A method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine

Abstract

The present application relates to the technical fields of medicine and intermediate preparation, and particularly relates to a synthesis method of 2-cyclopropylamino-3-nitro-6-chloropyridine. The preparation method comprises the following steps: taking 2,6-dichloro-3-nitropyridine and cyclopropylamine as raw materials, taking silica gel as a catalyst, and performing substitution reaction on 2,6-dichloro-3-nitropyridine and cyclopropylamine in the presence of the catalyst and an organic solvent to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine. In view of the problems of poor reaction selectivity, cumbersome purification operation and difficulty in amplification existing in the preparation of 2-cyclopropylamino-3-nitro-6-chloropyridine, the present application uses silica gel as a catalyst, greatly reduces the generation of by-products, improves the reaction selectivity and yield, avoids the use of column chromatography purification, and only needs to be beaten to obtain qualified products.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine and intermediate preparation, and particularly relates to a synthesis method of 2-cyclopropylamino-3-nitro-6-chloropyridine. BACKGROUND

[0002] 2-2-cyclopropylamino-3-nitro-6-chloropyridine is widely used in innovative drug molecular design and development as an active structure skeleton of an antitumor drug, so the research on the industrial production method of the compound is very crucial.

[0003] A conventional preparation method is reported in patent US2018 / 185362, in which cyclopropylamine is added to a toluene solution of 2,6-dichloro-3-nitropyridine cooled to zero degrees in an inert gas environment, the reaction is ended after 2 hours, and the product is obtained by column chromatography purification, with a reaction yield of 72%, and the technical route is as shown in the following formula (I). Figure 1 The method is simple in operation, but the production of the by-product with the 6-position chlorine substituted needs to use column chromatography purification, and it is not easy to scale up production, which limits the application of 2-cyclopropylamino-3-nitro-6-chloropyridine. SUMMARY

[0004] In view of the deficiencies in the prior art, the present application provides a synthesis method of 2-cyclopropylamino-3-nitro-6-chloropyridine, which uses 2,6-dichloro-3-nitropyridine and cyclopropylamine as the reaction raw materials, and performs an amination substitution reaction under the synergistic action of a silica gel catalyst and an ether organic solvent to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine. The present application significantly improves the reaction selectivity by synergistically controlling the low temperature, the silica gel catalysis and the ether solvent, and controls the proportion of the by-product with the 6-position chlorine substituted to be below 2%. After the reaction is completed, high-purity 2-cyclopropylamino-3-nitro-6-chloropyridine can be obtained only by filtering and beating, without the need for column chromatography purification, so as to simplify the purification process and be suitable for industrial scale-up production.

[0005] In order to achieve the above-mentioned purposes, the technical scheme adopted by the present application is as follows:

[0006] The first object of the present application is to provide the above-mentioned synthesis method of 2-cyclopropylamino-3-nitro-6-chloropyridine, which comprises the following steps:

[0007] 2,6-dichloro-3-nitropyridine and cyclopropylamine are used as the raw materials, and the silica gel is used as the catalyst, and under the condition that the catalyst and the organic solvent exist, the nucleophilic substitution reaction of 2,6-dichloro-3-nitropyridine and cyclopropylamine is performed to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine. For the nucleophilic substitution reaction, the conventional operation is to use an alkali as an acid-binding agent, and the silica gel is neutral, so it is generally not considered to be used.

[0008] Preferably, the molar ratio of 2,6-dichloro-3-nitropyridine to cyclopropylamine is 2-5:1.

[0009] Preferably, the molar ratio of 2,6-dichloro-3-nitropyridine to cyclopropylamine is 2:1.

[0010] Preferably, the conditions of the nucleophilic substitution reaction are as follows: reaction at -5℃ to -10℃ for 3h to 5h. By controlling the temperature below -5℃, the rate of side reactions can be significantly reduced, thereby reducing the proportion of by-products to <2%. In addition, under low temperature conditions, the strong electron-withdrawing effect of the nitro group selectively activates the 2-position chlorine atom, further strengthening the main reaction direction.

[0011] Preferably, the mass ratio of silica gel to 2,6-dichloro-3-nitropyridine is 0.01-0.1:1.

[0012] Preferably, the mass ratio of silica gel to 2,6-dichloro-3-nitropyridine is 0.02:1.

[0013] Preferably, the main component of the silica gel is silicon dioxide, and the present application uses 200-300 mesh or 100-200 mesh.

[0014] Preferably, the organic solvent is selected from ether organic solvents.

[0015] Preferably, the ether organic solvent is selected from methyl tert-butyl ether or tetrahydrofuran.

