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

HRID 1942731
Notes
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Reaction equation

HRID 1942731 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]([CH2:26][CH3:27])=[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:28]1[CH2:31][CH:30]([C:32]([O:34]C)=[O:33])[CH2:29]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:28]4[CH2:29][CH:30]([C:32]([OH:34])=[O:33])[CH2:31]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]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 20132751Methyl azetidine-3-carboxylateHCID 58494142[3-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]acetaldehyde

Product 1

HCID 545762901-{2-[3-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylic acid
Yield 26.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]acetaldehyde (D52) (100 mg), methyl 3-azetidinecarboxylate (57.4 mg) and acetic acid (1.428 μL) in dichloromethane (DCM) (8 mL) and N,N-dimethylformamide (DMF) (0.400 mL) stirred under nitrogen at room temperature for 20 min was added sodium triacetoxyborohydride (106 mg). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated, separated between water and EA, the water phase was extracted by EA. The organic phases were concentrated in vacuo. The residue was dissolved in Isopropanol (8.00 mL) and water (0.800 mL), 20% sodium hydroxide (0.5 mL) was added, then the reaction mixture stirred at room temperature for overnight. The mixture was neutralized with acetic acid, the resulting solution was concentrated and the residue was 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-ethylphenyl]ethyl}-3-azetidinecarboxylic acid (E23) (32 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.12 (3H, t), 1.35 (6H, d), 2.92 (4H, m), 3.44 (2H, m), 3.63 (1H, m), 4.29 (4H, m), 4.86 (1H, m), 7.38 (3H, m), 7.74 (1H, d), 8.02 (1H, dd), 8.14 (1H, d), 10.18 (1H, br s), 13.18 (1H, br s). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C25H28ClN3O3S requires 485. found 486.2 (M+H+).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customseparated between water and EA
  3. extractionthe water phase was extracted by EA
  4. concentrationThe organic phases were concentrated in vacuo
  5. dissolutionThe residue was dissolved in Isopropanol (8.00 mL)
  6. additionwater (0.800 mL), 20% sodium hydroxide (0.5 mL) was added
  7. stirringthe reaction mixture stirred at room temperature for overnight
  8. concentrationthe resulting solution was concentrated
  9. customthe residue was purified by Mass Directed AutoPrep

Sources & evidence

ORD record
ord-e0ced4bf092542a4900a58d006ca0e1f
Source dataset
uspto-grants-2013_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08389508B2

Reaction notes

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