CN115772121A - Preparation method of 2-methylamino-3-hydroxymethylpyridine - Google Patents

Preparation method of 2-methylamino-3-hydroxymethylpyridine Download PDF

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CN115772121A
CN115772121A CN202111036136.4A CN202111036136A CN115772121A CN 115772121 A CN115772121 A CN 115772121A CN 202111036136 A CN202111036136 A CN 202111036136A CN 115772121 A CN115772121 A CN 115772121A
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compound
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molar ratio
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sodium borohydride
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徐安佗
周宁
王圣奔
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Nantong Nuotai Biological Pharmaceutical Co ltd
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Abstract

The invention provides a novel preparation process of 2-methylamino-3-pyridinemethanol and isaconazole onium sulfate, which specifically comprises the steps of reducing 2-methylamine-3-pyridinecarboxylic acid by NaBH4 in the presence of an auxiliary reagent to prepare 2-methylamino-3-pyridinemethanol.

Description

Preparation method of 2-methylamino-3-hydroxymethylpyridine
Technical Field
The application belongs to the technical field of drug synthesis, and particularly relates to a preparation method of 2-methylamino-3-hydroxymethylpyridine.
Background
Isavuconazole onium sulfate and ravuconazole are triazole antifungal drugs, and a preparation method for preparing isavuconazole hydrochloride is disclosed in patent WO 2001032652. The route of which is shown below,
Figure BDA0003247028940000011
wherein, 2-methylamino-3-hydroxymethyl pyridine is a key intermediate for preparing isaconazole hydrochloride and isaconazole onium sulfate, WO2001032652 discloses that 2-chloronicotinic acid is used as a starting material, reacts with oxalyl chloride to prepare 2-chloronicotinoyl chloride, and then reacts with potassium tert-butoxide to prepare 2-chloronicotinoyl chloride; then reacting with methylamine/methanol solution to obtain 2-methylamino-3-pyridine carboxylic acid tert-butyl ester; then reducing by lithium aluminum hydride to obtain a target product intermediate 2-methylamino-3-hydroxymethyl pyridine, wherein the reaction formula is as follows:
Figure BDA0003247028940000021
in the above process, methylamine reacts not only with chlorine of 2-chloronicotinoyl chloride but also with t-butyl formate, and the product is relatively complicated. Lithium aluminum hydride is not only expensive, but also needs no water in reaction, and is easy to flush or explode due to careless treatment, so that the scale-up is not easy.
WO2001032652 also discloses a method for preparing 2-amino methyl nicotinate by reacting 2-amino nicotinic acid as a starting material with 2-chloro-1, 3-dimethyl imidazoline chloride; then reacting with formic acid in an acetic anhydride solution to obtain 2-formamido methyl nicotinate; then reducing by lithium aluminum hydride to obtain a target product intermediate 2-methylamino-3-hydroxymethyl pyridine, wherein the reaction formula is as follows:
Figure BDA0003247028940000022
the starting material 2-amino nicotinic acid in the method is expensive, and acetic anhydride is also a controlled chemical; lithium aluminum hydride is not only expensive, but also needs no water in reaction, and is easy to flush or explode due to careless treatment, so that the scale-up is not easy.
Patent WO2010089993 discloses that 2-chloronicotinic acid is used as a starting material, and reacts with methylamine hydrochloride, potassium carbonate and cuprous bromide in a DMF solvent at 100 ℃ to prepare 2-methylamino-3-picolinic acid, and then the 2-methylamino-3-hydroxymethylpyridine which is a target product is obtained by reduction with lithium aluminum hydride. The reaction formula is as follows:
Figure BDA0003247028940000031
the method has the advantages that DMF is a high-boiling point strong polar solvent, the treatment is troublesome, and the yield is not high. And lithium aluminum hydride is not only high in price, but also needs no water in reaction, so that the material washing or explosion is easy to occur due to careless treatment, and the amplification is not easy.
CN 110317165 discloses the use of NaBH 4 The method for reducing 2-chloronicotinic acid tert-butyl ester into 2-methylamino-3-hydroxymethyl pyridine comprises the following steps:
Figure BDA0003247028940000032
the tert-butyl carboxylate compound used in the method has great steric hindrance and great reduction difficulty, and the reduction reaction can be realized at higher temperature by using a highly active reducing agent (such as LiALH4, borane and the like). CN 110317165 discloses a method for preparing NaBH 4 After the one-shot addition, the mixture was refluxed in a THF/Tol. The method has very large safety risk because the material is fed once and then reflows
CN 108822027 discloses the use of NaBH 4 And FeCl 3 A method for reducing 2-methylamino-3-picolinic acid into 2-methylamino-3-hydroxymethylpyridine.
