Benzothiazole → 4-((5R,7R)-7-(benzo[d]thiazol-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluorobenzonitrile

HRID 2036034

Reaction equation

HRID 2036034 reaction equation
[Li]CCCC.CCCCCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[C@@H:30]1[N:34]2[CH:35]=[N:36][CH:37]=[C:33]2[C:32](=[O:38])[CH2:31]1)[C:25]#[N:26]>C1COCC1>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C@:32]1([OH:38])[C:33]2[N:34]([CH:35]=[N:36][CH:37]=2)[C@@H:30]([C:29]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=2[F:21])[CH2:31]1

Participants

6

Reactant 4

HCID 7222BenzothiazoleHCID 8058HexaneHCID 67216150(R)-3-fluoro-4-(7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrileHCID 178418339Butyllithium

Product 1

HCID 532366664-((5R,7R)-7-(benzo[d]thiazol-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluorobenzonitrileYield 22.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a 1.6 M solution of n-BuLi in hexane (0.29 mL, 0.46 mmol) cooled to −78° C. was added a solution of benzo[d]thiazole (56 mg, 0.42 mmol) in THF (1 mL). The crude was stirred at −78° C. for 1 hr. This solution was then cannulated to a solution of 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (50 mg, 0.21 mmol) in THF (1 mL) cooled at −78° C. After stirring at −78° C. for 2 hrs, the crude was warmed to room temperature. The crude was stirred at room temperature for 1 hr. The crude was quenched with sat. NH4Cl. The crude was diluted in EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude was purified via preparation plate using 7% (2M NH3 in MeOH)/CH2Cl2 to give 18 mg of the entitled product as the major diastereomer. MS 377.0 (M+H); LCMS condition A, retention time 1.23 min. 1H NMR (400 MHz, CDCl3) δ ppm 3.09 (dd, 1H), 3.84 (dd, 1H), 5.96 (d, 1H), 7.02 (s, 1H), 7.24-7.53 (m, 6H), 7.85 (d, 1H), 7.93 (d, 1H).

Workup

  1. temperaturecooled at −78° C
  2. stirringAfter stirring at −78° C. for 2 hrs
  3. temperaturethe crude was warmed to room temperature
  4. stirringThe crude was stirred at room temperature for 1 hr
  5. customThe crude was quenched with sat. NH4Cl
  6. additionThe crude was diluted in EtOAc
  7. washThe organic layer was washed with brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe crude was purified via preparation plate

Sources & evidence

ORD record
ord-6498c70402a84667b06d15b2cfafa645
Source dataset
uspto-grants-2013_11
Patent number
US08575160B2

Linked notes

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