CN115925702A - Method for purifying imidazo [4,5-C ] pyridine derivative and imidazo [4,5-C ] pyridine derivative - Google Patents

Abstract

The invention provides a purification method of an imidazo [4,5-C ] pyridine derivative and the imidazo [4,5-C ] pyridine derivative, and particularly relates to the technical field of medicines. The purification method comprises the following steps: adding the crude imidazo [4,5-C ] pyridine derivative into a first extracting agent for extraction, wherein the first extracting agent comprises a mixed solution of methyl tert-butyl ether and n-heptane. The purification method can obtain the imidazo [4,5-C ] pyridine derivatives in solid form, is convenient to transfer and store, is simple and convenient to operate, and is suitable for mass production.

Description

Purification method of imidazo [4,5-C ] pyridine derivative and imidazo [4,5-C ] pyridine derivative

Technical Field

The invention relates to the technical field of medicines, in particular to a purification method of an imidazo [4,5-C ] pyridine derivative and the imidazo [4,5-C ] pyridine derivative.

Background

PD-1 inhibitors have excellent therapeutic effects in the immunotherapy of various cancers and other immune-related diseases. CN114650993A discloses a new class of PD-1 inhibitors, one of which has the following chemical formula:

among them, imidazo [4,5-C ] pyridine derivatives, such as tert-butyl 1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-C ] pyridine-5-carboxylate, can be used as a starting material for the production of such compounds.

In the prior art, a plurality of documents report a purification method of imidazo [4,5-C ] pyridine derivatives, and although the purity is high, the product is oily liquid and is not easy to transfer and store. Therefore, there is a need for further research on a method for purifying an imidazo [4,5-C ] pyridine derivative, which is easy to handle, and which allows the product to be easily transferred and stored.

Disclosure of Invention

To overcome the deficiencies in the art described above, the present application provides a method for purifying imidazo [4,5-C ] pyridine derivatives. The method comprises the following steps: adding a crude imidazo [4,5-C ] pyridine derivative into a first extracting agent for extraction, wherein the first extracting agent comprises a mixed solution of methyl tert-butyl ether and n-heptane, the imidazo [4,5-C ] pyridine derivative has the following structural formula,

wherein R1 and R2 are respectively and independently selected from any one of alkyl, benzyl, tert-butyloxycarbonyl and benzyloxycarbonyl.

In some embodiments, the volume ratio of methyl tert-butyl ether to n-heptane is (1.

In some embodiments, the volume ratio of the crude imidazo [4,5-C ] pyridine derivative to the mixture of methyl tert-butyl ether and n-heptane is (1.

In some embodiments, after the crude imidazo [4,5-C ] pyridine derivative is added to the first extractant for extraction, step A or step B is further included, wherein,

the step A is to collect a methyl tert-butyl ether phase, wash, dry and concentrate the methyl tert-butyl ether phase to obtain a pure imidazo [4,5-C ] pyridine derivative;

and step B, respectively collecting a methyl tert-butyl ether phase and a water phase, adding a second extracting agent into the water phase for extraction, combining organic phases, washing, drying and concentrating to obtain a pure imidazo [4,5-C ] pyridine derivative.

In some embodiments, in step B, the second extractant comprises any one or more of ethyl acetate, methyl acetate, ethyl formate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, benzene, acetonitrile, acetone.

In some embodiments, the imidazo [4,5-C ] pyridine derivative includes at least tert-butyl 1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-C ] pyridine-5-carboxylate, which has the formula:

in some embodiments, the organic compound represented by formula (2) is prepared by reacting 1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine with methanol and di-tert-butyl dicarbonate as a starting material, according to the following synthetic route:

in some embodiments, the organic compound represented by formula (2) is obtained by adding methanol and di-tert-butyl dicarbonate to a water solvent to perform a first reaction for a certain period of time, and adding di-tert-butyl dicarbonate again to perform a second reaction.

