A purification method of imidazo[4,5-C]pyridine derivatives and imidazo[4,5-C]pyridine derivatives

Abstract

The present invention provides a purification method of an imidazo[4,5-C]pyridine derivative and an imidazo[4,5-C]pyridine derivative, and specifically relates to the field of pharmaceutical technology. The purification method comprises the following steps: adding a crude imidazo[4,5-C]pyridine derivative to a first extractant for extraction, wherein the first extractant comprises a mixed solution of methyl tert-butyl ether and n-heptane. The purification method of the present invention can obtain a solid imidazo[4,5-C]pyridine derivative, which is easy to transfer and store, simple to operate, and suitable for mass production.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a method for purifying an imidazo[4,5-C]pyridine derivative and an imidazo[4,5-C]pyridine derivative thereof. Background Art

[0002] PD-1 inhibitors have good therapeutic effects in the immunotherapy of various cancers and other immune-related diseases. CN114650993A discloses a new type of PD-1 inhibitor, one of which has the following chemical formula:

[0003]

[0004] Among them, imidazo[4,5-C]pyridine derivatives, for example, tert-butyl 1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-C]pyridine-5-carboxylate, can be used as a raw material for producing the compound.

[0005] In the prior art, there are many documents reporting the purification methods of imidazo[4,5-C]pyridine derivatives. Although the purity is high, the product is an oily liquid and is not easy to transfer and store. Therefore, it is necessary to further study a simple and easy-to-operate purification method of imidazo[4,5-C]pyridine derivatives to make the product state easier to transfer and store. Summary of the invention

[0006] In order to overcome the deficiencies in the above-mentioned technologies, the present application provides a method for purifying an imidazo[4,5-C]pyridine derivative. The method comprises the following steps: adding a crude imidazo[4,5-C]pyridine derivative to a first extractant for extraction, wherein the first extractant comprises a mixture of methyl tert-butyl ether and n-heptane, and the structural formula of the imidazo[4,5-C]pyridine derivative is as follows:

[0007]

[0008] Wherein, R1 and R2 are each independently selected from any one of an alkyl group, a benzyl group, a tert-butyloxycarbonyl group, and a benzyloxycarbonyl group.

[0009] In some embodiments, the volume ratio of methyl tert-butyl ether to n-heptane is (1:2)-(1:20).

[0010] In some embodiments, the volume ratio of the crude imidazo[4,5-C]pyridine derivative to the mixed solution of methyl tert-butyl ether and n-heptane is (1:2)-(2:1).

[0011] In some embodiments, after the crude imidazo[4,5-C]pyridine derivative is added to the first extractant for extraction, the method further comprises step A or step B, wherein:

[0012] The step A is to collect the methyl tert-butyl ether phase, wash, dry and concentrate to obtain a pure imidazo[4,5-C]pyridine derivative;

[0013] The step B is to collect the methyl tert-butyl ether phase and the aqueous phase respectively, add the second extractant to the aqueous phase for extraction, combine the organic phases, wash, dry and concentrate to obtain a pure imidazo[4,5-C]pyridine derivative.

[0014] In some embodiments, in step B, the second extractant includes any one or more of ethyl acetate, methyl acetate, ethyl formate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, benzene, acetonitrile, and acetone.

[0015] In some embodiments, the imidazo[4,5-C]pyridine derivative comprises at least 1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-C]pyridine-5-carboxylic acid tert-butyl ester, the structural formula of which is as follows:

[0016]

[0017] In some embodiments, the preparation method of the organic compound represented by formula (2) comprises using 1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine as a starting material, reacting with methanol and di-tert-butyl dicarbonate to obtain the organic compound, and the synthesis route is:

[0018]

[0019] In some embodiments, the specific steps of obtaining the organic compound represented by formula (2) are: adding methanol and di-tert-butyl dicarbonate to a water solvent for a first reaction for a period of time, and then adding di-tert-butyl dicarbonate again for a second reaction.

