CN108395436B

CN108395436B - Preparation method of imidazopyrazine pharmaceutical intermediate

Info

Publication number: CN108395436B
Application number: CN201810453709.5A
Authority: CN
Inventors: 王强; 李燕; 郝秋霞; 刘可
Original assignee: Peoples Hospital of Hebi
Current assignee: Peoples Hospital of Hebi
Priority date: 2018-05-14
Filing date: 2018-05-14
Publication date: 2021-01-12
Anticipated expiration: 2038-05-14
Also published as: CN108395436A

Abstract

The invention relates to a preparation method of an imidazopyrazine medical intermediate, which comprises the following steps: (a) adding 2-amino-3, 5-dibromopyrazine and ammonia water into an autoclave, heating to 110-150 ℃ under the protection of nitrogen for reaction, cooling, performing suction filtration to obtain a filter cake, and drying to obtain a compound II; (b) dissolving the compound II in N, N-dimethylformamide, dropwise adding triethyl orthoformate and formic acid, heating and refluxing under the protection of nitrogen, and purifying to obtain a compound III; (c) and adding the compound III, N-methyl pyrrolidone, ammonia water and copper sulfate pentahydrate into another autoclave, heating to 130-170 ℃ under the protection of nitrogen, reacting, and purifying. This allows to reduce the synthesis steps of the final product, thus improving its yield and purity.

Description

Preparation method of imidazopyrazine pharmaceutical intermediate

Technical Field

The invention belongs to the field of medical intermediates, and particularly relates to a preparation method of an imidazopyrazine medical intermediate.

Background

Bruton's Tyrosine Kinase (BTK) is a key signaling molecule in the B cell receptor signaling complex, a key protein kinase for lymphocyte survival and proliferation. The BTK inhibitor plays a role in resisting cancers by inhibiting BTK of tumor cells, and the BTK inhibitor ibrutinib is a 4' -aminopyrido [3,4-d ] pyridine compound which is combined with chemotherapeutic drugs or other targeted anticancer drugs for treatment, so that the curative effect on the tumors can be improved.

The Chinese invention with the patent number of 201710028449.2 discloses an imidazopyrazine compound and a preparation method and application thereof; the imidazopyrazine compound is pharmaceutically acceptable salt, stereoisomer or prodrug thereof, and the application of the compound, the pharmaceutically acceptable salt, the stereoisomer or prodrug thereof in preparing a medicament for preventing and/or treating diseases and/or symptoms related to Bruton tyrosine kinase overactivity of a subject. The imidazopyrazine compound can obtain a final product with high yield and high purity by changing a synthetic route in the preparation process, so that a key imidazopyrazine medical intermediate needs to be synthesized.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a preparation method of an imidazopyrazine pharmaceutical intermediate.

In order to achieve the purpose, the invention adopts the technical scheme that: a preparation method of an imidazopyrazine medical intermediate comprises the following steps:

(a) adding 2-amino-3, 5-dibromopyrazine and ammonia water into an autoclave, heating to 110-150 ℃ under the protection of nitrogen for reaction, cooling, performing suction filtration to obtain a filter cake, and drying to obtain a compound II;

(b) dissolving the compound II in N, N-dimethylformamide, dropwise adding triethyl orthoformate and formic acid, heating and refluxing under the protection of nitrogen, and purifying to obtain a compound III;

(c) and adding the compound III, N-methyl pyrrolidone, ammonia water and copper sulfate pentahydrate into another autoclave, heating to 130-170 ℃ under the protection of nitrogen, reacting, and purifying.

Preferably, in the step (b), the solvent is removed by rotary evaporation after heating and refluxing, methanol is added for dissolution, and silica gel column chromatography purification is carried out to obtain the compound III.

Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages: the preparation method of the imidazopyrazine medical intermediate adopts specific steps and a synthetic route to respectively obtain the compound II and the compound III, so that the synthetic steps of a final product can be reduced, and the yield and the purity of the final product can be improved.

Drawings

FIG. 1 is a flow chart of a preparation method of an imidazopyrazine pharmaceutical intermediate of the present invention;

FIG. 2 is a nuclear magnetic spectrum of a compound II in the preparation method of the imidazopyrazine pharmaceutical intermediate;

FIG. 3 is a nuclear magnetic spectrum of a compound III in the preparation method of the imidazopyrazine pharmaceutical intermediate.

Detailed Description

The preparation method of the imidazopyrazine medical intermediate comprises the following steps: (a) adding 2-amino-3, 5-dibromopyrazine and ammonia water into an autoclave, heating to 110-150 ℃ under the protection of nitrogen for reaction, cooling, performing suction filtration to obtain a filter cake, and drying to obtain a compound II; (b) dissolving the compound II in N, N-dimethylformamide, dropwise adding triethyl orthoformate and formic acid, heating and refluxing under the protection of nitrogen, and purifying to obtain a compound III; (c) and adding the compound III, N-methyl pyrrolidone, ammonia water and copper sulfate pentahydrate into another autoclave, heating to 130-170 ℃ under the protection of nitrogen, reacting, and purifying. By using specific steps and synthetic routes to obtain compound II and compound III, respectively, it is possible to reduce the synthetic steps of the final product and thus to improve its yield and purity. In the step (b), the solvent is removed by rotary evaporation after heating and refluxing, methanol is added for dissolution, and silica gel column chromatography purification is carried out to obtain the compound III so as to improve the purity of the compound III.

