Preparation method for chiral pyrrolopyrimidine compound
Provided are a preparation method for a chiral pyrrolopyrimidine compound and a related intermediate. In the method, a compound of formula A and a compound of formula 6 or a salt thereof are reacted to obtain a compound of formula 7 or a compound of formula 14, and a compound of formula I is prepared from the compound of formula 7 or the compound of formula 14. Also provided are the intermediate used, a preparation method for the intermediate and a use of the intermediate in the preparation of the compound of formula I. The preparation method has characteristics such as brief steps, a high stereoselectivity, a high utilization ratio of atoms, mild reaction conditions and a convenient post-treatment. The method avoids using an expensive asymmetric reaction catalyst, and is suitable for industrial production.
1. A method for preparing a compound of formula I, comprising reacting a compound of formula A with a compound of formula 6 or a salt thereof to obtain a compound of formula 7 or a compound of formula 14, and preparing the compound of formula I from the compound of formula 7 or the compound of formula 14:
wherein R 1 is selected from the group consisting of H and an amino-protecting group; and R A is selected from the group consisting of H and CH 3 .
2. The method of claim 1 , comprising reacting a compound of formula 5 with the compound of formula 6 or a salt thereof to obtain the compound of formula 7, and preparing the compound of formula I from the compound of formula 7:
wherein R 1 is selected from the group consisting of H and an amino-protecting group.
3. The method of claim 2 , wherein the process for preparing the compound of formula I from the compound of formula 7 comprises: a) a reaction of converting carboxy group into amido group, b) a reaction of converting amido group into cyano group, c) a reaction of linking amino group on a pyrazole ring with a protecting group, d) a reaction of removing the protective group of amino group on the pyrazole ring, and/or e) a reaction of removing R 1 .
4. The method of claim 2 , wherein R 1 in the compound of formula 7 is an amino-protecting group, and the process for preparing the compound of formula I from the compound of formula 7 comprises the following steps: (1) linking amino group on a pyrazole ring of the compound of formula 7 with a protecting group; (2) converting carboxy group of the compound obtained from step (1) into amido group; (3) converting amido group of the compound obtained from step (2) into cyano group; (4) removing the protective group of amino group on the pyrazole ring of the compound obtained from step (3), and (5) removing R 1 prior to step (1), after step (1) but prior to step (2), after step (2) but prior to step (3), after step (3) but prior to step (4), after step (4), or at the same time as step (4); or
R 1 in the compound of formula 7 is H, and the process for preparing the compound of formula I from the compound of formula 7 comprises the following steps: (1) linking amino group on a pyrazole ring of the compound of formula 7 with a protecting group; (2) converting carboxy group of the compound obtained from step (1) into amido group; (3) converting amido group of the compound obtained from step (2) into cyano group; and (4) removing the protective group of amino group on the pyrazole ring of the compound obtained from step (3).
5. The method of claim 1 , comprising reacting a compound of formula 13 with a compound of formula 6 or a salt thereof to obtain a compound of formula 14, and preparing the compound of formula I from the compound of formula 14:
wherein R 1 is selected from the group consisting of H and an amino-protecting group.
6. The method of claim 5 , wherein the process for preparing the compound of formula I from the compound of formula 14 comprises f) a reaction of converting amido group into cyano group, g) a reaction of linking amino group on a pyrazole ring with a protecting group, h) a reaction of removing the protective group of amino group on the pyrazole ring, and/or i) a reaction of removing R 1 .
7. The method of claim 5 , wherein R 1 in the compound of formula 14 is an amino-protecting group, and the process for preparing the compound of formula I from the compound of formula 14 comprises the following steps: (1) linking amino group on a pyrazole ring of the compound of formula 14 with a protecting group; (2) converting amido group of the compound obtained from step (1) into cyano group; (3) removing the protective group of amino group on the pyrazole ring of the compound obtained from step (2), and (4) removing R 1 prior to step (1), after step (1) but prior to step (2), after step (2) but prior to step (3), after step (3), or at the same time as step (3); or
R 1 in the compound of formula 14 is H, and the process for preparing the compound of formula I from the compound of formula 14 comprises the following steps: (1) linking amino group on a pyrazole ring of the compound of formula 14 with a protecting group; (2) converting amido group of the compound obtained from step (1) into cyano group; and (3) removing the protective group of amino group on the pyrazole ring of the compound obtained from step (2).
8. The method of claim 1 , wherein the amino-protecting groups is selected from the group consisting of hydroxymethyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(4-trifluoromethylbenzenesulfonyl)ethoxycarbonyl, tert-butyloxycarbonyl, 1-adamantyloxocarbonyl, 2-adamantylcarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, cyclohexyloxycarbonyl, 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, vinyl, 2-chloroethyl, 2-benzenesulfonylethyl, p-nitrobenzenesulfonyl, p-methylbenzenesulfonyl, benzenesulfonyl, methanesulfonyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N′,N′-dimethylhydrazino, methoxymethyl, tert-butyloxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, tri(C 1-4 alkyl)silyl, 1,1-diethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, and N-pivaloyloxymethyl.
