Water → HCID 68183323, compound

HRID 1615571Notes

Reaction equation

HRID 1615571 reaction equation
[NH2:1][CH2:2][CH2:3][CH:4]([C:12]1[CH:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:14][C:13]=1[C:23]([O:25]CC)=O)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O.[O-]CC.[Na+].O>C(O)C.CCOC(C)=O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]2[CH2:3][CH2:2][NH:1][C:23](=[O:25])[C:13]3[S:14][C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[CH:16][C:12]2=3)=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 962WaterHCID 6422Trifluoroacetic acidHCID 2723922Sodium ethoxideHCID 68191118HCID 68191118, compound

Product 1

HCID 68183323HCID 68183323, compoundYield 71.9%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A 100 mL rbf was charged with a solution of ethyl 3-[3-amino-1-(4-chlorophenyl)propyl]-5-(morpholin-4-yl)thiophene-2-carboxylate.TFA (842 mg, 1.61 mmol) in ethanol (10.0 mL) and 21% sodium ethoxide (21:79, Sodium ethoxide: ethanol, 4.81 mL, 12.9 mmol). The rbf was equipped with a reflux condenser and the reaction was heated to 80° C. In 3 h, the solution was cooled and distributed between water and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined org layer was washed with brine (×2), dried, and concentrated to provide a yellow solid. Purification on a silica gel column (continuous gradient from CH2Cl2 to 8% MeOH/CH2Cl2) provided 420 mg of 4-(4-chlorophenyl)-2-(morpholin-4-yl)-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one as a yellow solid (71.9% yield). LCMS: (AA) ES+ 363, 365; 1H NMR (400 MHz, DMSO-d6) δ 7.81-7.71 (s, 1H), 7.41-7.32 (m, 2H), 7.18-7.09 (m, 2H), 5.64-5.55 (s, 1H), 4.38-4.27 (dd, J=7.9, 5.1 Hz, 1H), 3.70-3.58 (t, J=4.9 Hz, 4H), 3.14-3.06 (d, J=4.3 Hz, 2H), 3.06-2.96 (t, J=4.9 Hz, 4H), 2.24-2.13 (m, 1H), 2.03-1.90 (m, 1H). Racemic 4-(4-chlorophenyl)-2-(morpholin-4-yl)-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one (0.42 g) was separated into enantiomers on a Chiralpak IA 30×250 mm 5 micron column using a 60/40/0.1 Hexane-EtOH-DEA mixture and a flow rate of 35 mL/min. Peak one (195 mg) was collected with retention times of 10-18 min and peak two (208 mg) was collected with retention times of 26.5-38.5 min. Absolute configuration of the obtained enantiomers is unknown.

Workup

  1. customThe rbf was equipped with a reflux condenser
  2. temperaturethe solution was cooled
  3. extractionThe aqueous layer was extracted with EtOAc (×2)
  4. washThe combined org layer was washed with brine (×2)
  5. customdried
  6. concentrationconcentrated
  7. customto provide a yellow solid
  8. customPurification on a silica gel column (continuous gradient from CH2Cl2 to 8% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-7cc066f509b34a78b687c69cc906e9e4
Source dataset
uspto-grants-2014_07
Patent number
US08765746B2

Reaction notes

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