Preparation method of 2, 5-dimethoxypyridine-4-yl boric acid

Abstract

The invention belongs to the technical field of chemical synthesis of medicines, and particularly relates to a preparation method of 2, 5-dimethoxypyridine-4-yl boric acid, which comprises preparation of a compound III, preparation of a compound shown as a formula IV, preparation of a compound shown as a formula V, preparation of a compound shown as a formula VI, preparation of a compound shown as a formula VII and preparation of a compound shown as a formula I. The method has the beneficial effects that the reaction condition is mild, the process flow is simple and convenient, the requirement on equipment is relatively low, the purity of the obtained product is high, and industrial production is facilitated.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemical synthesis, and in particular to a method for preparing 2,5-dimethoxypyridin-4-ylboronic acid. Background Art

[0002] 2,5-dimethoxypyridine-4-boric acid is a widely used pharmaceutical intermediate, especially playing an important role in the research of new drugs. As recorded in the U.S. patent publication with publication number US2016 / 0052884 A1, 1-BOC-2,2-dimethylpiperidin-4-one can be used as an intermediate to prepare drugs for the treatment or prevention of cardiovascular diseases, thromboembolic diseases, edema and ophthalmic diseases; and the document J.Med.Chem.2023,66,12203-12224 reported that 2,5-dimethoxypyridine-4-boric acid is used as an intermediate to prepare FXIa inhibitor compounds for the prevention or treatment of diseases such as arterial thrombosis, venous thrombosis, and arteriovenous bypass thrombosis. Summary of the invention

[0003] Different from the production process in the prior art, the present invention proposes a new process for preparing (2,5-dimethoxypyridin-4-yl)boric acid in a simple and high yield manner, which is achieved by the following technical scheme:

[0004] A method for preparing 2,5-dimethoxypyridin-4-ylboronic acid, the reaction formula of which is as follows:

[0005]

[0006]

[0007] The following steps are involved:

[0008] S1. In a four-necked bottle equipped with a thermometer and mechanical stirring, methanol, acetic acid, and the compound of formula II were added in sequence, and reduced Fe powder was added in batches at room temperature. The temperature was raised to 60°C and the reaction was carried out for 2 hours. After the reaction was completed, the temperature was lowered to 20°C, the solid was filtered out, and the filtrate was evaporated to dryness to obtain a brown solid, i.e., the compound of formula III;

[0009] S2. In a first reaction bottle equipped with a thermometer, mechanical stirring, and a constant pressure dropping funnel device, add the compound represented by formula III, acetonitrile, and water in sequence, cool to 0°C, add sodium nitrite aqueous solution dropwise, and control the temperature at 0-5°C. After the addition is complete, control the temperature at 0-5°C and continue stirring for 1 hour. Add acetic acid and sulfuric acid to the second reaction bottle, heat to 60°C, drop the prepared diazonium salt into the first reaction bottle, react for 2 hours, and after the reaction is complete, cool the reaction solution to 20°C, add water, extract with DCM, wash with sodium carbonate solution, wash with saturated brine, and remove the solvent under reduced pressure to obtain an off-white solid, i.e., a compound of formula IV;

[0010] S3, methanol, compound of formula IV, and sodium methoxide were added to the third reaction bottle in sequence, and the mixture was heated under reflux for 2 hours. After the reaction was completed, methanol was evaporated from the reaction solution under reduced pressure, water was added, stirred, and filtered to obtain a white solid, namely compound of formula V;

[0011] S4, add DMF and the compound of formula V to the fourth reaction bottle, cool to 5°C, add iodomethane dropwise, control the temperature to less than 10°C, and keep warm for 3 hours after the addition is complete. After the reaction is complete, add the reaction solution into water, extract with EA, wash with saturated brine, and evaporate the solvent under reduced pressure to obtain a white solid, i.e., the compound of formula VI;

[0012] S5. In the fifth reaction bottle, add the compound of formula VI, dissolve it in tetrahydrofuran, protect it with nitrogen, cool it to -78°C in a dry ice / ethanol bath, stir it for 15 minutes, slowly add lithium diisopropylamide dropwise to the reaction solution, the addition is completed after 30 minutes, stir it for 3 hours at -78°C in a dry ice / ethanol bath, then add triisopropyl borate dropwise, heat it naturally to 10°C, stir it for 3 hours, after the reaction is completed, add dilute hydrochloric acid to the reaction solution, adjust the pH to 3-4, stir it for 15 minutes, evaporate it under reduced pressure to remove the solvent, mix the residue with acetonitrile to obtain a white solid, i.e. the compound of formula I.

