Synthesis process of novel tyrosine kinase inhibitor intermediate

Abstract

The invention relates to the technical field of medicine synthesis, and discloses a synthesis process of a novel tyrosine kinase inhibitor intermediate, which comprises the following steps: 1, adopting a mixed alkali scheme, namely a potassium carbonate and cesium carbonate mixed system, and replacing cesium carbonate with cheap potassium carbonate; and 2, constructing an amino group with a protecting group by adopting a Ullmann coupling strategy catalyzed by cuprous ions. And step 3, carrying out simple Boc removal reaction to obtain the target molecule. According to the method, the use of the energetic raw material nitropyrazole is avoided, the 4-bromopyrazole which is relatively low in price, relatively high in safety and stable in supply is adopted, the limitation difficulty of material purchase and transportation is reduced, the production safety is improved, the production cost is greatly reduced, the palladium catalytic hydrogenation reaction is avoided, the production risk is reduced, and the production cost is reduced. And the production cost is further reduced, so that the industrial production is simpler, more convenient and more feasible.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a synthesis process of a novel tyrosine kinase inhibitor intermediate. Background Art

[0002] Tyrosine kinase inhibitor intermediates play a vital role in drug synthesis. Tyrosine kinase inhibitors (TKIs) are a class of compounds that can inhibit the activity of tyrosine kinase. They can act as competitive inhibitors of the binding of adenosine triphosphate (ATP) to tyrosine kinase, or as tyrosine analogs, blocking the activity of tyrosine kinase, thereby inhibiting cell proliferation. This type of inhibitor is of great significance in the development of anti-tumor drugs.

[0003] In patent WO2020119819, a synthetic route is used. The problem with the above technology is that this route uses nitropyrazole as a raw material. Since the molecular structure of the raw material is relatively small and the nitrogen and oxygen content is high, it is an energetic substance. Whether it is produced or used, it has certain risks. A large amount of strongly acidic substances are used in the production of this raw material, which is very unfriendly to the environment, so its price remains high. Many factors limit the production and supply of this raw material, and the subsequent nitro reduction also requires the use of precious metal catalysts and hydrogenation equipment, which further increases the production cost. Summary of the Invention

[0004] In view of the problems existing in the prior art, the present invention provides a synthesis process for a novel tyrosine kinase inhibitor intermediate that can overcome the above problems or at least partially solve the above problems.

[0005] The present invention is achieved by providing a novel synthesis process for a tyrosine kinase inhibitor intermediate, the process comprising the following steps:

[0006] The first step is to adopt a mixed alkali solution, that is, a mixed system of potassium carbonate and cesium carbonate, using cheap potassium carbonate to replace cesium carbonate;

[0007] Step 2: Use the cuprous ion-catalyzed Ullmann coupling strategy to construct an amino group with a protecting group.

[0008] Step 3: Only a simple Boc removal reaction is required to obtain the target molecule.

[0009] Step 4: Synthesize new TYK2 inhibitor intermediates based on the new route.

[0010] Preferably, the mixing ratio of potassium carbonate and cesium carbonate is 2:1 to 9:1.

[0011] Compared with the prior art, the present invention has the following beneficial effects:

[0012] The present invention avoids the use of an energetic raw material, nitropyrazole, and adopts 4-bromopyrazole, which is relatively low in price, highly safe, and in stable supply, thereby reducing the difficulties in material procurement and transportation, improving production safety, greatly reducing production costs, and avoiding palladium-catalyzed hydrogenation reaction. This not only reduces production risks but also further reduces production costs, thereby making industrial production more convenient and feasible. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The embodiment of the present invention provides a new synthetic route for tyrosine kinase inhibitor intermediates. DETAILED DESCRIPTION

[0014] In order to further understand the content, features and effects of the present invention, the following embodiments are given as examples and described in detail with reference to the accompanying drawings.

[0015] The structure of the present invention is described in detail below with reference to the accompanying drawings.

[0016] like Figure 1 As shown, the embodiment of the present invention provides a novel synthesis process of a tyrosine kinase inhibitor intermediate, which comprises the following steps:

[0017] The first step is to adopt a mixed alkali solution, that is, a mixed system of potassium carbonate and cesium carbonate, using cheap potassium carbonate to replace cesium carbonate;

[0018] By using cheap potassium carbonate instead of cesium carbonate, the alkalinity of the reaction system is guaranteed, and the coordination effect of cesium ions can be utilized to achieve the primary goal of significantly reducing costs without affecting the reaction conditions.

[0019] Step 2: Using cuprous ion-catalyzed Ullmann coupling strategy, an amino group with a protecting group was constructed;

[0020] The cuprous ion-catalyzed Ullmann coupling strategy is an important organic synthesis method. It uses cuprous ions as catalysts to promote the coupling reaction between halogenated aromatic compounds to produce biaryl compounds. The traditional Ullmann reaction requires high temperature and excess copper. However, in recent years, the addition of suitable ligands has reduced the amount of copper used to a catalytic amount, making the reaction more economical and practical.

[0021] It successfully avoids the palladium-carbon catalytic hydrogenation used when using nitropyrazole as raw material, reduces production risks, makes it easier to achieve industrialized production, and further reduces costs.

[0022] Step 3: Only a simple Boc removal reaction is required to obtain the target molecule.

[0023] The Boc removal reaction is a crucial step in organic chemical synthesis, primarily used to remove the tert-butyloxycarbonyl (Boc) protecting group from amino groups. This reaction is typically performed under acidic conditions, with commonly used acids including hydrochloric acid, dioxane, and trifluoroacetic acid. The protected amino group is released by forming a tert-butyl carbocation and then removing the tert-butyl group. Depending on the stability of the substrate, the Boc removal reaction can be performed under alkaline or neutral conditions, but acidic conditions are most commonly used.

[0024] Step 4: Synthesize new TYK2 inhibitor intermediates based on the new route.

[0025] Preferably, the mixing ratio of potassium carbonate and cesium carbonate is 2:1 to 9:1.

[0026] It should be noted that, in this document, relational terms such as first and second, etc., are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "comprises," "comprising," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a list of elements includes not only those elements but also other elements not explicitly listed, or elements inherent to such process, method, article, or apparatus.

[0027] The above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Although the present invention has been disclosed as a preferred embodiment as above, it is not intended to limit the present invention. Any technician familiar with this patent will not depart from the scope of the technical solution of the present invention.

Claims

1. A novel synthesis process for a tyrosine kinase inhibitor intermediate, characterized by: The process includes the following steps: The first step is to adopt a mixed alkali solution, that is, a mixed system of potassium carbonate and cesium carbonate, using cheap potassium carbonate to replace cesium carbonate; Step 2: Use the cuprous ion-catalyzed Ullmann coupling strategy to construct an amino group with a protecting group. Step 3: Only a simple Boc removal reaction is required to obtain the target molecule. Step 4: Synthesize new TYK2 inhibitor intermediates based on the new route.

2. The process for synthesizing a novel tyrosine kinase inhibitor intermediate according to claim 1, wherein: The mixing ratio of potassium carbonate and cesium carbonate is 2:1 to 9:1.

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