[0016] Preferably, the specific operation for preparing 2-cyclopropylamino-3-nitro-6-chloropyridine is as follows:

[0017] Cyclopropylamine is added to the mixture of organic solvent, 2,6-dichloro-3-nitropyridine and silica gel and stirred for reaction. After the complete reaction of 2,6-dichloro-3-nitropyridine, the mixture is subjected to filtration, extraction, drying, concentration and beating treatment in sequence to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine. If the addition of cyclopropylamine is too fast, the proportion of by-products will increase, and the reaction yield and product purity will decrease.

[0018] Preferably, the extraction reagent is methyl tert-butyl ether, ethyl acetate or dichloromethane.

[0019] Compared with the prior art, the present application has the following beneficial effects:

[0020] 1. The present application provides a method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine, taking 2,6-dichloro-3-nitropyridine and cyclopropylamine as raw materials, taking silica gel as catalyst, and under the condition of the presence of catalyst and organic solvent, 2,6-dichloro-3-nitropyridine and cyclopropylamine are subjected to nucleophilic substitution reaction to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine. In view of the problems of poor reaction selectivity, cumbersome purification operation and difficulty in amplification existing in the preparation of 2-cyclopropylamino-3-nitro-6-chloropyridine, the present application controls the reaction temperature to be lower than-5℃, uses silica gel catalytic system and ether organic solvent, significantly improves the reaction selectivity, controls the proportion of by-product to be less than 2%, and the by-product can be efficiently removed by conventional beating operation, thereby simplifying the purification process and being suitable for industrial amplification production.

[0021] 2. In the prior art, using conventional triethylamine, diisopropylethylamine or sodium carbonate as an acid binding agent, and using toluene, ethyl acetate, acetonitrile, dichloromethane or DMF as a solvent, cannot avoid the generation of by-products, and the proportion of by-products is about 5% to 20%. The present application significantly improves the substitution selectivity of the chlorine atom at the 2-position by synergistically controlling the low temperature, silica gel as catalyst and ether solvent. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 The present application provides a method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine, taking 2,6-dichloro-3-nitropyridine and cyclopropylamine as raw materials, taking silica gel as catalyst, and under the condition of the presence of catalyst and organic solvent, 2,6-dichloro-3-nitropyridine and cyclopropylamine are subjected to nucleophilic substitution reaction to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine. In view of the problems of poor reaction selectivity, cumbersome purification operation and difficulty in amplification existing in the preparation of 2-cyclopropylamino-3-nitro-6-chloropyridine, the present application controls the reaction temperature to be lower than-5℃, uses silica gel catalytic system and ether organic solvent, significantly improves the reaction selectivity, controls the proportion of by-product to be less than 2%, and the by-product can be efficiently removed by conventional beating operation, thereby simplifying the purification process and being suitable for industrial amplification production.

[0023] Figure 2 The present application provides a method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine, taking 2,6-dichloro-3-nitropyridine and cyclopropylamine as raw materials, taking silica gel as catalyst, and under the condition of the presence of catalyst and organic solvent, 2,6-dichloro-3-nitropyridine and cyclopropylamine are subjected to nucleophilic substitution reaction to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine. In view of the problems of poor reaction selectivity, cumbersome purification operation and difficulty in amplification existing in the preparation of 2-cyclopropylamino-3-nitro-6-chloropyridine, the present application controls the reaction temperature to be lower than-5℃, uses silica gel catalytic system and ether organic solvent, significantly improves the reaction selectivity, controls the proportion of by-product to be less than 2%, and the by-product can be efficiently removed by conventional beating operation, thereby simplifying the purification process and being suitable for industrial amplification production. DETAILED DESCRIPTION

[0024] The technical solutions of the present application will be described below in conjunction with the data in the embodiments of the present application, obviously, the described embodiments are only a part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor belong to the scope of protection of the present application.

[0025] It should be noted that the professional terms used in the present application are only for the purpose of describing the specific embodiments, and are not intended to limit the scope of protection of the present application, unless otherwise specified, the various raw materials, reagents, instruments and equipment used in the following embodiments of the present application can be purchased from the market or prepared by the existing method.

[0026] In the prior art, 2-cyclopropylamino-3-nitro-6-chloropyridine is usually prepared by a method reported in patent US2018 / 185362, which involves adding cyclopropylamine to a toluene solution of 2,6-dichloro-3-nitropyridine cooled to zero degrees in an inert gas environment. However, due to the generation of by-products substituted with chlorine at the 6-position, the product purification requires column chromatography, a complex and difficult-to-scale-up operation, which affects the efficiency and cost of industrial production.

[0027] To solve the problems in the prior art, the present application provides a synthesis method of 2-cyclopropylamino-3-nitro-6-chloropyridine, which comprises the following steps: taking 2,6-dichloro-3-nitropyridine and cyclopropylamine as raw materials, and using silica gel as a catalyst, 2,6-dichloro-3-nitropyridine and cyclopropylamine are subjected to nucleophilic substitution reaction in the presence of the catalyst and an organic solvent to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine.

