Preparation method of empastine raw material medicine

Abstract

The invention discloses a preparation method of an ensafenetine raw material medicine, and belongs to the field of medicine synthesis. The preparation method comprises the following steps: by taking 9, 10-dimethoxy-2-(2, 4, 6-trimethyl phenyl imino)-3, 4, 6, 7-tetrahydro-2H-pyrimido [6, 1-a] isoquinoline-4-ketone (SM) as a raw material, reacting with cycloethylamine under an alkaline condition, and washing, drying and concentrating the reaction to obtain an intermediate I; under the conditions of pressurization and heating, the intermediate I reacts with urea to prepare the ensafenetine drug molecule, the two-step yield is 67% or above, the purity is 99% or above, the method is simple in operation process, the product is easy to purify, the yield is high, the product purity is high, and a new method is provided for preparation of an ensafenetine raw material medicine.

Description

Technical Field

[0001] The present invention specifically relates to the synthesis of ensifentrine raw material medicine, belonging to the technical field of pharmaceutical synthesis. Background Art

[0002] Ensifentrine is a novel drug molecule, mainly used for the treatment of chronic obstructive pulmonary disease (COPD) and other respiratory diseases. As a dual-action drug, it inhibits the inflammatory response in the lungs and improves airway patency, demonstrating potential efficacy and clinical value. In recent years, Ensifentrine has attracted extensive attention in the pharmaceutical field.

[0003]

[0004] It was reported in the patent published by Spargo et al. in 2018 that 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one was used as the starting material, reacted with bromoacetonitrile under alkaline conditions to form intermediate a1, intermediate a1 was reduced to generate intermediate a2 under the condition of Raney nickel / H2, and then reacted with potassium cyanate to finally obtain the target product. The product of this route has high purity, but the steps are cumbersome, the price of bromoacetonitrile is relatively expensive, and the product is not easily controllable during hydrogenation reduction, which is not conducive to industrial production. The synthesis route is as follows:

[0005]

[0006] Another reaction route under this patent uses 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one as the starting material, reacts with 2-(2-bromoethyl)isoindoline-1,3-dione under the catalysis of potassium carbonate and sodium iodide to synthesize intermediate b1, intermediate b1 reacts with hydrazine hydrate in chloroform / ethanol solvent to form intermediate b2, and then reacts with potassium cyanate to finally obtain the target product. The product of this route has high purity, but the atom utilization rate is too low, and chloroform is also used, which is not conducive to production. The synthesis route is as follows:

[0007]

[0008] Therefore, it is necessary to find a synthesis route with safe and reliable production, low cost, economic and green, and simple operation. Summary of the Invention

[0009] In view of the deficiencies in the prior art, the problem to be solved by the present invention is to provide a method for synthesizing encephentine raw material drug: using SM as the raw material, reacting with cyclohexylamine under alkaline conditions, and obtaining intermediate I through washing with water, drying, and concentration; under the conditions of pressurization and heating, reacting intermediate I with urea to prepare the encephentine drug molecule. The technical solution of the present invention to solve the above problems is as follows:

[0010] (1) Add SM to a reactor, add an organic solvent, stir to dissolve, add a base, slowly add cyclohexylamine, stir, and heat to reflux; after the reaction is completed, add water dropwise to the reaction vessel, stir, let it stand for liquid separation, collect the organic phase, add a desiccant, stir and dry, centrifuge to separate, collect the organic phase liquid, and concentrate to obtain solid intermediate I.

[0011] (2) Add the dried solid intermediate I to a high-pressure reaction kettle, add ethanol and urea, stir, pressurize and heat; after the reaction is completed, cool down for crystallization, centrifuge to separate, and collect the solid.

[0012] (3) Add the solid obtained in the above (2) to a container, add a solvent, heat up and stir, cool down for crystallization, centrifuge, and collect the solid to obtain the product encephentine.

[0013] The base in step (1) is one or two of sodium acetate, lithium carbonate, cesium carbonate, sodium carbonate, sodium ethoxide, potassium tert-butoxide, preferably potassium carbonate, and the addition amount is in a molar ratio of SM:base = 1:1.2 - 1:2. The addition amount of cyclohexylamine is SM:cyclohexylamine = 1:1.2 - 1:2.3, preferably SM:base = 1:1.5, SM:cyclohexylamine = 1:1.4; the addition amount of urea in step (2) is SM:urea = 1:1.3 - 1:3, preferably SM:urea = 1:2.

