Process for the preparation of 2-amino-3-formylpyridine and uses thereof

Abstract

The present application relates to a kind of preparation methods of 2-methylamino-3-formylpyridine, comprising the following steps: 3-cyanopyridine and dimethyl sulfate are heated to reflux reaction in organic solvent I, then base is added, continue to react under heating reflux condition, and obtain intermediate product 2-methylamino-3-formylpyridine.The raw material used in the preparation method of the present application is cheap and easy to obtain, the preparation process has few side reactions, and is easy to purify.Only the steps of extraction and heavy crystallization are needed to achieve high purity, and strict control of anhydrous reaction conditions is not required.The yield and purity are high, and the prepared 2-methylamino-3-formylpyridine is suitable for industrial large-scale production of 2-methylamino-3-hydroxymethylpyridine, and further preparation of eslicarbazepine acetate and / or eslicarbazepine acetate sulfate.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing 2-methylamino-3-formylpyridine. Background Technology

[0002] 2-Methylamino-3-hydroxymethylpyridine (CAS No: 32399-12-5) is an intermediate in the synthesis of isaconazole hydrochloride and isaconazole sulfate.

[0003] Its synthesis process mainly includes the following methods:

[0004] Method 1:

[0005] WO2001032652 reports the preparation of 2-methylamino-3-hydroxymethylpyridine from 2-chloronicotinic acid via a four-step reaction. The final step involves the reduction of tert-butyl 2-methylamino-3-pyridinecarboxylate with lithium aluminum hydride to yield the product 2-methylamino-3-hydroxymethylpyridine. Methylamine reacts not only with 2-chloronicotinyl chloride but also with tert-butyl formate, resulting in numerous byproducts. The synthetic route is as follows:

[0006]

[0007] Method 2:

[0008] WO2001032652 also revealed another synthesis route:

[0009]

[0010] Method 3: WO2010089993 discloses a method for preparing 2-methylamino-3-pyridinecarboxylic acid from 2-chloronicotinic acid with methylamine hydrochloride, followed by hydrogenation reduction to obtain the product 2-methylamino-3-hydroxymethylpyridine. This method uses the high-boiling-point, highly polar solvent DMF, which is cumbersome in post-processing and results in low yields. The synthetic route is as follows:

[0011]

[0012] Method 4:

[0013] US68212238 uses 2-aminonicotinic acid as a starting material, and obtains the product through a three-step reaction. However, 2-aminonicotinic acid is expensive and unsuitable for large-scale industrial production. The synthetic route is as follows:

[0014]

[0015] The synthesis methods in the aforementioned patents all use lithium aluminum hydride as a hydrogenation reducing agent. This reagent is expensive and prone to explosion, and the process requires a strictly anhydrous environment, which is not conducive to industrial production.

[0016] Method 5:

[0017] CN110317165 discloses a method for preparing 2-methylamino-3-hydroxymethylpyridine from compound A in the presence of Lewis acid and metal borohydride. This patented method has significant steric hindrance and low reactivity in the reaction of tert-butyl carboxylate. The synthetic route is as follows:

[0018]

[0019] Method 6:

[0020] CN108822027 discloses a method for preparing 2-methylamino-3-hydroxymethylpyridine, which uses an intermediate from the synthetic route WO2010089993 as a starting material. The reaction formula is as follows:

[0021]

[0022] Methods 5 and 6 use potassium / sodium borohydride instead of lithium aluminum hydride, but they contain more impurities and have lower yields.

[0023] Method 7:

[0024] CN115872926A discloses a method for preparing 2-methylamino-3-hydroxymethylpyridine. This patented method avoids the use of lithium aluminum hydride or metallic boron hydrides, but it involves numerous steps, a long synthesis time, and low yield. The synthetic route is as follows:

[0025]

[0026] However, the above-mentioned patented method for preparing 2-methylamino-3-hydroxymethylpyridine still has drawbacks such as low yield, high raw material cost or limited purchase, and complicated post-processing. Summary of the Invention

[0027] To address the shortcomings of existing synthetic methods for preparing 2-methylamino-3-hydroxymethylpyridine, an intermediate in the production of isaconazole hydrochloride and isaconazole ontium sulfate, which are unsuitable for industrial operation due to factors such as the use of high-boiling solvents, difficulty in post-processing, the use of flammable and explosive substances requiring strict anhydrous conditions, and numerous byproducts resulting in low purity and low yield, this invention provides a method suitable for the industrial production of 2-methylamino-3-formyl groups, and subsequently for the preparation of 2-methylamino-3-hydroxymethylpyridine. This method achieves high purity and high yield of 2-methylamino-3-formyl groups using inexpensive and readily available raw materials, and represents a promising process for the large-scale industrial production of 2-methylamino-3-formyl groups.

[0028] The present invention provides the following technical solutions to solve the above problems.