[0013] Preferably, in S1, the molar ratio of the compound represented by formula II to the reduced Fe powder is 1.0:2.0-1.0:4.0.

[0014] Preferably, in S2, the molar ratio of the compound represented by formula III to sodium nitrite is 1.0:1.0-1.0:2.0.

[0015] Preferably, in S3, the molar ratio of the compound of formula IV to sodium methoxide is 1.0:1.5-1.0:2.0.

[0016] Preferably, in S4, the molar ratio of the compound of formula V to methyl iodide is 1.0:1.5-1.0:2.0.

[0017] Preferably, in S5, the molar ratio of the compound of formula VI to lithium diisopropylamide and triisopropyl borate is 1.0:1.0:1.5-1.0:1.5:2.0.

[0018] The invention has the following beneficial effects: the process uses 2-chloro-5-nitropyridine as a starting material, MEOH as a solvent, reduces Fe powder, and reduces to 2-chloro-5-aminopyridine under an acetic acid system; 2-chloro-5-aminopyridine reacts with sodium nitrite, acetic acid, and sulfuric acid to form 2-chloro-5-hydroxypyridine; 2-chloro-5-hydroxypyridine reacts with methanol and sodium methoxide to form 2-methoxy-5-hydroxypyridine; 2-methoxy-5-hydroxypyridine reacts with DMF and iodomethane to form 2,5-dimethoxypyridine; 2,5-dimethoxypyridine reacts with lithium diisopropylamide, tetrahydrofuran, and triisopropyl borate to form (2,5-dimethoxypyridine-4-yl)boric acid. The process route optimizes factors such as reaction reagents and reaction solvents, so that the reaction conditions are mild, the process flow is simple, the requirements for equipment are relatively low, the obtained product has high purity, and is conducive to industrial production. DETAILED DESCRIPTION

[0019] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0020] At the same time, the meaning of "and / or" or "and / or" appearing in the full text includes three options. Taking "A and / or B" as an example, it includes option A, or option B, or a option in which both A and B are satisfied.

[0021] In addition, in the present invention, descriptions such as "first", "second", etc. are only used for descriptive purposes and cannot be understood as indicating or implying their relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In addition, the technical solutions between the various embodiments can be combined with each other, but they must be based on the ability of ordinary technicians in the field to implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be deemed that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0022] Example 1, a method for preparing 2,5-dimethoxypyridin-4-ylboronic acid, the reaction formula of which is shown below:

[0023]

[0024] Wherein, the synthetic reaction formula of the compound 2-chloro-5-aminopyridine of formula III is as follows:

[0025]

[0026] Specifically, 1L of methanol, 300ml of acetic acid, and 100g of 2-chloro-5-nitropyridine were added to a 2L four-necked bottle equipped with a thermometer and mechanical stirring, and 104g of Fe powder for reduction was added in batches at room temperature. The reaction temperature was raised to 60°C and the reaction was carried out for 2 hours. After the reaction was completed, the temperature was lowered to 20°C, the solid was filtered out, and the filtrate was evaporated to dryness to obtain 75g of brown solid with a yield of 93% and a purity of 98%.

[0027] 1 HNMR (400MHz, CDCl3) δ (ppm): δ7.76 (d, 1H), 7.00 (d, 1H), 6.90 (dd, 3.0Hz, 1H), 3.87 (s, 2H).

[0028] The synthetic reaction formula of the compound 2-fluoro-6-(trifluoromethyl)benzoic acid of formula IV is as follows:

[0029]

[0030] Specifically: in a 2L four-necked bottle equipped with a thermometer, mechanical stirring, and a constant pressure dropping funnel device, add 75g of 2-chloro-5-aminopyridine, 500ml of acetonitrile, and 100ml of water, cool to 0°C, add sodium nitrite aqueous solution dropwise, and control the temperature at 0-5°C. After the addition is complete, control the temperature at 0-5°C, continue stirring for 1 hour, add 100ml of acetic acid and 50ml of sulfuric acid to another reaction bottle and heat to 60°C, drop the prepared diazonium salt into the first reaction bottle, react for 2 hours, and after the reaction is complete, cool the reaction solution to 20°C, add 1L of water, extract with DCM (500*2), wash with sodium carbonate solution, wash with saturated brine, and remove the solvent under reduced pressure to obtain 49g of off-white solid with a purity of 94% and a yield of 65%.

