Sodium Methoxide → 4-Quinazolineacetic acid, 8-fluoro-3,4-dihydro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-

HRID 661332Notes

Reaction equation

HRID 661332 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[C@@H:7]2[CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>C(#N)C.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:16][CH2:17]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[CH:7]2[CH2:38][C:39]([OH:41])=[O:40]

Participants

5

Reactant 2

HCID 10942334Sodium MethoxideHCID 57857528(R)-2-(8-Fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetic acid

Product 1

HCID 99160994-Quinazolineacetic acid, 8-fluoro-3,4-dihydro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-Yield 108.4%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6342AcetonitrileSolvent

Procedure

(R)-{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid (50 g) is dissolved in acetonitrile (500 ml) and treated with sodium methoxide (30% strength in methanol, 32.4 ml) and then stirred under reflux for 60 h. After cooling to room temperature, the mixture is concentrated to one half in vacuo, then it is adjusted to pH 7.5 using hydrochloric acid (20% strength, ca. 20 ml), MIBK (200 ml) is added and it is readjusted to pH 7 using hydrochloric acid (20% strength). The phases are separated, and the organic phase is dried over sodium sulphate and concentrated in a rotary evaporator to give a hard foam. The residue is dissolved in ethanol (150 ml) and concentrated, then again dissolved in ethanol (150 ml) and concentrated. A total of 54.2 g of (±)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid are thus obtained in quantitative yield as an amorphous solid.

Workup

  1. temperatureunder reflux for 60 h
  2. concentrationthe mixture is concentrated to one half in vacuo
  3. additionis added
  4. customThe phases are separated
  5. dry with materialthe organic phase is dried over sodium sulphate
  6. concentrationconcentrated in a rotary evaporator
  7. customto give a hard foam
  8. concentrationconcentrated
  9. dissolutionagain dissolved in ethanol (150 ml)
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-900511dee02c4065a2f5f782598b1b7d
Source dataset
uspto-grants-2011_12
Patent number
US08084604B2

Reaction notes

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