CN115772121A - The preparation method of 2-methylamino-3-hydroxymethylpyridine - Google Patents

Abstract

The invention provides a new preparation process of 2-methylamino-3-pyridinemethanol and isavuconazolium sulfate, which specifically adopts the process of passing 2-methylamino-3-pyridinecarboxylic acid in the presence of auxiliary reagents. NaBH4 reduction, preparation obtains 2-methylamino-3-pyridinemethanol, the method of the present invention utilizes the intermediate of carboxylic acid in situ condition to be converted into active ester, then uses relatively mild reductant NaBH4 to active ester intermediate The corresponding alcohol products are obtained by reduction, avoiding the use of highly dangerous reducing agents and the generation of highly toxic compound borane, greatly improving production safety and significantly reducing production costs.

Description

The preparation method of 2-methylamino-3-hydroxymethylpyridine

technical field

The application belongs to the technical field of drug synthesis, and in particular relates to a preparation method of 2-methylamino-3-hydroxymethylpyridine.

Background technique

Isavuconazonium sulfate and ravconazole are triazole antifungal drugs. Patent WO2001032652 discloses a preparation method for isavuconazonium hydrochloride. Its route is as follows,

Among them, 2-methylamino-3-hydroxymethylpyridine is a key intermediate for preparing isavuconazole hydrochloride and isavuconazole sulfate, and WO2001032652 discloses that 2-chloronicotinic acid is used as a starting material , react with oxalyl chloride to prepare 2-chloronicotinyl chloride, then react with potassium tert-butoxide to obtain 2-chloronicotinic acid tert-butyl ester; then react with methylamine/methanol solution to obtain 2-methylamino-3-pyridinecarboxylic acid tert-butyl Butyl fat; then through lithium aluminum hydride reduction, obtain the method for target product intermediate 2-methylamino-3-hydroxymethylpyridine, the reaction formula is as follows:

In the above method, methylamine not only reacts with the chlorine of 2-chloronicotinyl chloride, but also reacts with tert-butyl formate, and the product will be more complicated. Moreover, lithium aluminum hydride is not only expensive, but also needs to be anhydrous for the reaction. If it is not handled carefully, it is easy to cause punching or explosion, and it is not easy to scale up.

WO2001032652 also discloses that 2-aminonicotinic acid is used as a starting material, reacted with 2-chloro-1,3-dimethyl imidazoline chloride to prepare 2-aminonicotinic acid methyl ester; and then mixed with formic acid in acetic anhydride solution Reaction, obtain 2-formamido nicotinic acid methyl ester; Then through lithium aluminum hydride reduction, obtain target product intermediate 2-methylamino-3-hydroxymethylpyridine, reaction formula is as follows:

The starting material of the above method, 2-aminonicotinic acid, is expensive, and acetic anhydride is also a controlled chemical; and lithium aluminum hydride is not only expensive, but also requires anhydrous reaction, and it is easy to cause punching or explosion if it is not handled carefully, and it is not easy to scale up.

Patent WO2010089993 discloses that 2-chloronicotinic acid is used as a starting material, reacted with methylamine hydrochloride, potassium carbonate, and cuprous bromide in a DMF solvent at 100°C to prepare 2-methylamino-3- Picolinic acid is then reduced by lithium aluminum hydride to obtain the target product intermediate 2-methylamino-3-hydroxymethylpyridine. The reaction formula is as follows:

In this method, DMF is a high-boiling-point strong polar solvent, which is cumbersome to handle and the yield is not high. Moreover, lithium aluminum hydride is not only expensive, but also needs to be anhydrous for the reaction. If it is not handled carefully, it is easy to cause punching or explosion, and it is not easy to scale up.

CN 110317165 discloses a method for reducing 2-chloronicotinic acid tert-butyl ester to 2-methylamino-3-hydroxymethylpyridine using NaBH ₄ :

The tert-butyl carboxylate compound used in the method has a large steric hindrance and is difficult to be reduced, and usually requires the use of highly active reducing agents (such as LiALH4, borane, etc.) to achieve the reduction reaction at a higher temperature. And the disclosed method of CN 110317165 is to reflux in THF/Tol. mixed solvent after adding _NaBH at one time. Because this method is reflowed after one-time feeding, the safety risk is very large

CN 108822027 discloses a method for reducing 2-methylamino-3-pyridinecarboxylic acid to 2-methylamino-3-hydroxymethylpyridine using _NaBH4 and _FeCl3 .