[0029] A method for preparing 2-methylamino-3-formyl groups includes the following steps:

[0030] 3-Cyanopyridine and dimethyl sulfate were heated under reflux in organic solvent I. Then, a base was added and the reaction was continued under reflux to give the intermediate product 2-methylamino-3-carboxypyridine.

[0031] This invention uses 3-cyanopyridine (also known as nicotinic acid nitrile) as a raw material, which is mainly used as an intermediate in pharmaceuticals, feed additives, and pesticides. Its price is lower than that of existing technologies using 2-chloronicotinic acid or 2-aminonicotinic acid as raw materials, offering a cost advantage for industrial production. The intermediate product 2-methylamino-3-formylpyridine is prepared in a one-pot process by reflux reaction of 3-cyanopyridine and dimethyl sulfate under alkaline conditions. The preparation process and post-processing are simple.

[0032] Furthermore, the molar ratio of 3-cyanopyridine to dimethyl sulfate is 1:1-2, preferably 1:1.1-1.3. For example, 1:1.1, 1:1.2, 1:1.3, etc.

[0033] Furthermore, the reaction between 3-cyanopyridine and dimethyl sulfate is carried out by heating for 1-5 hours, followed by the addition of an alkali and continued heating for another 1-5 hours. The heating reaction is carried out at 60-85°C. The alkali is one or a combination of sodium hydroxide and potassium hydroxide, and the amount of alkali used is 2-3 times the molar amount of 3-cyanopyridine.

[0034] Furthermore, the reaction solvent for 3-cyanopyridine and dimethyl sulfate is one or a combination of two of tetrahydrofuran and 2-methyltetrahydrofuran. Tetrahydrofuran has a boiling point of approximately 66°C, while 2-methyltetrahydrofuran has a boiling point of approximately 78°C. The higher reflux temperature favors the reaction, therefore 2-methyltetrahydrofuran is preferred. However, solvents with excessively high boiling points, such as toluene, should be avoided, as the high reflux temperature hinders the reaction and may even prevent the successful acquisition of the product.

[0035] Furthermore, the metal borohydride is selected from one or a combination of two of sodium borohydride and potassium borohydride, and the amount of metal borohydride used is 1-1.5 times the amount of the intermediate product 2-methylamino-3-carboxypyridine.

[0036] The contribution of this invention to the prior art lies in the one-step reaction of the inexpensive and readily available raw material 3-cyanopyridine with dimethyl sulfate to obtain the intermediate product 2-methylamino-3-formylpyridine. The inventors hypothesize that the following intermediate reaction occurs in step (S1):

[0037]

[0038] 3-Cyanopyridine first undergoes a methylation reaction with dimethyl sulfate, followed by an addition reaction with sodium hydroxide or potassium hydroxide. The product of this process leads to ring opening of pyridine. After cis-trans isomerization, ring closure, and methyl migration, 2-methylamino-3-formylpyridine is obtained.

[0039] Further, organic solvent I is selected from at least one of tetrahydrofuran and 2-methyltetrahydrofuran; the post-reaction treatment is as follows: after the reaction is completed, cool to room temperature, add water and allow to stand for separation, take the organic phase, extract the aqueous layer with organic solvent I, combine the organic phases, wash, dry, and recrystallize the crude product to obtain the intermediate product 2-methylamino-3-formylpyridine. The solvent used for recrystallization is at least one of petroleum ether, n-hexane, and n-heptane; there is no particular limitation on the amount of recrystallization solvent, which is generally 3-6 times the mass of the product.

[0040] The present invention also provides a method for preparing 2-methylamino-3-hydroxymethylpyridine, comprising the following steps:

[0041] (S1) 3-cyanopyridine and dimethyl sulfate were reacted under reflux in organic solvent I, and then a base was added and the reaction was continued under reflux to give the intermediate product 2-methylamino-3-formylpyridine.

[0042] (S2) The intermediate product 2-methylamino-3-carboxypyridine and sodium borohydride were reacted in organic solvent II, and then water was added to continue the reaction to prepare the product 2-methylamino-3-hydroxymethylpyridine.

[0043] This invention uses 3-cyanopyridine and dimethyl sulfate as raw materials to first prepare 2-methylamino-3-formylpyridine, and then reduces it under the action of metal borohydride to obtain 2-methylamino-3-hydroxymethylpyridine. The synthetic route is as follows:

[0044]

[0045] Further, in step (S2), organic solvent II is selected from at least one of methanol, ethanol, isopropanol, acetone, and diethyl ether. The post-treatment of step (S2) involves concentration, extraction with ethyl acetate 1-3 times, combining the organic phases, concentrating and drying, and recrystallizing the crude product to obtain 2-methylamino-3-hydroxymethylpyridine. The recrystallization solvent is selected from at least one of petroleum ether, n-hexane, n-heptane, and ethyl acetate, preferably a mixture of n-heptane and ethyl acetate in a volume ratio of 1-2:1-2.