9. A method for preparing the compound of formula 7 of claim 1 , comprising reacting a compound of formula 5 with a compound of formula 6 or a salt thereof to obtain the compound of formula 7:
wherein R 1 is selected from the group consisting of H and an amino-protecting group.
10. The method of claim 9 , wherein the amino-protecting groups is selected from the group consisting of hydroxymethyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(4-trifluoromethylbenzenesulfonyl)ethoxycarbonyl, tert-butyloxycarbonyl, 1-adamantyloxocarbonyl, 2-adamantylcarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, cyclohexyloxycarbonyl, 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, vinyl, 2-chloroethyl, 2-benzenesulfonylethyl, p-nitrobenzenesulfonyl, p-methylbenzenesulfonyl, benzenesulfonyl, methanesulfonyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N′,N′-dimethylhydrazino, methoxymethyl, tert-butyloxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, tri(C 1-4 alkyl)silyl, 1,1-diethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, and N-pivaloyloxymethyl.
11. A method for preparing the compound of formula 14 of claim 1 , comprising reacting a compound of formula 13 with a compound of formula 6 or a salt thereof to obtain the compound of formula 14:
wherein R 1 is selected from the group consisting of H and an amino-protecting group.
12. The method of claim 11 , wherein the amino-protecting groups is selected from the group consisting of hydroxymethyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(4-trifluoromethylbenzenesulfonyl)ethoxycarbonyl, tert-butyloxycarbonyl, 1-adamantyloxocarbonyl, 2-adamantylcarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, cyclohexyloxycarbonyl, 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, vinyl, 2-chloroethyl, 2-benzenesulfonylethyl, p-nitrobenzenesulfonyl, p-methylbenzenesulfonyl, benzenesulfonyl, methanesulfonyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N′,N′-dimethylhydrazino, methoxymethyl, tert-butyloxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, tri(C 1-4 alkyl)silyl, 1,1-diethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, and N-pivaloyloxymethyl.
13. A compound of formula 13:
wherein R 1 is selected from the group consisting of H and an amino-protecting group.
14. The compound of claim 13 , wherein the amino-protecting groups is selected from the group consisting of hydroxymethyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(4-trifluoromethylbenzenesulfonyl)ethoxycarbonyl, tert-butyloxycarbonyl, 1-adamantyloxocarbonyl, 2-adamantylcarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, cyclohexyloxycarbonyl, 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, vinyl, 2-chloroethyl, 2-benzenesulfonylethyl, p-nitrobenzenesulfonyl, p-methylbenzenesulfonyl, benzenesulfonyl, methanesulfonyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N′,N′-dimethylhydrazino, methoxymethyl, tert-butyloxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, tri(C 1-4 alkyl)silyl, 1,1-diethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, and N-pivaloyloxymethyl.
15. The method of claim 8 , wherein the amino-protecting groups is selected from the group consisting of hydroxymethyl, 2-(trimethylsilyl)ethoxymethyl, N-pivaloyloxymethyl, p-nitrobenzenesulfonyl, p-methylbenzenesulfonyl, benzenesulfonyl, methanesulfonyl, and benzyl.
16. The method of claim 8 , wherein the amino-protecting groups is hydroxymethyl or 2-(trimethylsilyl)ethoxymethyl.
17. The method of claim 10 , wherein the amino-protecting groups is selected from the group consisting of hydroxymethyl, 2-(trimethylsilyl)ethoxymethyl, N-pivaloyloxymethyl, p-nitrobenzenesulfonyl, p-methylbenzenesulfonyl, benzenesulfonyl, methanesulfonyl, and benzyl.
18. The method of claim 12 , wherein the amino-protecting groups is selected from the group consisting of hydroxymethyl, 2-(trimethylsilyl)ethoxymethyl, N-pivaloyloxymethyl, p-nitrobenzenesulfonyl, p-methylbenzenesulfonyl, benzenesulfonyl, methanesulfonyl, and benzyl.
19. The compound of claim 14 , wherein the amino-protecting groups is selected from the group consisting of hydroxymethyl, 2-(trimethylsilyl)ethoxymethyl, N-pivaloyloxymethyl, p-nitrobenzenesulfonyl, p-methylbenzenesulfonyl, benzenesulfonyl, methanesulfonyl, and benzyl.
20. The compound of claim 14 , wherein the amino-protecting groups is hydroxymethyl and 2-(trimethylsilyl)ethoxymethyl.