[0020] In some embodiments, in the method for preparing the organic compound represented by formula (2), at least one of the following conditions is satisfied:

[0021] The mass ratio of the substrate to water is (1:2)-(1:4);

[0022] In the first reaction, the mass ratio of the substrate to methanol is (1:3)-(1:4); the molar ratio of the substrate to di-tert-butyl dicarbonate is (1:2)-(2:1); the reaction temperature is 15°C-25°C, and the reaction time is 1h-3h;

[0023] In the second reaction, the molar ratio of the substrate to di-tert-butyl dicarbonate is (2:1)-(4:1); the reaction temperature is 15°C-25°C, and the reaction time is 7h-9h.

[0024] The present application also provides an imidazo[4,5-C]pyridine derivative, which is purified by any of the above purification methods.

[0025] Compared with the prior art, the beneficial effects of the present application include: by using MTBE-n-heptane as the extraction solvent, a solid imidazo[4,5-C]pyridine derivative can be obtained, which is convenient for transfer and storage and easy to operate, and is suitable for large-scale process production. DETAILED DESCRIPTION

[0026] For ease of understanding of the present invention, the present invention will be described more fully below with reference to relevant embodiments. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0028] The present invention provides a method for purifying an imidazo[4,5-C]pyridine derivative, comprising the following steps: adding a crude imidazo[4,5-C]pyridine derivative to a first extractant for extraction, wherein the first extractant comprises a mixed solution of methyl tert-butyl ether and n-heptane, and the structural formula of the imidazo[4,5-C]pyridine derivative is as follows:

[0029]

[0030] Wherein, R1 and R2 are each independently selected from any one of an alkyl group, a benzyl group, a tert-butyloxycarbonyl group, and a benzyloxycarbonyl group.

[0031] Imidazolo[4,5-C]pyridine derivatives are important raw materials for the synthesis of new anticancer drugs. In existing methods, most of the products prepared are oily liquids, which are difficult to store and transport, and are not suitable for large-scale production.

[0032] The invention adopts a mixed solution of methyl tert-butyl ether (MTBE) and n-heptane (n-Heptane) as an extractant, and can purify a high-purity solid imidazo[4,5-C]pyridine derivative, which greatly facilitates transfer and storage.

[0033] In the present invention, the main advantage of selecting a mixed solution of methyl tert-butyl ether (MTBE) and n-heptane (n-Heptane) as the extractant is that a solid imidazo[4,5-C]pyridine derivative can be obtained.

[0034] In the present invention, R1 and R2 may be the same or different.

[0035] In some specific embodiments, the alkyl group may be methyl, ethyl, propyl, or the like.

[0036] In some embodiments, the volume ratio of methyl tert-butyl ether and n-heptane is (1:2)-(1:20). In some specific embodiments, the volume ratio of methyl tert-butyl ether and 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, or 1:2.

[0037] The inventors of the present application have found that when the volume ratio of methyl tert-butyl ether to n-heptane exceeds the above range, it will not be possible to increase the purity to a higher level, resulting in a liquid product; when the volume ratio of the two is within the above ratio range, a better extraction effect can be obtained, such as the product can be purified without recrystallization or column chromatography, thereby obtaining a solid product.

[0038] In some embodiments, the volume ratio of the mixture of crude methyl tert-butyl ether of imidazo[4,5-C]pyridine derivative and n-heptane is (1:2)-(2:1). In some specific embodiments, the volume ratio of the mixture of crude methyl tert-butyl ether of imidazo[4,5-C]pyridine derivative and n-heptane is 1:1, 1:1.5, 1:2, 2:1.

[0039] 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 tert-butyl ether and n-heptane is within the above ratio range, a better extraction effect can be obtained.

[0040] In some embodiments, after the crude imidazo[4,5-C]pyridine derivative is added to the first extractant for extraction, the method further comprises step A or step B, wherein:

[0041] Step A is to collect the methyl tert-butyl ether phase, wash, dry and concentrate to obtain a pure imidazo[4,5-C]pyridine derivative;

[0042] Step B is to collect the methyl tert-butyl ether phase and the aqueous phase respectively, add the second extractant to the aqueous phase for extraction, combine the organic phases, wash, dry and concentrate to obtain a pure imidazo[4,5-C]pyridine derivative.

