Sodium Hydroxide → 1-((2S)-3-{4-[5-(5-Diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-2-hydroxy-propyl)-azetidine-3-carboxylic acid

HRID 1685795Notes

Reaction equation

HRID 1685795 reaction equation
Cl.C[O:3][C:4](C1CCN1)=[O:5].[CH2:10]([N:12]([CH2:39][CH3:40])[CH2:13][C:14]1[S:15][C:16]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([O:32][CH2:33][C@@H:34]4[CH2:36][O:35]4)=[C:27]([CH2:37][CH3:38])[CH:26]=3)[N:21]=2)=[CH:17][C:18]=1[CH3:19])[CH3:11].CC[N:43]([CH:47]([CH3:49])C)[CH:44](C)C.[OH-].[Na+]>CO>[CH2:10]([N:12]([CH2:13][C:14]1[S:15][C:16]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([O:32][CH2:33][C@@H:34]([OH:35])[CH2:36][N:43]4[CH2:44][CH:49]([C:4]([OH:5])=[O:3])[CH2:47]4)=[C:27]([CH2:37][CH3:38])[CH:26]=3)[N:21]=2)=[CH:17][C:18]=1[CH3:19])[CH2:39][CH3:40])[CH3:11]

Participants

6

Reactant 4

HCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 22476057Methyl azetidine-2-carboxylate hydrochlorideHCID 86646463HCID 86646463, compound

Product 1

HCID 672657031-((2S)-3-{4-[5-(5-Diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-2-hydroxy-propyl)-azetidine-3-carboxylic acidYield 78.6%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Conditions

Temperature
70 °C

Procedure

To a solution of azetidine-2-carboxylic acid methyl ester hydrochloride (51 mg, 340 μmol) in methanol (1 mL), a solution of diethyl-{5-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-amine (30 mg, 68 μmol) in methanol (1 mL) followed by DIPEA (90 mg, 679 μmol) is added. The mixture is stirred at 70° C. for 22 h before it is cooled to rt and 3 M aq. NaOH (0.35 mL) is added. The mixture is stirred at rt for 18 h before it is separated by prep. HPLC (Waters XBridge Prep C18, 75×30 mm ID, 10 μm, eluting with a gradient of acetonitrile in water containing 0.5% of sat. aq. ammonia) to give the title compound (29 mg) as a resin; LC-MS*: tR=0.74 min; [M+1]+=543.09; 1H NMR (D6-DMSO): δ1.03 (t, J=7.0 Hz, 6H), 1.21 (t, J=7.5 Hz, 3H), 2.22 (s, 3H), 2.33 (s, 3H), 2.58 (q, J=7.0 Hz, 4H), 2.62-2.69 (m, 1H), 2.73 (q, J=7.3 Hz, 2H), 3.10-3.17 (m, 1H), 3.18-3.22 (m, 1H), 3.22-3.28 (m, 2H), 3.42-3.51 (m, 2H), 3.66-3.72 (m, 1H), 3.73 (s, 2H), 3.74-3.80 (m, 2H), 7.72 (s, 2H), 7.80 (s, 1H).

Workup

  1. additionis added
  2. temperatureis cooled to rt
  3. stirringThe mixture is stirred at rt for 18 h before it
  4. customis separated by prep
  5. washHPLC (Waters XBridge Prep C18, 75×30 mm ID, 10 μm, eluting with a gradient of acetonitrile in water containing 0.5% of sat. aq. ammonia)

Sources & evidence

ORD record
ord-c516f719ac1d445199a8e4b016f4bc16
Source dataset
uspto-grants-2012_04
Patent number
US08148410B2

Reaction notes

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