4-Methylmorpholine → (+/-)-1-[3-(Benzhydrylidene-amino)-4-cyano-benzyl]-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2-carboxylic acid methyl ester

HRID 1433020Notes

Reaction equation

HRID 1433020 reaction equation
[CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([N:21]=[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:14]=1)=[O:4].[Cl:35][C:36]1[S:40][C:39]([O:41][CH2:42][C:43](O)=[O:44])=[CH:38][CH:37]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:43](=[O:44])[CH2:42][O:41][C:39]2[S:40][C:36]([Cl:35])=[CH:37][CH:38]=2)[CH2:8][C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([N:21]=[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=1)=[O:4]

Participants

8

Reactant 4

HCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 111831442-[(5-Chlorothiophen-2-yl)oxy]acetic acidHCID 54153171(+/-)-1-[3-(Benzhydrylidene-amino)-4-cyano-benzyl]-6-oxo-piperazine-2-carboxylic acid methyl ester

Product 1

HCID 54009384(+/-)-1-[3-(Benzhydrylidene-amino)-4-cyano-benzyl]-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2-carboxylic acid methyl esterYield 92%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 516892Sodium BicarbonateSolvent

Procedure

To a solution containing (±)-1-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-6-oxo-piperazine-2-carboxylic acid methyl ester (1.17 g, 2.6 mmol), EXAMPLE 784, Part B, 5-chlorothiophen-2-yloxyacetic acid (0.5 g, 2.6 mmol), EXAMPLE 24, and N-methylmorpholine (0.58 g, 5.72 mmol) in anhydrous DMF (10 mL) is added HATU (1.09 g, 2.86 mmol) at ambient temperature. After 1.5 h, the reaction mixture is diluted with CH2Cl2 (100 mL) and aqueous NaHCO3 (100 mL) and the layers are separated. The aqueous phase is washed four times with CH2Cl2 (100 mL) and the combined organic phase is washed once with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude amide is purified by flash silica gel chromatography (hexane/EtOAc, 4:1 to 1:2) to afford 1.5 g of the title compound which is used directly in the next reaction. 1H NMR (300 MHz, CDCl3, ˜2:1 mixture of rotomers) major rotomer: δ3.55 (d, J=15.2 Hz, 1H), 3.60 (m, 1H), 3.69 (m, 5H), 4.37 (d, J=17.7 Hz, 1H), 4.62 (m, 2H), 4.79 (d, J=13.3 Hz, 1H), 5.35 (d, J=15.2 Hz, 1H), 6.05 (d, J=3.9 Hz, 1H), 6.52 (m. 2H), 6.84 (d, J=8.1 Hz, 1H), 7.18-7.49 (m, 11H), 7.76 (m, 1H) ppm; MS (ISP loop): m/z 627 (M+H).

Workup

  1. customthe layers are separated
  2. washThe aqueous phase is washed four times with CH2Cl2 (100 mL)
  3. washthe combined organic phase is washed once with brine
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude amide is purified by flash silica gel chromatography (hexane/EtOAc, 4:1 to 1:2)

Sources & evidence

ORD record
ord-9e2bb215ffcc42a0bac4a9a95e2443cc
Source dataset
uspto-grants-2009_11
Patent number
US07612075B2

Reaction notes

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