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US 9,309,249 B2Granted
Entecavir synthesis method and intermediate compound thereof
AssigneeZhejiang Ausun Pharmaceutical Co., Ltd.
InventorZhiguo Zheng
Life of this patent
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Abstract
The present invention relates to a preparation method for a medicine and an intermediate compound thereof, specifically, relates to a preparation method for entecavir, an intermediate compound thereof, and a synthesis method for the intermediate compound.
Claims27
A method for preparation of the compound of formula 1,
- comprising the following steps:
- reacting compound 4
- with 2-protected amino-6-substituted purine compound 5
- to give the coupling reaction product 6
- wherein
- R1 and R2, which are the same or different, are independently selected from hydroxy-protecting groups of the following Groups (i) to (iii):
- (i) R1 and R2, independent of each other, are selected from alkyl, halo-alkyl, benzyl, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si or Et3Si;
- or
- (ii) R1 and R2, independent of each other, are selected from t-BuMe2Si, t-BuPh2Si, benzoyl, tetrahydropyran-2-yl, benzoyl in which the phenyl ring bears substituent(s), and biphenyl-4-formyl, provided that R1 and R2 are not both t-BuMe2Si;
- R and R′, which are the same or different, are independently selected from hydrogen, alkoxycarbonyl or aralkoxycarbonyl, provided that R and R′ are not both hydrogen;
- X is halo, alkoxy, halo-alkoxy or aralkoxy;
- Thereafter when R1 and R2 are both acyl protective groups or neither of them is acyl protective group, removing hydroxy-protecting groups from compound 6, to give compound 7
- wherein X, R1, R2, R and R′ are defined as above;
- Thereafter hydrolysis of compound 7 to give the compound of formula 1
- or
- when neither of R1 and R2 is acyl protective group, deprotecting compound 6 while hydrolysis in one-pot manner, to directly yield the compound of formula 1
- wherein X, R1, R2, R and R′ are defined as above, or
- when one, but only one of R1 and R2 is acyl protective group, deprotecting compound 6 to give compound 8
- which is then hydrolyzed to give compound 1
- or is converted to compound 7 followed by hydrolysis to give compound 1.
17 more elements
A compound having the following formula:
- wherein
- R1 and R2, which are the same or different, are independently selected from hydrogen or hydroxy-protecting groups of the following Groups (i) to (iii):
- (i) R1 and R2, independent of each other, are selected from alkyl, halo-alkyl, benzyl, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si or Et3Si, or
- (ii) R1 and R2, independent of each other, are selected from t-BuMe2Si, t-BuPh2Si, benzoyl, tetrahydropyran-2-yl, benzoyl in which the phenyl ring bears substituent(s), and biphenyl-4-formyl, provided that R1 and R2 are not both t-BuMe2Si;
- or
- (iii) R1 and R2 together with the five-member carbocycle to which they are attached form one of the following fused ring systems:
- wherein R3 is hydrogen atom, C1-6 alkyl, phenyl or substituted phenyl in which the substituent on said phenyl is selected from methoxy, ethoxy, halo, phenyl and nitro;
- R4 and R5, which are the same or different, are independently selected from C1-6 alkyl or aryl;
- wherein the symbol * represents the attachment point through which said fused ring is attached to the remaining moiety of the molecule;
- R and R′, which are the same or different, are independently selected from hydrogen, alkoxycarbonyl or aralkoxycarbonyl, provided that R and R′ are not both hydrogen;
- X is halo, alkoxy, halo-alkoxy or aralkoxy.