[0046] The present invention also provides the use of 2-methylamino-3-carboxypyridine in the synthesis of isaconazole hydrochloride and / or isaconazole onium sulfate.

[0047] Compared with the prior art, the superior effects of the present invention are as follows:

[0048] I. The raw materials used in this invention are inexpensive and readily available, and the entire reaction process only requires two steps to obtain the product 2-methylamino-3-hydroxymethylpyridine with high purity and high yield.

[0049] Second, the preparation process of this invention has few side reactions, is easy to purify, and produces products with high purity.

[0050] Third, the functional group that needs to be reduced in the intermediate product of this invention is an aldehyde group, while the existing technology mostly uses an ester group. The conditions for hydrogenation reduction of aldehyde groups are milder than those for ester groups. Therefore, it is not necessary to use reducing reagents such as lithium aluminum hydride, and the reaction does not require anhydrous operation.

[0051] Fourth, the preparation process of this invention is simple, the raw materials are inexpensive and readily available, the reaction does not require strict control of conditions, and the yield and purity are both high. It is a method that is very suitable for the large-scale industrial production of 2-methylamino-3-hydroxymethylpyridine. Attached Figure Description

[0052] Figure 1 This is the HPLC chromatogram of the intermediate product 2-methylamino-3-formylpyridine obtained in Example 1.

[0053] Figure 2 This is the HPLC chromatogram of 2-methylamino-3-hydroxymethylpyridine, the product obtained in Example 7. Detailed Implementation

[0054] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be described in detail below. The following embodiments are provided to better understand this invention, but do not limit the invention. Unless otherwise specified, the experimental methods in the following embodiments are conventional methods.

[0055] Example 1

[0056] 3-Cyanopyridine (104.1 g, 1 mol), 800 g of 2-methyltetrahydrofuran solvent, and dimethyl sulfate (138.7 g, 1.1 mol) were added to a reaction flask and refluxed for 3 hours. Under reflux, a 50% sodium hydroxide solution (2 mol NaOH) was added dropwise, and the reaction was continued under reflux for another 2 hours. The temperature was lowered to 20-25 °C, water was added, and the mixture was allowed to stand and separate into layers. The aqueous layer was extracted once with 2-methyltetrahydrofuran, and the organic phases were combined, washed twice with saturated brine, dried, and concentrated. The crude product was recrystallized from n-heptane to give the intermediate product 2-methylamino-3-carboxypyridine with a purity of 93.8% and a molar yield of 67.4%.

[0057] Figure 1 This is the HPLC chromatogram of 2-methylamino-3-formylpyridine, the product obtained in Example 1.

[0058] The 1H NMR spectrum of the intermediate product 2-methylamino-3-formylpyridine is as follows: 1H-NMR(CDCl3): δ3.11(3H,d),6.63-6.66(1H,m),7.76(1H,d),8.37(1H,d),9.80(1H,s).

[0059] Example 2

[0060] Other conditions and procedures were the same as in Example 1, except that the amount of dimethyl sulfate used was 1.3 mol. The final product was 2-methylamino-3-formylpyridine with a purity of 93.5% and a molar yield of 71.6%.

[0061] Example 3

[0062] Other conditions and procedures were the same as in Example 1, except that the amount of dimethyl sulfate used was 1.5 mol. The final product was 2-methylamino-3-formylpyridine with a purity of 93.0% and a molar yield of 68.2%.

[0063] Example 4

[0064] Other conditions and procedures were the same as in Example 1, except that the amount of dimethyl sulfate used was 1.8 mol. The final product was 2-methylamino-3-formylpyridine with a purity of 91.2% and a molar yield of 57.9%.

[0065] A comparison of Examples 1-4 reveals that the optimal amount of dimethyl sulfate (DMS) is 1.1-1.3 times that of 3-cyanopyridine. Within this range, increasing the amount of DMS can improve the yield. Further increasing the amount of DMS results in a decrease in both purity and yield, possibly because the hydrogen-based solution is methylated by excessive DMS.

[0066] Example 5

[0067] Other conditions and procedures were the same as in Example 2, except that NaOH was replaced with an equimolar amount of KOH. The final product was 2-methylamino-3-formylpyridine with a purity of 93.7% and a molar yield of 70.8%. This indicates that both NaOH and KOH can be used without significantly affecting the reaction.

[0068] Example 6

[0069] Other conditions and procedures were the same as in Example 2, except that the solvent 2-methyltetrahydrofuran was replaced with an equal mass of tetrahydrofuran. The final product was 2-methylamino-3-formylpyridine with a purity of 93.4% and a molar yield of 74.5%. Tetrahydrofuran has a boiling point of approximately 66°C, while 2-methyltetrahydrofuran has a boiling point of approximately 78°C. The higher reflux temperature favored the reaction.

