Water → HCID 90413919, compound

HRID 1746632Notes

Reaction equation

HRID 1746632 reaction equation
[CH2-:1][C:2]([CH3:4])=[O:3].[O:5]=[CH:6][C@@H:7]([C@@H:9]([C@@H:11]([CH2:13][OH:14])O)[OH:10])[OH:8].[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCCCCCC>[CH3:1][C:2]1([CH3:4])[O:10][C@@H:9]2[CH:7]([CH2:6][O:5][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:8][CH:13]([OH:14])[C@@H:11]2[O:3]1

Participants

8

Reactant 4

HCID 962WaterHCID 6456Trityl chloride2×HCID 8471TriethylamineHCID 178521087HCID 178521087, compound

Product 1

HCID 90413919HCID 90413919, compound

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×HCID 8900HeptaneSolvent

Conditions

Temperature
-7.5 °C

Procedure

To compound 1 (almost 120 kg) and 1590 kg DCM was added 152 kg of trityl chloride at −5 to −10° C. under nitrogen atm. in a 2000 L reactor and a solution of TEA (triethylamine) (71 kg) and DMAP (2.88 kg) in DCM 175 kg was slowly added. The reaction mixture was stirred at −5 to −10° C. for 32 hr and warmed to 15-20° C. (4° C./h) and kept at 15-20° C. for 12 h after which time LC-MS showed trityl chloride<2%. The reaction was quenched by 20 kg water, the organic phase was separated, dried and concentrated to a residue, and MTBE (methyl tert-butyl ether) (500 kg) was added, with stirring to result in a clear solution. Water (600 kg) was added, and the mixture was stirred for 3 h, then 500 kg heptane was added, cooled to −5° C.-0° C. and stirred for 3 h. A small amount of yellow solid precipitated, filtered by a centrifuge. Then the organic layer washed with saturated NH4Cl solution (600 kg), pH was adjusted with 0.5 N aqueous citric acid to pH=3-4, and the organic layer collected, dried with Na2SO4, filtered and concentrated under vacuum to get crude compound (2), (3aR,6aR)-2,2-dimethyl-6-((trityloxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-ol, as oil. This crude (2) (228.5 kg) was purified by silica gel column (1.0× of silica gel was used to pre-absorb the crude material, 2.3× of silica gel was used to pack the column), eluted by the solvent (EA (ethyl acetate): PE (petroleum ether)=1:8), to get 93 kg (four batches) of (2) dispersed in toluene (assay by HPLC).

Workup

  1. temperaturewarmed to 15-20° C. (4° C./h)
  2. waitkept at 15-20° C. for 12 h
  3. customThe reaction was quenched by 20 kg water
  4. customthe organic phase was separated
  5. customdried
  6. concentrationconcentrated to a residue, and MTBE (methyl tert-butyl ether) (500 kg)
  7. additionwas added
  8. stirringwith stirring
  9. customto result in a clear solution
  10. stirringthe mixture was stirred for 3 h
  11. temperaturecooled to −5° C.-0° C.
  12. stirringstirred for 3 h
  13. customA small amount of yellow solid precipitated
  14. filtrationfiltered by a centrifuge
  15. washThen the organic layer washed with saturated NH4Cl solution (600 kg)
  16. customthe organic layer collected
  17. dry with materialdried with Na2SO4
  18. filtrationfiltered
  19. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-cd7da9a8051447a09962c752bf34f3bf
Source dataset
uspto-grants-2015_10
Patent number
US09150520B2

Reaction notes

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