In some embodiments, in the method for preparing an organic material represented by formula (2), at least one of the following conditions is satisfied:

the mass ratio of the substrate to water is (1;

in the first reaction, the mass ratio of the substrate to methanol is (1; the molar ratio of the substrate to di-tert-butyl dicarbonate is (1; the reaction temperature is 15-25 ℃, and the reaction time is 1-3 h;

in the second reaction, the molar ratio of the substrate to di-tert-butyl dicarbonate is (2; the reaction temperature is 15-25 ℃, and the reaction time is 7-9 h.

The application also provides an imidazo [4,5-C ] pyridine derivative which is obtained by purifying by any one of the purification methods.

Compared with the prior art, the beneficial effect of this application includes: MTBE-n-heptane is selected as an extraction solvent, so that the imidazo [4,5-C ] pyridine derivative in a solid form can be obtained, is convenient to transfer and store, is simple and convenient to operate, and is suitable for mass production.

Detailed Description

In order that the invention may be more fully understood, reference will now be made to the accompanying examples. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

The invention provides a purification method of an imidazo [4,5-C ] pyridine derivative, which comprises the following steps: adding the crude imidazo [4,5-C ] pyridine derivative into a first extracting agent for extraction, wherein the first extracting agent comprises a mixed solution of methyl tert-butyl ether and n-heptane, the imidazo [4,5-C ] pyridine derivative has the following structural formula,

wherein R1 and R2 are respectively and independently selected from any one of alkyl, benzyl, tert-butyloxycarbonyl and benzyloxycarbonyl.

Imidazo [4,5-C ] pyridine derivatives are important raw materials for synthesizing novel anticancer drugs, and most prepared oily liquids are difficult to store and transport in the existing method, so the method is not suitable for large-scale production.

The invention adopts the mixed solution of methyl tert-butyl ether (MTBE) and n-Heptane (n-Heptane) as an extracting agent, can purify the imidazo [4,5-C ] pyridine derivative with higher purity and solid state, and is greatly convenient for transfer and storage.

In the present invention, the main advantage of selecting a mixture of methyl tert-butyl ether (MTBE) and n-Heptane (n-Heptane) as extractant is that imidazo [4,5-C ] pyridine derivatives can be obtained in solid form.

In the present invention, R1 and R2 may be the same or different.

In some specific embodiments, the alkyl group can be methyl, ethyl, propyl, and the like.

In some embodiments, the volume ratio of methyl tert-butyl ether to n-heptane is (1: 20. 1: 19. 1: 18. 1: 17. 1: 16. 1: 15. 1: 14. 1: 13. 1: 12. 1: 11. 1: 10. 1: 9. 1: 8. 1: 7. 1: 6. 1: 5. 1: 4. 1: 3. 1:2.

the inventors of the present application have found that when the volume ratio of methyl t-butyl ether to n-heptane is outside the above range, the higher purity cannot be increased, resulting in the product being in a liquid state; when the volume ratio of the two is in the above ratio range, a better extraction effect can be obtained, for example. The product can be purified without recrystallization or column chromatography to produce a solid product.

In some embodiments, the volume ratio of the mixture of crude imidazo [4,5-C ] pyridine derivative methyl tert-butyl ether and n-heptane is (1: 1. 1:1.5, 1:2. 2:1.

the inventors of the present application have found that when the volume ratio of the crude imidazo [4,5-C ] pyridine derivative to the mixed solution of methyl t-butyl ether and n-heptane is in the above ratio range, a better extraction effect can be obtained.

In some embodiments, after the crude imidazo [4,5-C ] pyridine derivative is added to the first extractant for extraction, step A or step B is further included, wherein,

step A, collecting a methyl tert-butyl ether phase, washing, drying and concentrating to obtain a pure imidazo [4,5-C ] pyridine derivative;

and step B, respectively collecting a methyl tert-butyl ether phase and a water phase, adding a second extracting agent into the water phase for extraction, combining organic phases, washing, drying and concentrating to obtain a pure imidazo [4,5-C ] pyridine derivative.

