Preparation method of 3-methyl-3-ethyl-2, 4-dicyanoglutarimide

Abstract

The invention discloses a preparation method of 3-methyl-3-ethyl-2, 4-dicyanoglutarimide, and belongs to the field of chemical drug synthesis in the field of biological medicine. The method comprises the following steps: step 1, mixing cyanoacetate, butanone, ammonium acetate and a solvent, and introducing ammonia gas or putting ammonia into the solvent in advance; 2, cooling crystallization and centrifugal treatment are carried out, and obtained centrifugate is returned to the step 1 for reuse; 3, adding water to dissolve a solid phase obtained through centrifugation, and adding acid to adjust the PH to be acidic; and step 4, cooling crystallization is carried out, and an obtained solid phase is 3-methyl-3-ethyl-2, 4-dicyanoglutarimide.

Description

Technical Field

[0001] The present invention relates to the field of chemical drug synthesis in the field of biomedicine, and in particular to a method for preparing 3-methyl-3-ethyl-2,4-dicyanoglutarimide. Background Art

[0002] 3-Methyl-3-ethyl-2,4-dicyanoglutarimide (1) is an important intermediate in the synthesis of the central nervous system stimulant bemegride (megimide).

[0003]

[0004] Literature reports (Zhao Jianhuang et al., Chinese Journal of Pharmaceutical Sciences, 1991, 26(12): 742; Organic Syntheses Coll. Vol. 4, p441(1963)) indicate that the synthesis of 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1) is carried out by using methyl cyanoacetate or ethyl cyanoacetate and butanone as raw materials, and reacting with ammonia under the catalysis of ammonium acetate to form an ammonium salt of 1, which is then neutralized with hydrochloric acid. Figure 1 .

[0005] The ammonia in the Guareschi reaction can be introduced into the alcohol in advance or directly into the reaction solution. The molar number of ammonia exceeds the molar number of methyl / ethyl cyanoacetate. The reaction temperature is room temperature or in a refrigerator. The reaction time is long and the reaction is incomplete. The mother liquor after filtration often needs to be harvested for the second or third time to increase the yield of 1 to 70%. The operation is cumbersome and time-consuming. The ammonia nitrogen content in the waste liquid is very high, which increases the difficulty of sewage treatment. Summary of the invention

[0006] In view of the deficiencies in the prior art, the present invention provides a method for preparing 3-methyl-3-ethyl-2,4-dicyanoglutarimide.

[0007] The purpose of the present invention can be achieved through the following technical solutions:

[0008] The first aspect of the present invention relates to a method for preparing 3-methyl-3-ethyl-2,4-dicyanoglutarimide, comprising the following steps:

[0009] Step 1: cyanoacetate, butanone, ammonium acetate and a solvent are mixed, and ammonia gas is introduced or ammonia is pre-added into the solvent;

[0010] Step 2: cooling, crystallization and centrifugation, and the obtained centrifuge liquid is returned to step 1 for reuse;

[0011] Step 3: Dissolve the solid phase obtained by centrifugation in water and add acid to adjust the pH to acidic;

[0012] Step 4: Cooling and crystallization, the resulting solid phase is 3-methyl-3-ethyl-2,4-dicyanoglutarimide.

[0013] One of the reactants is cyanoacetate, commonly used ones are methyl cyanoacetate and ethyl cyanoacetate; the second reactant is butanone, namely methyl ethyl ketone and methyl ethyl ketone; the third reactant is ammonia; the catalyst is ammonium acetate; the solvent is the corresponding alcohol: methanol, ethanol. In view of the availability of sources and costs, methyl cyanoacetate should be preferably used as the reactant and methanol as the reaction solvent.

[0014] Ammonia can be introduced into alcohol in advance to prepare an alcohol solution of ammonia for feeding, or ammonia can be introduced into the reaction liquid. The amount of ammonia should exceed the theoretical amount, but too much amount will also cause waste.

[0015] The Guareschi reaction is usually carried out at room temperature or below, such as refrigeration temperature (Organic Syntheses Coll. Vol. 4, p441 (1963)), but the reaction often takes a long time and is incomplete. Changing it to room temperature or slightly above room temperature, preferably not higher than 35 degrees Celsius, the reaction is faster and more complete without consuming any energy.