[0014] The solvent in step (1) is one or more of THF, methyl tert-butyl ether, dioxane, dimethylfuran, preferably THF, and the addition amount is 4 - 8 times the mass of SM, preferably 5 times the solvent amount; the solvent in step (3) is one or more of isopropanol, acetone, methanol, and the addition amount is 5 - 10 times the mass of SM, preferably 6 times the solvent amount.

[0015] The reaction time in step (1) is 4 - 6 h, and the reaction temperature is 60 - 110 °C; the reaction time in step (2) is 4 - 6 h, the reaction temperature is 80 - 100 °C, and the pressure is 0.2 - 0.4 MPa, preferably 0.3 MPa.

[0016] The temperature in step (3) is 70 - 80 °C, the stirring time after heating up is 2 - 3 h, the cooling rate is 10 °C / h, and the stirring time after cooling down is 0.5 - 1 h.

[0017] In the original process, there are problems such as the high price of bromoacetonitrile, the difficulty in controlling the hydrogenation reduction products, and cyanide by-products. Therefore, relatively inexpensive cyclohexylamine is used, and potassium cyanate is replaced with urea, etc.

[0018] The beneficial effects of the present invention are as follows:

[0019] (1) The present invention has good reaction safety and reliability, low cost, and the solvent can be recycled and reused, which can effectively reduce production costs and energy consumption.

[0020] (2) The present invention can significantly reduce waste, emissions and resource consumption, has less impact on the environment, and has higher environmental friendliness.

[0021] (3) This reaction has a high atom utilization rate and reaction efficiency, can effectively improve the yield of the target product, and reduce the waste of raw materials at the same time.

[0022] (4) The operation of this reaction is simple, the obtained product has a high yield and high purity (the two-step yield is more than 67%, and the purity is more than 99%; compared with the far process, the yield is 40%), and it has good prospects for industrial scale-up. Detailed implementation mode

[0023] In order to further understand the present invention, the preferred implementation modes of the present invention will be described below in conjunction with examples. However, it should be understood that these descriptions are only to further illustrate the features and advantages of the present invention, rather than a limitation on the claims of the present invention.

[0024]

[0025] Example 1

[0026] (1) Add SM (8.0 g, M = 391, 20.4 mmol) to a 250 mL three-necked flask, add THF (40 mL), stir to dissolve, add lithium carbonate (1.8 g, M = 73.89, 24.5 mmol), slowly add cyclohexylamine (1.0 g, M = 43.07, 24.5 mmol), heat to reflux, react for 4 h. After the reaction is completed, add water dropwise (50 mL * 2) to the reaction vessel, stir, let it stand for liquid separation, collect the organic phase, add anhydrous sodium sulfate, stir and dry, centrifuge, collect the organic phase, and concentrate the organic phase to obtain solid intermediate I.

[0027] (2) Dry the solid under vacuum at 45 °C; add the dried solid intermediate I to a high-pressure reaction kettle, add 40 mL of ethanol, add urea (1.8 g, M = 60.06, 30.6 mmol), stir, heat to 100 °C, and maintain the pressure in the kettle at 0.2 MPa; after the reaction is completed, cool down for crystallization, centrifuge to obtain a solid.

[0028] (3) Add the solid obtained in (2) above into a 250 mL flask, add 40 mL of acetone, heat until dissolved and clear, stir for 1 h, cool down to crystallize, to 20 °C, centrifuge, collect the solid, to obtain the product encefinetine, with a two-step yield of 67.1% and a purity of 98.9%.

[0029] Example 2

[0030] (1) Add SM (8.0 g, M = 391, 20.4 mmol) into a 250 mL three-necked flask, add THF (50 mL), stir to dissolve, add cesium carbonate (9.9 g, M = 325.82, 30.6 mmol), slowly add cyclohexylamine (1.3 g, M = 43.07, 30.6 mmol), heat to reflux, react for 4 h. After the reaction is completed, add water dropwise (50 mL * 2) to the reaction vessel, stir, let it stand for liquid separation, collect the organic phase, add anhydrous sodium sulfate, stir to dry, centrifuge and separate, collect the organic phase, and concentrate the organic phase to obtain the solid of intermediate I.