[0031] 1 HNMR (400MHz, DMSO-d6) δ (ppm): δ7.26-7.30 (dd, 2H), 7.95 (s, 1H), 10.23 (s, 1H).

[0032] The synthesis reaction formula of the compound 2-methoxy-5-aminopyridine of formula V is as follows:

[0033]

[0034] Specifically, 250 ml of methanol, 49 g of 2-chloro-5-hydroxypyridine, and 24.6 g of sodium methoxide were added to a 500 ml reaction bottle, and the mixture was heated under reflux for 2 hours. After the reaction was completed, the methanol was evaporated under reduced pressure from the reaction solution, 500 ml of water was added, stirred, and filtered to obtain 44 g of a white solid with a purity of 98% and a yield of 94%.

[0035] 1 HNMR (400MHz, CDCl3) δ (ppm): 7.78 (dd, 1H), 7.23 (dd, 1H), 6.68 (dd, 1H), 3.89 (s, 3H).

[0036] The synthetic reaction formula of the compound 2,5-dimethoxypyridine of formula VI is as follows:

[0037]

[0038] Specifically: add 250 ml of DMF and 44 g of 2-methoxy-5-aminopyridine into a 500 ml reaction bottle, cool to 5°C, add 75 g of iodomethane dropwise, control the temperature to less than 10°C, and keep warm for 3 hours after the addition is completed. After the reaction is completed, add the reaction solution into 1 L of water, extract with (300*2) EA, wash with saturated brine, and evaporate the solvent under reduced pressure to obtain 39 g of white solid with a purity of 98% and a yield of 79%.

[0039] 1 HNMR (400MHz, CDCl3) δ (ppm): 3.81 (s, 3H), 3.89 (s, 3H), 6.69 (d, 1H), 7.21 (dd, 1H), 7.80 (d, 1H).

[0040] The synthetic reaction formula of the compound of formula I (2,5-dimethoxypyridin-4-yl)boronic acid is as follows:

[0041]

[0042] Specifically: in a 500ml reaction bottle, 39.0g of 2,5-dimethoxypyridine was dissolved in 200ml of tetrahydrofuran. After nitrogen protection, the mixture was cooled to -78°C in a dry ice / ethanol bath. After stirring for 15 minutes, 121ml of lithium diisopropylamide was slowly added dropwise to the reaction solution. The addition was completed after 30 minutes. After stirring at -78°C in a dry ice / ethanol bath for 3 hours, 78.6g of triisopropyl borate was added dropwise. The mixture was naturally heated to 10°C and stirred for 3 hours. After the reaction was completed, dilute hydrochloric acid was added to the reaction solution, the pH was adjusted to 3-4, and after stirring for 15 minutes, the solvent was removed by evaporation under reduced pressure. The residue was mixed with acetonitrile to obtain 40g of a white solid with a purity of 98% and a yield of 70%.

[0043] 1HNMR (400MHz, DMSO-d6) δ (ppm): δ 8.19 (s, 2H), 7.75 (d, 1H), 6.74 (d, 1H), 3.76 (d, 6H).

[0044] The invention uses 2-chloro-5-nitropyridine as a raw material, MEOH as a solvent, reduces Fe powder, and reduces to 2-chloro-5-aminopyridine in an acetic acid system; 2-chloro-5-aminopyridine reacts with sodium nitrite, acetic acid and sulfuric acid to 2-chloro-5-hydroxypyridine; 2-chloro-5-hydroxypyridine reacts with methanol and sodium methoxide to 2-methoxy-5-hydroxypyridine; 2-methoxy-5-hydroxypyridine reacts with DMF and iodomethane to 2,5-dimethoxypyridine; 2,5-dimethoxypyridine reacts with lithium diisopropylamide, tetrahydrofuran and triisopropyl borate to (2,5-dimethoxypyridine-4-yl)boric acid, and provides a new production process of 2,5-dimethoxypyridine-4-ylboric acid. Because the process route optimizes factors such as reaction reagents and reaction solvents, the reaction conditions are mild, the process flow is simple, the equipment requirements are relatively low, the obtained product has high purity, and is conducive to industrial production.

