# US 10,766,901 B2 · Preparation method for chiral pyrrolopyrimidine compound > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,766,901 B2 - Document ID: US10766901B2 - Status: Granted - Kind: B2 - Application number: 16/309,882 - Filed: 2017-06-15 - Published: 2019-07-11 - Granted: 2020-09-08 - Earliest claimed: 2016-06-16 - Assignees: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.; Lianyungang Runzhong Pharmaceutical Co., Ltd.; Centaurus Biopharma Co., Ltd. - Applicants: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.; Lianyungang Runzhong Pharmaceutical Co., Ltd.; Centaurus Biopharma Co., Ltd. - Inventors: Xiquan Zhang; Aiming Zhang; Zhou Zhou; Huadong Yao; Jie Xie - Web page: https://patentgrep.com/patent/US10766901B2 ## CPC - C07D 487/04: Ortho-condensed systems - Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS ## Abstract 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. ## Claims ### Claim 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 R1 is selected from the group consisting of H and an amino-protecting group; and RA is selected from the group consisting of H and CH3. ### Claim 2 (depends on 1) 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 R1 is selected from the group consisting of H and an amino-protecting group. ### Claim 3 (depends on 2) 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 R1. ### Claim 4 (depends on 2) The method of claim 2, wherein R1 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 R1 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 R1 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). ### Claim 5 (depends on 1) 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 R1 is selected from the group consisting of H and an amino-protecting group. ### Claim 6 (depends on 5) 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 R1. ### Claim 7 (depends on 5) The method of claim 5, wherein R1 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 R1 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 R1 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). ### Claim 8 (depends on 1) 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(C1-4 alkyl)silyl, 1,1-diethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, and N-pivaloyloxymethyl. ### Claim 9 (depends on 1) 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 R1 is selected from the group consisting of H and an amino-protecting group. ### Claim 10 (depends on 9) 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(C1-4 alkyl)silyl, 1,1-diethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, and N-pivaloyloxymethyl. ### Claim 11 (depends on 1) 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 R1 is selected from the group consisting of H and an amino-protecting group. ### Claim 12 (depends on 11) 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(C1-4 alkyl)silyl, 1,1-diethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, and N-pivaloyloxymethyl. ### Claim 13 A compound of formula 13: wherein R1 is selected from the group consisting of H and an amino-protecting group. ### Claim 14 (depends on 13) 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(C1-4 alkyl)silyl, 1,1-diethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, and N-pivaloyloxymethyl. ### Claim 15 (depends on 8) 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. ### Claim 16 (depends on 8) The method of claim 8, wherein the amino-protecting groups is hydroxymethyl or 2-(trimethylsilyl)ethoxymethyl. ### Claim 17 (depends on 10) 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. ### Claim 18 (depends on 12) 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. ### Claim 19 (depends on 14) 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. ### Claim 20 (depends on 14) The compound of claim 14, wherein the amino-protecting groups is hydroxymethyl and 2-(trimethylsilyl)ethoxymethyl.