[0028] To solve the problems in the prior art, such as poor reaction selectivity, cumbersome purification operation, and difficulty in scaling up, the present application provides a simple and efficient method suitable for scaling up. By using silica gel as a catalyst, the generation of by-products is greatly reduced, the reaction selectivity and yield are improved, and the use of column chromatography for purification is avoided. Only slurry is needed to obtain qualified products. It is speculated that the catalytic effect of silica gel is attributed to the fact that the surface of silica gel is rich in silicon hydroxyl groups (-Si-OH). These hydroxyl groups can activate the leaving group through hydrogen bonding or proton transfer, making it more easily substituted by an amine group.

[0029] In order for those skilled in the art to have a clearer understanding of the technical solutions of the present application, the technical solutions of the present application will be described in detail below with specific examples:

[0030] Example 1

[0031] A synthesis method of 2-cyclopropylamino-3-nitro-6-chloropyridine comprises the following steps:

[0032] In a 1L reaction bottle, 300mL of methyl tert-butyl ether, 50.0g (259.1mmol, 1.0eq) of 2,6-dichloro-3-nitropyridine and 1.0g of silica gel were sequentially added, cooled to-5℃, and 29.6g (518.2mmol, 2eq) of cyclopropylamine was slowly added. After the addition was completed, it was kept at-5℃ for about 3h. Thin layer chromatography silica gel plate monitoring showed that the reaction was complete. After filtration, water washing, methyl tert-butyl ether extraction, combined organic layers, saturated brine washing, anhydrous sodium sulfate drying, filtration and concentration, methyl tert-butyl ether slurry, 51.7g of 2-cyclopropylamino-3-nitro-6-chloropyridine was obtained, which was a white solid with a purity of 99.2% and a yield of 93.4%.

[0033] 1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J = 8.7 Hz, 1H), 6.64 (s, J = 8.7 Hz, 1H), 3.07-3.01 (m, 1H), 0.96-0.91 (m, 2H), 066-0.61 (m, 2H).

[0034] Example 2

[0035] A method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine is the same as the preparation method of Example 1, except that the amount of cyclopropylamine is replaced by 1 eq instead of 2 eq, comprising the following steps:

[0036] In a 1 L reaction bottle, 300 mL of methyl tert-butyl ether, 50.0 g (259.1 mmol, 1.0 eq) of 2,6-dichloro-3-nitropyridine and 1.0 g of silica gel were sequentially added, cooled to -5°C, and 14.8 g (259.1 mmol, 1 eq) of cyclopropylamine was slowly added. After the addition was completed, it was kept at -5°C for about 7 h. Thin layer chromatography silica gel plate monitoring showed that there was a small amount of raw material left in the reaction, filtered, washed with water, extracted with methyl tert-butyl ether, combined the organic layers, washed with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated, and column chromatography on silica gel to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine 47.2 g, white solid, yield 85.3%.

[0037] Example 3

[0038] A method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine is the same as the preparation method of Example 1, except that the amount of cyclopropylamine is replaced by 5 eq instead of 2 eq, comprising the following steps:

[0039] In a 1 L reaction bottle, 300 mL of methyl tert-butyl ether, 50.0 g (259.1 mmol, 1.0 eq) of 2,6-dichloro-3-nitropyridine and 1.0 g of silica gel were sequentially added, cooled to -5°C, and 74.0 g (1300 mmol, 5 eq) of cyclopropylamine was slowly added. After the addition was completed, it was kept at -5°C for about 3 h. Thin layer chromatography silica gel plate monitoring showed that the reaction was complete, filtered, washed with water, extracted with methyl tert-butyl ether, combined the organic layers, washed with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated, and slurried with methyl tert-butyl ether to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine 51.3 g, white solid, yield 92.7%.

[0040] Example 4

[0041] A method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine, which is identical to the preparation method of Example 1, except that the amount of silica gel is replaced from 1.0 g to 0.5 g, comprising the following steps:

[0042] In a 1 L reaction bottle, 300 mL of methyl tert-butyl ether, 50.0 g (259.1 mmol, 1.0 eq) of 2,6-dichloro-3-nitropyridine and 0.5 g of silica gel were sequentially added, cooled to -5°C, and 29.6 g (518.2 mmol, 2 eq) of cyclopropylamine was slowly added. After the addition was completed, it was maintained at -5°C for about 3 h. Thin layer chromatography silica gel plate monitoring showed that the reaction was completed, filtered, washed with water, extracted with methyl tert-butyl ether, combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and slurried with methyl tert-butyl ether to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine 50.7 g, white solid, with a yield of 91.6%.

