4-Methylmorpholine → (+/-)-1-(4-Amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-carboxylic acid amide

HRID 1433019Notes

Reaction equation

HRID 1433019 reaction equation
[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[C:18](=[O:19])[CH2:17][N:16]([S:20]([C:23]4[S:27][C:26]5[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:25]=5[CH:24]=4)(=[O:22])=[O:21])[CH2:15][CH:14]3[C:33](O)=[O:34])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C[N:37]1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.N>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[C:18](=[O:19])[CH2:17][N:16]([S:20]([C:23]4[S:27][C:26]5[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:25]=5[CH:24]=4)(=[O:21])=[O:22])[CH2:15][CH:14]3[C:33]([NH2:37])=[O:34])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1

Participants

6

Reactant 3

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 17985189(+/-)-1-(4-Amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-carboxylic acid

Product 1

HCID 54450058(+/-)-1-(4-Amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-carboxylic acid amideYield 58.9%

Reagents, catalysts & solvents 2

HCID 222AmmoniaCatalystHCID 6228DimethylformamideSolvent

Procedure

To a mixture containing (±)-1-(4-amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-carboxylic acid (45 mg, 0.08 mmol), EXAMPLE 800, N-methylmorpholine (18 mg, 0.18 mmol), and HATU (35 mg, 0.09 mmol) in anhydrous DMF (1 mL) is added NH3 (7N in MeOH, 2 drops, approx. 0.5 mmol). The heterogeneous mixture is stirred 16 h at ambient temprature and then concentrated to dryness. The residue is dissolved in water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 25 mg (46%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.63 (d, J=16.0 Hz, 1H), 4.01 (m, 4H), 5.17 (d, J=16.6 Hz, 1H), 7.58 (m, 3H), 8.08 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.26 (d, J=8.6 Hz, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.74 (s, 1H), 9.63 (br s, 2H) ppm; MS (ISP loop): m/z 531 (M+H).

Workup

  1. concentrationconcentrated to dryness
  2. dissolutionThe residue is dissolved in water
  3. custompurified by reverse-phase HPLC [Buffer A: water

Sources & evidence

ORD record
ord-d461fa8fde0445829d4390266c7430c8
Source dataset
uspto-grants-2009_11
Patent number
US07612075B2

Reaction notes

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