Entecavir intermediate, synthetic method thereof and synthetic method for entecavir
AssigneeLaunch-Pharma Technologies, Ltd.
InventorsYehua Jin, Fayang Qiu, Hua Xu, Fang Wang
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Abstract
The disclosure relates to an entecavir intermediate, a synthetic method therefor, and the synthetic method for entecavir by using the intermediate. According to the disclosure, the synthetic methods for entecavir and the intermediate thereof have the advantages of being controllable in chirality, high in yield and product purity, wide in source of raw materials, cheap and available in reagents, simple in reactions, convenient to operate, environmentally friendly, and suitable for industrial amplification production.
Claims20
An entecavir intermediate, wherein the entecavir intermediate is selected from the following compounds
- wherein R is methyl or ethyl.
A synthetic method for the entecavir intermediate having the structure shown in Formula 10, comprising the following steps of:
- (c) reacting the compound of Formula 3 with an esterification reagent in the presence of a base to produce the compound of Formula 4;
- (d) epoxide reacting the compound of Formula 4 in the presence of an epoxide reagent to produce the compound of Formula 5;
- (e) epoxide ring-opening reacting the compound of Formula 5 under the action of an acid to produce the compound of Formula 6;
- (f) dihydroxy acetone reacting the compound of Formula 6 with a hydroxyl acetonide protection reagent under the action of an acid catalyst to produce the compound of Formula 7;
- (g) Favorskii rearrangement reacting the compound of Formula 7 under the action of the base to produce the compound of Formula 8;
- (h) reduction reacting the compound of Formula 8 under the action of a reducing agent to produce the compound of Formula 9;
- (i) removing the hydroxyl protecting group of the compound of Formula 9 under the catalysis of the acid, and oxidation reacting the compound of Formula 9 under the action of an oxidizing agent to produce the compound of Formula 10;
- and
- the reaction formulas are as follows:
- wherein R is methyl or ethyl.
A synthetic method for the entecavir intermediate having the structure shown in Formula 12, comprising the following steps of:
- (j) Baeyer-Villiger oxidative rearrangement reacting the compound of Formula 10 under the action of a base and peroxide to produce the compound of Formula 11;
- (k) epoxide reacting the compound of Formula 11 under the action of a catalyst and an oxidizing agent to produce the compound of Formula 12;
- and
- the reaction formulas are as follows:
A synthetic method for entecavir, comprising the following steps of:
- (l) protecting hydroxyl in the compound of Formula 12 to produce the compound of Formula 13;
- (m) epoxide isomerization reacting the compound of Formula 13 with an epoxide isomerization reagent to produce the compound of Formula 14;
- (n) reacting the compound of Formula 14 with the compound of Formula 16 under Mitsunobu reaction conditions to produce the compound of Formula 15;
- (o) carrying out a hydrolysis reaction on the compound of Formula 15, removing the hydroxyl protecting group and the amino protecting group thereof, and producing the compound of Formula 1 to give entecavir;
- and
- the reaction formulas are as follows:
- wherein R1 and R2 are protecting groups of the hydroxyl, and R1 and R2 are each independently selected from the protecting groups of the following classes:
- (1) silicyl, (2) alkyl, (3) alkoxymethyl, (4) benzyloxymethyl and substituted benzyloxymethyl, (5) alkoxyethyl, (6) benzyl and benzyl substituted by a phenyl ring, (7) acyl, (8) alkoxyacyl, and (9) siloxymethyl.
Dependencies are inferred from the claim text.