Methylamine → (3R)-3-(3-chloro-5-fluorophenyl)-3-(3-isopropyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine

HRID 1819671Notes

Reaction equation

HRID 1819671 reaction equation
Cl[CH2:2][CH2:3][C@@H:4]([N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH:22]([CH3:24])[CH3:23])[S:14]1(=[O:26])=[O:25])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1.[CH3:27][NH2:28]>>[Cl:12][C:7]1[CH:6]=[C:5]([C@H:4]([N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([CH:22]([CH3:23])[CH3:24])[S:14]2(=[O:25])=[O:26])[CH2:3][CH2:2][NH:28][CH3:27])[CH:10]=[C:9]([F:11])[CH:8]=1

Participants

3

Reactant 2

HCID 6329MethylamineHCID 690592361-[(1R)-3-chloro-1-(3-chloro-5-fluorophenyl)propyl]-3-isopropyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide

Product 1

HCID 16657071(3R)-3-(3-chloro-5-fluorophenyl)-3-(3-isopropyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amineYield 70%

Procedure

1-[(1R)-3-chloro-1-(3-chloro-5-fluorophenyl)propyl]-3-isopropyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1.75 g, 4.19 mmol) and ethanolic solution of methylamine (33% in ethanol, 30 mL) was heated at 85° C for 4 hours with stirring in a sealed reaction vessel. Upon cooling, all volatiles were removed under reduced pressure. The resulting residue was dissolved in dichloromethane (50 mL), washed with aqueous potassium carbonate (20 mL), dried (anhydrous sodium sulfate), and concentrated. Purification by Isco CombiFlash Companion column chromatography (silica gel, 0-15% methanol/dichloromethane, with 0.5% triethylamine additive) gave 1.22 g (70%) of (3R)-3-(3-chloro-5-fluorophenyl)-3-(3-isopropyl-2,2-dioxido-2,1,3-benzothia diazol-1(3H)-yl)-N-methylpropan-1-amine as a white foam, which was dissolved in dichloromethane (20 mL) and treated with an ethereal solution of hydrochloric acid (1 M, 3.3 mL, 3.3 mmol). To the resulting solution was added hexane until white powder formed, which was collected, washed with hexane, and dried in vacuo to yield (3R)-3-(3-chloro-5-fluorophenyl)-3-(3-isopropyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine hydrochloride as a white powder. MS (ES) m/z 411.9 ([M+H]30 ); HRMS: calculated for C19H23CIFN3O2S+H+, 412.1256; found (ESI, [M+H]30), 412.1266.

Workup

  1. temperatureUpon cooling
  2. customall volatiles were removed under reduced pressure
  3. dissolutionThe resulting residue was dissolved in dichloromethane (50 mL)
  4. washwashed with aqueous potassium carbonate (20 mL)
  5. dry with materialdried (anhydrous sodium sulfate)
  6. concentrationconcentrated
  7. customPurification by Isco CombiFlash Companion column chromatography (silica gel, 0-15% methanol/dichloromethane, with 0.5% triethylamine additive)

Sources & evidence

ORD record
ord-a25f27d04e4743c9aaeead38988211a2
Source dataset
uspto-grants-2009_10
Patent number
US07601744B2

Reaction notes

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