Synthesis method of 2-cyclopropylamino-3-nitro-6-chloropyridine

Abstract

The invention relates to the technical field of medicine and intermediate preparation, in particular to a synthetic 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 carrying out substitution reaction on the 2, 6-dichloro-3-nitropyridine and the cyclopropylamine in the presence of the catalyst and an organic solvent, so as to obtain the 2-cyclopropylamino-3-nitro-6-chloropyridine. Aiming at the problems of poor reaction selectivity, troublesome purification operation and difficulty in amplification in the existing preparation of 2-cyclopropylamino-3-nitro-6-chloropyridine, silica gel is used as a catalyst, so that the generation of byproducts is greatly reduced, the reaction selectivity and the yield are improved, the use of column chromatography purification is avoided, and a qualified product can be obtained only by pulping.

Description

Technical Field

[0001] The present invention relates to the technical field of medicine and intermediate preparation, and in particular to a method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine. Background Art

[0002] 2-2-Cyclopropylamino-3-nitro-6-chloropyridine, as the active structural skeleton of anti-tumor drugs, is widely used in the design and development of innovative drug molecules. Therefore, the research on the industrial production method of this compound is very critical.

[0003] Patent US2018 / 185362 reports a conventional preparation method, in which cyclopropylamine is added to a toluene solution of 2,6-dichloro-3-nitropyridine cooled to zero degrees Celsius under an inert gas environment. The reaction is terminated after 2 hours, and the product is purified by column chromatography with a reaction yield of 72%. The technical route is as follows: Figure 1 This method is simple to operate, but due to the production of a byproduct with 6-chlorine substituted, column chromatography purification is required, making it difficult to scale up production, which limits the application of 2-cyclopropylamino-3-nitro-6-chloropyridine. Summary of the Invention

[0004] In view of the deficiencies in the prior art, the present invention provides a method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine. The present invention uses 2,6-dichloro-3-nitropyridine and cyclopropylamine as reaction raw materials, and carries out 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 invention significantly improves the reaction selectivity by synergistically controlling low temperature, silica gel catalysis and ether solvents, and controls the production ratio of by-products in which 6-chlorine is substituted to below 2%. After the reaction is completed, only filtration and beating are required to obtain high-purity 2-cyclopropylamino-3-nitro-6-chloropyridine, without the need for column chromatography purification, thereby simplifying the purification process and being suitable for industrial scale-up production.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is:

[0006] A first object of the present invention is to provide a method for synthesizing the above-mentioned 2-cyclopropylamino-3-nitro-6-chloropyridine, comprising the following steps:

[0007] Using 2,6-dichloro-3-nitropyridine and cyclopropylamine as raw materials and silica gel as a catalyst, in the presence of a catalyst and an organic solvent, 2,6-dichloro-3-nitropyridine and cyclopropylamine undergo a nucleophilic substitution reaction to yield 2-cyclopropylamino-3-nitro-6-chloropyridine. While a base is typically used as a binding acid in nucleophilic substitution reactions, silica gel is generally not considered due to its neutral nature.

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

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

[0010] Preferably, the nucleophilic substitution reaction is carried out at -5°C to -10°C for 3 to 5 hours. By controlling the temperature below -5°C, the rate of side reactions can be significantly reduced, thereby reducing the proportion of by-products to <2%. Furthermore, at low temperatures, 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 to 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 silica gel is silicon dioxide, and the present invention 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:

[0017] Cyclopropylamine is added to a mixture of an organic solvent, 2,6-dichloro-3-nitropyridine, and silica gel, and the mixture is stirred for reaction. After the 2,6-dichloro-3-nitropyridine is completely reacted, the mixture is filtered, extracted, dried, concentrated, and pulped to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine. Adding cyclopropylamine too quickly will increase byproducts, reducing the reaction yield and product purity.

