Acetic Acid → 1-{2-[3-{5-[3-Cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-5-fluoro-2-(methyloxy)phenyl]ethyl}-3-azetidinecarboxylic acid

HRID 1942728Notes

Reaction equation

HRID 1942728 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH2:27][CH:28]=O)[C:5]([O:25][CH3:26])=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:17]([CH:20]=3)[C:18]#[N:19])=[N:10][N:9]=2)[CH:7]=1.[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[C:18]([C:17]1[CH:20]=[C:13]([C:11]2[S:12][C:8]([C:6]3[C:5]([O:25][CH3:26])=[C:4]([CH2:27][CH2:28][N:30]4[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]4)[CH:3]=[C:2]([F:1])[CH:7]=3)=[N:9][N:10]=2)[CH:14]=[CH:15][C:16]=1[CH2:21][CH:22]([CH3:23])[CH3:24])#[N:19]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 931923-azetidinecarboxylic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 866590035-{5-[5-Fluoro-2-(methyloxy)-3-(2-oxoethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(2-methylpropyl)benzonitrile

Product 1

HCID 545795901-{2-[3-{5-[3-Cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-5-fluoro-2-(methyloxy)phenyl]ethyl}-3-azetidinecarboxylic acidYield 21%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of 5-{5-[5-fluoro-2-(methyloxy)-3-(2-oxoethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(2-methylpropyl)benzonitrile (D37) (75 mg) and 3-azetidinecarboxylic acid (37 mg) in dichloromethane (DCM) (15 mL) stirred at room temperature was added AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (58.2 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA/THF/MeCN for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated. The residue was purified by Mass Directed AutoPrep to give 1-{2-[3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-5-fluoro-2-(methyloxy)phenyl]ethyl}-3-azetidinecarboxylic acid (E15) (19 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 0.94 (6H, d), 1.99 (1H, m), 2.33 (1H, m), 2.67 (4H, m), 2.77 (2H, d), 3.17 (4H, m), 3.80 (3H, s), 7.47 (1H, dd), 7.68 (1H, d), 7.90 (1H, dd), 8.34 (1H, dd), 8.50 (1H, d). δF (DMSO-d6, 376 MHz): −117.2. MS (ES): C26H27FN4O3S requires 494. found 495.2 (M+H+).

Workup

  1. stirringStirring
  2. waitcontinued for overnight
  3. customto quench
  4. customthe reaction, and DCM
  5. customwas removed by evaporation
  6. extractionThe mixture was extracted by EA/THF/MeCN for 3 times
  7. washThe combined organic solution was washed by brine
  8. dry with materialdried over anhydrous Na2SO4
  9. filtrationThe dried solution was filtered
  10. concentrationconcentrated
  11. customThe residue was purified by Mass Directed AutoPrep

Sources & evidence

ORD record
ord-e37e6fa77ff74be9b1e5e3de3886b7e5
Source dataset
uspto-grants-2013_03
Patent number
US08389508B2

Reaction notes

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