The crude imidazo [4,5-C ] pyridine derivative is added to a mixture of methyl tert-butyl ether and n-heptane for extraction, and is allowed to stand for separation into three phases, for example, from the top down, an n-heptane phase, an MTBE phase and an aqueous phase, with the imidazo [4,5-C ] pyridine derivative being present in the MTBE phase in the major part and in the aqueous phase in the minor part. Based on the method, the step A can be adopted, the MTBE phase is directly collected, washed, dried and concentrated to obtain the pure imidazo [4,5-C ] pyridine derivative; in order to further improve the yield, a step B can be adopted, wherein the methyl tert-butyl ether phase and the aqueous phase are respectively collected, the aqueous phase is further extracted to obtain an extraction phase, and the organic phase is combined to obtain the extraction phase after the aqueous phase is extracted and mixed with the MTBE phase, and then the extraction phase is washed, dried and concentrated to obtain the pure imidazo [4,5-C ] pyridine derivative.

In some embodiments, the second extractant comprises any one or more of ethyl acetate, methyl acetate, ethyl formate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, benzene, acetonitrile, acetone.

The two-time extraction process may be performed once or a plurality of times, for example, two, three, four, five or more times, respectively.

In some embodiments, the washing process can be with water, or with aqueous sodium chloride solution, or both, and in other embodiments, the concentration of aqueous sodium chloride solution is 3wt% to 10wt%, for example, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, 10wt%. The number of washing is not limited.

In some embodiments, the drying agent for the drying process comprises one of anhydrous magnesium sulfate, anhydrous sodium sulfate.

In some embodiments, the organic phase is also cooled to below 15 degrees, for example below 10 degrees, prior to drying.

In some embodiments, the imidazo [4,5-C ] pyridine derivative includes at least tert-butyl 1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-C ] pyridine-5-carboxylate, which has the formula:

in the following examples, each raw material was a commercially available raw material unless otherwise specified.

In some embodiments, tert-butyl 1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-C ] pyridine-5-carboxylate may be commercially available or may be synthesized in the laboratory, and the application is not limited thereto.

In some embodiments, a method of laboratory synthesis of tert-butyl 1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-C ] pyridine-5-carboxylate comprises:

the compound is prepared by taking 1-methyl-4, 5,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine as an initial raw material and reacting the initial raw material with methanol and di-tert-butyl dicarbonate, and the synthetic route is as follows:

in some embodiments, the above preparation method comprises adding methanol and di-tert-butyl dicarbonate to a water solvent to perform a first reaction for a certain period of time, and adding di-tert-butyl dicarbonate again to perform a second reaction.

In some embodiments, the mass ratio of substrate to water is (1.

In some embodiments, in the first reaction, the mass ratio of substrate to methanol is (1; the molar ratio of the substrate to di-tert-butyl dicarbonate is (1; the reaction temperature is 15-25 ℃, and the reaction time is 1-3 h.

In some embodiments, the molar ratio of substrate to di-tert-butyl dicarbonate in the second reaction is (2; the reaction temperature is 15-25 ℃, and the reaction time is 7-9 h.

The application also provides an imidazo [4,5-C ] pyridine derivative which is obtained by purifying through the purification method. The imidazo [4,5-C ] pyridine derivative obtained by the purification method is solid, is convenient to store and transport, and is suitable for mass production.

The present application is further illustrated by the following specific examples. The following reagents are all commercially available unless otherwise indicated.

Preparation example

Preparation of Compound II (organic Compound represented by the formula (2))

The preparation example provides a preparation method of a compound II, which has the following reaction formula:

the method comprises the following reaction steps:

1000mL of water and 292.9g of Compound I (2.14mol, 1.0eq) were charged to a reaction vessel, 1340mL of MeOH and 324.8g of K were added ₂ CO ₃ (2.35mol, 1.1eq), 465.9g of Boc were added dropwise ₂ O (2.14mol, 1.0eq), the temperature is controlled at 20 +/-5 ℃, the dropwise addition is finished, and 139.8g of Boc is dropwise added after 2 hours of reaction ₂ O (0.64mo, 0.3eq), reacted for 8h. After the reaction is finished, concentrating the reaction solution into 500mL of concentrated solution, and subtracting 20mL of concentrated solutionConcentration under pressure gave 25.8g of a pale yellow oil, 75.5% pure.