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

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

[0020] 1. The present invention provides a method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine. Using 2,6-dichloro-3-nitropyridine and cyclopropylamine as raw materials and silica gel as a catalyst, in the presence of a catalyst and an organic solvent, 2,6-dichloro-3-nitropyridine and cyclopropylamine undergo a nucleophilic substitution reaction to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine. To address the problems of poor reaction selectivity, cumbersome purification operations, and difficulty in scale-up in existing preparations of 2-cyclopropylamino-3-nitro-6-chloropyridine, the present invention significantly improves reaction selectivity by regulating the reaction temperature below -5°C, employing a silica gel catalyst system, and employing an ether organic solvent. The reaction ratio of by-products is controlled to below 2%, and the by-products can be efficiently removed through conventional beating operations, thereby simplifying the purification process and making it suitable for industrial scale-up production.

[0021] 2. In the prior art, the use of conventional triethylamine, diisopropylethylamine, or sodium carbonate as acid-binding agents and toluene, ethyl acetate, acetonitrile, dichloromethane, or DMF as solvents inevitably results in the formation of by-products, with the proportion of by-products ranging from approximately 5% to 20%. The present invention significantly improves the substitution selectivity of the 2-chlorine atom by synergistically controlling low temperatures, using silica gel as a catalyst, and using ether solvents. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the existing technical roadmap for the preparation of 2-cyclopropylamino-3-nitro-6-chloropyridine.

[0023] Figure 2 The present invention provides a technical roadmap for preparing 2-cyclopropylamino-3-nitro-6-chloropyridine. DETAILED DESCRIPTION

[0024] The following will clearly and completely describe the technical solution of the present invention in conjunction with the data in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

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

[0026] In the prior art, 2-cyclopropylamino-3-nitro-6-chloropyridine is typically prepared by adding cyclopropylamine to a toluene solution of 2,6-dichloro-3-nitropyridine cooled to zero degrees Celsius under an inert gas atmosphere, as reported in US Patent No. 2018 / 185362. However, the formation of a byproduct of 6-chlorine substitution requires column chromatography for product purification, a complex and difficult-to-scale operation, which in turn affects the efficiency and cost of industrial production.

[0027] In response to the problems existing in the above-mentioned prior art, the present invention provides a method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine, comprising the following steps: using 2,6-dichloro-3-nitropyridine and cyclopropylamine as raw materials, using silica gel as a catalyst, and in the presence of a catalyst and an organic solvent, conducting a nucleophilic substitution reaction between 2,6-dichloro-3-nitropyridine and cyclopropylamine to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine.

[0028] In view of the problems of poor reaction selectivity, cumbersome purification operation and difficulty in amplification in the prior art, the present invention provides a method for efficient, simple and suitable amplification. By using silica gel as a catalyst, the generation of by-products is greatly reduced, the reaction selectivity and yield are improved, the use of column chromatography purification is avoided, and qualified products can be obtained by only beating. It is speculated that the catalytic effect of silica gel is attributed to the rich silanol (-Si-OH) on the surface of silica gel, which can activate leaving groups through hydrogen bonds or proton transfer, making it easier to be replaced by amino groups.

[0029] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments:

[0030] Example 1

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

[0032] In a 1L reaction flask, 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 added in sequence. The mixture was cooled to -5°C and 29.6g (518.2mmol, 2eq) of cyclopropylamine was slowly added. After the addition was complete, the reaction was maintained at -5°C for approximately 3h. Thin-layer chromatography on silica gel indicated the reaction was complete. The mixture was filtered, washed with water, and extracted with methyl tert-butyl ether. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and slurried with methyl tert-butyl ether to obtain 51.7g of 2-cyclopropylamino-3-nitro-6-chloropyridine as a white solid with a purity of 99.2% and a yield of 93.4%.

[0033] 1H NMR (400MHz, Chloroform-d) δ8.31 (d, J = 8.7Hz, 1H), 6.64 (s, J = 8.7Hz, 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 in Example 1, except that the amount of cyclopropylamine is replaced by 1 eq from 2 eq, comprising the following steps:

[0036] To a 1L reaction flask, 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 added sequentially. The mixture was cooled to -5°C and 14.8g (259.1mmol, 1eq) of cyclopropylamine was slowly added. After the addition was complete, the reaction was maintained at -5°C for approximately 7 hours. Thin-layer chromatography on silica gel indicated a small amount of residual starting material. The reaction was filtered, washed with water, and extracted with methyl tert-butyl ether. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 47.2g of 2-cyclopropylamino-3-nitro-6-chloropyridine as a white solid in an 85.3% yield.