[0070] Example 7

[0071] 2-Methylamino-3-carboxypyridine (68.1 g, 0.5 mol) and 500 g of ethanol were added to a reaction flask. Sodium borohydride (18.9 g, 0.5 mol) was added in three batches at 18-25 °C, with each batch containing approximately the same amount. After the addition was complete, the reaction was continued at 18-25 °C for 3 hours. Water was then added and the mixture was stirred for another 5 hours. The ethanol was removed by concentration, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried and concentrated. The crude product was recrystallized from ethyl acetate and n-heptane (v / v = 1:1) to give 2-methylamino-3-hydroxymethylpyridine with a purity of 97.2% and a molar yield of 92.1%.

[0072] Figure 2 This is the HPLC chromatogram of 2-methylamino-3-hydroxymethylpyridine, the product obtained in Example 7.

[0073] The 1H NMR spectrum of the product 2-methylamino-3-hydroxymethylpyridine is as follows: 1 H NMR (CDCl3): 3.01 (d, 3H), 4.58 (s, 2H), 6.49-6.52 (m, 1H), 7.21 (d, 1H), 8.04 (d, 1H).

[0074] Comparative Example 1

[0075] Other conditions and procedures were the same as in Example 2, except that the solvent 2-methyltetrahydrofuran was replaced with an equal mass of toluene. The product 2-methylamino-3-formylpyridine was not obtained. Toluene has a boiling point of 110.6°C; the temperature was too high, causing uncontrollable side reactions.

[0076] Comparative Example 2

[0077] Other conditions and procedures were the same as in Example 1, except that the solvent 2-methyltetrahydrofuran was replaced with an equal mass of water. 2-Methylamino-3-formylpyridine was not obtained. The presence of water may have caused dimethyl sulfate to decompose at high temperatures.

[0078] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A process for the preparation of 2-methylamino-3-formylpyridine, characterized in that, The method comprises the following steps: 3-cyanopyridine and dimethyl sulfate are heated to reflux in an organic solvent I, and then a base is added, and the reaction is continued under heating to reflux to obtain the product 2-methylamino-3-formylpyridine, wherein the organic solvent I is selected from one or a combination of two of tetrahydrofuran and 2-methyltetrahydrofuran; the molar ratio of 3-cyanopyridine to dimethyl sulfate is 1:1.1-1.5; the reaction of 3-cyanopyridine and dimethyl sulfate is heated to reflux for 1-5 h, and then the base is added and the reaction is continued under heating to reflux for 1-5 h.

2. The production method according to claim 1, characterized by, The molar ratio of 3-cyanopyridine to dimethyl sulfate is 1:1.1-1.

3.

3. The production method according to claim 1, characterized by, The base is one or a combination of two of sodium hydroxide and potassium hydroxide, and the amount of the base is 2-3 times the molar amount of 3-cyanopyridine.

4. The production method according to claim 1, characterized by, The method further comprises a post-treatment step: after the reaction is completed, cooling to room temperature, adding water and standing to separate into layers, taking the organic phase, extracting the water layer with the organic solvent I, combining the organic phases, washing, drying, recrystallizing the crude product, and obtaining the intermediate product 2-methylamino-3-formylpyridine.

5. The production method according to claim 4, characterized by, The recrystallization solvent is one or a combination of two or more of petroleum ether, n-hexane, and n-heptane.

6. A process for the preparation of 2-methylamino-3-hydroxymethylpyridine, characterized in that The method comprises the following steps: (S1) preparing 2-methylamino-3-formylpyridine according to any one of the methods in claims 1-5; (S2) reacting the 2-methylamino-3-formylpyridine obtained in step (S1) with sodium borohydride in an organic solvent II, and then adding water to continue the reaction to obtain the product 2-methylamino-3-hydroxymethylpyridine.

7. The production method according to claim 6, characterized by, In step (S2), the metal borohydride is selected from one or a combination of two of sodium borohydride and potassium borohydride, and the amount of the metal borohydride is 1-1.5 times the amount of substance of the intermediate product 2-methylamino-3-formylpyridine; and / or The organic solvent II is selected from one or a combination of two or more of methanol, ethanol, isopropanol, acetone, and diethyl ether; and / or Step (S2) is followed by post-treatment, which comprises the following steps: concentration, extraction with ethyl acetate for 1-3 times, combining the organic phases, concentration and drying, recrystallization of the crude product to obtain the product 2-methylamino-3-hydroxymethylpyridine; and the recrystallization solvent is selected from one or a combination of two or more of petroleum ether, n-hexane, n-heptane, and ethyl acetate.

8. The preparation method according to claim 6, characterized in that, The recrystallization solvent is a mixed solvent of n-heptane and ethyl acetate in a volume ratio of 1-2:1-2.

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