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Dimethylamine, hydrochloride → Ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-(dimethylamino)propyl]-5-(morpholin-4-yl)thiophene-2-carboxylate

HRID 2401895
Notes
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Reaction equation

HRID 2401895 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][CH:21]=O)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].Cl.[CH3:32][NH:33][CH3:34].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.CCOC(C)=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][N:33]([CH3:34])[CH3:32])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 5

HCID 10473Dimethylamine, hydrochlorideHCID 516892Sodium BicarbonateHCID 517045Sodium AcetateHCID 5003444Sodium cyanoborohydrideHCID 86667483Ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-oxopropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate

Product 1

HCID 66747499
Ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-(dimethylamino)propyl]-5-(morpholin-4-yl)thiophene-2-carboxylate
Yield 71.9%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-oxopropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate (38.0 mg, 0.0813 mmol) (from example 56, step 1) in methanol (1.00 mL) was added dimethylamine hydrochloride (9.94 mg, 0.122 mmol), sodium acetate (8.00 mg, 0.0976 mmol), and sodium cyanoborohydride (6.13 mg, 0.0976 mmol). The reaction was stirred at rt for 2 h. The mixture was distributed between NaHCO3(aq) saturated solution and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was dried and concentrated. Purification on a silica gel column (gradient elution, 0-15% MeOH/CH2Cl2) provided ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-(dimethylamino)propyl]-5-(morpholin-4-yl)thiophene-2-carboxylate as a yellow syrup (29.0 mg, 71.8% yield). LCMS: (AA) ES+ 496, 498, 500; 1H NMR (400 MHz, CDCl3) δ 7.52-7.44 (d, J=1.9 Hz, 1H), 7.41-7.34 (m, 1H), 7.33-7.27 (m, 1H), 5.54-5.40 (t, J=7.7 Hz, 1H), 4.38-4.27 (q, J=7.1 Hz, 2H), 3.88-3.76 (t, J=4.9 Hz, 4H), 3.58-3.49 (dd, J=5.7, 4.0 Hz, 4H), 2.57-2.31 (m, 3H), 2.29-2.24 (s, 6H), 2.24-2.16 (m, 1H), 1.41-1.30 (t, J=7.1 Hz, 3H).

Workup

  1. extractionThe aqueous layer was extracted with EtOAc (×2)
  2. customThe combined organic layer was dried
  3. concentrationconcentrated
  4. customPurification
  5. washon a silica gel column (gradient elution, 0-15% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-7cfd425bb7a448c7b91356d0ac186c3d
Source dataset
uspto-grants-2014_08
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08796268B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes