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

Patent metadata

Field	Value
Publication number	US-10851100-B2
Application number	US-201716461336-A
Country	US
Kind code	B2
Filing date	Nov 22, 2017
Priority date	Nov 23, 2016
Publication date	Dec 1, 2020
Grant date	Dec 1, 2020

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.

First claim

What is claimed is:

1. A compound of formula (I) or a stereoisomer thereof:

wherein,
R 1 is hydrogen or an amino protecting group;
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 compound of formula (I) or a stereoisomer thereof according to claim 1 ,
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;
R 2 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; and
R 3 is selected from the group consisting of hydrogen and methyl.

3. The compound of formula (I) or a stereoisomer thereof according to claim 1 , wherein the compound has a structure of formula (Ia) below,

4. The compound of formula (I) or a stereoisomer thereof according to claim 1 , wherein the compound has a structure of formula (Ib) below,

5. The compound of formula (I) or a stereoisomer thereof according to claim 1 , wherein the compound has a structure of formula (Ic) below,

6. A method for preparing the compound of formula (I) according to claim 1 , characterized in that the method comprises a step of reacting a compound of formula (A) with a compound of formula (B),

wherein, X is halogen.

7. The method according to claim 6 , characterized in that the method is a reaction of a compound of formula (A) with a compound of formula (B1) to obtain a compound of formula (Ia),

8. The method according to claim 7 , characterized in that the method is a reaction of a compound of formula (A1) with a compound of formula (B1) to obtain a compound of formula (Ib),

9. The method according to claim 8 , characterized in that the method is a reaction of a compound of formula (A2) with a compound of formula (B2) to obtain a compound of formula (Ic),

10. A compound of formula (I′) or a stereoisomer thereof:

wherein R 2 and R 3 are as defined in claim 1 .

11. The compound of formula (I′) or a stereoisomer thereof according to claim 10 , wherein the compound has a structure of formula (I′-1) below,

12. The compound of formula (I) or a stereoisomer thereof according to claim 2 , wherein, R 2 is p-toluenesulfonyl.

Assignees

• Jiangsu Hengrui Medicine Co

Inventors

• Liu Bing
• Bian Lin
• Gao Xiaohui

Classifications

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07D487/04 Primary

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• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title