8 more elements
A compound selected from:
- 9-[(1S,3R,4S)-4-tert-butyldimethylsilyloxy-3-(tert-butyldimethylsilyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-tert-butyldimethylsilyloxy-3-(tert-butyldimethylsilyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-N-(tert-butyloxycarbonyl)-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-tert-butyldimethylsilyloxy-3-(tert-butyldimethylsilyloxymethyl)-2-methylene-cyclopentyl]-6-methoxy-9H-purine-2-carbamic acid tert-butyl ester;
- 6-benzyloxy-9-[(1S,3R,4S)-4-tert-butyldimethylsilyloxy-3-(tert-butyldimethylsilyloxymethyl)-2-methylene-cyclopentyl]-9H-purine-2-carbamic acid tert-butyl ester;
- 6-tert-butyloxy-9-[(1S,3R,4S)-4-tert-butyldimethylsilyloxy-3-(tert-butyldimethylsilyloxymethyl)-2-methylene-cyclopentyl]-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-benzyloxy-3-(benzyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 6-chloro-9-[(1S, 3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl]-9H-purine-2-carbamic acid tert-butyl ester;
- 6-chloro-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl]-N-(tert-butyloxycarbonyl)-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl]-6-methoxy-9H-purine-2-carbamic acid tert-butyl ester;
- 6-benzyloxy-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl]-9H-purine-2-carbamic acid tert-butyl ester;
- 6-tert-butyloxy-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylene-cyclopentyl]-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-3-(tert-butyldimethylsilyloxymethyl)-4-(tetrahydropyran-2-yloxy)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-3-(tert-butyldimethylsilyloxymethyl)-4-(tert-butyldiphenylsilyloxy)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-3-(tert-butyldimethylsilyloxymethyl)-4-(biphenyl-4-formyloxy)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-3-(tert-butyldimethylsilyloxymethyl)-4-benzoyloxy-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-3-(tert-butyldiphenylsilyloxymethyl)-4-(tetrahydropyran-2-yloxy)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-tert-butyldimethylsilyloxy-3-(tert-butyldiphenylsilyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-(biphenyl-4-formyloxy)-3-(tert-butyldiphenylsilyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-(tert-butyldiphenylsilyloxy)-3-(tert-butyldiphenylsilyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-benzoyloxy-3-(tert-butyldiphenylsilyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-benzoyloxy-3-(benzoyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-(tetrahydropyran-2-yloxy)-3-(benzoyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-tert-butyldimethylsilyloxy-3-(benzoyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-(tert-butyldiphenylsilyloxy)-3-(benzoyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-(biphenyl-4-formyloxy)-3-(benzoyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-benzoyloxy-3-(biphenyl-4-formyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-(tetrahydropyran-2-yloxy)-3-(biphenyl-4-formyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-tert-butyldimethylsilyloxy-3-(biphenyl-4-formyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-(tert-butyldiphenylsilyloxy)-3-(biphenyl-4-formyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-(biphenyl-4-formyloxy)-3-(tetrahydropyran-2-yloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-tert-butyldimethylsilyloxy-3-(tetrahydropyran-2-yloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- 9-[(1S,3R,4S)-4-(biphenyl-4-formyloxy)-3-(biphenyl-4-formyloxymethyl)-2-methylene-cyclopentyl]-6-chloro-9H-purine-2-carbamic acid tert-butyl ester;
- (4aR,6S,7aS)-6-chloro-9-(2,2-di-tert-butyl-5-methylene-hexahydro-cyclopenta[1,3,2]dioxasilin-6-yl)-9H-purine-2-carbamic acid tert-butyl ester;
- (2S,4aR,6S,7aS)-6-chloro-9-(2-methyl-5-methylene-hexahydro-cyclopenta[1,3]dioxin-6-yl)-9H-purine-2-carbamic acid tert-butyl ester;
- (2R,4aR,6S,7aS)-6-chloro-9-(2-methyl-5-methylene-hexahydro-cyclopenta[1,3]dioxin-6-yl)-9H-purine-2-carbamic acid tert-butyl ester;
- or
- (4aR,6S,7aS)-6-chloro-9-(2-methyl-5-methylene-hexahydro-cyclopenta[1,3]dioxin-6-yl)-9H-purine-2-carbamic acid tert-butyl ester.
34 more elements
A compound having the formula 4,
- wherein
- R1 and R2, which are the same or different, are independently selected from hydroxy-protecting groups of the following Groups (i) to (iii):
- (i) R1 and R2, independent of each other, are selected from alkyl, halo-alkyl, benzyl, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si or Et3Si;
- or
- (ii) R1 and R2, independent of each other, are selected from t-BuMe2Si, t-BuPh2Si, benzoyl, tetrahydropyran-2-yl, benzoyl in which the phenyl ring bears substituent(s), and biphenyl-4-formyl, provided that R1 and R2 are not both t-BuMe2Si;
- (iii) R1 and R2 together with the five-member carbocycle to which they are attached form one of the following fused ring systems:
- wherein R3 is hydrogen atom, C1-6 alkyl, phenyl or substituted phenyl in which the substituent on said phenyl is selected from methoxy, ethoxy, halo, phenyl and nitro;
- R4 and R5, which are the same or different, are independently selected from C1-6 alkyl or aryl;
- wherein the symbol * represents the attachment point through which said fused ring is attached to the remaining moiety of the molecule.
6 more elements
A compound selected from:
- (1R,3R,4S)-4-(tert-butyldimethylsilyloxy)-3-[(tert-butyldimethylsilyloxy)methyl]-2-methylene-cyclopentanol;
- (1R,3R,4S)-4-benzyloxy-3-(benzyloxymethyl)-2-methylene-cyclopentanol;
- (1R,3R,4S)-4-(tertahydropyran-2-yloxy)-3-(tert-butyldimethylsilyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-(tert-butyldiphenylsilyloxy)-3-(tert-butyldimethylsilyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-(biphenyl-4-formyloxy)-3-(tert-butyldimethylsilyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-benzoyloxy-3-(tert-butyldimethylsilyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-(tetrahydropyran-2-yloxy)-3-(tert-butyldiphenylsilyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-tert-butyldimethylsilyloxy-3-(tert-butyldiphenylsilyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-(biphenyl-4-formyloxy)-3-(tert-butyldiphenylsilyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-(tert-butyldiphenylsilyloxy)-3-(tert-butyldiphenylsilyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-benzoyloxy-3-(tert-butyldiphenylsilyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-benzoyloxy-3-(benzoyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-(tetrahydropyran-2-yloxy)-3-(benzoyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-tert-butyldimethylsilyloxy-3-(benzoyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-(tert-butyldiphenylsilyloxy)-3-(benzoyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-(biphenyl-4-formyloxy)-3-(benzoyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-benzoyloxy-3-(biphenyl-4-formyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-(tetrahydropyran-2-yloxy)-3-(biphenyl-4-formyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-tert-butyldimethylsilyloxy-3-(biphenyl-4-formyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-(tert-butyldiphenylsilyloxy)-3-(biphenyl-4-formyloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-(biphenyl-4-formyloxy)-3-(tetrahydropyran-2-yloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-tert-butyldimethylsilyloxy-3-(tetrahydropyran-2-yloxymethyl)-2-methylene-1-cyclopentanol;
- (1R,3R,4S)-4-(biphenyl-4-formyloxy)-3-(biphenyl-4-formyloxymethyl)-2-methylene-1-cyclopentanol;
- (4aR,6R,7aS)-2,2-di-tert-butyl-5-methylene-6-hydroxy-6H-hexahydro-cyclopenta[d][1,3,2]dioxasiline;
- (2S,4aR,6S,7aS)-2-methyl-5-methylene-6-hydroxy-6H-tetrahydro-cyclopenta[1,3]dioxane;
- (2R,4aR,6S,7aS)-2-methyl-5-methylene-6-hydroxy-6H-tetrahydro-cyclopenta[1,3]dioxane;
- or
- (4aR,6S,7aS)-2-methyl-5-methylene-6-hydroxy-6H-tetrahydro-cyclopenta[1,3]dioxane.
25 more elements
Dependencies are inferred from the claim text.