Acetic Acid → 1-{2-[3-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-methylphenyl]ethyl}-4-piperidinecarboxylic acid

HRID 1942756Notes

Reaction equation

HRID 1942756 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH3:26])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH3:26])=[C:19]([CH2:23][CH2:24][N:27]4[CH2:28][CH2:29][CH:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]

Participants

8

Reactant 6

HCID 176Acetic AcidHCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 70770Ethyl 4-piperidinecarboxylateHCID 5049666Sodium triacetoxyborohydrideHCID 58494176HCID 58494176, compound

Product 1

HCID 545784621-{2-[3-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-methylphenyl]ethyl}-4-piperidinecarboxylic acidYield 22.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-methylphenyl]acetaldehyde (D106) (120 mg, 0.310 mmol) in Dichloromethane (DCM) (20 mL) stirred at room temperature was added ethyl 4-piperidinecarboxylate (195 mg, 1.241 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (131 mg, 0.620 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was quenched with water and DCM was evaporated in vacuo. The residue was dissolved in Isopropanol (8 mL), and sodium hydroxide (50 mg, 1.250 mmol) was added. The reaction was stirred for 2 hours. 1M HCl solution was added until pH=6-7. Isopropanol was removed. The mixture was extracted by EA/THF/MeCN for 3 times. The combined organic solution was washed with brine. The solution was concentrated and purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-methylphenyl]ethyl}-4-piperidinecarboxylic acid (E74) (35 mg) as a off-white solid. δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 1.55 (2H, m), 1.81 (2H, m), 2.05 (2H, m), 2.19 (1H, m), 2.46 (3H, s), 2.50 (2H, m), 2.87 (4H, m), 4.86 (1H, dt), 7.26 (1H, m), 7.36 (2H, m), 7.68 (1H, d), 8.02 (1H, dd), 8.14 (1H, d), 12.18 (1H, br. s.). MS (ES): C26H30ClN3O3S requires 499.2. found 500.2 (M+H+).

Workup

  1. waitThe reaction mixture was continuously stirred overnight
  2. customThe reaction was quenched with water and DCM
  3. customwas evaporated in vacuo
  4. dissolutionThe residue was dissolved in Isopropanol (8 mL)
  5. stirringThe reaction was stirred for 2 hours
  6. customIsopropanol was removed
  7. extractionThe mixture was extracted by EA/THF/MeCN for 3 times
  8. washThe combined organic solution was washed with brine
  9. concentrationThe solution was concentrated
  10. custompurified by Mass Directed AutoPrep

Sources & evidence

ORD record
ord-b837354e44ab4b22b3243b838720d7f4
Source dataset
uspto-grants-2013_03
Patent number
US08389508B2

Reaction notes

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