[0043] The crude imidazo[4,5-C]pyridine derivative is added to a mixture of methyl tert-butyl ether and n-heptane for extraction, and the mixture is allowed to stand for stratification, and is separated into three phases, for example, from top to bottom, it is divided into n-heptane phase, MTBE phase, and aqueous phase. Most of the imidazo[4,5-C]pyridine derivative is present in the MTBE phase, and a small part is present in the aqueous phase. Based on this, step A can be adopted to directly collect the MTBE phase, wash it, dry it, and concentrate it to obtain a pure imidazo[4,5-C]pyridine derivative; in order to further improve the yield, step B can be adopted to separately collect the methyl tert-butyl ether phase and the aqueous phase, further extract the aqueous phase to obtain an extraction phase, wherein combining the organic phase means that the extraction phase after the aqueous phase is extracted is mixed with the MTBE phase, and then washed, dried, and concentrated to obtain a pure imidazo[4,5-C]pyridine derivative.

[0044] In some embodiments, the second extractant includes any one or more of ethyl acetate, methyl acetate, ethyl formate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, benzene, acetonitrile, and acetone.

[0045] The two extraction processes can be performed once or multiple times, for example, twice, three times, four times, five times or more times.

[0046] In some embodiments, the washing process can be washed with water or with a sodium chloride aqueous solution, or the two can be washed alternately. In other embodiments, the concentration of the sodium chloride aqueous solution is 3wt%-10wt%, for example, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, 10wt%. The number of washings is not limited.

[0047] In some embodiments, the desiccant used in the drying process includes one of anhydrous magnesium sulfate and anhydrous sodium sulfate.

[0048] In some embodiments, before drying, the organic phase is cooled to below 15 degrees, such as below 10 degrees.

[0049] In some embodiments, the imidazo[4,5-C]pyridine derivative comprises at least 1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-C]pyridine-5-carboxylic acid tert-butyl ester, the structural formula of which is as follows:

[0050]

[0051] In the following examples, unless otherwise specified, all raw materials are commercially available.

[0052] 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 synthesized in a laboratory, which is not limited in the present application.

[0053] In some embodiments, the method for laboratory synthesis of tert-butyl 1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-C]pyridine-5-carboxylate comprises:

[0054] 1-methyl-4,5,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine is used as the starting material and reacted with methanol and di-tert-butyl dicarbonate. The synthetic route is as follows:

[0055]

[0056] In some embodiments, the preparation method comprises adding methanol and di-tert-butyl dicarbonate to a water solvent for a first reaction for a period of time, and then adding di-tert-butyl dicarbonate again for a second reaction.

[0057] In some embodiments, the mass ratio of substrate to water is (1:2)-(1:4).

[0058] In some embodiments, in the first reaction, the mass ratio of the substrate to methanol is (1:3)-(1:4); the molar ratio of the substrate to di-tert-butyl dicarbonate is (1:2)-(2:1); the reaction temperature is 15°C-25°C, and the reaction time is 1h-3h.

[0059] In some embodiments, in the second reaction, the molar ratio of the substrate to di-tert-butyl dicarbonate is (2:1)-(4:1); the reaction temperature is 15°C-25°C, and the reaction time is 7h-9h.

[0060] The present application also provides an imidazo[4,5-C]pyridine derivative, which is purified by the above purification method. The imidazo[4,5-C]pyridine derivative obtained by the above purification method is solid, easy to store and transport, and suitable for mass production.

[0061] The present application is further described below using specific examples. The following reagents are all commercially available unless otherwise specified.

[0062] Preparation Example

[0063] Preparation of Compound II (Organic Compound Represented by Formula (2))

[0064] This preparation example provides a preparation method of compound II, and the reaction formula is as follows:

[0065]

[0066] The process comprises the following reaction steps:

[0067] Add 1000mL water and 292.9g compound I (2.14mol, 1.0eq) to the reaction vessel, add 1340mL MeOH and 324.8g K2CO3 (2.35mol, 1.1eq), add 465.9g Boc2O (2.14mol, 1.0eq) dropwise, control the temperature at 20±5℃, add 139.8g Boc2O (0.64mo, 0.3eq) dropwise after 2 hours of reaction, and react for 8h. After the reaction is completed, the reaction solution is concentrated to 500mL of concentrated solution, and 20mL of concentrated solution is concentrated under reduced pressure to obtain 25.8g of light yellow oil with a purity of 75.5%.

