Trityl chloride → HCID 68562783, compound

HRID 1292421Notes

Reaction equation

HRID 1292421 reaction equation
[NH2:1][C:2]1[NH:3][C:4](=[O:18])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[C:9]=2[N:10]=1.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:19]([N:3]1[C:4](=[O:18])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH:13]([CH2:16][O:17][C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:14][OH:15])[C:9]=2[N:10]=[C:2]1[NH2:1])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1

Participants

6

Reactant 3

HCID 6456Trityl chlorideHCID 135398740GanciclovirHCID 178418321HCID 178418321, compound2×

Product 1

HCID 68562783HCID 68562783, compoundYield 63.2%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent3×

Conditions

Temperature
50 °C

Procedure

2-(2-Amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol (ganciclovir) was bis-tritylated at the N and O functionalities as follows: to a slurry of 4.1 kg ganciclovir, 9.5 g DMAP, and 8.65 kg TEA in dimethylformamide (38.3 kg ) at 50° C. was added a solution of 11.9 kg trityl-chloride in 38.2 kg dimethylformamide over 25 minutes. The reaction mixture was heated and stirred at 50° C. overnight. The following morning the reaction was complete by HPLC. This yields a mixture of N-trityl-ganciclovir, O-trityl-ganciclovir, N,O-bis-trityl-ganciclovir, and tris-trityl-ganciclovir in a approximate ratio of mono to bis to tri-substituted ganciclovir of 1:2:1. The tris-trityl-ganciclovir which is dimethylformamide insoluble is then filtered from the dimethylformamide mixture by cooling the reaction mixture to 10° C. and filtering out the tris-trityl-ganciclovir. The tris-tritylated-ganciclovir was washed with 10 kg dimethylformamide, and the transfer lines were washed with 2.3 kg dimethylformamide. The mono- and bis-tritylated-ganciclovir were then precipitated from this dimethylformamide solution by warming the bistrityl-ganciclovir/monotrityl-ganciclovir/dimethylformamide solution to 20° C. and adding 90 kg water over 1 hour. An additional 60 kg water was then added. Some purification of the bistrityl-ganciclovir from the monotrityl-ganciclovir occurs at this point. The temperature of the above mixture rose to 32° C. The mixture was seeded with 0.5 g of N,O-bistrityl-ganciclovir and allowed to age overnight at room temperature. The following morning crystals had formed. The solid was filtered out. Further purification of the bis-trityl-ganciclovir was achieved by washing the solid with 50 kg of water and then with 21 kg of ethyl acetate. The solid was dried under a stream of nitrogen overnight and then in a vacuum oven (~50° C., ~650 millitorr, nitrogen sweep) for 4 days. Yield: 63.2%. Weight: 7.51 kg. HPLC: greater than 90% N,O-bistrityl-ganciclovir, impurities 1.8%.

Workup

  1. temperatureThe reaction mixture was heated
  2. customThis yields
  3. filtrationis then filtered from the dimethylformamide mixture
  4. temperatureby cooling the reaction mixture to 10° C.
  5. filtrationfiltering out the tris-trityl-ganciclovir
  6. washThe tris-tritylated-ganciclovir was washed with 10 kg dimethylformamide
  7. washthe transfer lines were washed with 2.3 kg dimethylformamide
  8. customThe mono- and bis-tritylated-ganciclovir were then precipitated from this dimethylformamide solution
  9. temperatureby warming the bistrityl-ganciclovir/monotrityl-ganciclovir/dimethylformamide solution to 20° C.
  10. additionadding 90 kg water over 1 hour
  11. additionAn additional 60 kg water was then added
  12. customSome purification of the bistrityl-ganciclovir from the monotrityl-ganciclovir
  13. customrose to 32° C
  14. customallowed to age overnight at room temperature
  15. customThe following morning crystals had formed
  16. filtrationThe solid was filtered out
  17. customFurther purification of the bis-trityl-ganciclovir
  18. washby washing the solid with 50 kg of water
  19. customThe solid was dried under a stream of nitrogen overnight
  20. waitin a vacuum oven (~50° C., ~650 millitorr, nitrogen sweep) for 4 days

Sources & evidence

ORD record
ord-94ad610b4ed54d8e8fc7a7d4be9e6380
Source dataset
uspto-grants-1998_05
Patent number
US05756736

Reaction notes

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