CN 104961675 discloses a method for reducing 2-methylamino-3-pyridinecarboxylic acid to 2-methylamino-3-hydroxymethylpyridine by reflux reaction in toluene using red aluminum.

The above methods all need to use some dangerous reducing agents, such as LiAlH ₄ , red aluminum, and borane generated in situ using NaBH ₄ or KBH _4. Borane is highly toxic and explosive. There are very big safety hazards in the process of enlarging the production. In addition, the use of lithium aluminum hydride for reduction requires strict anhydrous, dangerous reaction and high cost.

Contents of the invention

In order to solve the above-mentioned problems existing in the prior art, the present invention provides a kind of intermediate that utilizes carboxylic acid to be converted into active ester under the in-situ condition, then uses relatively mild reductant NaBH ₄ to reduce active ester intermediate, obtained The method for corresponding alcohol products avoids the use of highly dangerous reducing agents and the generation of highly toxic compound borane.

At first, the invention provides a kind of preparation method of 2-methylamino-3-pyridinemethanol, described method comprises the following steps:

Compound a1 is prepared by reduction with NaBH ₄ in the presence of auxiliary reagents;

Wherein said auxiliary reagent is cyanuric chloride or CDI.

In one embodiment of the present invention, the auxiliary reagent is cyanuric chloride, and the preparation method of the 2-methylamino-3-pyridinemethanol comprises the following steps:

Compound a1 was added to an organic solvent of N-methylmorpholine and cyanuric chloride, stirred at room temperature, and filtered to obtain filtrate I;

The filtrate I was reacted with sodium borohydride to obtain the target compound A.

Further preferably, the molar ratio of cyanuric chloride to compound a1 is 1 to 1.5:1, the molar ratio of N-methylmorpholine to compound a1 is 1 to 1.5:1; the molar ratio of sodium borohydride to compound a1 It is 1-2:1, preferably 1.5-2:1.

In one embodiment of the present invention, the molar ratio of cyanuric chloride to compound a1 is 1.1～1.2:1, the molar ratio of N-methylmorpholine to compound a1 is 1.1～1.2:1; sodium borohydride and The molar ratio of compound a1 is 1.5-2:1.

Further in the above method, the organic solvent is one or more of THF, DEM, and toluene, preferably, the organic solvent is THF.

In one embodiment of the present invention, the above method, wherein the temperature of the filtrate I is cooled to -5°C to 5°C before the filtrate I is reacted with sodium borohydride.

In one embodiment of the present invention, the above method also includes the step of purifying the reaction solution after the reaction, the purification step includes separating the reaction solution, extracting, and recrystallizing with n-Hexane/chloroform to obtain Compound A Pure.

In one embodiment of the present invention, a kind of preparation method of 2-methylamino-3-pyridinemethanol is provided, comprising the following steps:

(1) Add cyanuric chloride to the THF solution, then add N-methylmorpholine at room temperature, then add compound a1 to the THF solution of cyanuric chloride and N-methylmorpholine, stir at room temperature, filter, Obtain filtrate I;

The preferred molar ratio of cyanuric chloride to compound a1 is 1-1.5:1, the molar ratio of N-methylmorpholine to compound a1 is 1-1.5:1; the molar ratio of sodium borohydride to compound a1 is 1-2 :1, more preferably 1.5 to 2:1.

(2) Cool the filtrate I to -5°C-5°C, preferably to 0°C, then slowly add sodium borohydride dissolved in water dropwise therein, and react at -5°C-5°C, preferably cold 0°C, to obtain target compound A;

Further preferably, after the reaction, separate the liquids, extract with dichloromethane, combine the organic phases, concentrate, and recrystallize (preferably use n-hexane/chloroform for recrystallization) to obtain the target compound.