[0068] Example 1

[0069] Purification of compound II

[0070] Take 20mL of the compound II concentrate prepared in the preparation example, add 20mL of MTBE-n-heptane mixed solution (MTBE: n-Heptane volume ratio is 1:10) and extract three times (the solution is divided into three phases, from top to bottom, n-heptane phase, MTBE, and aqueous phase), collect the MTBE phase and the aqueous phase respectively; add 15mL of EA to the aqueous phase and extract three times, collect the EA phase, mix the EA phase with MTBE, combine the organic phase, wash the organic phase with 10mL of water once, and wash it with 10mL of 5wt% sodium chloride aqueous solution twice. Cool the organic phase to below 10 degrees, add anhydrous magnesium sulfate to dry, and concentrate under reduced pressure to obtain 18.7g of compound II as a white solid with a purity of 98.88%.

[0071] Example 2

[0072] Purification of compound II

[0073] Take 10g of commercially available compound II (light yellow oil, HPLC purity 95.8%), add 10mL of water to fully dissolve it, add 10mL of MTBE-n-heptane mixed solution (MTBE: n-Heptane volume ratio is 1:10) to extract three times (the solution is divided into three phases, from top to bottom, n-heptane phase, MTBE, and aqueous phase), collect the MTBE phase and the aqueous phase respectively; add 8mL of EA to the aqueous phase and extract three times, collect the EA phase, mix the EA phase with MTBE, combine the organic phase, wash the organic phase with 5mL of water once, and wash it twice with 5mL of 5wt% sodium chloride aqueous solution. Cool the organic phase to below 10 degrees, add anhydrous magnesium sulfate to dry, and concentrate under reduced pressure to obtain 9.45g of white solid with HPLC purity of 99.0%.

[0074] Example 3

[0075] Purification of compound II

[0076] Take 10g of commercially available compound II (light yellow oil, HPLC purity 95.8%), add 10mL of water to fully dissolve it, add 10mL of MTBE-n-heptane mixed solution (MTBE:n-Heptane volume ratio is 1:10) and extract three times (the solution is divided into three phases, from top to bottom, n-heptane phase, MTBE, and water phase), take the MTBE phase, wash the MTBE phase with 5mL of water once, and wash it twice with 5mL of 5wt% sodium chloride aqueous solution. Cool the organic phase to below 10 degrees, add anhydrous magnesium sulfate to dry, and concentrate under reduced pressure to obtain 8.48g of white solid with HPLC purity of 99.2%.

[0077] Example 4

[0078] Purification of compound II

[0079] Take 10g of commercially available compound II (light yellow oil, HPLC purity 95.8%), add 10mL of water to fully dissolve it, add 10mL of MTBE-n-heptane mixed solution (MTBE: n-Heptane volume ratio is 5:10) to extract three times (the solution is divided into three phases, from top to bottom, n-heptane phase, MTBE, and aqueous phase), collect the MTBE phase and the aqueous phase respectively; add 8mL of EA to the aqueous phase and extract three times, collect the EA phase, mix the EA phase with MTBE, combine the organic phase, wash the organic phase with 5mL of water once, and wash it twice with 5mL of 5wt% sodium chloride aqueous solution. Cool the organic phase to below 10 degrees, add anhydrous magnesium sulfate to dry, and concentrate under reduced pressure to obtain 8.72g of white solid with HPLC purity of 99.0%.

[0080] Comparative Example 1

[0081] Purification of compound II

[0082] Take 20mL of the concentrated solution of compound II prepared in the preparation example, add 30mL of ethyl acetate to extract three times, combine the organic phases, add 15mL of EA to the aqueous phase and extract three times, combine the organic phases, wash the organic phase once with 10mL of water, and wash twice with 10mL of 5wt% sodium chloride aqueous solution. Cool the organic phase to below 10 degrees, add anhydrous magnesium sulfate to dry, and concentrate under reduced pressure to obtain 17.8g of colorless oil compound II with a purity of 89.64%.