[0016] The ammonium salt of the product 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1) has a certain solubility in alcohols such as methanol and ethanol. Therefore, the amount of alcohol used should be as small as possible, such as 0.5 to 5 times the weight of the cyanoacetate, preferably 1 to 2 times; the crystallization temperature of the ammonium salt should be as low as possible, preferably below the freezing point, more preferably below -10°C. Compared with crystallization in a reaction kettle, crystallization in a cold storage below -10°C is most conducive to energy saving.

[0017] The byproduct of the Guareschi reaction is an alcohol that is the same as the solvent. Therefore, the mother liquor after centrifugation of the ammonium salt contains unreacted cyanoacetate, butanone, ammonia, ammonium acetate, solvent alcohol and unprecipitated ammonium salt, which can be used as the reaction solvent in the next batch of production. This can reduce the trouble of waste liquid treatment, reduce emissions, and reduce the amount of reaction solvent alcohol, thereby significantly reducing costs.

[0018] The ammonium salt of the product 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1) does not need to be dried. It has a high solubility in hot water. Therefore, after being dissolved in hot water, it can be acidified with an acid to free the product 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1). The product has a low solubility in cold water and precipitates. The acids that can be used include hydrochloric acid, sulfuric acid, etc. In view of cost, hydrochloric acid is preferred.

[0019] The second aspect of the present invention relates to the use of the above-mentioned preparation method of 3-methyl-3-ethyl-2,4-dicyanoglutarimide in the preparation of central nervous system stimulants or their intermediates.

[0020] Beneficial effects of the present invention:

[0021] Compared with the preparation methods in the prior art, the improved preparation method of 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1) provided by the present invention has the following advantages: the mother liquor of the Guareschi reaction can be reused and the discharge is small; the reaction at room temperature and the crystallization of low-temperature freezing are more complete and the yield is high; the working time is shortened, it is suitable for continuous production and the comprehensive production cost is low. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The present invention will be further described below in conjunction with the accompanying drawings.

[0023] Figure 1 A synthetic route map for the prior art;

[0024] Figure 2 The present invention is a flow chart of the preparation method of the present invention. DETAILED DESCRIPTION

[0025] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0026] Example 1 Preparation of 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1)

[0027] In a 100L reaction kettle, 20.0kg (201.84 mole) of methyl cyanoacetate, 7.28kg (100.92 mole) of butanone, 100g (1.30 mole) of ammonium acetate and 30kg of methanol were added in sequence. Ammonia was passed through the reaction solution under stirring at room temperature. The rate of passing ammonia was preferably such that ammonia would not overflow from the reaction solution. The amount of ammonia passed through was not less than 3.5kg (205.9 mol). After the passing of ammonia, stirring was continued at the same temperature for 10 hours. The reaction solution was then placed in a cold storage below -10°C for full crystallization and centrifuged. The centrifuge solution A was used for the next batch. An appropriate amount of purified water was added to the filter cake (i.e., the wet product of ammonium salt), and the mixture was heated to dissolve. The pH was adjusted with concentrated hydrochloric acid to make the Congo red test paper acidic. The reaction solution was placed in a cold storage at -5°C for crystallization. The mixture was centrifuged, washed with purified water and dried to obtain 15.8kg of white crystals of 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1). The yield was 76.1% and the melting point was 193-194°C.

[0028] Example 2 Preparation of 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1)

[0029] The centrifugal liquid A in Example 1 was used to replace methanol. If the centrifugal liquid A was less than 30 kg, 30 kg of methanol was added. The other parts were the same as in Example 1. 20.7 kg of white crystals of 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1) were obtained. The yield was 100% and the melting point was 193-195°C.

[0030] Example 3 Preparation of 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1)

[0031] 22.8 kg (201.6 mole) of ethyl cyanoacetate was used to replace the methyl cyanoacetate in Example 1, and ethanol was used to replace the methanol in Example 1. The other conditions were the same as in Example 1, and 16.1 kg of white crystals of 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1) were obtained with a yield of 77.7% and a melting point of 194-195°C.

