Triethylamine → 1-[4-(3-{1-[(2,2-Difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylbenzyl)piperazin-1-yl]ethanone

HRID 515239Notes

Reaction equation

HRID 515239 reaction equation
[F:1][C:2]1([F:27])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:16]=[C:17]([CH2:22]O)[CH:18]=[CH:19][C:20]=3[CH3:21])=[CH:12][CH:13]=2)[N:8]([CH3:24])[S:7]1(=[O:26])=[O:25].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[C:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])[CH3:41].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[F:27][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=3[CH3:21])[CH2:22][N:46]3[CH2:47][CH2:48][N:43]([C:40](=[O:42])[CH3:41])[CH2:44][CH2:45]3)=[CH:12][CH:13]=2)[N:8]([CH3:24])[S:7]1(=[O:25])=[O:26]

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 837951-AcetylpiperazineHCID 67409954(3-{1-[(2,2-Difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3 dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylphenyl)methanol

Product 1

HCID 674237841-[4-(3-{1-[(2,2-Difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylbenzyl)piperazin-1-yl]ethanone

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
80 °C

Procedure

(3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylphenyl)methanol (39-1) (7.3 g, 18.4 mmol, 1.0 eq) was dissolved in NMP (90 mL) and triethylamine (7.7 mL, 55.2 mmol, 3.0 eq) was added followed by mesyl chloride (1.6 mL, 20.3 mmol, 1.1 eq). After 20 minutes, 1-acetylpiperazine (3.3 g, 25.7 mmol, 2.0 eq) and DIPEA (9.0 mL, 51.3 mmol, 3.0 eq) were added. The resulting mixture stirred at 80° C. for 2 hours minutes. The mixture was cooled, diluted with EtOAc (300 mL), washed with sodium bicarbonate (50 mL), water (6×50 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (330 g SiO2, 0-20% IPA in DCM) to afford 1-[4-(3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylbenzyl)piperazin-1-yl]ethanone (39-2) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 7.36 (d, J=8.0 Hz, 1 H); 7.35 (s, 1 H); 7.25 (s, 2 H); 7.08 (d, J=8.0 Hz, 1 H); 3.97 (d, J=6.8 Hz, 2 H); 3.56 (s, 2 H); 3.54 (dt, J=5.2, 20.4 Hz, 4 H); 3.38 (s, 3 H); 2.46 (dt, J=5.2, 18.8 Hz, 4 H); 2.35 (s, 3 H); 2.21 (m, 1 H); 2.07 (s, 3 H); 1.67 (m, 1 H); 1.43 (m, 1 H). HRMS m/z (M+H) 506.2029 found, 506.2032 required.

Workup

  1. temperatureThe mixture was cooled
  2. washwashed with sodium bicarbonate (50 mL), water (6×50 mL) and brine (50 mL)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude residue was purified by flash chromatography (330 g SiO2, 0-20% IPA in DCM)

Sources & evidence

ORD record
ord-485a0f84969b467db3d906da91f32834
Source dataset
uspto-grants-2015_08
Patent number
US09108937B2

Reaction notes

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