2-cyano-5-dimethylamino-2, 4-pentadiene amide compounds and uses thereof

Abstract

The invention provides 2-cyano-5-dimethylamino-2, 4-pentadienamide (a compound as shown in a formula I), # imgabs0, and the compound is a brand new compound. The 2-chloronicotinamide can be synthesized in one step through the compound shown in the formula I. The process route for preparing the 2-chloronicotinamide is shorter, the production cost is low, the reaction conditions are milder, the yield is high, the operation is simple, and the industrial production amplification practicability is high. In addition, the process route is less in three wastes and is more environment-friendly.

Description

Technical Field

[0001] The present invention relates to the field of chemical synthesis, and in particular to a 2-cyano-5-dimethylamino-2,4-pentadienamide compound and application thereof in the preparation of 2-chloronicotinamide. Background Art

[0002] Nicotinamide is the amide form of vitamin B3, and its derivatives are a class of heterocyclic compounds with multiple biological activities. They are also important raw materials and intermediates for the synthesis of pesticides and medicines. Therefore, the study of the synthesis of nicotinamide compounds is of great significance in the fields of medicine, pesticides and drug molecule design and development.

[0003] At present, 2-chloronicotinamide is mainly synthesized by 2-chloronicotinic acid, specifically, 2-chloronicotinic acid is acylated with thionyl chloride and then ammonia or ammonia water is added to synthesize 2-chloronicotinamide. For example, the document "Synthesis, Cyrstal Structure, Fungicidal Activity and Molecular Docking of Nicotinic Acyl Urea Derivatives (Pei-Pei Zhang, 2019)" reports that 2-chloronicotinic acid is used as a raw material, reacted with thionyl chloride to generate acyl chloride (Compound 1), and then reacted with ammonia water to generate 2-chloronicotinamide. The acylating agent thionyl chloride used in this route has a strong pungent odor and is toxic to a certain extent, so it is not suitable for large-scale use; and the synthesis of the target product requires two steps, and the route is long.

[0004]

[0005] Developing a production process suitable for industrial-scale production of 2-chloronicotinamide is a goal pursued by technical researchers in this field. Summary of the invention

[0006] After years of research, the applicant's laboratory has developed a simple process for producing 2-chloronicotinamide, which does not require the use of toxic thionyl chloride and only requires one step. The production process of the present invention has a shorter production process route, a higher yield, and good industrial prospects.

[0007] Specifically, the present invention provides a 2-cyano-5-dimethylamino-2,4-pentadienamide (compound of formula I),

[0008]

[0009] This compound is a completely new compound.

[0010] The present invention also provides a 2-chloronicotinamide production process, which comprises synthesizing 2-chloronicotinamide in a single step by 2-cyano-5-dimethylamino-2,4-pentadienamide (compound of formula I) under the action of hydrogen chloride, and the synthesis route is as follows:

[0011]

[0012] Beneficial effects:

[0013] The preparation process of the present invention has at least the following advantages:

[0014] 1) Using the new 2-cyano-5-dimethylamino-2,4-pentadienamide (compound of formula I) to synthesize 2-chloronicotinamide has a shorter process route, lower production cost, milder reaction conditions, higher yield, simple operation, and strong practicality for industrial production and scale-up;

[0015] 2) The process route of the present invention produces less three wastes and is more environmentally friendly. DETAILED DESCRIPTION

[0016] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0017] The specific embodiments of the present invention are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0018] The present invention first provides a compound of formula I: 2-cyano-5-dimethylamino-2,4-pentadienamide,

[0019]

[0020] Another aspect of the present invention provides a method for preparing 2-chloronicotinamide, which comprises the following steps: reacting the compound of formula I with hydrogen chloride to obtain 2-chloronicotinamide.

[0021] Its synthetic route is as follows:

[0022] .

[0023] The above reaction is preferably carried out in an organic solvent, and the organic solvent is selected from halogenated alkanes, benzenes, ketones, and ether solvents, preferably benzene, toluene, dichloroethane, dichloromethane, tetrahydrofuran, monochloromethane, and acetone.

[0024] The reaction temperature of the above reaction is 0-100°C, preferably 30-100°C, and the reaction time is 1-10h, preferably 1-5h.

[0025] The synthesis method of the compound of formula I of the present invention comprises the following steps:

[0026] Step (1), reacting phosgene with N,N-dimethylformamide to obtain a compound of formula III;

[0027] Step (2), reacting the compound of formula III with vinyl ethyl ether and then adding dimethylamine solution to react to prepare the compound of formula II;

[0028] Step (3), the compound of formula II is reacted with cyanoacetamide to prepare a compound of formula I, wherein the structures of formula II and formula III are as follows:

[0029]

[0030] Preferably, the phosgene in step (1) is triphosgene (also known as triphosgene or solid phosgene). When the phosgene is triphosgene, the synthesis route is as follows:

[0031]

[0032] The molar ratio of triphosgene to N,N-dimethylformamide is preferably 1-2:3.

