CN114409654A

CN114409654A - Intermediate synthesis method of BTK inhibitor

Info

Publication number: CN114409654A
Application number: CN202111659739.XA
Authority: CN
Inventors: 范敏华; 聂良邓; 周学来; 张震; 陈林渺
Original assignee: Anhui Puli Pharmaceutical Co ltd
Current assignee: Anhui Puli Pharmaceutical Co ltd
Priority date: 2021-12-30
Filing date: 2021-12-30
Publication date: 2022-04-29

Abstract

The invention provides a synthesis method of an intermediate of a BTK inhibitor, which comprises the following steps: will contain a compound

The organic solution reacts with an organic solution of a format reagent isopropyl magnesium chloride lithium chloride to obtain a reaction solution A; reacting the reaction solution A with a compound

After the reaction, the organic solution is added into an ammonium chloride solution for quenching, then extraction and layering are carried out, and the organic layer is decompressed and concentrated to obtain an intermediate of the target compound BTK inhibitor. The synthesis method provided by the invention has the advantages of mild reaction conditions, sufficient raw material conversion, high yield of the obtained compound and less impurities.

Description

Intermediate synthesis method of BTK inhibitor

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing an intermediate of a BTK inhibitor.

Background

As the process advances, the intermediate requirements for BTK inhibitors increase, and the preformulations do not match: under the existing synthesis method for producing the intermediate of the BTK inhibitor, the dangerous material butyl lithium is mainly used as a raw material and needs to be carried out under severe reaction conditions such as ultralow temperature and the like, so that the preparation of the intermediate of the BTK inhibitor is limited.

Because the intermediate compound of the BTK inhibitor in the prior art has poor safety, harsh reaction conditions, low production efficiency and many defects, a compound preparation method which has good safety, mild reaction conditions, high production efficiency and easy operation is needed on the basis. In view of the above, the present application proposes a method for synthesizing an intermediate of a BTK inhibitor.

Disclosure of Invention

The invention aims to provide a method for synthesizing an intermediate of a BTK inhibitor, which has the advantages of good safety, mild reaction conditions, high production efficiency and easiness in operation.

The invention adopts the following technical scheme to solve the technical problems:

a method for synthesizing an intermediate of a BTK inhibitor, comprising the steps of:

(1) will contain a compound

The organic solution reacts with an organic solution of a format reagent isopropyl magnesium chloride lithium chloride to obtain a reaction solution A;

(2) reacting the reaction solution A with a compound

After the reaction, the organic solution is added into an ammonium chloride solution for quenching, then extraction and layering are carried out, and the organic layer is decompressed and concentrated to obtain an intermediate of the target compound BTK inhibitor.

The specific reaction equation is as follows:

further, the solvent used in the organic solution includes tetrahydrofuran.

Further, the reaction temperature in the step (1) is-10-5 ℃, and the reaction time is 1-4 hours.

Further, the reaction temperature in the step (2) is-10-5 ℃, and the reaction time is 2-6 h.

Further, the concentration of the ammonium chloride is 10-30%.

Further, the extract was ethyl acetate.

Furthermore, the internal temperature in the decompression concentration process is less than or equal to 45 ℃, and the vacuum degree is less than or equal to 0.08 Mpa.

The invention has the advantages that:

the invention aims to overcome the defects of poor safety, harsh reaction conditions, low production efficiency and the like in the compound preparation process in the prior art, and provides a compound preparation method which has the advantages of good safety, mild reaction conditions, high production efficiency and easiness in operation. The method avoids using dangerous material butyl lithium, and can obtain yield higher than the original reaction condition without reacting under ultralow temperature. The process has the advantages of mild reaction conditions, full conversion of raw materials, high yield of the obtained compound and less impurities.

Drawings

FIG. 1 is a liquid chromatogram of an intermediate prepared to yield a BTK inhibitor using a prior art synthetic route;

FIG. 2 is a liquid chromatogram of an intermediate of a BTK inhibitor in example 1 of the present invention.

Detailed Description

The invention is further illustrated by the following examples, which are intended to illustrate, but not to limit the invention further.

In the prior art, an organic solution containing a compound I and an organic solution containing butyl lithium react at a temperature of-65 to-80 ℃ to obtain a reaction solution, then the reaction solution reacts with an organic solution containing a compound II at a temperature of-65 to-80 ℃, the reaction solution is added into an ammonium chloride solution for quenching, then a solvent ethyl acetate is used for extraction and delamination, an organic layer is concentrated, and the ethyl acetate is used for pulping and filtering to obtain an intermediate of a target compound BTK inhibitor; the specific reaction equation is as follows:

the invention provides another intermediate synthesis method of the BTK inhibitor, which avoids using dangerous material butyl lithium and can obtain yield higher than the original reaction condition without reacting under ultralow temperature.