Figure BDA0003247028940000033
CN 104961675 discloses a reduction of 2-methylamino-3-pyridinecarboxylic acid to 2-methylamino-3-hydroxymethylpyridine by reflux reaction in toluene using red aluminum.
In the above methods, some dangerous reducing agents, such as LiAlH, are required 4 Red aluminum, using NaBH 4 Or KBH 4 And the borane generated in situ is extremely toxic and explosive, and has great potential safety hazard in the industrial amplification production process. In addition, lithium aluminum hydride is used for reduction, strict anhydrous is required, the reaction is dangerous, and the cost is high.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a method for converting carboxylic acid into intermediates such as active ester and the like under the in-situ condition and then using a relatively mild reducing agent NaBH 4 Method for reducing active ester intermediate to obtain corresponding alcohol product, and avoiding reducing agent with high riskUse, and production of the highly toxic compound borane.
Firstly, the invention provides a preparation method of 2-methylamino-3-pyridinemethanol, which comprises the following steps:
Figure BDA0003247028940000041
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.
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:
Figure BDA0003247028940000042
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.
Further preferably, the molar ratio of the cyanuric chloride to the compound a1 is 1 to 1.5, the molar ratio of 1, n-methylmorpholine to the compound a1 is 1 to 1.5; the molar ratio of sodium borohydride to compound a1 is 1-2, preferably 1.5-2.
In one embodiment of the invention, the molar ratio of the cyanuric chloride to compound a1 is 1.1 to 1.2, the molar ratio of n-methylmorpholine to compound a1 is 1.1 to 1.2; the molar ratio of the sodium borohydride to the compound a1 is 1.5-2.
In a further embodiment of the above method, the organic solvent is one or more of THF, DEM, and toluene, and preferably, the organic solvent is THF.
In an embodiment of the present invention, the above method, wherein the temperature of the filtrate I is cooled to-5 ℃ to 5 ℃ before the filtrate I is reacted with the sodium borohydride.
In one embodiment of the present invention, the above method further comprises 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 compound a.
In one embodiment of the present invention, there is provided a method for preparing 2-methylamino-3-pyridinemethanol, comprising the steps of:
Figure BDA0003247028940000051
(1) Adding cyanuric chloride into a THF solution, adding N-methylmorpholine at room temperature, adding a compound a1 into the THF solution of the cyanuric chloride and the N-methylmorpholine, stirring at room temperature, and filtering to obtain a filtrate I;
the preferred molar ratio of cyanuric chloride to compound a1 is from 1 to 1.5: the mol ratio of 1, N-methylmorpholine to the compound a1 is 1-1.5: 1; the molar ratio of the sodium borohydride to the compound a1 is 1-2: 1, more preferably 1.5 to 2:1.
(2) Cooling the filtrate I to-5 ℃, preferably to 0 ℃, then slowly dropwise adding sodium borohydride dissolved in water into the filtrate I, and reacting at-5 ℃, preferably at 0 ℃ to obtain a target compound A;
more preferably, after completion of the reaction, the reaction mixture is separated, extracted with dichloromethane, the organic phases are combined, concentrated, and recrystallized (preferably, from n-hexane/chloroform) to obtain the target compound.
In another embodiment of the present invention, there is provided a method for preparing 2-methylamino-3-pyridinemethanol, comprising the steps of: passing compound a1 through NaBH in the presence of auxiliary reagent CDI 4 Reducing and preparing;
Figure BDA0003247028940000061
in one embodiment of the present invention, a method for preparing 2-methylamino-3-pyridinemethanol comprises the following steps:
adding CDI into an organic solvent of the compound a1 to serve as a reaction liquid II;
adding sodium borohydride into an organic solvent to obtain a reaction solution III;
and 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.
More preferably, the method further comprises adding citric acid into the reaction mixture after the reaction is finished, and then separating to obtain the compound a, wherein the molar ratio of the citric acid to the compound a1 is preferably 1-2: 1.
further preferably, the molar ratio of CDI to compound a1 is 1 to 1.5, more preferably the molar ratio of CDI to compound a1 is 1.2 to 1.3; the molar ratio of sodium borohydride to compound a1 is 3 to 4.
Further preferably, the organic solvent is one or more of THF, DEM, and toluene, and more preferably, the organic solvent is THF.
