Trifluoroacetic acid → HCID 178429774, compound
Reaction equation
[CH2:1]=[C:2]1[C@H:6]([CH2:7][OH:8])[C@@H:5]([OH:9])[CH2:4][C@@H:3]1[N:10]1[C:14]2[N:15]=[C:16]([NH2:20])[NH:17][C:18](=[O:19])[C:13]=2[N:12]=[CH:11]1.C(O)(C(F)(F)F)=[O:22]>>[CH2:1]=[C:2]1[C@H:6]([CH2:7][OH:8])[C@@H:5]([OH:9])[CH2:4][C@@H:3]1[N:10]1[C:14]2[NH:15][C:16]([NH2:20])=[N:17][C:18](=[O:19])[C:13]=2[N:12]=[CH:11]1.[OH2:22]Participants
Procedure
Finally, M6 (e.g., ethylidene protection) was converted to entecavir with high reactivity in the presence of aqueous TFA solution or other aqueous organic/inorganic acid solutions. After purification, the desired entecavir monohydrate was obtained with high quality in high yield. The use of crystalline intermediates within our synthetic process for entecavir allows the manufacture of high quality API since the quality can be controlled at the various intermediates. This reaction may be carried out at 70° C. for about 1 hour. Two steps, namely, neutralization (e.g., using TFA) and extraction, may be needed in making entecavir monohydrate from M6. The yield is relatively high (e.g., 70%). The purification of entecavir monohydrate may be conducted through crystallization from water and methanol. In contrast, in BMS′ process, three steps are needed to make entecavir monohydrate from BMS′s compound 57, which corresponds to M6 of the present application, and the yield is relatively low (32.4%).
Workup
- customAfter purification
Sources & evidence
- ORD record
- ord-8f3fe8abda784147b553a357a76420bd
- Source dataset
- uspto-grants-2013_07
- Patent number
- US08481728B2
Reaction notes
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