Triethylamine → Tert-butyl 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)piperazine-1-carboxylate

HRID 515240Notes

Reaction equation

HRID 515240 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.[N:40]1([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.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:43]3[CH2:44][CH2:45][N:40]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41][CH2:42]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 143452tert-Butyl piperazine-1-carboxylateHCID 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 67412149Tert-butyl 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)piperazine-1-carboxylate

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) (1.5 g, 3.8 mmol, 1.0 eq) was dissolved in NMP (19 mL) and triethylamine (1.6 mL, 11.4 mmol, 3.0 eq) was added followed by mesyl chloride (0.59 mL, 7.6 mmol, 2.0 eq). After 20 minutes, tert-butyl piperazine-1-carboxylate (1.8 g, 9.7 mmol, 3.0 eq) and DIPEA (2.8 mL, 16.2 mmol, 5.0 eq) were added. The resulting mixture stirred at 80° C. for 2 hours minutes. The mixture was cooled, diluted with EtOAc (200 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, 0-80% EtOAc in hexanes) to afford tert-butyl 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)piperazine-1-carboxylate (43-1) as a tan solid. HRMS m/z (M+H) 564.2446 found, 564.2451 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, 0-80% EtOAc in hexanes)

Sources & evidence

ORD record
ord-703c147c7d844dbf99e70771c6468aed
Source dataset
uspto-grants-2015_08
Patent number
US09108937B2

Reaction notes

Loading…