{3-[1-(1-Acetyl-piperidin-4-yl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-N-methoxymethyl-benzene-sulfonamide. This intermediate was then treated with a 9:1 TFA/water mixture (1 mL) and stirred at 60° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure, then taken up with AcOEt and washed with a saturated solution of NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM/MeOH 95:5) affording 9 mg of the title compound. HPLC (254 nm): Rt: 5.22 min; 1H NMR (DMSO-d6) Shift: 10.66 (br. s., 1H), 8.48 (s, 1H), 8.38-8.43 (m, 2H), 7.51-7.60 (m, 1H), 7.40-7.49 (m, 2H), 7.29-7.38 (m, 2H), 7.21-7.27 (m, 1H), 7.11 (d, J=6.0 Hz, 2H), 4.44-4.55 (m, 2H), 3.90-3.96 (m, 1H), 3.17-3.28 (m, 1H), 2.69-2.78 (m, 1H), 2.07-2.18 (m, 2H), 2.04 (s, 3H), 1.91-1.99 (m, 1H), 1.74-1.84 (m, 1H); HRMS (ESI) calcd for C27H25F3N5O3S [M+H]+ 556.1625. found 556.1620.

Workup

  1. washwashed with saturated aqueous NaHCO3 and brine
  2. dry with materialdried over Na2SO4
  3. customevaporated to dryness
  4. customThe crude product was purified by flash chromatography (DCM/MeOH 97:3)

Sources & evidence

ORD record
ord-3a71ca3752334d54a865b43c2bc541f6
Source dataset
uspto-grants-2015_08
Patent number
US09114137B2

Reaction notes

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