1,1'-Carbonyldiimidazole → 4-(4-Amino-quinazolin-7-ylmethyl)-3-oxo-piperazine-1-carboxylic acid 5-chloro-thiophen-2-ylmethyl ester

HRID 1432970Notes

Reaction equation

HRID 1432970 reaction equation
[Cl:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=1.[C:9](N1C=CN=C1)(N1C=CN=C1)=[O:10].[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][C:34]3=[O:39])=[CH:29][CH:30]=2)[N:25]=[CH:24][N:23]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.O.CO>[Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]([N:36]2[CH2:37][CH2:38][N:33]([CH2:32][C:28]3[CH:27]=[C:26]4[C:31]([C:22]([NH2:21])=[N:23][CH:24]=[N:25]4)=[CH:30][CH:29]=3)[C:34](=[O:39])[CH2:35]2)=[O:10])=[CH:4][CH:3]=1

Participants

7

Reactant 3

HCID 682631,1'-CarbonyldiimidazoleHCID 12554178(5-Chlorothiophen-2-yl)methanolHCID 179851741-(4-Aminoquinazoline-7-ylmethyl)piperazine-2-one

Product 1

HCID 541684024-(4-Amino-quinazolin-7-ylmethyl)-3-oxo-piperazine-1-carboxylic acid 5-chloro-thiophen-2-ylmethyl ester

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolventHCID 22242641Methanol--water (1/1)Solvent

Procedure

To a solution of 5-chloro-2-thiophene-methanol (0.10 g, 0.67 mmol, prepared by NaBH4 reduction of 5-chloro-2-thiophene-carboxaldehyde) in 6 mL of CH2Cl2 is added 1,1′-carbonyldiimidazole (0.11 g, 0.67 mmol). The mixture is stirred at room temperature for 3 hours. Then 1-(4-aminoquinazoline-7-ylmethyl)piperazine-2-one (0.17 g, 0.67 mmol, EXAMPLE 72) and a catalytic amount of DMAP is added to the solution and the resulting mixture is heated at 35° C. for 18 hours. The mixture is dissolved in water/MeOH and the crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN. The appropriate fractions are combined and lyoppholized to provide the title compound as a white solid. ESI MS, [M+H]+=432,434 (Cl pattern).

Workup

  1. temperaturethe resulting mixture is heated at 35° C. for 18 hours
  2. customthe crude product is purified by RP-HPLC
  3. washeluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN

Sources & evidence

ORD record
ord-9adc40a79db74eb884011a7a4f14d6d2
Source dataset
uspto-grants-2009_11
Patent number
US07612075B2

Reaction notes

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