Further, in the above method, the sodium borohydride is added to an organic solvent as the reaction liquid III, wherein the organic solvent is preferably a mixture of THF and water, and the volume ratio of THF to water can be varied within a wide range in order to facilitate the dissolution of the sodium borohydride in the organic solvent, in the present invention, the volume ratio of THF to water is preferably 1 to 3, for example 3.
Further, in the above method, in the process of adding the reaction solution II to the reaction solution III, the internal temperature of the reaction solution III does not exceed 20 ℃.
In one embodiment of the present invention, there is provided a method for preparing 2-methylamino-3-pyridinemethanol, comprising the steps of:
adding CDI into a THF solution of the compound a1 to serve as a reaction solution II;
adding sodium borohydride into a mixed solution of THF and water to serve as a reaction solution 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 ℃, adding citric acid into the reaction mixed liquid after the reaction is finished, and then separating to obtain a compound A;
wherein, the molar ratio of CDI to the compound a1 is 1 to 1.5, and the preferred molar ratio of CDI to the compound a1 is 1.2 to 1.3; the molar ratio of the sodium borohydride to the compound a1 is 3-4; the molar ratio of the citric acid to the compound a1 is 1-2;
the volume ratio of THF to water in the mixture of THF and water is preferably 1 to 3, for example 3.
Further, after citric acid was added to the reaction mixture, the reaction mixture 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, there is provided a method for preparing the compound a 1: the compound a1 is obtained by reacting the compound a2 with methylamine under alkaline conditions:
Figure BDA0003247028940000081
preferably, the base is selected from sodium hydroxide, potassium carbonate or lithium hydroxide, more preferably sodium hydroxide;
further preferably, the molar ratio of methylamine to compound a2 is 5 to 10:1, preferably 8:1; the molar ratio of the base to the compound a2 is 1-2: 1, preferably 1 to 1.5.
Further, the preparation method of the compound a1 comprises the steps of reacting the compound a2 with methylamine in a suitable solvent such as methanol under an alkaline (preferably NaOH) condition, cooling the reaction liquid to 0-5 ℃ after the reaction is completed, filtering to remove generated sodium chloride, and removing the solvent through reduced pressure distillation to obtain a crude product of the compound a 1.
Further preferably, the method further comprises a step of purifying the crude product, for example, adding tetrahydrofuran to the obtained crude product, refluxing, cooling and filtering, and evaporating the solvent from the filtrate under reduced pressure to obtain 2-methylamine-3-pyridinecarboxylic acid.
In another aspect, the present invention further provides a preparation method of isavuconazole onium sulfate, which comprises the preparation method of compound a described in the present invention.
The invention has the beneficial effects that:
firstly, the invention provides a method for preparing 2-methylamino-3-pyridinemethanol and isaconazole onium sulfate by adopting auxiliary reagent cyanuric chloride or CDI, the method firstly converts compound a1 into an active ester intermediate by adopting auxiliary reagent cyanuric chloride or CDI, and the active ester intermediate can be converted into a corresponding alcohol product by mild reduction reaction conditions. The method avoids the potential safety hazards such as flushing or explosion easily caused by careless treatment because LiAlH4 and red aluminum are used as reducing agents and no water needs to be strictly controlled in the reaction process in the prior art, thereby obviously improving the safety and greatly reducing the production cost.
Secondly, the technical proposal of the invention adopts the auxiliary reagent cyanuric chloride or CDI to prepare the active ester of the compound a1, the reaction activity of the active ester reduced into alcohol is greatly improved, and milder NaBH is used 4 Or the intermediate generated by the reaction of the compound with water can complete the reduction reaction, thereby avoiding the use of borane with higher activity and higher danger.
Thirdly, the reduction reaction step of the invention avoids the reaction of sodium borohydride in the presence of sulfuric acid/Lewis acid by using specific active ester, thereby avoiding the generation of the virulent intermediate borane, and simultaneously has better reaction yield and higher safety, and is particularly suitable for industrial scale-up production application.
Interpretation of the terms abbreviations:
THF: tetrahydrofuran;
DCM: dichloromethane;
CDI: n, N' -carbonyldiimidazole;
DME: ethylene glycol dimethyl ether.
Detailed Description
The technical solutions and advantages of the present invention are further explained below with reference to specific embodiments, and it should be noted that the features in the embodiments and examples in the present application may be combined with each other without conflict. Unless otherwise specified, reagents used in the present invention are commercially available.
