Acetic Acid → 6-Fluoro-3-(2-methyl-pyridin-3-yl)-2-[(3-pyrrolidin-1-ylmethyl-phenylamino)-methyl]-3h-quinazolin-4-one

HRID 1169262Notes

Reaction equation

HRID 1169262 reaction equation
[CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[N:10]=[C:9]2[CH:20]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:22]1([CH2:27][C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:20][NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[C:28]([CH2:27][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH:29]=1)[N:8]([C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:17]2=[O:18]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 10964073-(Pyrrolidin-1-ylmethyl)anilineHCID 5049666Sodium triacetoxyborohydrideHCID 12088009HCID 12088009, compound

Product 1

HCID 104785826-Fluoro-3-(2-methyl-pyridin-3-yl)-2-[(3-pyrrolidin-1-ylmethyl-phenylamino)-methyl]-3h-quinazolin-4-one

Reagents, catalysts & solvents 1

HCID 63651,1-DichloroethaneSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of 3-(2-methyl-pyridin-3-yl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.158 g, 0.56 mmol), 3-pyrrolidin-1-ylmethylaniline (0.050 g, 0.28 mmol), and acetic acid (0.16 mL, 2.8 mmol) in dichloroethane (15 mL) was chilled to 0° C. and sodium triacetoxyborohydride (0.297 g, 1.4 mmol) was added. The reaction was stirred for 1 hour at 0° C. and then allowed to warm to ambient temperature and stirred for 16 hours. The reaction was quenched by addition of saturated aqueous bicarbonate and continued stirring for 30 minutes. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (35 g) with elution proceeding as follows: 10% methanol/0.5% ammonium hydroxide/chloroform (50 mL), nil; (75 mL), unweighed impurity; (50 mL), unweighed 3-(2-methyl-pyridin-3-yl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-methanol; (50 mL), unweighed mixed fraction; (100 mL), 0.031 g (25%) of 3-(2-methyl-pyridin-3-yl)-6-fluoro-2-[(3-pyrrolidin-1-ylmethyl-phenylamino)-methyl]-3H-quinazolin-4-one as a yellow foam which had: 1H NMR δ 8.72 (d, J=5 Hz, 1H), 7.92 (dd, J=3, 8 Hz, 1H), 7.82 (dd, J=5, 9 Hz, 1H), 7.58-7.52 (m, 2H), 7.39 (dd, J=5, 8 Hz, 1H), 7.08 (t, J=8 Hz, 1H), 6.67-6.64 (m, 2H), 6.37 (d, J=8 Hz, 1H), 5.10 (s, 1H), 3.90 (dd, J=4.5, 17 Hz, 1H), 3.70 (dd, J=5, 17 Hz, 1H), 3.56 (ABq, Δv1-3=21 Hz, J=12.5 Hz, 2H), 2.54 (s, 4H), 2.36 (s, 3H), 1.78 (s, 4H); APCI MS m/z=444 (P+1).

Workup

  1. temperatureto warm to ambient temperature
  2. stirringstirred for 16 hours
  3. customThe reaction was quenched by addition of saturated aqueous bicarbonate
  4. stirringcontinued stirring for 30 minutes
  5. customThe phases were separated
  6. extractionthe aqueous layer was extracted with methylene chloride
  7. washThe combined organic phase was washed with brine
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated
  10. customchromatographed on silica gel (35 g) with elution proceeding

Sources & evidence

ORD record
ord-78a2b0aa89174fc4b58b650b571eb1d3
Source dataset
uspto-grants-2003_09
Patent number
US06627755B1

Reaction notes

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