[0045] It should be understood that the purpose of these embodiments is only to illustrate the present invention and is not intended to limit the protection scope of the present invention. In addition, it should also be understood that after reading the technical content of the present invention, those skilled in the art can make various changes, modifications and / or variations to the present invention, and all of these equivalent forms also fall within the protection scope defined by the appended claims of this application.

Claims

1. A method for preparing 2,5-dimethoxypyridin-4-ylboronic acid, characterized in that: The reaction formula is as follows: The following steps are involved: S1. In a four-necked bottle equipped with a thermometer and mechanical stirring, methanol, acetic acid, and the compound of formula II were added in sequence, and reduced Fe powder was added in batches at room temperature. The temperature was raised to 60°C and the reaction was carried out for 2 hours. After the reaction was completed, the temperature was lowered to 20°C, the solid was filtered out, and the filtrate was evaporated to dryness to obtain a brown solid, i.e., the compound of formula III; S2. In a first reaction bottle equipped with a thermometer, mechanical stirring, and a constant pressure dropping funnel device, add the compound represented by formula III, acetonitrile, and water in sequence, cool to 0°C, add sodium nitrite aqueous solution dropwise, and control the temperature at 0-5°C. After the addition is complete, control the temperature at 0-5°C and continue stirring for 1 hour. Add acetic acid and sulfuric acid to the second reaction bottle, heat to 60°C, drop the prepared diazonium salt into the first reaction bottle, react for 2 hours, and after the reaction is complete, cool the reaction solution to 20°C, add water, extract with DCM, wash with sodium carbonate solution, wash with saturated brine, and remove the solvent under reduced pressure to obtain an off-white solid, i.e., a compound of formula IV; S3, methanol, compound of formula IV, and sodium methoxide were added to the third reaction bottle in sequence, and the mixture was heated under reflux for 2 hours. After the reaction was completed, methanol was evaporated from the reaction solution under reduced pressure, water was added, stirred, and filtered to obtain a white solid, namely compound of formula V; S4, add DMF and the compound of formula V to the fourth reaction bottle, cool to 5°C, add iodomethane dropwise, control the temperature to less than 10°C, and keep warm for 3 hours after the addition is complete. After the reaction is complete, add the reaction solution into water, extract with EA, wash with saturated brine, and evaporate the solvent under reduced pressure to obtain a white solid, i.e., the compound of formula VI; S5. In the fifth reaction bottle, add the compound of formula VI, dissolve it in tetrahydrofuran, protect it with nitrogen, cool it to -78°C in a dry ice / ethanol bath, stir it for 15 minutes, slowly add lithium diisopropylamide dropwise to the reaction solution, the addition is completed after 30 minutes, stir it for 3 hours at -78°C in a dry ice / ethanol bath, then add triisopropyl borate dropwise, heat it naturally to 10°C, stir it for 3 hours, after the reaction is completed, add dilute hydrochloric acid to the reaction solution, adjust the pH to 3-4, stir it for 15 minutes, evaporate it under reduced pressure to remove the solvent, mix the residue with acetonitrile to obtain a white solid, i.e. the compound of formula I.

2. The method for preparing 2,5-dimethoxypyridin-4-ylboronic acid according to claim 1, characterized in that: In S1, the molar ratio of the compound represented by formula II to the reduced Fe powder is 1.0:2.0-1.0:4.

0.

3. The method for preparing 2,5-dimethoxypyridin-4-ylboronic acid according to claim 1, characterized in that: In S2, the molar ratio of the compound represented by formula III to sodium nitrite is 1.0:1.0-1.0:2.

0.

4. The method for preparing 2,5-dimethoxypyridin-4-ylboronic acid according to claim 1, characterized in that: In S3, the molar ratio of the compound of formula IV to sodium methoxide is 1.0:1.5-1.0:2.

0.

5. The method for preparing 2,5-dimethoxypyridin-4-ylboronic acid according to claim 1, characterized in that: In S4, the molar ratio of the compound of formula V to methyl iodide is 1.0:1.5-1.0:2.

0.

6. The method for preparing 2,5-dimethoxypyridin-4-ylboronic acid according to claim 1, characterized in that: In S5, the molar ratio of the compound of formula VI to lithium diisopropylamide and triisopropyl borate is 1.0:1.0:1.5-1.0:1.5:2.0.

Images