Formaldehyde → 1-[(4-Methylmorpholin-2-yl)methyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide

HRID 1818777Notes

Reaction equation

HRID 1818777 reaction equation
Cl.[NH:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:10]2(=[O:25])=[O:24])[CH2:3]1.C=O.[C:28]([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.O>[CH3:28][N:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[S:10]2(=[O:25])=[O:24])[CH2:3]1

Participants

7

Reactant 4

HCID 712FormaldehydeHCID 516892Sodium BicarbonateHCID 5003444Sodium cyanoborohydrideHCID 687142541-(Morpholin-2-ylmethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide hydrochloride

Product 1

HCID 249373751-[(4-Methylmorpholin-2-yl)methyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxideYield 98%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

To a solution of 1-(morpholin-2-ylmethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide hydrochloride (Example 1, 76 mg, 0.20 mmol) in methanol (2 mL) was added a solution of formaldehyde (37% in water, 0.15 mL) and the mixture was stirred for 30 minutes. Sodium cyanoborohydride (38 mg, 0.60 mmol, 3 equiv.) was added portionwise and the mixture was stirred for an additional 3 hours. Saturated aqueous sodium bicarbonate (5 mL) was added slowly followed by the addition of water (5 mL). The reaction mixture was extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with brine, dried (anhydrous sodium sulfate), and concentrated. The crude liquid residue was purified by Isco flash column chromatography (silica gel, 0-10% methanol/dichloromethane) to give 70 mg (98%) of 1-[(4-methylmorpholin-2-yl)methyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as viscous colorless liquid. This free base was dissolved in dichloromethane (3 mL) and was treated with an ethereal solution of hydrochloric acid (1 M, 0.3 mL, 0.3 mmol). To the resulting solution was added hexane until white powder formed, which was collected, washed with hexane, and dried in vacuo to yield 76 mg (96%) of 1-[(4-methylmorpholin-2-yl)methyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide hydrochloride. MS (ESI) m/z 360.2 ([M+H]+).

Workup

  1. stirringthe mixture was stirred for an additional 3 hours
  2. extractionThe reaction mixture was extracted with ethyl acetate (2×15 mL)
  3. washThe combined organic extracts were washed with brine
  4. dry with materialdried (anhydrous sodium sulfate)
  5. concentrationconcentrated
  6. customThe crude liquid residue was purified by Isco flash column chromatography (silica gel, 0-10% methanol/dichloromethane)

Sources & evidence

ORD record
ord-a02870a9a4294a8da8b6a32f998246a0
Source dataset
uspto-grants-2009_10
Patent number
US07601722B2

Reaction notes

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