Tetrahydrofuran → 2-(3-{1-[(2,2-Difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-2-fluorophenyl)propan-2-ol

HRID 515236Notes

Reaction equation

HRID 515236 reaction equation
[F:1][C:2]1([F:30])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[C:16]([F:26])=[C:17]([CH:23]=[CH:24][CH:25]=3)C(OCC)=O)=[CH:12][CH:13]=2)[N:8]([CH3:27])[S:7]1(=[O:29])=[O:28].[CH3:31][Mg]Br.[CH2:34]1[CH2:38][O:37]CC1>>[F:1][C:2]1([F:30])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[C:16]([F:26])=[C:17]([C:38]([OH:37])([CH3:34])[CH3:31])[CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:13]=2)[N:8]([CH3:27])[S:7]1(=[O:29])=[O:28]

Participants

4

Reactant 3

HCID 8028TetrahydrofuranHCID 68245322Ethyl 3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-2-fluorobenzoateHCID 178418573HCID 178418573, compound

Product 1

HCID 674099752-(3-{1-[(2,2-Difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-2-fluorophenyl)propan-2-ol

Conditions

Temperature
-78 °C

Procedure

Ethyl 3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-2-fluorobenzoate (37-1) (240 mg, 0.54 mmol, 1.0 eq) was dissolved in THF (4 mL). The reaction mixture was cooled to −78° C. and methylmagnesium bromide (0.91 mL, 2.7 mmol, 3.0 M, 5.0 eq) was added. The resulting mixture stirred at ambient temperature for 30 minutes. The reaction was quenched by the addition of NH4Cl (2 mL), extracted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (40 g SiO2, 10-70% EtOAc in hexanes) to afford 2-(3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-2-fluorophenyl)propan-2-ol (37-2) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.81 (td, J=1.6, 7.6 Hz, 1 H); 7.59 (td, J=1.6, 7.6 Hz, 1 H); 7.42 (dd, J=2.0, 8.0 Hz, 1 H); 7.23 (t, J=7.6 Hz, 1 H); 7.06 (d, J=8.0 Hz, 1 H); 3.81-4.03 (m, 2 H); 3.49 (s, 3 H); 2.15 (m, 1 H); 1.69 (s, 6 H); 1.66 (m, 1 H); 1.39 (m, 1 H). HRMS m/z (M+H) 428.1242 found, 428.1250 required.

Workup

  1. customThe reaction was quenched by the addition of NH4Cl (2 mL)
  2. extractionextracted with EtOAc (50 mL)
  3. washwashed with water (10 mL) and brine (10 mL)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude residue was purified by flash chromatography (40 g SiO2, 10-70% EtOAc in hexanes)

Sources & evidence

ORD record
ord-5698607f0c5749c999bb14d43f0c6837
Source dataset
uspto-grants-2015_08
Patent number
US09108937B2

Reaction notes

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