Example 1

Purification of Compound II

20mL of the compound II concentrate prepared in the preparation example was added to 20mL of an MTBE-n-Heptane mixed solution (MTBE: n-Heptane in a volume ratio of 1: 10) and extracted three times (the solution was divided into three phases, i.e., an n-Heptane phase, MTBE phase, and aqueous phase from top to bottom), and the MTBE phase and the aqueous phase were collected, respectively; 15mL of EA was added to the aqueous phase and extracted three times, the EA phases were collected, the EA phases were mixed with MTBE, the organic phases were combined, and the organic phase was washed once with 10mL of water and twice with 10mL of 5wt% aqueous sodium chloride solution. The organic phase was cooled to below 10 ℃, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 18.7g of compound II as a white solid with a purity of 98.88%.

Example 2

Purification of Compound II

Taking 10g of a commercial compound II (a light yellow oily substance, with HPLC purity of 95.8%), adding 10mL of water to fully dissolve the compound II, adding 10mL of a mixed solution of TBE and n-Heptane (MTBE: n-Heptane volume ratio of 1: 10), extracting for three times (the solution is divided into three phases, and the n-Heptane phase, the MTBE phase and the water phase are respectively collected from top to bottom); 8mL of EA was added to the aqueous phase and extracted three times, the EA phases were collected, the EA phases were mixed with MTBE, the organic phases were combined, and the organic phase was washed once with 5mL of water and twice with 5mL of 5wt% aqueous sodium chloride solution. The organic phase was cooled to below 10 ℃, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 9.45g of a white solid with HPLC purity 99.0%.

Example 3

Purification of Compound II

10g of the commercially available compound II (pale yellow oil, HPLC purity 95.8%) was taken, 10mL of water was added to dissolve it sufficiently, 10mL of a mixed solution of MTBE and n-Heptane (MTBE: n-Heptane volume ratio: 1: 10) was added and extracted three times (the solution was three-phase, n-Heptane phase, MTBE, and aqueous phase from top to bottom), and the MTBE phase was taken and washed once with 5mL of water and twice with 5mL of a 5wt% aqueous sodium chloride solution. The organic phase was cooled to below 10 ℃, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 8.48g of a white solid with HPLC purity 99.2%.

Example 4

Purification of Compound II

Taking 10g of a commercial compound II (a light yellow oily substance, with HPLC purity of 95.8%), adding 10mL of water to fully dissolve the compound II, adding 10mL of a mixed solution of TBE and n-Heptane (MTBE: n-Heptane volume ratio of 5: 10), extracting for three times (the solution is divided into three phases, and the n-Heptane phase, the MTBE phase and the water phase are respectively collected from top to bottom); 8mL of EA was added to the aqueous phase and extracted three times, the EA phases were collected, the EA phases were mixed with MTBE, the organic phases were combined, and the organic phase was washed once with 5mL of water and twice with 5mL of 5wt% aqueous sodium chloride solution. The organic phase was cooled to below 10 ℃, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 8.72g of a white solid with HPLC purity of 99.0%.

Comparative example 1

Purification of Compound II

20mL of the compound II concentrate prepared in preparation example were extracted three times with 30mL of ethyl acetate, the organic phases were combined, the aqueous phase was extracted three times with 15mL of EA, the organic phases were combined, the organic phase was washed once with 10mL of water and twice with 10mL of 5wt% aqueous sodium chloride solution. The organic phase was cooled to below 10 ℃, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 17.8g of compound II as a colorless oily substance with a purity of 89.64%.

Comparative example 2

Purification of Compound II

20mL of the compound II concentrate prepared in preparation example were extracted three times with 30mL of MTBE, the organic phases were combined, and the organic phase was washed once with 10mL of water and twice with 10mL of 5wt% aqueous sodium chloride solution. The organic phase was cooled to below 10 ℃, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 18.3g of compound II as a colorless oily substance with a purity of 97.43%.