[0032] Example 4 Preparation of 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1)

[0033] The centrifugal liquid B in Example 3 was used to replace ethanol. If the centrifugal liquid B was less than 30 kg, 30 kg of ethanol was added. The other parts were the same as in Example 3. 20.75 kg of white crystals of 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1) were obtained. The yield was 100.2% and the melting point was 193-194°C.

[0034] Reference Example 1 Preparation of 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1)

[0035] The method was carried out according to Organic Syntheses Coll. Vol. 4, p441 (1963).

[0036] In a 100L reaction kettle, 22.0kg (201.84 mole) of methyl cyanoacetate, 7.28kg (100.92 mole) of butanone, 100g (1.30 mole) of ammonium acetate and 33.5kg of ethanol containing 3.5kg of ammonia were added in sequence, stirred at refrigerator temperature for 12 hours, centrifuged, a proper amount of purified water was added to the filter cake (i.e., wet ammonium salt), heated to dissolve, the pH was adjusted with concentrated hydrochloric acid to make the Congo red test paper acidic, cooled in an ice-water bath to crystallize, centrifuged, washed with purified water and dried to obtain 10.5kg of white crystals of 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1), with a yield of 50.7% and a melting point of 194-195°C.

[0037] The mother liquor of ammonium salt was centrifuged and placed at refrigerator temperature for 1 day before centrifugation again. The filter cake was treated as described above to obtain 1.1 kg of white crystals of 3-methyl-3-ethyl-2,4-dicyanoglutarimide (1).

[0038] In the description of this specification, the description with reference to the terms "one embodiment", "example", "specific example", etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0039] The above shows and describes the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of the present invention to be protected.

Claims

1. A method for preparing 3-methyl-3-ethyl-2,4-dicyanoglutarimide, characterized in that: The following steps are involved: Step 1: cyanoacetate, butanone, ammonium acetate and a solvent are mixed, and ammonia gas is introduced or ammonia is pre-added into the solvent; Step 2: cooling, crystallization and centrifugation, and the obtained centrifuge liquid is returned to step 1 for reuse; Step 3: Dissolve the solid phase obtained by centrifugation in water and add acid to adjust the pH to acidic; Step 4: Cooling and crystallization, the resulting solid phase is 3-methyl-3-ethyl-2,4-dicyanoglutarimide.

2. The method for preparing 3-methyl-3-ethyl-2,4-dicyanoglutarimide according to claim 1, characterized in that: The temperature of cooling and crystallization in the step 2 is below -10°C.

3. The method for preparing 3-methyl-3-ethyl-2,4-dicyanoglutarimide according to claim 1, characterized in that: The cooling and crystallization temperature in step 4 is below -5°C.

4. The method for preparing 3-methyl-3-ethyl-2,4-dicyanoglutarimide according to claim 1, characterized in that: The mass ratio / molar ratio of the cyanoacetate, butanone and ammonium acetate is: 20:7.28:0.

1.

5. The method for preparing 3-methyl-3-ethyl-2,4-dicyanoglutarimide according to claim 1, characterized in that: The cyanoacetate is methyl cyanoacetate or ethyl cyanoacetate.

6. The method for preparing 3-methyl-3-ethyl-2,4-dicyanoglutarimide according to claim 1, characterized in that: The solvent is methanol or ethanol.

7. The method for preparing 3-methyl-3-ethyl-2,4-dicyanoglutarimide according to claim 1, characterized in that: The acid is hydrochloric acid or sulfuric acid.

8. The method for preparing 3-methyl-3-ethyl-2,4-dicyanoglutarimide according to claim 1, characterized in that: The reaction temperature in the step 1 is not higher than 35 degrees Celsius.

9. Use of the preparation method of 3-methyl-3-ethyl-2,4-dicyanoglutarimide according to any one of claims 1 to 8 in the preparation of central nervous system stimulants or their intermediates.

10. Use of the method for preparing 3-methyl-3-ethyl-2,4-dicyanoglutarimide according to any one of claims 1 to 8 according to claim 9 in preparing central nervous system stimulants or intermediates thereof, characterized in that: The central nervous system stimulant is Bemeg.

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