The following detailed description of preferred embodiments of the invention is provided:

example 1

The present embodiment provides a method for preparing an imidazopyrazine pharmaceutical intermediate, as shown in fig. 1, which includes the following steps:

(a) adding 2-amino-3, 5-dibromopyrazine (10 g, 39.54 mmol, 1 eq) and ammonia water (50 mL, available on the market) into a 100mL autoclave, and heating to 130 ℃ under the protection of nitrogen to react overnight (10-12 hours); cooling, filtering, and vacuum drying the obtained solid to obtain 5.0g of a compound II, wherein nuclear magnetic analysis is as follows:¹H NMR (400 MHz, DMSO-d ₆) δ (ppm): 7.17 (s, 1H), 6.37 (s, 2H), 6.06 (s, 2H)。ESI-MS m/z calcd: C₄H₅BrN₄([M+H]⁺) 188.97, found: 189.4, as shown in FIG. 2;

(b) to a 250mL single neck flask was added compound II (7.8 g, 41.3 mmol, 1 eq), 80mL DMF (i.e., N-dimethylformamide) was added with constant stirring to dissolve compound II, triethyl orthoformate (7.34 g, 49.5 mmol, 1.2 eq) and 20mL formic acid (rate about 1 drop/sec) were added dropwise, and the mixture was heated under reflux under nitrogen for 24h (at this time TLC detection)Substantially free of starting materials); removing the solvent by spinning off, adding methanol for dissolving, and purifying by silica gel column chromatography to obtain 5g of a compound III, wherein nuclear magnetic resolution is as follows:¹H NMR (400 MHz, DMSO-d ₆) δ (ppm): 13.76 (brs, 1H), 8.79(s, 1H), 8.56 (s, 1H)。ESI-MS m/z calcd: C₅H₃BrN₄([M-H]^-) 196.95, found 196.6, as shown in FIG. 3;

(c) adding compound III (1 g, 5 mmol, 1 eq), NMP (N-methylpyrrolidone, 5 mL), 10mL ammonia water and 130mg copper sulfate pentahydrate into a 100mL autoclave, replacing nitrogen, heating to 150 ℃ and reacting for 12h (no raw material detected by TLC); column chromatography purification to obtain 500mg of compound I (purity 99.5%), nuclear magnetic resolution:¹H NMR (400 MHz, DMSO-d ₆) δ (ppm): 12.58 (brs, 1H), 8.14(brs, 1H), 7.75 (brs, 1H)，6.28 (brs, 1H). ESI-MS m/z calcd: C₅H₅N₅([M-H]^-); 134.05, found:134.1。

example 2

This example provides a process for preparing an imidazopyrazine pharmaceutical intermediate, which is substantially the same as in example 1, except that: in the step (a), the reaction temperature is 110 ℃; in step (c), the reaction temperature was 130 ℃ and the amount of the product obtained was substantially the same as in example 1; the purity of the final product was 99.2%.

Example 3

This example provides a process for preparing an imidazopyrazine pharmaceutical intermediate, which is substantially the same as in example 1, except that: in the step (a), the reaction temperature is 150 ℃; in step (c), the reaction temperature was 170 ℃ and the amount of the product obtained was substantially the same as in example 1; the purity of the final product was 99.0%.

Comparative example 1

This example provides a process for the preparation of an imidazopyrazine pharmaceutical intermediate, which is substantially identical to that of example 1, except that: triethyl orthoformate was not added dropwise in step (b), and only 3g of compound III (purity 88.5%) were finally obtained.

Comparative example 2

This example provides a process for the preparation of an imidazopyrazine pharmaceutical intermediate, which is substantially identical to that of example 1, except that: in step (c), no copper sulfate pentahydrate was added and compound I could not be obtained.

The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.

Claims

1. A process for the preparation of an imidazopyrazine pharmaceutical intermediate, which is defined as compound I and has the structural formula

It is characterized by comprising the following steps:

(a) adding 10g of 2-amino-3, 5-dibromopyrazine and 50mL of ammonia water into a 100mL autoclave, heating to 130 ℃ under the protection of nitrogen, and reacting for 10-12 hours overnight; cooling, filtering, and vacuum drying the obtained solid to obtain 5.0g of a compound II; the structural formula of the compound II is

(b) Adding 7.8g of compound II into a 250mL single-neck bottle, adding 80mL of DMF (dimethyl formamide) under the condition of continuous stirring to dissolve the compound II, dropwise adding 7.34g of triethyl orthoformate and 20mL of formic acid, and heating and refluxing for reaction for 24h under the condition of nitrogen protection; removing the solvent by spinning off, adding methanol for dissolving, and purifying by silica gel column chromatography to obtain 5g of compound III; the structural formula of the compound III is

(c) Adding 1g of compound III, 5mL of NMP, 10mL of ammonia water and 130mg of copper sulfate pentahydrate into a 100mL autoclave, replacing nitrogen, and heating to 150 ℃ for reaction for 12 hours; purifying by column chromatography to obtain 500mg of compound I.