[0083] Comparative Example 2

[0084] Purification of compound II

[0085] Take 20 mL of the concentrated solution of compound II prepared in the preparation example, add 30 mL of MTBE and extract three times, combine the organic phases, wash the organic phase once with 10 mL of water, and wash twice with 10 mL of 5 wt% sodium chloride aqueous solution. Cool the organic phase to below 10 degrees, add anhydrous magnesium sulfate to dry, and concentrate under reduced pressure to obtain 18.3 g of colorless oily compound II with a purity of 97.43%.

[0086] Comparative Example 3

[0087] Purification of compound II

[0088] 20 mL of the concentrated solution of Compound II prepared in the Preparation Example was added with 30 mL of ethyl acetate for extraction. The organic phases were combined twice, concentrated, and subjected to column chromatography to obtain 13.5 g of Compound II as a colorless oil with a purity of 98.7%.

[0089] Comparative Example 4

[0090] Purification of compound II

[0091] Take 20 mL of the concentrated solution of compound II prepared in the preparation example, add 30 mL of n-heptane to extract twice, combine the organic phases, add 20 mL of ethyl acetate to extract twice, combine the organic phases and concentrate, wash the organic phase once with 10 mL of water, and wash twice with 10 mL of 5 wt% sodium chloride aqueous solution. Cool the organic phase to below 10 degrees, add anhydrous magnesium sulfate to dry, and concentrate under reduced pressure to obtain 17.9 g of colorless oily compound II with a purity of 98.14%.

[0092] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0093] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for purifying an imidazo[4,5-C]pyridine derivative, characterized in that: The method comprises the following steps: adding a crude imidazo[4,5-C]pyridine derivative into water to fully dissolve the crude product, and then adding the crude product into a first extractant for extraction; the first extractant is a mixture of methyl tert-butyl ether and n-heptane, and the structural formula of the imidazo[4,5-C]pyridine derivative is as follows:

2. A method for purifying the imidazo[4,5-C]pyridine derivative as claimed in claim 1, characterized in that: The volume ratio of the methyl tert-butyl ether to n-heptane is (1:2)-(1:20).

3. A method for purifying the 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 the mixed solution of methyl tert-butyl ether and n-heptane is (1:2)-(2:1).

4. A method for purifying an imidazo[4,5-C]pyridine derivative as claimed in claim 1, characterized in that: After the crude imidazo[4,5-C]pyridine derivative is added to the first extractant for extraction, the step A or B is also included, wherein: The step A is to collect the methyl tert-butyl ether phase, wash, dry and concentrate to obtain a pure imidazo[4,5-C]pyridine derivative; The step B is to collect the methyl tert-butyl ether phase and the aqueous phase respectively, add the second extractant to the aqueous phase for extraction, combine the organic phases, wash, dry and concentrate to obtain a pure imidazo[4,5-C]pyridine derivative.

5. A method for purifying an imidazo[4,5-C]pyridine derivative as claimed in claim 4, characterized in that: In step B, the second extractant is 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 the imidazo[4,5-C]pyridine derivative according to claim 1, characterized in that: The preparation method of the organic compound represented by formula (2) comprises: using 1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine as a starting material, reacting with methanol and di-tert-butyl dicarbonate to obtain the organic compound; the synthesis route is:

7. A method for purifying an imidazo[4,5-C]pyridine derivative as claimed in claim 6, characterized in that: The specific steps of obtaining the organic substance represented by formula (2) are as follows: adding methanol and di-tert-butyl dicarbonate to a water solvent for a first reaction, and after a period of time, adding di-tert-butyl dicarbonate again for a second reaction.

8. A method for purifying an imidazo[4,5-C]pyridine derivative as claimed in claim 7, characterized in that: In the method for preparing the organic compound represented by formula (2), at least one of the following conditions is satisfied: The mass ratio of the substrate to water is (1:2)-(1:4); In the first reaction, the mass ratio of the substrate to methanol is (1:3)-(1:4); the molar ratio of the substrate to di-tert-butyl dicarbonate is (1:2)-(2:1); the reaction temperature is 15°C-25°C, and the reaction time is 1h-3h; In the second reaction, the molar ratio of the substrate to di-tert-butyl dicarbonate is (2:1)-(4:1); the reaction temperature is 15°C-25°C, and the reaction time is 7h-9h.

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