Dicyclohexylcarbodiimide → (R)-9-[4-(N-Cbz-L-valyloxy)-2-(stearoyloxymethyl)butyl]guanine

HRID 458292Notes

Reaction equation

HRID 458292 reaction equation
C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:26][C@H:27]([C:31]([OH:33])=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O[CH2:35][CH2:36][C@@H:37]([CH2:50][O:51][C:52](=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:38][N:39]1[CH:47]=[N:46][C:45]2[C:44](=[O:48])[NH:43][C:42]([NH2:49])=[N:41][C:40]1=2>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:19]([O:18][C:16]([NH:26][C@H:27]([C:31]([O:33][CH2:35][CH2:36][C@@H:37]([CH2:50][O:51][C:52](=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:38][N:39]1[CH:47]=[N:46][C:45]2[C:44](=[O:48])[NH:43][C:42]([NH2:49])=[N:41][C:40]1=2)=[O:32])[CH:28]([CH3:29])[CH3:30])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1

Participants

6

Reactant 3

HCID 10868DicyclohexylcarbodiimideHCID 726987N-Carbobenzoxy-L-valineHCID 135481053(R)-9-[4-hydroxy-2-(stearoyloxymethyl)butyl]guanine

Product 1

HCID 135829462(R)-9-[4-(N-Cbz-L-valyloxy)-2-(stearoyloxymethyl)butyl]guanine

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
20 °C

Procedure

A solution of dicyclohexylcarbodiimide (1500 g, 7.27 moles) in THF (7 L) was added to a reactor containing a mixture of N-carbobenzyloxy-L-valine (3630 g, 14.5 moles) in THF (20 L). The resulting mixture was stirred at 20±5° C. for 1–2 hours. The product of Example 30, step e) (2500 g, 4.81 moles) and 4-dimethylaminopyridine (59 g, 0.48 moles) were charged to a second reactor. To this second reactor was filtered the THF mixture from the first reactor, followed with a rinse of THF (15 L). The resulting mixture was stirred at 20±5° C. for 1–3 hours. Water (600 mL) was added and the solution was concentrated under vacuum at not more than 45° C. The residual oil was taken up in ethyl acetate (14 L) and filtered. The filtrate was washed successively with 10% aqueous sodium bicarbonate (2×14 L) and 10% brine (14 L). The organic phase was concentrated under vacuum and the residue was dissolved in methanol (10 kg) at 50–60° C. The warm solution was added gradually to a mixture of acetonitrile (30 kg) and water (13 kg) at ambient temperature. The mixture was stirred 1 hour at 15° C., then filtered to isolate the crude product, which was dried at 40° C. under vacuum to provide the desired product as a white solid (3.9 kg).

Workup

  1. additioncontaining
  2. filtrationTo this second reactor was filtered the THF mixture from the first reactor
  3. washa rinse of THF (15 L)
  4. stirringThe resulting mixture was stirred at 20±5° C. for 1–3 hours
  5. additionWater (600 mL) was added
  6. concentrationthe solution was concentrated under vacuum at not more than 45° C
  7. filtrationfiltered
  8. washThe filtrate was washed successively with 10% aqueous sodium bicarbonate (2×14 L) and 10% brine (14 L)
  9. concentrationThe organic phase was concentrated under vacuum
  10. dissolutionthe residue was dissolved in methanol (10 kg) at 50–60° C
  11. additionThe warm solution was added gradually to a mixture of acetonitrile (30 kg) and water (13 kg) at ambient temperature
  12. stirringThe mixture was stirred 1 hour at 15° C.
  13. filtrationfiltered
  14. customto isolate the crude product, which
  15. customwas dried at 40° C. under vacuum

Sources & evidence

ORD record
ord-0e0f511937ec44c5a993d47425194bc0
Source dataset
uspto-grants-2007_03
Patent number
US07189849B2

Reaction notes

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