Formaldehyde → 1-[(3-{2-[3-Cyano-4-(2-methylpropyl)phenyl]-1,3-thiazol-5-yl}-2-ethylphenyl)methyl]-4-piperidinecarboxylic acid

HRID 1942747Notes

Reaction equation

HRID 1942747 reaction equation
[CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][CH:12]=1)[CH3:2].[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClCCl.C(O)(=O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:28]4[CH2:29][CH2:30][CH:31]([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]4)[CH:7]=[CH:6][CH:5]=3)=[CH:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[CH2:24][CH:25]([CH3:27])[CH3:26])#[N:22]

Participants

7

Reactant 4

HCID 712FormaldehydeHCID 70770Ethyl 4-piperidinecarboxylateHCID 5049666Sodium triacetoxyborohydrideHCID 866590095-[5-(2-Ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-(2-methylpropyl)benzonitrile

Product 1

HCID 545771581-[(3-{2-[3-Cyano-4-(2-methylpropyl)phenyl]-1,3-thiazol-5-yl}-2-ethylphenyl)methyl]-4-piperidinecarboxylic acidYield 20.5%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-(2-methylpropyl)benzonitrile (D92) (150 mg), ethyl 4-piperidinecarboxylate (63.0 mg) and acetic acid (0.1 mL) in dichloromethane (DCM) (10 mL) was stirred at room temperature for 15 min, then sodium triacetoxyborohydride (255 mg) was added. The mixture was stirred at room temperature for 2 h, then formaldehyde (0.11 mL) was added. The mixture was stirred at room temperature overnight. After concentration, the residue was partitioned between ethyl acetate and water, washed with saturated brine. The organic phase was collected and evaporated, the residue was dissolved in DMF (5 mL) and 2M NaOH (2 mL) solution was added. The mixture was stirred at 50° C. for 1 h, then cooled to room temperature. This reaction mixture was acidified with 2M HCl to pH 5-6, extracted with ethyl acetate for three times. The combined organic phase was concentrated and the residue purified by Mass Directed AutoPrep to afford 1-[(3-{2-[3-cyano-4-(2-methylpropyl)phenyl]-1,3-thiazol-5-yl}-2-ethylphenyl)methyl]-4-piperidinecarboxylic acid (E42) (40 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 0.92 (6H, d), 1.02 (3H, t), 1.78 (2H, m), 1.98 (2H, m), 2.07 (2H, m), 2.73 (2H, d), 2.83 (2H, m), 3.19 (2H, m), 3.46 (2H, m), 4.41 (2H, m), 7.48 (2H, t), 7.63 (2H, m), 7.96 (1H, s), 8.22 (1H, dd), 8.35 (1H, d), 9.23 (1H, br s), 12.58 (1H, br s). δF (DMSO-d6, 376 MHz): −74.2. MS (ES): C29H33N3O2S requires 487. found 488.3 (M+H+).

Workup

  1. stirringThe mixture was stirred at room temperature overnight
  2. concentrationAfter concentration
  3. customthe residue was partitioned between ethyl acetate and water
  4. washwashed with saturated brine
  5. customThe organic phase was collected
  6. customevaporated
  7. dissolutionthe residue was dissolved in DMF (5 mL)
  8. addition2M NaOH (2 mL) solution was added
  9. stirringThe mixture was stirred at 50° C. for 1 h
  10. temperaturecooled to room temperature
  11. extractionextracted with ethyl acetate for three times
  12. concentrationThe combined organic phase was concentrated
  13. customthe residue purified by Mass Directed AutoPrep

Sources & evidence

ORD record
ord-7ed7befd50ad4385a3caae640f038158
Source dataset
uspto-grants-2013_03
Patent number
US08389508B2

Reaction notes

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