In the invention, the prior art is improved, and a method for synthesizing an intermediate of a BTK inhibitor is provided, which comprises the following steps:

(1) will contain a compound

(2) reacting the reaction solution A with a compound

Wherein the solvent used in the organic solution comprises tetrahydrofuran; the reaction temperature in the step (1) is-10-5 ℃, and the reaction time is 1-4 h; the reaction temperature in the step (2) is-10-5 ℃, and the reaction time is 2-6 h; the concentration of the ammonium chloride is 10-30%; the extract liquor is ethyl acetate; the internal temperature in the decompression concentration process is less than or equal to 45 ℃, and the vacuum degree is less than or equal to 0.08 Mpa.

The following specific examples are provided to further illustrate the present invention by way of preferred examples only and are not intended to represent limiting reaction conditions for the synthesis provided by the present invention:

example 1

Example 1 providesA method for synthesizing an intermediate of a BTK inhibitor, comprising the steps of: containing compounds I

Reacting the tetrahydrofuran organic solution with a tetrahydrofuran organic solution of a format reagent isopropyl magnesium chloride lithium chloride at 0 ℃ for 1 hour to obtain a reaction solution, and then reacting the reaction solution with a compound II

Reacting the tetrahydrofuran organic solution for 2 hours at 0 ℃, adding the tetrahydrofuran organic solution into an ammonium chloride solution with the concentration of 20 percent for quenching, extracting by using a solvent of ethyl acetate, layering, concentrating the organic layer under reduced pressure at the internal temperature of 45 ℃ and the vacuum degree of 0.08Mpa, pulping by using ethyl acetate, and filtering to obtain an intermediate of the target compound BTK inhibitor.

The specific reaction equation is as follows:

the product prepared in the prior art was subjected to liquid chromatography analysis tests under the following conditions in table 1:

table 1: purity chromatography method-liquid phase

The liquid chromatogram obtained according to the above test conditions is shown in fig. 1 and 2, the data of the liquid chromatogram in fig. 1 corresponds to table 2 below, and the data of the liquid chromatogram in fig. 2 corresponds to table 3 below.

Table 2:

as can be seen from fig. 1 and table 2: the product peaks at 21.6min, the liquid phase purity is 96.39%, the impurity content is more, and the impurity content exceeds 0.5% in 21.8min and 25.8 min; the quality of the product is poor.

Table 3:

	time of liquid phase peak	Peak area	Peak area ratio	Peak height
					1	9.729	9237	0.073	693
2	17.626	6005	0.047	1740
					3	18.680	1121	0.009	166
4	19.383	2141	0.017	658
					5	19.569	1123	0.009	417
6	20.339	1771	0.014	629
					7	20.705	4334	0.034	1512
8	21.529	12380697	97.675	3584282
					9	21.695	47110	0.372	12588
10	21.794	52927	0.418	16047
					11	22.498	4788	0.038	1644
12	22.921	2419	0.019	872
					13	22.988	1994	0.009	393

As can be seen from fig. 2 and table 3: the product peaks at 21.6min, the liquid phase purity is 97.67%, and all other impurities are less than 0.5%; meets the quality standard of the product.

Finally, it should be noted that: the above embodiments are only used to illustrate the present invention and do not limit the technical solutions described in the present invention; it will be understood by those skilled in the art that the present invention may be modified and equivalents may be substituted; all such modifications and variations are intended to be included herein within the scope of this disclosure and the present invention and protected by the following claims.

Claims

1. A method for synthesizing an intermediate of a BTK inhibitor is characterized by comprising the following steps:

(1) will contain a compound

(2) reacting the reaction solution A with a compound

2. A process of synthesizing an intermediate of a BTK inhibitor according to claim 1, wherein the solvent used in the organic solution comprises tetrahydrofuran.

3. The method for synthesizing the intermediate of a BTK inhibitor according to claim 2, wherein the reaction temperature in the step (1) is-10 to 5 ℃ and the reaction time is 1 to 4 hours.

4. The method for synthesizing the intermediate of a BTK inhibitor according to claim 1, wherein the reaction temperature in the step (2) is-10 to 5 ℃ and the reaction time is 2 to 6 hours.

5. A process according to claim 1, wherein the concentration of ammonium chloride is 10-30%.

6. A process of synthesizing an intermediate of a BTK inhibitor according to claim 1, wherein said extract is ethyl acetate.

7. The method for synthesizing the intermediate of a BTK inhibitor according to claim 1, wherein the internal temperature during the vacuum concentration is not more than 45 ℃ and the vacuum degree is not more than 0.08 MPa.