Example 1: preparation of 2-methylamine-3-pyridinecarboxylic acid (Compound a 1)
Figure BDA0003247028940000101
To 200 g of 40% methylamine (2.58mol, 8.0 eq.) in methanol was added 50 g of 2-chloronicotinic acid (0.32mol, 1.0 eq.) and 12.69 g of sodium hydroxide (0.32mol, 1.0 eq.). Stirring at 90 ℃, cooling the reaction liquid to 0-5 ℃ after the reaction is finished, and filtering to remove the generated sodium chloride. The solvent was removed by distillation under the reduced pressure to give a crude product of compound a 1. 150 ml of tetrahydrofuran was added to the crude product, and the mixture was refluxed, cooled and filtered, and the solvent was distilled off from the filtrate under reduced pressure to obtain 43 g of 2-methylamine-3-pyridinecarboxylic acid (89.6%).
Example 2: preparation of 2-methylamino-3-pyridinemethanol
Figure BDA0003247028940000102
20.28 g of cyanuric chloride (0.11mol, 1.1eq.) are dissolved in 60 ml of THF, and 11.13 g of N-methylmorpholine (0.11mol, 1.1eq.) are added at room temperature. To the white suspension obtained above was added 15.22 g of compound a1 (0.1mol, 1.0 eq.) dissolved in 30 ml of THF. After stirring at room temperature for a further 3 hours, filtration was carried out. The filtrate was cooled to 0 ℃ and a solution of 5.67 g of sodium borohydride (0.15mol, 1.5eq.) dissolved in 25 ml of water was slowly added dropwise thereto. Stirring was continued at 0 ℃ and after completion of the reaction, the phases were separated, the aqueous phase was extracted with DCM, the organic phases were combined, washed with 20% brine, dried and concentrated. The crude product was recrystallized from n-hexane/chloroform to yield 11.2 g of product (81% yield).
Examples 3 to 6: preparation of 2-methylamino-3-pyridinemethanol
Preparation of 2-methylamino-3-pyridinemethanol by the method of reference example 2, the reaction substrate charge ratios are shown in table 1 below, wherein eq represents the molar equivalence ratio.
Table 1: examples 3 to 5 feed ratios
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 solvent THF THF THF
Yield of 73％ 80％ 78％
Note that: eq represents molar equivalence ratio.
Example 6: preparation of 2-methylamino-3-pyridinemethanol
Figure BDA0003247028940000111
15.22 g of the compound a1 (0.1mol, 1.0 eq.) was dissolved in 45 ml of anhydrous tetrahydrofuran, and 19.46 g of CDI (0.12mol, 1.2eq.) was slowly added thereto as a reaction solution II. In a separate reaction vessel, 11.35 g of sodium borohydride (0.3 mol,3.0 eq.) were dissolved in 30 ml of tetrahydrofuran and 20 ml of water, and the temperature was adjusted to 0 ℃ and the reaction solution was designated as reaction solution III. After the reaction solution II was stirred at room temperature for 1 hour, the reaction solution II was slowly dropped into the reaction solution III (ensuring that the internal temperature of the reaction solution III did not exceed 20 ℃). After the dropwise addition, stirring is continued at room temperature until the reaction is completed. The reaction was quenched by the addition of 19.21 g of citric acid (0.1mol, 1.0 eq.). The reaction solution was separated into layers, and the aqueous phase was extracted with dichloromethane. The combined organic phases were concentrated and recrystallized from n-hexane/chloroform to give 12.16 g of product (yield: 88%).
Example 7: preparation of 2-methylamino-3-pyridinemethanol
Preparation of 2-methylamino-3-pyridinemethanol by way of reference example 6, the reaction substrate charge ratios are shown in Table 2 below, wherein eq represents the molar equivalence ratio.
Table 2: examples 7 to 9 feed ratios
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 solvent THF THF THF
Yield of 83％ 87％ 86％
And (3) annotation: eq represents molar equivalence ratio.
In light of the foregoing description of the preferred embodiments according to the present application, it is to be understood that various changes and modifications may be made by those skilled in the art without departing from the scope of the invention as defined by the appended claims. The technical scope of the present application is not limited to the contents of the specification, and 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:
    Figure FDA0003247028930000011
    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:
    Figure FDA0003247028930000012
    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:
    Figure FDA0003247028930000021
    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:
    Figure FDA0003247028930000022
    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.
CN202111036136.4A 2021-09-06 2021-09-06 Preparation method of 2-methylamino-3-hydroxymethylpyridine Pending CN115772121A (en)

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