Sodium Bicarbonate → Letermovir

HRID 2410228Notes

Reaction equation

HRID 2410228 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 86633820HCID 86633820, compound

Product 1

HCID 45138674LetermovirYield 85%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

(2S,3S)-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) (10.1 g, containing 14 ppm of Pd) are suspended in ethyl acetate (100 ml) and shaken with saturated aqueous sodium bicarbonate solution (100 ml) until both phases are clear. The phases are separated and the organic phase is concentrated in a rotary evaporator. The residue is dissolved in 1,4-dioxane (100 ml) and 1N sodium hydroxide solution (31.2 ml) and stirred at room temperature for 3 h. Subsequently, the pH is adjusted to 7.5 using 1N hydrochloric acid (ca. 17 ml), MIBK (80 ml) is added, then the pH is readjusted to 7.0 using 1N hydrochloric acid (ca. 2 ml). The phases are separated, and the organic phase is dried over sodium sulphate and concentrated. The residue is dissolved in ethanol (40 ml) and concentrated, then dissolved in ethanol (40 ml) again and concentrated and dried at 50° C. in a high vacuum. The solidified foam is dried at 45° C. for 18 h in the VDO using entraining nitrogen. A total of 5.05 g of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid are obtained as an amorphous solid, corresponding to 85.0% of theory.

Workup

  1. customThe phases are separated
  2. concentrationthe organic phase is concentrated in a rotary evaporator
  3. dissolutionThe residue is dissolved in 1,4-dioxane (100 ml)
  4. additionis added
  5. customThe phases are separated
  6. dry with materialthe organic phase is dried over sodium sulphate
  7. concentrationconcentrated
  8. dissolutionThe residue is dissolved in ethanol (40 ml)
  9. concentrationconcentrated
  10. dissolutiondissolved in ethanol (40 ml) again
  11. concentrationconcentrated
  12. customdried at 50° C. in a high vacuum
  13. customThe solidified foam is dried at 45° C. for 18 h in the VDO

Sources & evidence

ORD record
ord-31fdd7477425446a8e909e3bae047c3c
Source dataset
uspto-grants-2014_08
Patent number
US08816075B2

Reaction notes

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