3-Hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylic acid benzyl ester → 2-[4-(2-Hydroxymethyl-piperazin-1-yl)-7-methyl-quinazolin-2-yl]-phenol

HRID 2062255Notes

Reaction equation

HRID 2062255 reaction equation
C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[N:18]=2)[CH:13]([CH2:35][OH:36])[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:36][CH2:35][CH:13]1[CH2:12][NH:11][CH2:16][CH2:15][N:14]1[C:17]1[C:26]2[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=2)[N:20]=[C:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])[N:18]=1

Participants

4

Reactant 1

HCID 1361213213-Hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylic acid benzyl ester

Product 1

HCID 1361213512-[4-(2-Hydroxymethyl-piperazin-1-yl)-7-methyl-quinazolin-2-yl]-phenol

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

To 3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylic acid benzyl ester (200 mg, 0.41 mmol) in 1.7 mL of methanol was added 39 mg of Pd/C (10% weight Pd on carbon). The reaction mixture was subjected to hydrogenation using a H2 balloon for 3 h. The reaction mixture was filtered through Celite and the solvent was removed to give 2-[4-(2-hydroxymethyl-piperazin-1-yl)-7-methyl-quinazolin-2-yl]-phenol. This amine was treated with (R)-2-hydroxy-4-methyl-pentanoic acid (60 mg, 0.45 mmol), BOP (200 mg, 0.45 mmol) and 115 μL of triethylamine in 1.6 mL of DMF at room temperature for 12 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and 20 mL of water, and the organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was subjected to purification using 60-100% EtOAc-hexanes to give (R)-2-hydroxy-1-{3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pentan-1-one. LC/MS: m/z 465 (M+H)+ at 2.77 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).

Workup

  1. customfor 3 h
  2. filtrationThe reaction mixture was filtered through Celite
  3. customthe solvent was removed

Sources & evidence

ORD record
ord-dd2936927f664f1ea671d7e9486ce33a
Source dataset
uspto-grants-2012_10
Patent number
US08283354B2

Reaction notes

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