[0043] Example 5

[0044] A method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine, which is identical to the preparation method of Example 1, except that the amount of silica gel is replaced from 1.0 g to 5 g, comprising the following steps:

[0045] In a 1 L reaction bottle, 300 mL of methyl tert-butyl ether, 50.0 g (259.1 mmol, 1.0 eq) of 2,6-dichloro-3-nitropyridine and 5 g of silica gel were sequentially added, cooled to -5°C, and 29.6 g (518.2 mmol, 2 eq) of cyclopropylamine was slowly added. After the addition was completed, it was maintained at -5°C for about 3 h. Thin layer chromatography silica gel plate monitoring showed that the reaction was completed, filtered, washed with water, extracted with methyl tert-butyl ether, combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and slurried with methyl tert-butyl ether to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine 51.1 g, white solid, with a yield of 92.3%.

[0046] Example 6

[0047] A method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine, which is identical to the preparation method of Example 1, except that the reaction temperature is replaced from -5°C to -10°C, comprising the following steps:

[0048] In a 1 L reaction flask, 300 mL of methyl tert-butyl ether, 50.0 g (259.1 mmol, 1.0 eq) of 2,6-dichloro-3-nitropyridine and 1.0 g of silica gel were added successively, cooled to 10 °C, and 29.6 g (518.2 mmol, 2 eq) of cyclopropylamine was added slowly. After the addition was completed, the reaction was maintained at -10 °C for about 3 h. Thin layer chromatography on silica gel plate monitoring showed that the reaction was completed. Filtration, water washing, methyl tert-butyl ether extraction, combined organic layers, saturated brine washing, anhydrous sodium sulfate drying, filtration and concentration, and methyl tert-butyl ether slurry gave 51.7 g of 2-cyclopropylamino-3-nitro-6-chloropyridine as a white solid.

[0049] Comparative Example 1

[0050] A method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine was the same as that of Example 1, except that the silica gel was replaced by a base triethylamine, comprising the following steps:

[0051] In a 100 mL reaction flask, 50 mL of methyl tert-butyl ether, 10.0 g (51.8 mmol, 1.0 eq) of 2,6-dichloro-3-nitropyridine and 10 mL of triethylamine were added successively, cooled to -5 °C, and 3.5 g (62.2 mmol, 1.2 eq) of cyclopropylamine was added slowly. After the addition was completed, the reaction was maintained at -5 °C for about 4 h. LCMS showed that the reaction was completed but 10% of by-product 4 was generated. Filtration, water washing, methyl tert-butyl ether extraction, combined organic layers, saturated brine washing, anhydrous sodium sulfate drying, filtration and concentration, and silica gel column purification gave 2-cyclopropylamino-3-nitro-6-chloropyridine 7.7 g as a white solid with a yield of 69.6%.

[0052]

[0053] It should be noted that when numerical ranges are involved in the present application, both the endpoints and any number between the endpoints should be considered as possible selections. Since the same steps and examples are used, the preferred embodiments are described in the present application to prevent redundancy.

[0054] Although the preferred embodiments of the present application have been described, those skilled in the art who understand the basic inventive concept can make additional changes and modifications to the embodiments. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications falling within the scope of the present application.

Claims

1. A method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine, characterized in that, Includes the following steps: Using 2,6-dichloro-3-nitropyridine and cyclopropylamine as raw materials, and silica gel as a catalyst, 2,6-dichloro-3-nitropyridine and cyclopropylamine underwent a nucleophilic substitution reaction in the presence of the catalyst and methyl tert-butyl ether to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine. The conditions for the nucleophilic substitution reaction are: reaction at -10℃ to -5℃ for 3 to 5 hours.

2. The method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine according to claim 1, characterized in that, The molar ratio of 2,6-dichloro-3-nitropyridine to cyclopropylamine is 2~5:

1.

3. The method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine according to claim 2, characterized in that, The molar ratio of 2,6-dichloro-3-nitropyridine to cyclopropylamine is 2:

1.

4. The method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine according to claim 1, characterized in that, The mass ratio of silica gel to 2,6-dichloro-3-nitropyridine is 0.01~0.1:

1.

5. The method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine according to claim 4, characterized in that, The mass ratio of silica gel to 2,6-dichloro-3-nitropyridine is 0.02:

1.

6. The method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine according to claim 1, characterized in that, The specific steps for preparing 2-cyclopropylamino-3-nitro-6-chloropyridine are as follows: Cyclopropylamine was added to a mixture of methyl tert-butyl ether, 2,6-dichloro-3-nitropyridine and silica gel and stirred to react. After the 2,6-dichloro-3-nitropyridine had completely reacted, the mixture was successively filtered, extracted, dried, concentrated and pulped to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine.

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