1-Hydroxybenzotriazole → HCID 68504999, compound

HRID 1712003Notes

Reaction equation

HRID 1712003 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[C:11]([N:23]3[CH2:28][CH2:27][CH:26]([NH:29][CH3:30])[CH2:25][CH2:24]3)[N:10]=2)=[C:4]([F:31])[CH:3]=1.C(OC([N:39]1[CH2:46][CH2:45][CH2:44][C@H:40]1[C:41]([OH:43])=O)=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[C:11]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]([CH3:30])[C:41](=[O:43])[C@@H:40]4[CH2:44][CH2:45][CH2:46][NH:39]4)[CH2:27][CH2:28]3)[N:10]=2)=[C:4]([F:31])[CH:3]=1

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 850831,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)-HCID 516892Sodium BicarbonateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 68509908HCID 68509908, compound

Product 1

HCID 68504999HCID 68504999, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

N-(4-chloro-2-fluorophenyl)-6,7-dimethoxy-2-[4-(methylamino)piperidin-1-yl]quinazoline-4-amine (445 mg), 1-(tert-butoxycarbonyl)-L-proline (323 mg), HOBt (135 mg) and EDCI hydrochloride (290 mg) were added in that order to DMF (10 mL), followed by stirring at room temperature for 24 hours. Ethyl acetate and a saturated sodium bicarbonate aqueous solution were added to the reaction solution, and the organic layer was separated. Next, the organic layer was washed with saturated brine, dried over magnesium sulfate and then filtered. The solvent was evaporated under a reduced pressure. By purifying the residue by silica gel flash column chromatography (chloroform-MeOH), N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N-methyl-L-prolinamide was obtained. This was dissolved in ethyl acetate (10 mL), and 4 M HCl/ethyl acetate solution (0.5 mL) was added thereto. By evaporating the solvent under a reduced pressure and recrystallizing the resulting residue from EtOH-diethyl ether, N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N-methyl-L-prolinamide dihydrochloride (481 mg) was obtained as pale yellow powder.

Workup

  1. customthe organic layer was separated
  2. washNext, the organic layer was washed with saturated brine
  3. dry with materialdried over magnesium sulfate
  4. filtrationfiltered
  5. customThe solvent was evaporated under a reduced pressure
  6. customBy purifying the residue by silica gel flash column chromatography (chloroform-MeOH)

Sources & evidence

ORD record
ord-e5fad0c63e814ce5a0fbd395fbf38b8a
Source dataset
uspto-grants-2010_09
Patent number
US07790884B2

Reaction notes

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