Trifluoroacetic acid → HCID 59371389, compound

HRID 2095379Notes

Reaction equation

HRID 2095379 reaction equation
C(O)(C(F)(F)F)=O.C([O:12][C:13]([N:15]1[CH2:18][CH2:17][C@H:16]1[CH2:19][O:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH:31]3[CH:29]([CH2:30]3)[CH2:28]2)[CH:24]=[N:25][CH:26]=1)=[O:14])(C)(C)C.ClC(O[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=O.[OH-].[Na+]>C(Cl)Cl.O>[CH2:37]([O:12][C:13]([N:15]1[CH2:18][CH2:17][C@H:16]1[CH2:19][O:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:28][CH:29]3[CH:31]([CH2:30]3)[CH2:32]2)[CH:24]=[N:25][CH:26]=1)=[O:14])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 10387Benzyl chloroformateHCID 14798Sodium HydroxideHCID 59371328HCID 59371328, compound

Product 1

HCID 59371389HCID 59371389, compoundYield 67%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of CF3COOH, H2O, and CH2Cl2 (10:1:40, 153 mL) was added to a 250 mL round-bottom flask containing 3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-azabicyclo[3.1.0]hexane (6.00 g, 15.8 mmol). The flask was capped with a glass stopper, and the reactants were stirred at room temperature for 14 h. The reaction mixture was concentrated with a rotary evaporator (bath up to 35° C.) and was further dried with an oil pump (35° C.). The residue was dissolved in water (30 mL) and THF (100 mL). The mixture was stirred in an ice bath. Aqueous NaOH solution (5 N, approximately 20 mL) was added dropwise to adjust the pH of the solution to 10 (as monitored by spotting a few μL of the solution on pH paper). Benzyl chloroformate (4.9 mL, 31.6 mmol, 2.0 equiv.) was added dropwise over 30 min. During the addition, the pH of the solution was kept between 9 and 10 by gradually adding 5 N NaOH solution (approximately 20 mL). The pH of the solution was adjusted to 10 at the end of the addition. The ice bath was removed, and the mixture was stirred at room temperature for 18 h. The product was extracted into EtOAc (150+2×100 mL). The combined organic phases were concentrated, and the residue was purified by CC (SiO2, 25×3.8 cm, EtOAc/hexanes 3:1) to give the product as a colorless oil (4.00 g, 67%). 1H NMR (CDCl3, 500 MHz) δ 7.68 (br s, 1H), 7.63 (s, 1H), 7.38-7.26 (m, 5H), 6.40 (br s, 1H), 5.13 (s, 1H, J=12.2 Hz), 5.09 (s, 1H, J=8.8 Hz), 4.65-4.58 (m, 1H), 4.50-4.23 (m, 1H), 4.17-4.10 (m, 1H), 4.06-3.96 (m, 2H), 3.51 (d, 2H, J=8.8 Hz), 3.40 (d, 1H, J=8.3 Hz), 2.47-2.32 (m, 2H), 1.70 (t, 2H, J=3.4 Hz), 0.79 (td, 1H, J=7.6, 4.9 Hz), 0.33 (q, 1H, J=3.8 Hz). MS (EI) m/z 379 (M+, 10%), 288 (1.9%), 177 (4.8%), 176 (9.1%), 175 (11%), 148 (5.0%), 91 (100%). The product of a second run solidified on standing at room temperature; mp 80-81.5° C.

Workup

  1. additionwas added to a 250 mL round-bottom flask
  2. customThe flask was capped with a glass stopper
  3. concentrationThe reaction mixture was concentrated with a rotary evaporator (bath up to 35° C.) and
  4. customwas further dried with an oil pump (35° C.)
  5. dissolutionThe residue was dissolved in water (30 mL)
  6. stirringThe mixture was stirred in an ice bath
  7. additionAqueous NaOH solution (5 N, approximately 20 mL) was added dropwise
  8. additionDuring the addition
  9. additionThe pH of the solution was adjusted to 10 at the end of the addition
  10. customThe ice bath was removed
  11. stirringthe mixture was stirred at room temperature for 18 h
  12. extractionThe product was extracted into EtOAc (150+2×100 mL)
  13. concentrationThe combined organic phases were concentrated
  14. customthe residue was purified by CC (SiO2, 25×3.8 cm, EtOAc/hexanes 3:1)

Sources & evidence

ORD record
ord-4965c85b6e924441b56f6081c5e9384f
Source dataset
uspto-grants-2013_05
Patent number
US08445684B2

Reaction notes

Loading…