In another embodiment of the present invention, a method for preparing 2-methylamino-3-pyridinemethanol is provided, comprising the following steps: preparing compound a1 by reducing it with NaBH ₄ in the presence of auxiliary reagent CDI;

In a specific embodiment of the present invention, a kind of preparation method of 2-methylamino-3-pyridinemethanol comprises the following steps:

Adding CDI to the organic solvent of compound a1 as reaction solution II;

Sodium borohydride is added to the organic solvent as reaction solution III;

The reaction solution II was slowly added to the reaction solution III, and the internal temperature of the reaction solution III was controlled not to exceed 20 ° C. After the reaction was completed, compound A was isolated.

Further preferably, the above method also includes adding citric acid to the reaction mixture after the reaction, and then isolating compound A. Preferably, the molar ratio of citric acid to compound a1 is 1-2:1.

Further preferably, the molar ratio of CDI to compound a1 is 1-1.5:1, more preferably the molar ratio of CDI to compound a1 is 1.2-1.3:1; the molar ratio of sodium borohydride to compound a1 is 3-4:1 .

Further preferably, the organic solvent is one or more of THF, DEM, and toluene, more preferably, the organic solvent is THF.

Further, in the above method, the sodium borohydride is added to the organic solvent as the reaction solution III, wherein the organic solvent is preferably a mixture of THF and water, and the volume ratio of THF and water can be within a larger range The purpose is to facilitate the dissolution of sodium borohydride in the organic solvent. In the present invention, the volume ratio of THF to water is preferably 1-3:1, for example 3:2.

Further, in the above method, when the reaction solution II is added to the reaction solution III, the internal temperature of the reaction solution III does not exceed 20°C.

In a specific embodiment of the present invention, a kind of preparation method of 2-methylamino-3-pyridinemethanol is provided, comprising the following steps:

CDI was added to the THF solution of compound a1 as reaction solution II;

Sodium borohydride is added to the mixed solution with THF and water as reaction solution III;

Slowly add the reaction solution II to the reaction solution III, and control the internal temperature of the reaction solution III to not exceed 20°C. After the reaction is completed, add citric acid to the reaction mixture, and then separate to obtain compound A;

Wherein, the molar ratio of CDI and compound a1 is 1～1.5:1, and the molar ratio of preferred CDI and compound a1 is 1.2～1.3:1; The molar ratio of sodium borohydride and compound a1 is 3～4:1; Citric acid The molar ratio with compound a1 is 1～2:1;

Preferably, the volume ratio of THF to water in the mixture of THF and water is 1-3:1, such as 3:2.

Further, after adding citric acid to the reaction mixture, the reaction solution was extracted with DCM, the organic phases were combined, the solvent was removed under reduced pressure, and the residue was recrystallized (preferably with n-hexane/chloroform) to obtain purified compound A.

In one embodiment of the present invention, a method for preparing compound a1 is provided: compound a1 is obtained by reacting compound a2 with methylamine under basic conditions:

Preferably, the alkali is selected from sodium hydroxide, potassium hydroxide, potassium carbonate or lithium hydroxide, more preferably sodium hydroxide;

Further preferably, the molar ratio of methylamine to compound a2 is 5-10:1, preferably 8:1; the molar ratio of base to compound a2 is 1-2:1, preferably 1-1.5:1.

Further, the preparation method of compound a1 reacts compound a2 and methylamine in a suitable solvent such as methanol under basic (preferably NaOH) conditions, and after the reaction takes over, cool the reaction solution to 0-5°C and filter The generated sodium chloride was removed, and the solvent was distilled off under reduced pressure to obtain a crude product of compound a1.

Further preferably, a step of purifying the crude product is also included, for example, adding the obtained crude product into tetrahydrofuran, refluxing, cooling and filtering, and distilling the filtrate to remove the solvent under reduced pressure to obtain 2-methylamine-3-pyridinecarboxylic acid.

Another aspect of the present invention also provides a preparation method of isavuconazolium sulfate, which comprises the preparation method of compound A described in the present invention.

Beneficial effects of the present invention:

First, the present invention provides a method for preparing 2-methylamino-3-pyridylmethanol and isavuconazolium sulfate by using auxiliary reagent cyanuric chloride or CDI. Compound a1 is converted into an active ester intermediate that can be converted into the corresponding alcohol product by mild reduction reaction conditions. It avoids LiAlH4 and red aluminum as the reducing agent in the prior art. During the reaction process, anhydrous needs to be strictly controlled, and safety hazards such as flushing or explosion are likely to occur due to careless handling, thus significantly improving safety and greatly reducing production costs.

