Sodium Acetate → 1-{[3-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylic acid

HRID 1942733Notes

Reaction equation

HRID 1942733 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]([CH2:25][CH3:26])=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([O-])(=O)C.[Na+].Cl.[NH:33]1[CH2:36][CH:35]([C:37]([O:39]C)=[O:38])[CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH2:20][N:33]4[CH2:34][CH:35]([C:37]([OH:39])=[O:38])[CH2:36]4)[CH:22]=[CH:23][CH:24]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]

Participants

8

Reactant 4

HCID 517045Sodium AcetateHCID 5049666Sodium triacetoxyborohydrideHCID 21100040Methyl azetidine-3-carboxylate hydrochlorideHCID 584940603-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylbenzaldehyde

Product 1

HCID 545764991-{[3-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylic acidYield 32.8%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylbenzaldehyde (D53) (100 mg) in dichloromethane (DCM) (8 mL) and methanol (8.00 mL) was added sodium acetate (31.8 mg), hydrogen chloride-methyl 3-azetidinecarboxylate (1:1) (58.8 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (110 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1:1), 0.5M sodium hydroxide (2.58 mL) was added, the reaction solution was heated to 80° C. for 1 h. The solvent was removed in vacuo and the residue was acidified to pH=2-3. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylic acid (E25) (40 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.05 (3H, t), 1.28 (6H, d), 2.87 (2H, q), 3.19 (3H, m), 3.34 (2H, m), 3.60 (2H, s), 4.78 (1H, m), 7.23 (1H, t), 7.31 (1H, d), 7.38 (1H, d), 7.64 (1H, d), 7.94 (1H, dd), 8.07 (1H, d). δF (DMSO-d6, 376 MHz): −73.4. MS (ES): C24H26ClN3O3S requires 471. found 472.2 (M+H+).

Workup

  1. stirringthe reaction solution was stirred at room temperature overnight
  2. customThe solvent was removed in vacuo
  3. dissolutionthe residue was dissolved in ethyl acetate (30 mL)
  4. washthe organic phase was washed with water
  5. dry with materialdried over sodium sulphate
  6. concentrationconcentrated
  7. dissolutionThe residue was dissolved in isopropanol/water (10 mL, 1:1)
  8. addition0.5M sodium hydroxide (2.58 mL) was added
  9. customThe solvent was removed in vacuo
  10. extractionThe resulting solution was extracted with ethyl acetate (2*15 mL)
  11. dry with materialthe combined organic phases were dried over sodium sulphate
  12. concentrationconcentrated
  13. custompurified by Mass Directed AutoPrep

Sources & evidence

ORD record
ord-54e1b8dfe1d64801b08255b411ceb21e
Source dataset
uspto-grants-2013_03
Patent number
US08389508B2

Reaction notes

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