N,N'-dicyclohexyl-4-morpholinecarboxamidine → Hexadecyloxypropyl-cyclic cidofovir

HRID 624684Notes

Reaction equation

HRID 624684 reaction equation
[CH2:1]1[O:7][P:5]([OH:8])(=[O:6])[CH2:4][O:3][C@H:2]1[CH2:9][N:10]1[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[CH:12]=[CH:11]1.C1(NC(N2CCOCC2)=NC2CCCCC2)CCCCC1.Br[CH2:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]>>[CH3:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][CH2:40][O:6][P:5]1([O:7][CH2:1][C@H:2]([CH2:9][N:10]2[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[CH:12]=[CH:11]2)[O:3][CH2:4]1)=[O:8]

Participants

4

Reactant 3

HCID 21079N,N'-dicyclohexyl-4-morpholinecarboxamidineHCID 122873Cyclic HPMPCHCID 146546451-(3-Bromopropoxy)hexadecane

Product 1

HCID 483474Hexadecyloxypropyl-cyclic cidofovirYield 25%

Conditions

Temperature
80 °C

Procedure

To a heterogeneous solution of cyclic cidofovir (39 g, 0.131 mol., 1 equiv, purchased from Gilead Sciences) in N,N-DMF (2.0 L) under a nitrogen atmosphere was added N,N′-dicyclohexyl-4-morpholinecarboxamidine (DCMC) (0.131 mol, 38.51 g, 1 equiv.). This was stirred overnight. This dissolved most of the solid in the reaction mixture. To this solution was added 1-bromo-3-hexadecyloxypropane (238.45 g, 0.656 mol, 5 equiv.). The reaction mixture was heated to 80° C. and stirred for 6 hours. The crude reaction mixture was concentrated in vacuo at 80° C. The crude reaction mixture was absorbed on silica gel (300 g) and purified via column chromatography (800 g SiO2). The column was eluted with dichloromethane (6 L) to remove the excess 1-bromo-3-hexadecyloxypropane. The solvent phase was then switched to 9:1 CH2Cl2:EtOH (32 L). The product came off with this solvent system. Fractions 30-39 were combined to give hexadecyloxypropyl-cyclic cidofovir (17.8 g) in a 25% yield.

Workup

  1. dissolutionThis dissolved most of the solid in the reaction mixture
  2. stirringstirred for 6 hours
  3. customThe crude reaction mixture
  4. concentrationwas concentrated in vacuo at 80° C
  5. customThe crude reaction mixture
  6. customwas absorbed on silica gel (300 g)
  7. custompurified via column chromatography (800 g SiO2)
  8. washThe column was eluted with dichloromethane (6 L)
  9. customto remove the excess 1-bromo-3-hexadecyloxypropane

Sources & evidence

ORD record
ord-84376b9c88774c4e9a8cb86a91f2ce9c
Source dataset
uspto-grants-2016_04
Patent number
US09303051B2

Reaction notes

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