Secondly, the technical scheme of the present invention adopts the active ester of the compound a1 prepared by the auxiliary reagent cyanuric chloride or CDI, and its reactivity to _be reduced to alcohol is greatly improved. The reduction reaction can be completed, avoiding the use of more reactive and dangerous borane.

Third, the reduction reaction step of the present invention avoids the reaction of sodium borohydride in the presence of sulfuric acid/Lewis acid by using a specific active ester, thereby avoiding the generation of highly toxic intermediate borane, and has a good reaction yield. High efficiency and high security, especially suitable for industrial scale-up production applications.

Explanation of term abbreviations:

THF: Tetrahydrofuran;

DCM: dichloromethane;

CDI: N,N'-carbonyldiimidazole;

DME: Ethylene glycol dimethyl ether.

Detailed ways

The technical solutions and advantages of the present invention will be further explained below in conjunction with specific embodiments. It should be noted that, in the case of no conflict, the embodiments in the present application and the features in the embodiments can be combined with each other. Unless otherwise specified, the reagents used in the present invention are commercially available.

Embodiment 1: the preparation of 2-methylamine-3-pyridinecarboxylic acid (compound a1)

In 200 grams of 40% methylamine (2.58mol, 8.0eq.) in methanol solution, add 50 grams of 2-chloronicotinic acid (0.32mol, 1.0eq.) and 12.69 grams of sodium hydroxide (0.32mol, 1.0eq.) . Stir at 90°C. After the reaction, cool the reaction liquid to 0-5°C, and filter to remove the generated sodium chloride. The solvent was distilled off under reduced pressure to obtain a crude product of compound a1. The obtained crude product was added with 150 ml of THF, refluxed, cooled and filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 43 g of 2-methylamine-3-pyridinecarboxylic acid (89.6%).

Embodiment 2: Preparation of 2-methylamino-3-pyridinemethanol

20.28 g of cyanuric chloride (0.11 mol, 1.1 eq.) was dissolved in 60 ml of THF, and 11.13 g of N-methylmorpholine (0.11 mol, 1.1 eq.) was added at room temperature. To the white suspension obtained above was added 15.22 g of compound a1 (0.1 mol, 1.0 eq.) dissolved in 30 ml of THF. After stirring was continued for 3 hours at room temperature, it was filtered. The filtrate was cooled to 0°C, and a solution of 5.67 g of sodium borohydride (0.15 mol, 1.5 eq.) dissolved in 25 ml of water was slowly dropped into it. Stirring was continued at 0°C. After the reaction was completed, the layers were separated, the aqueous phase was extracted with DCM, the organic phases were combined, washed with 20% brine, dried, and concentrated. The obtained crude product was recrystallized with n-hexane/chloroform to obtain 11.2 g of product (yield 81%).

Embodiment 3～6: Preparation of 2-methylamino-3-pyridinemethanol

Referring to the method of Example 2 to prepare 2-methylamino-3-pyridinemethanol, the reaction substrate feeding ratio is shown in Table 1 below, where eq represents the molar equivalent ratio.

Table 1: Embodiment 3～5 charging ratio

Example 3 Example 4 Example 5 Compound a1 1eq 1eq 1eq Cyanuric chloride 1eq 1.5eq 1eq N-Methylmorpholine 1eq 1.5eq 1.5eq NaBH4 1eq 2eq 1.5eq Organic solvents THF THF THF yield 73% 80% 78%

Note: eq means molar equivalent ratio.

Embodiment 6: Preparation of 2-methylamino-3-pyridinemethanol

15.22 g of compound a1 (0.1 mol, 1.0 eq.) was dissolved in 45 ml of anhydrous tetrahydrofuran, and then 19.46 g of CDI (0.12 mol, 1.2 eq.) was slowly added, which was designated as reaction solution II. In another reaction vessel, 11.35 g of sodium borohydride (0.3 mol, 3.0 eq.) was dissolved in 30 ml of tetrahydrofuran and 20 ml of water, and the temperature was adjusted to 0° C., which was designated as reaction solution III. After the reaction solution II was stirred at room temperature for 1 hour, it was slowly dripped into the reaction solution III (to ensure that the internal temperature of the reaction solution III did not exceed 20° C.). After the dropwise addition was complete, stirring was continued at room temperature until the reaction was complete. Add 19.21 g of citric acid (0.1 mol, 1.0 eq.) to quench the reaction. The reaction solution was separated into layers, and the aqueous phase was extracted with dichloromethane. The combined organic phase was concentrated and recrystallized with n-hexane/chloroform to obtain 12.16 g of product (yield: 88%).

