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

HRID 1942734Notes

Reaction equation

HRID 1942734 reaction equation
[CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])[S:14][N:13]=1)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH:35]1[CH2:38][CH:37]([C:39]([O:41]C)=[O:40])[CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:14][N:13]=[C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:35]4[CH2:36][CH:37]([C:39]([OH:41])=[O:40])[CH2:38]4)[CH:7]=[CH:6][CH:5]=3)[N:16]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]

Participants

7

Reactant 4

HCID 517045Sodium AcetateHCID 5049666Sodium triacetoxyborohydrideHCID 21100040Methyl azetidine-3-carboxylate hydrochlorideHCID 866590055-{3-[2-Ethyl-3-(2-oxoethyl)phenyl]-1,2,4-thiadiazol-5-yl}-2-[(1-methylethyl)oxy]benzonitrile

Product 1

HCID 545765001-{2-[3-(5-{3-Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylic acidYield 17%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6344DichloromethaneSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 5-{3-[2-ethyl-3-(2-oxoethyl)phenyl]-1,2,4-thiadiazol-5-yl}-2-[(1-methylethyl)oxy]benzonitrile (D55) (150 mg) in dichloromethane (DCM) (7.5 mL) was added sodium acetate (31.4 mg), hydrogen chloride-methyl 3-azetidinecarboxylate (1:1) (58.1 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (122 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 (3.83 mL) was added, the reaction solution was heated to 90° C. for 1 h. The solvent was removed in vacuo and the residue was acidified to pH=3-4. 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-{2-[3-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylic acid (E26) (31 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.05 (3H, t), 1.31 (6H, d), 2.84 (4H, m), 3.35 (2H, m), 3.57 (1H, m), 4.20 (4H, m), 4.90 (1H, m), 7.28 (1H, t), 7.37 (1H, d), 7.44 (1H, d), 7.68 (1H, dd), 8.26 (1H, dd), 8.41 (1H, d). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C26H28N4O3S requires 476. found 477.2 (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 (3.83 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-1c426837b0de4e779b02c94617be44a6
Source dataset
uspto-grants-2013_03
Patent number
US08389508B2

Reaction notes

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