Triethylamine → (r)-2-Hydroxy-1-{3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pentan-1-one

HRID 2062256Notes

Reaction equation

HRID 2062256 reaction equation
[OH:1][CH2:2][CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[N:12]=[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[N:10]=1.[OH:27][C@H:28]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:29](O)=[O:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.O>[OH:27][C@H:28]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:29]([N:7]1[CH2:6][CH2:5][N:4]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[N:10]=2)[CH:3]([CH2:2][OH:1])[CH2:8]1)=[O:30]

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 439960(R)-2-hydroxy-4-methylpentanoic acidHCID 1361213512-[4-(2-Hydroxymethyl-piperazin-1-yl)-7-methyl-quinazolin-2-yl]-phenol

Product 1

HCID 136121485(r)-2-Hydroxy-1-{3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pentan-1-one

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

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. customthe organic layer was separated
  2. dry with materialdried over Na2SO4
  3. customThe solvent was removed under reduced pressure
  4. customthe residue was subjected to purification

Sources & evidence

ORD record
ord-61026de91cb9458ab363aba1ee03d4fb
Source dataset
uspto-grants-2012_10
Patent number
US08283354B2

Reaction notes

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