Sodium Bicarbonate → (R)-2-(8-Fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetic acid

HRID 2410229Notes

Reaction equation

HRID 2410229 reaction equation
CC1C=CC(C(O[C@H]([C@@H](OC(=O)C2C=CC(C)=CC=2)C(O)=O)C(O)=O)=O)=CC=1.[F:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[C:37]([N:40]1[CH2:45][CH2:44][N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=3)[CH2:42][CH2:41]1)[N:36]([C:54]1[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[CH:56][C:55]=1[O:64][CH3:65])[CH:35]2[CH2:66][C:67]([O:69]C)=[O:68].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[C:37]([N:40]1[CH2:41][CH2:42][N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=3)[CH2:44][CH2:45]1)[N:36]([C:54]1[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[CH:56][C:55]=1[O:64][CH3:65])[C@@H:35]2[CH2:66][C:67]([OH:69])=[O:68]

Participants

4

Reactant 2

HCID 516892Sodium BicarbonateHCID 86633821(2R,3R)-2,3-Bis[(4-methylbenzoyl)oxy]succinic acid methyl {8-fluoro-2-[4-(3-methoxyphenyl)-piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate

Product 1

HCID 57857528(R)-2-(8-Fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetic acidYield 91.6%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

(2R,3R)-2,3-Bis[(4-methylbenzoyl)oxy]succinic acid-methyl {8-fluoro-2-[4-(3-methoxyphenyl)-piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (1:1 salt) (170 g) are suspended in ethyl acetate (850 ml) and shaken with saturated aqueous sodium bicarbonate solution (850 ml) until both phases are clear (ca. 5 min.). The phases are separated, and the solvent of the organic phase is replaced at normal pressure with 1,4-dioxane up to a final temperature of 99° C. (a total of 2.55 l of solvent is distilled off and 2.55 l of 1,4-dioxane are employed in portions). The mixture is cooled to room temperature and stirred at room temperature for 18 h with 1N sodium hydroxide solution (525 ml). Subsequently, the pH is adjusted to 7.5 using concentrated hydrochloric acid (ca. 35 ml), MIBK (850 ml) is added, then the pH is readjusted to 7.0 using concentrated hydrochloric acid (ca. 10 ml). The phases are separated, and the organic phase is dried over sodium sulphate and concentrated. The residue is dissolved in ethanol (350 ml) and concentrated, then again dissolved in ethanol (350 ml) and concentrated at 50° C. A total of 91.6 g of (R)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid are thus obtained as an amorphous solid, corresponding to 91.6% of theory.

Workup

  1. custom(ca. 5 min.)
  2. customThe phases are separated
  3. customtemperature of 99° C.
  4. distillationis distilled off
  5. additionis added
  6. customThe phases are separated
  7. dry with materialthe organic phase is dried over sodium sulphate
  8. concentrationconcentrated
  9. dissolutionThe residue is dissolved in ethanol (350 ml)
  10. concentrationconcentrated
  11. dissolutionagain dissolved in ethanol (350 ml)
  12. concentrationconcentrated at 50° C

Sources & evidence

ORD record
ord-3d5fd9db6f6f4c02a064546ce75f4366
Source dataset
uspto-grants-2014_08
Patent number
US08816075B2

Reaction notes

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