Acetic Acid → HCID 59394941, compound

HRID 383435Notes

Reaction equation

HRID 383435 reaction equation
[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([NH:14][C:15]3[CH:20]=[C:19]([O:21]C(OC)=O)[C:18]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:17][C:16]=3[CH:31]3[CH2:36][CH2:35][N:34]([C:37](OC(C)(C)C)=O)[CH2:33][CH2:32]3)=[O:13])[CH2:9][NH:8][C:7]=2[CH:44]=1)#[N:2].C(O)(C(F)(F)F)=O.C=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].[OH-].[K+].Cl>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([NH:14][C:15]3[CH:20]=[C:19]([OH:21])[C:18]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:17][C:16]=3[CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[O:13])[CH2:9][NH:8][C:7]=2[CH:44]=1)#[N:2]

Participants

10

Reactant 8

HCID 176Acetic AcidHCID 313Hydrochloric AcidHCID 712FormaldehydeHCID 6422Trifluoroacetic acidHCID 14797Potassium HydroxideHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 59395023HCID 59395023, compound

Product 1

HCID 59394941HCID 59394941, compoundYield 7.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Tert-butyl 4-[2-[(6-cyano-3,4-dihydro-2H-1,4-benzoxazine-2-carbonyl)amino]-5-cyclopentyl-4-methoxycarbonyloxy-phenyl]piperidine-1-carboxylate (100 mg, 0.17 mmol) was taken up in dichloromethane (3 mL) and TFA (1 mL, 13 mmol) and allowed to stir for 10 min at room temperature. The mixture was concentrated in vacuo and the residue was dissolved in 1,2-dichloroethane (2 mL). Paraformaldehyde (5 mg, 0.17 mmol) and acetic acid (9 μL, 0.17 mmol) were added and the mixture was heated at 60° C. for 10 min. Sodium triacetoxyborohydride (105 mg, 0.50 mmol) was added and the reaction was stirred for an additional 10 min. The mixture was added to saturated aqueous NaHCO3 (50 mL) and was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in methanol (3 mL) and treated with solid KOH (93 mg, 1.65 mmol). The reaction was stirred for 20 min at room temperature, poured into 1N HCl (50 mL) and was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. HPLC purification (10-99% CH3CN/0.05% HCl) provided 6-cyano-N-(4-cyclopentyl-5-hydroxy-2-(1-methylpiperidin-4-yl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide (6 mg, 7% yield). LC/MS m/z 461.4 [M+H]+. 1H NMR (400.0 MHz, MeOD) δ 7.09 (d, J=1.8 Hz, 3H), 7.02 (s, 1H), 6.63 (d, J=1.6 Hz, 1H), 5.11 (dd, J=3.2, 4.6 Hz, 1H), 3.64 (dd, J=4.7, 12.0 Hz, 1H), 3.49-3.38 (m, 3H), 3.26 (q, obscured by solvent peak, J=9.2 Hz, 1H), 2.95 (s, 3H), 2.74-2.64 (m, 3H), 1.98-1.93 (m, 2H), 1.84-1.58 (m, 10H).

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. dissolutionthe residue was dissolved in 1,2-dichloroethane (2 mL)
  3. temperaturethe mixture was heated at 60° C. for 10 min
  4. stirringthe reaction was stirred for an additional 10 min
  5. extractionwas extracted with ethyl acetate (3×10 mL)
  6. dry with materialThe combined organic extracts were dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. dissolutionThe residue was dissolved in methanol (3 mL)
  10. stirringThe reaction was stirred for 20 min at room temperature
  11. extractionwas extracted with ethyl acetate (3×10 mL)
  12. dry with materialThe combined organic extracts were dried over MgSO4
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo
  15. customHPLC purification (10-99% CH3CN/0.05% HCl)

Sources & evidence

ORD record
ord-3a76997c39eb474f80545f6dcbac70dc
Source dataset
uspto-grants-2013_02
Patent number
US08367660B2

Reaction notes

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