[0033] The reaction in the above reaction step (1) is carried out in a solvent, and the solvent is selected from benzene, hydrocarbons, halogenated alkanes, alcohols, esters and ketones, preferably toluene, petroleum ether, dichloromethane, dichloroethane, methanol, ethanol, ethyl acetate and acetone; the reaction temperature of step (1) is 0-100°C, and the reaction time is 0.5-10h, preferably 0.5-3h.

[0034] In the above reaction step (2), the reaction of the compound of formula III with vinyl ether is carried out in a solvent, wherein the solvent is selected from benzene, hydrocarbons, halogenated alkanes, alcohols, esters and ketones, preferably one of toluene, petroleum ether, dichloromethane, dichloroethane, methanol, ethanol, ethyl acetate and acetone, and the reaction temperature is 0-100°C, preferably 30-100°C. Too low reaction temperature will affect the reaction yield; the reaction time is 0.5-10h, preferably 0.5-3h. After the reaction of the compound of formula III with vinyl ether is completed, dimethylamine (preferably aqueous solution or methanol solution of dimethylamine) is added to react again, and the reaction temperature is 0-100°C, preferably 30-100°C. Too low reaction temperature will affect the reaction yield; the reaction time is 0.5-10h, preferably 0.5-3h.

[0035] In the above reaction step (3), cyanoacetamide is first dissolved in an appropriate amount of solvent, and then the solution of the compound of formula II is added, and the compound of formula I is obtained by reaction under the action of a base, wherein the solvent is selected from benzene, hydrocarbons, halogenated alkanes, alcohols, esters and ketones, preferably one of toluene, petroleum ether, dichloromethane, dichloroethane, methanol, ethanol, ethyl acetate and acetone, and the reaction temperature is 0-100°C, preferably 30-100°C. Too low a reaction temperature will affect the reaction yield; the reaction time is 0.5-10h, preferably 1-3h. The base is selected from an organic base or an inorganic base, and the organic base is selected from one of pyridine, piperidine, triethylamine, sodium methoxide, sodium ethoxide and sodium tert-butoxide; the inorganic base is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide and sodium hydroxide. The molar ratio of the base to N,N-dimethylformamide is 1-3:1.

[0036] Preferably, the solvents in the above steps of preparing the compound of formula I may be the same.

[0037] The process for preparing 2-chloronicotinamide using the compound of formula I of the present invention is simple, overcomes the defects existing in the prior art, improves the yield, reduces the cost, and achieves better results.

[0038] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention. If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the art or the product instructions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased through regular channels.

[0039] The present invention will be described in detail below through examples.

[0040] In the following examples, unless otherwise specified, all raw materials used were commercially available. Specific embodiments

[0042] Example 12 Preparation of 5-cyano-2,4-pentadienamide

[0043] Take 44.5g of triphosgene and 21.9g of N,N-dimethylformamide, dissolve them in dichloroethane, react at 25°C for 2h, add a dichloroethane solution of vinyl ether (including 21.6g of vinyl ether) to the system after the reaction, react at 70°C for 1.5h, cool to room temperature after the reaction, add 56.4g of dimethylamine aqueous solution (40% mass fraction), react at 70°C for 1h, cool to room temperature after the reaction, add a dichloroethane solution of cyanoacetamide (including 25.2g of cyanoacetamide), and then add 50.6g of triethylamine, react at 80°C for 2h, remove the solvent after the reaction, wash with water and dry to obtain 47.6g of 2-cyano-5-dimethylamino-2,4-pentadienamide, with a yield of 96%.

[0044] NMR data: 1H NMR (300MHz, CDCl 3 )δ7.83-7.87(d,1H),δ7.03-7.07(d,1H),δ5.46-5.54(t,1H),δ3.15(s,3H),δ2.97(s,3H)

[0045] Example 3: Preparation of 2-cyano-5-dimethylamino-2,4-pentadienamide

[0046] Take 35.6g of triphosgene and 21.9g of N,N-dimethylformamide, dissolve them in toluene, react at 90°C for 50min, add a toluene solution of vinyl ethyl ether (including 21.6g of vinyl ethyl ether) to the system after the reaction, react at 100°C for 1h, cool to room temperature after the reaction, add 45.1g of dimethylamine aqueous solution (40% mass fraction), react at 100°C for 0.5h, cool to room temperature after the reaction, add a toluene solution of cyanoacetamide (including 25.2g of cyanoacetamide), and then add 16.2g of sodium methoxide, react at 90°C for 1h, remove the solvent after the reaction, wash with water and dry to obtain 46.6g of 2-cyano-5-dimethylamino-2,4-pentadienamide, with a yield of 94%.

[0047] Example 3 Preparation of 2-cyano-5-dimethylamino-2,4-pentadienamide

[0048] Take 38.5g of triphosgene and 21.9g of N,N-dimethylformamide, dissolve them in dichloromethane, react at 5°C for 3h, add a dichloromethane solution of vinyl ether (including 21.6g of vinyl ether) to the system after the reaction, react for 3h at 20°C, add 67.6g of dimethylamine methanol solution (30% mass fraction) after the reaction, react for 3h at 20°C, add a dichloromethane solution of cyanoacetamide (including 25.2g of cyanoacetamide) after the reaction, and then add 63.6g of sodium carbonate, react for 3h at 20°C, remove the solvent after the reaction, wash with water and dry to obtain 40.1g of 2-cyano-5-dimethylamino-2,4-pentadienamide, with a yield of 81%.