Embodiment 7: Preparation of 2-methylamino-3-pyridinemethanol

Referring to the method of Example 6 to prepare 2-methylamino-3-pyridinemethanol, the reaction substrate feeding ratio is shown in Table 2 below, where eq represents the molar equivalent ratio.

Table 2: Embodiment 7～9 charging ratio

Example 7 Example 8 Example 9 Compound a1 1eq 1eq 1eq CDI 1eq 1.5eq 1.2eq NaBH4 2eq 3eq 5eq citric acid 1 eq 1eq 1eq Organic solvents THF THF THF yield 83% 87% 86%

Note: eq means molar equivalent ratio.

Inspired by the above-mentioned ideal embodiment according to the present application, through the above-mentioned description content, relevant staff can make various changes and modifications within the scope of not departing from the technical idea of this application. The technical scope of this application is not limited to the content in the specification, but must be determined according to the scope of the claims.

Claims (10)

1. The preparation method of the 1.2-methylamino-3-pyridinemethanol is characterized by comprising the following steps:

   

   passing the compound a1 through NaBH in the presence of an auxiliary reagent ₄ Reducing and preparing;

   wherein the auxiliary reagent is cyanuric chloride or CDI.
2. 2. The method according to claim 1, wherein the auxiliary reagent is cyanuric chloride, the method comprising the steps of:

   

   adding the compound a1 into an organic solvent of N-methylmorpholine and cyanuric chloride, stirring at room temperature, and filtering to obtain a filtrate I;

   and (3) reacting the filtrate I with sodium borohydride to obtain a target compound A.
3. 3. The process according to claim 2, characterized in that the molar ratio of cyanuric chloride to compound a1 is 1 to 1.5, the molar ratio of n-methylmorpholine to compound a1 is 1 to 1.5; the molar ratio of sodium borohydride to compound a1 is 1-2, preferably 1.5-2.
4. 4. The method as claimed in claim 2, wherein the organic solvent is one or more of THF, DEM and toluene, and the temperature of filtrate I is cooled to-5 ℃ before reacting filtrate I with sodium borohydride.
5. 5. The method according to claim 2, further comprising a step of purifying the reaction solution after the reaction is finished, wherein the purification step comprises separating the reaction solution, extracting, and recrystallizing with n-hexane/chloroform to obtain a pure product of the compound A.
6. 6. The method of claim 1, wherein the co-reagent is CDI, the method comprising the steps of:

   

   adding CDI into an organic solvent of the compound a1 to serve as a reaction liquid II;

   adding gram of sodium borohydride into an organic solvent to serve as reaction liquid III;

   slowly adding the reaction liquid II into the reaction liquid III, controlling the internal temperature of the reaction liquid III to be not more than 20 ℃, and separating to obtain the compound A after the reaction is finished.
7. 7. The method according to claim 6, further comprising adding citric acid to the reaction mixture after the reaction is completed, and then separating to obtain Compound A.
8. 8. The process according to claim 7, wherein the molar ratio of CDI to compound a1 is from 1 to 1.5; the molar ratio of the sodium borohydride to the compound a1 is 2-5;

   further preferably, the organic solvent is one or more of THF, DEM and toluene, and preferably the organic solvent is THF.
9. 9. The process according to any one of claims 1 to 8, wherein compound a1 is obtained by reacting compound a2 with methylamine under basic conditions:

   

   preferably, the base is selected from sodium hydroxide, potassium carbonate or lithium hydroxide;

   further preferably, the molar ratio of methylamine to compound a2 is 5-10; the molar ratio of the base to the compound a2 is 1 to 2.
10. 10. A process for the preparation of isaconazole onium sulphate characterized in that it comprises the process according to any one of claims 1 to 8.