[0037] Example 3

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

[0039] In a 1L reaction flask, 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 added in sequence. The mixture was cooled to -5°C and 74.0g (1300mmol, 5eq) of cyclopropylamine was slowly added. After the addition was complete, the reaction was maintained at -5°C for approximately 3h. TLC monitoring of the silica gel plate indicated the reaction was complete. The mixture was filtered, washed with water, and extracted with methyl tert-butyl ether. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and slurried with methyl tert-butyl ether to obtain 51.3g of 2-cyclopropylamino-3-nitro-6-chloropyridine as a white solid in a yield of 92.7%.

[0040] Example 4

[0041] A method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine is the same as the preparation method in Example 1, except that the amount of silica gel is replaced by 0.5 g from 1.0 g. The method comprises the following steps:

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

[0043] Example 5

[0044] A method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine is the same as the preparation method in Example 1, except that the amount of silica gel is replaced by 5 g from 1.0 g. The method comprises the following steps:

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

[0046] Example 6

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

[0048] In a 1L reaction flask, 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 added in sequence. The mixture was cooled to 10°C and 29.6g (518.2mmol, 2eq) of cyclopropylamine was slowly added. After the addition was complete, the reaction was maintained at -10°C for approximately 3h. TLC monitoring of the silica gel plate indicated the reaction was complete. The mixture was filtered, washed with water, and extracted with methyl tert-butyl ether. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and slurried with methyl tert-butyl ether to obtain 51.7g 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 is the same as the method in Example 1, except that the silica gel is replaced with an acid-binding agent, triethylamine, and comprises the following steps:

[0051] To 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 sequentially. The mixture was cooled to -5°C, and 3.5 g (62.2 mmol, 1.2 eq) of cyclopropylamine was slowly added. After the addition was complete, the reaction was maintained at -5°C for approximately 4 h. LCMS indicated that the reaction was complete, but 10% of the byproduct 4 was produced. The mixture was filtered, washed with water, and extracted with methyl tert-butyl ether. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel column to obtain 7.7 g of 2-cyclopropylamino-3-nitro-6-chloropyridine as a white solid in a yield of 69.6%.

[0052]

[0053] It should be noted that when the present invention involves a numerical range, it should be understood that the two endpoints of each numerical range and any numerical value between the two endpoints can be selected. Since the steps and methods used are the same as those in the embodiment, in order to avoid redundancy, the present invention describes a preferred embodiment.

[0054] Although the preferred embodiments of the present invention have been described, those skilled in the art will be able to make additional changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

Claims

1. A method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine, characterized in that: The steps include: Using 2,6-dichloro-3-nitropyridine and cyclopropylamine as raw materials and silica gel as catalyst, in the presence of a catalyst and an organic solvent, 2,6-dichloro-3-nitropyridine and cyclopropylamine undergo nucleophilic substitution reaction to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine.

2. The synthetic method of 2-cyclopropylamino-3-nitro-6-chloropyridine according to claim 1, wherein The molar ratio of 2,6-dichloro-3-nitropyridine to cyclopropylamine is 2 to 5:

1.

3. The synthetic method of 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, wherein The conditions for the nucleophilic substitution reaction are: reaction at -5°C to -10°C for 3h to 5h.

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

1.

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

1.

7. The method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine according to claim 1, wherein The organic solvent is selected from ether organic solvents.

8. The method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine according to claim 7, wherein The ether organic solvent is selected from methyl tert-butyl ether or tetrahydrofuran.

9. The method for synthesizing 2-cyclopropylamino-3-nitro-6-chloropyridine according to claim 1, wherein The specific operation of preparing 2-cyclopropylamino-3-nitro-6-chloropyridine is as follows: Cyclopropylamine is added to a mixture of an organic solvent, 2,6-dichloro-3-nitropyridine and silica gel, and the mixture is stirred for reaction. After the 2,6-dichloro-3-nitropyridine is completely reacted, the mixture is filtered, extracted, dried, concentrated and pulped to obtain 2-cyclopropylamino-3-nitro-6-chloropyridine.

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