[0049] Example 4 Synthesis of 2-chloronicotinamide

[0050] 47.6 g of 2-cyano-5-dimethylamino-2,4-pentadienamide was dissolved in dichloroethane, hydrochloric acid gas was introduced, and the reaction was carried out at 70° C. for 2 h. After the reaction, the solvent was removed, and the mixture was washed with water and dried to obtain 44.2 g of 2-chloronicotinamide with a yield of 98%.

[0051] NMR data: 1H NMR (300MHz, DMSO) δ8.44-8.45 (d, 1H), δ8.02 (s, 1H), δ7.88-7.90 (d, 1H), δ7.74 (s, 1H), δ7.45-7.50 (q, 1H)

[0052] Example 5 Synthesis of 2-chloronicotinamide

[0053] 46.6 g of 2-cyano-5-dimethylamino-2,4-pentadienamide was dissolved in toluene, hydrochloric acid gas was introduced, and the reaction was carried out at 90° C. for 1 h. After the reaction, the solvent was removed, and the mixture was washed with water and dried to obtain 42.8 g of 2-chloronicotinamide with a yield of 97%.

[0054] Example 6 Synthesis of 2-chloronicotinamide

[0055] 40.1 g of 2-cyano-5-dimethylamino-2,4-pentadienamide was dissolved in dichloromethane, hydrochloric acid gas was introduced, and the reaction was carried out at 20°C for 3 h. After the reaction, the solvent was removed, and the mixture was washed with water and dried to obtain 35.0 g of 2-chloronicotinamide with a yield of 92%.

[0056] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made thereto based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims

1. A compound of formula I, 2. A method for preparing the compound of formula I according to claim 1, characterized in that: The following steps are included: Step (1), reacting phosgene with N,N-dimethylformamide to obtain a compound of formula III; Step (2), reacting the compound of formula III with vinyl ethyl ether and then adding dimethylamine solution to react to prepare the compound of formula II; Step (3), the compound of formula II is reacted with cyanoacetamide to prepare a compound of formula I, wherein the structures of formula II and formula III are as follows:

3. The preparation method according to claim 2, characterized in that: The reaction in step (1) is carried out in a solvent, and the solvent is selected from benzene, hydrocarbons, halogenated alkanes, alcohols, esters and ketones, preferably toluene, petroleum ether, dichloromethane, dichloroethane, methanol, ethanol, ethyl acetate and acetone. The reaction temperature of step (1) is 0-100° C., and the reaction time is 0.5-10 h, preferably 0.5-3 h.

4. The preparation method according to claim 2, characterized in that: In step (2), the reaction of the compound of formula III with vinyl ether is carried out in a solvent, wherein the solvent is selected from benzene, hydrocarbons, halogenated alkanes, alcohols, esters and ketones, preferably toluene, petroleum ether, dichloromethane, dichloroethane, methanol, ethanol, ethyl acetate and acetone. The reaction temperature is 0-100° C. and the reaction time is 0.5-10 h, preferably 0.5-3 h.

5. The preparation method according to claim 4, characterized in that: After the reaction of the compound of formula III with vinyl ethyl ether in step (2) is completed, dimethylamine is added to further react. The reaction temperature is 0-100° C. and the reaction time is 0.5-10 h, preferably 0.5-3 h. The dimethylamine is preferably an aqueous solution or a methanol solution.

6. The preparation method according to claim 2, characterized in that: In step (3), cyanoacetamide is first dissolved in an appropriate amount of solvent, and then a solution of a compound of formula II is added, and the mixture is reacted under the action of a base to obtain a compound of formula I, wherein the solvent is selected from benzene, hydrocarbons, halogenated alkanes, alcohols, esters and ketones, preferably one of toluene, petroleum ether, dichloromethane, dichloroethane, methanol, ethanol, ethyl acetate and acetone, the reaction temperature is 0-100° C., the reaction time is 0.5-10 h, preferably 1-3 h, the base is selected from an organic base or an inorganic base, the organic base is selected from one of pyridine, piperidine, triethylamine, sodium methoxide, sodium ethoxide and sodium tert-butoxide; the inorganic base is selected from one of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide and sodium hydroxide.

7. A method for preparing 2-chloronicotinamide, comprising the following steps: reacting a compound of formula I with hydrogen chloride to obtain 2-chloronicotinamide, Its synthetic route is as follows: 。 8. The preparation method according to claim 7, characterized in that: The reaction of the compound of formula I with hydrogen chloride is carried out in an organic solvent, wherein the organic solvent is selected from halogenated alkanes, benzenes, ketones, and ether solvents, preferably one of benzene, toluene, dichloroethane, dichloromethane, tetrahydrofuran, monochloromethane and acetone, the reaction temperature is 0-100° C., and the reaction time is 1-10 h, preferably 1-5 h.

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