Preparation method for and intermediate of pyrrolo six-membered heteroaromatic ring derivative

Abstract

Disclosed are an intermediate of a pyrrolo six-membered heteroaromatic ring derivative as a JAK inhibitor and a preparation method therefor, and a method for preparing a pyrrolo six-membered heteroaromatic ring derivative using the intermediate. The method improves the reaction yield, is simple and easy to operate and control, and is conducive to expanded industrial production.

What is claimed is: 
     
         1 . A method for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof, characterized in that the method comprises a step of obtaining the compound of formula (IV) from a compound of formula (I′) by an one-step reaction or multi-step reaction, 
       
         
           
           
               
               
           
         
         wherein, 
         R 2  is an amino protecting group; 
         R 3  is selected from the group consisting of hydrogen, C 1-6  alkyl and an amino protecting group; 
         the amino protecting group is selected from the group consisting of alkoxycarbonyl amino protecting group, acyl amino protecting group, sulfonyl amino protecting group and alkyl amino protecting group; 
         the alkoxycarbonyl amino protecting group is selected from the group consisting of benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, methoxycarbonyl and ethoxycarbonyl; 
         the acyl amino protecting group is selected from the group consisting of phthalyl, trifluoroacetyl, pivaloyl, benzoyl, formyl and acetyl; 
         the sulfonyl amino protecting group is selected from the group consisting of p-toluenesulfonyl, o-nitrobenzenesulfonyl and p-nitrobenzenesulfonyl; and 
         the alkyl amino protecting group is selected from the group consisting of trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, and benzyl. 
       
     
     
         2 . The method according to  claim 1 , characterized by obtaining the compound of formula (IV) from a compound of formula (I′-1) by an one-step reaction or multi-step reaction, 
       
         
           
           
               
               
           
         
       
     
     
         3 . A method for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof, characterized in that the method comprises a step of obtaining the compound of formula (IV) from a compound of formula (Ic) by an one-step reaction or multi-step reaction, 
       
         
           
           
               
               
           
         
       
     
     
         4 . A method for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof, characterized in that the method comprises a step of reacting a compound of formula (III) with a compound (C) to obtain the compound of formula (IV), 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method according to  claim 4 , characterized in that the compound of formula (III) is obtained by amino deprotection from a compound of formula (Ia), 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen or an amino protecting group; 
         R 2  is an amino protecting group; 
         the amino protecting group is selected from the group consisting of alkoxycarbonyl amino protecting group, acyl amino protecting group, sulfonyl amino protecting group and alkyl amino protecting group; 
         the alkoxycarbonyl amino protecting group is selected from the group consisting of benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, methoxycarbonyl and ethoxycarbonyl; 
         the acyl amino protecting group is selected from the group consisting of phthalyl, trifluoroacetyl, pivaloyl, benzoyl, formyl and acetyl; 
         the sulfonyl amino protecting group is selected from the group consisting of p-toluenesulfonyl, o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl; and 
         the alkyl amino protecting group is selected from the group consisting of trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, and benzyl. 
       
     
     
         6 . The method according to  claim 5 , characterized in that the amino deprotection reaction comprises the steps of, 
       
         
           
           
               
               
           
         
         step 1, removing an amino protecting group of the intermediate compound of formula (Ia) to obtain an intermediate compound of formula (II); and 
         step 2, removing an amino protecting group of the intermediate compound of formula (II) to obtain the compound of formula (III). 
       
     
     
         7 . The method according to  claim 6 , characterized in that the deprotection reaction comprises the steps of, 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method according  claim 5 , wherein R 1  is an alkoxycarbonyl amino protecting group, and the alkoxycarbonyl amino protecting group is selected from the group consisting of benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, and allyloxycarbonyl, and R2 is a sulfonyl amino protecting group, and the sulfonyl amino protecting group is selected from the group consisting of p-toluenesulfonyl, o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl. 
     
     
         9 . The method of  claim 8 , wherein R 1  is tert-butoxycarbonyl and R 2  is p-toluenesulfonyl. 
     
     
         10 . The method according to  claim 7 , characterized in that the deprotection reaction comprises the following steps of, 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method according to  claim 5 , characterized in that the compound of formula (III) is obtained by simultaneously removing the amino protecting groups of the compound of formula (Ia) by an one-step reaction, 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method according to  claim 11 , characterized in that the compound of formula (III) is obtained by simultaneously removing the amino protecting groups of a compound of formula (Ib) by an one-step reaction, 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method according to  claim 11 , wherein R 1  and R 2  are as defined in  claim 8 . 
     
     
         14 . The method according to  claim 12 , characterized in that the compound of formula (III) is obtained by removing the amino protecting groups of a compound of formula (Ic) by an one-step reaction, 
       
         
           
           
               
               
           
         
       
     
     
         15 . A method for preparing a pharmaceutically acceptable salt of a compound of formula (IV), comprising the steps according to  claim 1 , and a step of reacting the compound of formula (IV) with an acid to obtain the pharmaceutically acceptable salt thereof, wherein the acid is selected from the group consisting of an organic acid and an inorganic acid; the organic acid is selected from the group consisting of citric acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, maleic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid and methanesulfonic acid; the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid.