Ethyl Acetate → 4-Cyano-3-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-5-(morpholin-4-yl)thiophene-2-carboxylic acid

HRID 2402155Notes

Reaction equation

HRID 2402155 reaction equation
[C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH2:21][OH:22])=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[H-].[Na+].CCOC(C)=O>O1CCCC1.[Cl-].[Na+].O>[C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH2:21][OH:22])=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]

Participants

6

Reactant 3

HCID 8857Ethyl AcetateHCID 24758Sodium hydride2×HCID 66747681Ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate

Product 1

HCID 667476404-Cyano-3-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-5-(morpholin-4-yl)thiophene-2-carboxylic acidYield 18.2%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate (38.0 mg, 0.0810 mmol) in tetrahydrofuran (1.00 mL) was added NaH 60% in mineral oil (60:40, Sodium hydride:mineral Oil, 3.56 mg, 0.0890 mmol). The mixture was heated to 60° C. for 3 hrs. The reaction was cooled to rt and distributed between brine and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was washed with brine, dried, and concentrated to provide a yellow solid. Purification on HPLC (reverse phase, AA) provided 4-cyano-3-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-5-(morpholin-4-yl)thiophene-2-carboxylic acid as a white solid (6.5 mg, 18.2% yield). LCMS: (AA) ES+ 441, 443, 445; 1H NMR (400 MHz, MeOD) δ 7.50-7.45 (s, 1H), 7.45-7.37 (d, J=8.4 Hz, 1H), 7.30-7.22 (m, 1H), 5.79-5.63 (m, 1H), 3.83-3.71 (t, J=4.8 Hz, 4H), 3.60-3.50 (q, J=6.9, 6.0 Hz, 2H), 3.50-3.41 (d, J=3.2 Hz, 4H), 2.52-2.37 (m, 2H).

Workup

  1. temperatureThe reaction was cooled to rt
  2. extractionThe aqueous layer was extracted with EtOAc (×2)
  3. washThe combined organic layer was washed with brine
  4. customdried
  5. concentrationconcentrated
  6. customto provide a yellow solid
  7. customPurification on HPLC (reverse phase, AA)

Sources & evidence

ORD record
ord-1177989a26954180aafc14cb3740278c
Source dataset
uspto-grants-2014_08
Patent number
US08796271B2

Reaction notes

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