Sodium Bicarbonate → Letermovir

HRID 387190Notes

Reaction equation

HRID 387190 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 81.2%

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) (25.1 g) are suspended in ethyl acetate (250 ml) and shaken with saturated aqueous sodium bicarbonate solution (250 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 (250 ml) and 1N sodium hydroxide solution (77.4 ml) and stirred at room temperature for 18 h. Subsequently, the pH is adjusted to 7.5 using 1N hydrochloric acid (ca. 50 ml), MIBK (240 ml) is added, then the pH is readjusted to 7.0 using 1N hydrochloric acid (ca. 15 ml). The phases are separated, and the organic phase is dried over sodium sulphate and concentrated. The residue is dissolved in ethanol (90 ml) and concentrated, then again dissolved in ethanol (90 ml) and concentrated. The solidified foam is dried at 45° C. for 18 h in the VDO using entraining nitrogen. A total of 12 g of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydro-quinazolin-4-yl}acetic acid are thus obtained as an amorphous solid, corresponding to 81.2% 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 (250 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 (90 ml)
  9. concentrationconcentrated
  10. dissolutionagain dissolved in ethanol (90 ml)
  11. concentrationconcentrated
  12. customThe solidified foam is dried at 45° C. for 18 h in the VDO

Sources & evidence

ORD record
ord-fa6713229acd4e5c83b374f9ac4fab39
Source dataset
uspto-grants-2013_02
Patent number
US08372972B2

Reaction notes

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