Formaldehyde → HCID 44548577, compound

HRID 1512913Notes

Reaction equation

HRID 1512913 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH:26]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:28][C@H:29]([C:31]([O:33]C)=[O:32])[CH3:30].[BH-](OC(C)=O)(OC(C)=O)O[C:37](C)=O.[Na+].C=O>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][N:28]([CH3:37])[C@H:29]([C:31]([OH:33])=[O:32])[CH3:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]

Participants

7

Reactant 4

HCID 712FormaldehydeHCID 82335L-Alanine methyl esterHCID 5049666Sodium triacetoxyborohydrideHCID 591461517-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde

Product 1

HCID 44548577HCID 44548577, compoundYield 7.1%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
40 °C

Procedure

To a stirred solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde (D71) (150 mg), methyl L-alaninate (81 mg) and acetic acid (24 mg) in DCM (10 mL) was added NaBH(OAc)3 (167 mg). The mixture was stirred at 40° C. for 2 h, followed by addition of formaldehyde (120 mg). This mixture was stirred at 40° C. overnight. After concentration, the residue was dissolved in THF (5 mL), followed by addition of aqueous NaOH (2 M, 2 mL). The mixture was stirred at 60° C. overnight, and then acidified with aqueous HCl (2 M) to pH 4-5, partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate, and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-N-methyl-L-alanine (E54) (13 mg). δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 1.56 (3H, d), 2.75 (3H, s), 4.17 (1H, q), 4.54 (2H, q), 4.90 (1H, m), 7.35 (1H, t), 7.46 (1H, d), 7.75 (1H, d), 8.03 (1H, d), 8.10 (1H, d), 8.21 (1H, dd), 8.39 (1H, d), 11.46 (1H, br s). MS (ES): C24H26ClN4O4 requires 468; found 366.1 (M—C4H8NO2+).

Workup

  1. stirringThis mixture was stirred at 40° C. overnight
  2. concentrationAfter concentration
  3. dissolutionthe residue was dissolved in THF (5 mL)
  4. additionfollowed by addition of aqueous NaOH (2 M, 2 mL)
  5. stirringThe mixture was stirred at 60° C. overnight
  6. custompartitioned between ethyl acetate (25 mL) and water (25 mL)
  7. washThe organic phase was washed with water (25 mL) and brine (25 mL)
  8. dry with materialdried over anhydrous sodium sulphate
  9. customevaporated
  10. customto give the crude product, which
  11. customwas purified by Mass Directed Auto Prep

Sources & evidence

ORD record
ord-072cab5c3c124f24881456e271ae178f
Source dataset
uspto-grants-2012_07
Patent number
US08217028B2

Reaction notes

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