Methanol → 2',3'-Di-O-acetyl-5'-deoxy-5-fluoro-N4-(3,7,11,15-Tetramethyl-hexadecyl oxycarbonyl)cytidine

HRID 1910409Notes

Reaction equation

HRID 1910409 reaction equation
[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([F:23])[C:19]([NH2:20])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2].Cl[C:25]([O:27][CH2:28][CH2:29][CH:30]([CH3:47])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[O:26].CO>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([F:23])[C:19]([NH:20][C:25]([O:27][CH2:28][CH2:29][CH:30]([CH3:47])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[O:26])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2]

Participants

6

Reactant 3

HCID 887MethanolHCID 118096352',3'-di-O-acetyl-5'-deoxy-5-fluorocytidineHCID 585385033,7,11,15-Tetramethyl-hexadecyl chloroformate

Product 1

HCID 675449462',3'-Di-O-acetyl-5'-deoxy-5-fluoro-N4-(3,7,11,15-Tetramethyl-hexadecyl oxycarbonyl)cytidineYield 86.2%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 6344DichloromethaneSolvent

Procedure

To the ice-cooled solution containing 2′,3′-Di-O-acetyl-5′-deoxy-5-fluoroocytidine (5) (9.76 g, 29.64 mmol) in dry CH2Cl2 (40 ml) and anhydrous pyridine (5 ml), phytanyl chloroformate (12 g, 33 mmol) (6a) was added dropwise in order to keep the low reaction temperature. After stirring the mixture for overnight at room temperature, MeOH (1.3 ml) was added in one portion to stop the reaction. The mixture was evaporated to a syrup mass under reduced pressure. To this residue, diethyl ether (50 ml) was added and the suspension was stirred for 30 min at room temperature. The insoluble precipitate was filtered through a glass filter. The precipitate was washed with 30 ml of diethyl ether. The filtrate and the washings were collected, dried over anhydrous Na2SO4, and evaporated to dryness. The crude target compound was further purified using silica column chromatography CH2Cl2:MeOH=5:1 to give 2′,3′-Di-O-acetyl-5′-deoxy-5-fluoro-N4-(phytanyloxycarbonyl)cytidine (16.7 g, 84.1%) (7a). 1H NMR in CDCl3: δ0.83, 0.85, 0.86, 0.88 (4s, each 3H, CH3), 0.91 (d, 3H, J=6.6 Hz, CH3), 0.96-1.88 (m, 24H, CH2+CH), 1.47 (d, 3H, J=6.6 Hz, H-5), 2.10, 2.12 (2s, each 3H, OMe), 4.13-4.37 (m, 3H, H-4+CH2OC═ONH), 5.01 (t, 1H, J=5.4 Hz, H-2), 5.29 (t, 1H, J=5.8 Hz, H-3), 5.96 (d, 1H, J=3.8 Hz, H-1), 7.39 (br s, 1H, N—CH═C—F).

Workup

  1. additionwas added dropwise in order
  2. customthe reaction
  3. customThe mixture was evaporated to a syrup mass under reduced pressure
  4. additionTo this residue, diethyl ether (50 ml) was added
  5. stirringthe suspension was stirred for 30 min at room temperature
  6. filtrationThe insoluble precipitate was filtered through a glass
  7. filtrationfilter
  8. washThe precipitate was washed with 30 ml of diethyl ether
  9. customThe filtrate and the washings were collected
  10. dry with materialdried over anhydrous Na2SO4
  11. customevaporated to dryness
  12. customThe crude target compound was further purified

Sources & evidence

ORD record
ord-b780daf6d72144c08c519c2c7ca2caec
Source dataset
uspto-grants-2013_12
Patent number
US08603999B2

Reaction notes

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