Acetic Acid → 4-N-Benzoyl-5'-O-(tert-butyldimethylsilyl)-3'-O-methylthiomethyl-5-[3-(2,2,2-trifluoroacetamido)-prop-1-ynyl]-2'-deoxycytidine

HRID 2273461Notes

Reaction equation

HRID 2273461 reaction equation
[C:1]([NH:9][C:10]1[C:30]([C:31]#[C:32][CH2:33][NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[CH:29][N:13]([C@@H:14]2[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:41])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+].[CH3:58][S:59]([CH3:61])=O>>[C:1]([NH:9][C:10]1[C:30]([C:31]#[C:32][CH2:33][NH:34][C:35](=[O:40])[C:36]([F:37])([F:38])[F:39])=[CH:29][N:13]([C@@H:14]2[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[C@@H:16]([O:17][CH2:58][S:59][CH3:61])[CH2:15]2)[C:12](=[O:41])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 5

HCID 176Acetic AcidHCID 679Dimethyl SulfoxideHCID 7918Acetic AnhydrideHCID 516892Sodium BicarbonateHCID 866136124-N-Benzoyl-5'-O-(tert-butyldimethylsilyl)-5-[3-(2,2,2-trifluoroacetamido)-prop-1-ynyl]-2'-deoxycytidine

Product 1

HCID 866642624-N-Benzoyl-5'-O-(tert-butyldimethylsilyl)-3'-O-methylthiomethyl-5-[3-(2,2,2-trifluoroacetamido)-prop-1-ynyl]-2'-deoxycytidineYield 50%

Procedure

The starting material (13) (2.85 g, 4.79 mmol) was dissolved in dry DMSO (40 ml) under N2 atmosphere. Acetic acid (2.7 ml, 47.9 mmol) and acetic anhydride (14.4 ml, 143.7 mmol) were added sequentially and slowly to the starting material, which was then stirred for 18 h at room temperature. Saturated NaHCO3 (150 ml) solution was carefully added to the reaction mixture. The aqueous layer was extracted with EtOAc (3×150 ml). The organic layers were combined, dried (MgSO4), filtered and evaporated to yield an orange liquid that was subsequently azeotroped with toluene (4×150 ml) until material solidified. Crude residue purified on silica gel (petroleum ether:EtOAc 3:1 to 2:1) to yield a yellow crystalline solid (14) (1.58 g, 50%). 1H NMR (d6 DMSO): δ 0.00 (s, 6H, CH3), 0.78 (s, 9H, tBu), 1.99 (s, 3H, CH3), 2.09 (m, 1H, H-2′), 2.28 (m, 1H, H-2′), 3.66 (d, 1H, J=11.5, 2.9 Hz, H-5′), 3.74 (dd, 1H, J=11.3, 2.9 Hz, H-5′), 3.99 (m, 1H, H-4′), 4.09 (m, 1H, CH2NH), 4.29 (m, 1H, H-3′), 4.61 (s, 2H, CH2S), 6.00 (m, 1H, H-1′), 7.37 (m, 2H, Ph), 7.50 (m, 2H, Ph), 7.80 (d, 1H, J=7.55 Hz, HAr), 7.97 (s, 1H, H-6), 9.79 (br t, 1H, NHCH2), 12.64 (br s, 1H, NH). Mass (−ve electrospray) calcd for C29H37F3N4O6SSi 654.79. found 653.2.

Workup

  1. extractionThe aqueous layer was extracted with EtOAc (3×150 ml)
  2. dry with materialdried (MgSO4)
  3. filtrationfiltered
  4. customevaporated
  5. customto yield an orange liquid that
  6. customwas subsequently azeotroped with toluene (4×150 ml) until material
  7. customCrude residue purified on silica gel (petroleum ether:EtOAc 3:1 to 2:1)

Sources & evidence

ORD record
ord-c365451358cb4b03bdf269bd28dbafcc
Source dataset
uspto-grants-2015_09
Patent number
US09121060B2

Reaction notes

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