Comparative example 3

Purification of Compound II

20mL of the compound II concentrated solution prepared in the preparation example is added with 30mL of ethyl acetate for extraction, and the organic phases are combined twice, concentrated and subjected to column chromatography to obtain 13.5g of colorless oily compound II with the purity of 98.7%.

Comparative example 4

Purification of Compound II

20mL of the compound II concentrate prepared in preparation example were extracted twice with 30mL of n-heptane, the organic phases were combined, the aqueous phase was extracted twice with 20mL of ethyl acetate, the combined organic phases were concentrated, and the organic phase was washed once with 10mL of water and twice with 10mL of 5% by weight aqueous sodium chloride solution. The organic phase was cooled to below 10 ℃, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 17.9g of compound II as a colorless oily substance with a purity of 98.14%.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is specific and detailed, but not to be understood as limiting the scope of the invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. A method for purifying an imidazo [4,5-C ] pyridine derivative, characterized by comprising the steps of: adding the crude imidazo [4,5-C ] pyridine derivative into a first extracting agent for extraction; the first extractant comprises a mixed solution of methyl tert-butyl ether and n-heptane, the structural formula of the imidazo [4,5-C ] pyridine derivative is shown as follows,

wherein, R1 and R2 are respectively and independently selected from any one of alkyl, benzyl, tert-butyloxycarbonyl and benzyloxycarbonyl.

2. A purification method of an imidazo [4,5-C ] pyridine derivative as described in claim 1, characterized in that the volume ratio of the methyl tert-butyl ether to n-heptane is (1.

3. A purification method of an imidazo [4,5-C ] pyridine derivative according to claim 1, characterized in that the volume ratio of the crude imidazo [4,5-C ] pyridine derivative to a mixed solution of methyl tert-butyl ether and n-heptane is (1.

4. A method for purifying an imidazo [4,5-C ] pyridine derivative according to claim 1, which comprises a step A or a step B after the extraction by adding a crude imidazo [4,5-C ] pyridine derivative to a first extractant,

the step A is to collect a methyl tert-butyl ether phase, wash, dry and concentrate the methyl tert-butyl ether phase to obtain a pure imidazo [4,5-C ] pyridine derivative;

and step B, respectively collecting a methyl tert-butyl ether phase and a water phase, adding a second extracting agent into the water phase for extraction, combining organic phases, washing, drying and concentrating to obtain a pure imidazo [4,5-C ] pyridine derivative.

5. A method for purifying imidazo [4,5-C ] pyridine derivatives according to claim 4, wherein in step B, the second extraction agent comprises any one or more of ethyl acetate, methyl acetate, ethyl formate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, benzene, acetonitrile and acetone.

6. A method for purifying an imidazo [4,5-C ] pyridine derivative according to any one of claims 1 to 5, which comprises at least tert-butyl 1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-C ] pyridine-5-carboxylate, and has the following structural formula:

7. a method for purifying imidazo [4,5-C ] pyridine derivatives according to claim 6, wherein the organic compound represented by formula (2) is prepared by reacting 1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-C ] pyridine with methanol and di-tert-butyl dicarbonate as a starting material, according to the following synthetic route:

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8. the method for purifying an imidazo [4,5-C ] pyridine derivative according to claim 7, wherein the organic compound represented by formula (2) is obtained by adding methanol and di-tert-butyl dicarbonate to an aqueous solvent to carry out a first reaction, and after a lapse of time, adding di-tert-butyl dicarbonate again to carry out a second reaction.

9. A method for purifying an imidazo [4,5-C ] pyridine derivative according to claim 8, wherein at least one of the following conditions is satisfied in the process for producing an organic compound represented by the formula (2):

the mass ratio of the substrate to water is (1;

in the first reaction, the mass ratio of the substrate to methanol is (1; the molar ratio of the substrate to di-tert-butyl dicarbonate is (1; the reaction temperature is 15-25 ℃, and the reaction time is 1-3 h;

in the second reaction, the molar ratio of the substrate to di-tert-butyl dicarbonate is (2; the reaction temperature is 15-25 ℃, and the reaction time is 7-9 h.

10. Imidazo [4,5-C ] pyridine derivatives purified by the purification process according to any one of claims 1 to 9.