Intermediate and process for preparing entecavir using same
View Patent ↗The present invention relates to a novel, high-yield and low-cost method for preparing entecavir, [1-S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, an antiviral agent, and novel intermediates used therein.
1. A method of preparing entecavir of formula (1), comprising the steps of
(a) conducting olefination of an α-hydroxy ketone compound of formula (2) to obtain an exomethylene compound of formula (3);
(b) carrying out a Mitsunobu reaction of the exomethylene compound of formula (3) with a purine derivative to obtain a nucleoside compound of formula (4);
(c) removing the protecting groups of the nucleoside compound of formula (4) to obtain a compound of formula (5); and
(d) hydrolyzing the compound of formula (5):
wherein
R 1 and R 2 are each independently H or a hydroxy-protecting group, or R 1 and R 2 are fused together to form a cyclic hydroxy-protecting group;
R 3 is selected from the group consisting of H, alkylsilyl, and allylsilyl; and
X is selected from the group consisting of chloro, iodo, and benzyloxy.
2. The method of claim 1 , wherein the hydroxy-protecting group is selected from the group consisting of trityl, benzyl, methoxybenzyl, p-nitrobenzyl, benzoyl, a substituted benzoyl, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, thexyldimethylsilyl, allyl, methoxymethyl, (2-methoxyethoxy)methyl, and tetrahydropyranyl.
3. The method of claim 1 , wherein the cyclic hydroxy-protecting group is selected from the group consisting of benzylidene, naphthylidene, 4-phenylbenzylidene, cyclic acetal, cyclic ketal, cyclic carbonate, cyclic orthoester, and cyclic 1,3-(1,1,3,3-tetraisopropyl)disiloxanediyl.
4. The method of claim 1 , wherein the olefination is conducted by subjecting the α-hydroxy ketone compound of formula (2) to a reaction with a mixture of Nysted reagent and TiCl 4 , a Wittig reagent, or a Tebbe reagent.
5. The method of claim 1 , wherein the purine derivative is selected from the group consisting of a 2-amino-6-halopurine derivative of formula (12), a 6-O-benzylguanine derivative, and a mixture thereof:
wherein X is selected from the group consisting of chloro, iodo, and benzyloxy.
6. The method of claim 1 , wherein the compound of formula (2) is prepared by a method comprising the step of subjecting a ketone compound of formula (6) to a reaction with a sulfonate derivative in the presence of a base to obtain a silyl enolether of formula (7) and treating the silyl enolether of formula (7) with a peroxide:
wherein R 1 to R 3 are the same as described in claim 1 .
7. The method of claim 6 , wherein the sulfonate derivative is selected from the group consisting of tert-butyldimethylsilyl trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, and a mixture thereof.
8. The method of claim 6 , wherein the compound of formula (6) is prepared by a method comprising the steps of
conducting a chiral reduction reaction of a cyclopentenone compound of formula (8) with borane dimethylsulfide in the presence of (R)-methyl-CBS (Corey-Bakshi-Shibata) catalyst to obtain a chiral cyclopentenol compound of formula (9);
subjecting the resulting chiral cyclopentenol compound of formula (9) to a reaction with a silane derivative in the presence of a base, or removing the protecting groups of the chiral cyclopentenol compound of formula (9) followed by treating with a carbonyl or an alcohol derivative to obtain a cyclopentene compound of formula (10);
subjecting the resulting cyclopentene compound of formula (10) to a reaction with a borane derivative to obtain a cyclopentanol compound of formula (11); and
carrying out an oxidation reaction by treating cyclopentanol compound of formula (11) with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one:
wherein R 1 to R 2 are the same as described in claim 1 .
9. The method of claim 8 , wherein the silane derivative is selected from the group consisting of tert-butyldiphenylsilyl chloride, chlorotrimethylsilane, tert-butyldimethylchlorosilane, and a mixture thereof.
10. The method of claim 8 , wherein the carbonyl derivative is selected from the group consisting of naphthylaldehyde, naphthylaldehyde dimethylacetal, benzaldehyde, benzaldehyde dimethylacetal, 4-phenylbenzaldehyde, 4-phenylbenzaldehyde dimethylacetal, and a mixture thereof.