[0031] (2) Dry the solid under vacuum at 45 °C; add the dried solid of intermediate I into a high-pressure reaction kettle, add 40 mL of ethanol, add urea (2.5 g, M = 60.06, 40.8 mmol), stir, heat to 100 °C, and maintain the pressure in the kettle at 0.3 MPa; after the reaction is completed, cool down to crystallize, centrifuge and separate to obtain the solid.

[0032] (3) Add the solid obtained in (2) above into a 250 mL flask, add 40 mL of methanol, heat until dissolved and clear, stir for 1 h, cool down to crystallize, to 20 °C, centrifuge, collect the solid, to obtain the product encefinetine, with a two-step yield of 67.7% and a purity of 99.3%.

[0033] Example 3

[0034] (1) Add SM (12.0 g, M = 391, 30.6 mmol) into a 250 mL three-necked flask, add THF (60 mL), stir to dissolve, add lithium carbonate (2.9 g, M = 73.89, 39.8 mmol), slowly add cyclohexylamine (1.8 g, M = 43.07, 42.9 mmol), heat to reflux, react for 4 h. After the reaction is completed, add water dropwise (50 mL * 2) to the reaction vessel, stir, let it stand for liquid separation, collect the organic phase, add anhydrous sodium sulfate, stir to dry, centrifuge and separate, collect the organic phase, and concentrate the organic phase to obtain the solid of intermediate I.

[0035] (2) Dry the solid under vacuum at 45 °C; add the dried solid of intermediate I into a high-pressure reaction kettle, add 60 mL of ethanol, add urea (2.9 g, M = 60.06, 49.1 mmol), stir, heat to 100 °C, and maintain the pressure in the kettle at 0.3 MPa; after the reaction is completed, cool down to crystallize, centrifuge and separate to obtain the solid.

[0036] (3) Add the solid obtained in the above (2) to a 250 mL flask, add 60 mL of isopropanol, heat until dissolved and clear, stir for 1 h, cool down to crystallize, to 20 °C, centrifuge, collect the solid, to obtain the product encephentine, with a two-step yield of 67.2% and a purity of 99.1%.

[0037] Example 4

[0038] (1) Add SM (12.0 g, M = 391, 30.6 mmol) to a 250 mL three-necked flask, add dimethylfuran (60 mL), stir to dissolve, add potassium carbonate (7.63 g, M = 138.2, 55.2 mmol), slowly add cyclohexylamine (2.4 g, M = 43.07, 55.2 mmol), heat to reflux, react for 4 h. After the reaction is completed, add water dropwise (50 mL * 2) to the reaction vessel, stir, let it stand and separate layers, collect the organic phase, add anhydrous sodium sulfate, stir to dry, centrifuge and separate, collect the organic phase, and concentrate the organic phase to obtain the solid of intermediate I.

[0039] (2) Dry the solid under vacuum at 45 °C; add the dried solid of intermediate I to a high-pressure reaction kettle, add 60 mL of ethanol, add urea (3.3 g, M = 60.06, 55.2 mmol), stir, heat to 100 °C, and maintain the pressure in the kettle at 0.25 MPa; after the reaction is completed, cool down to crystallize, centrifuge and separate to obtain the solid.

[0040] (3) Add the solid obtained in the above (2) to a 250 mL flask, add 60 mL of isopropanol, heat until dissolved and clear, stir for 1 h, cool down to crystallize, to 20 °C, centrifuge, collect the solid, to obtain the product encephentine, with a two-step yield of 67.6% and a purity of 99.1%.

[0041] Example 5

[0042] (1) Add SM (8.0 g, M = 391, 20.4 mmol) to a 250 mL three-necked flask, add dimethylfuran (50 mL), stir to dissolve, add lithium carbonate (3.1 g, M = 73.89, 40.8 mmol), slowly add cyclohexylamine (1.8 g, M = 43.07, 42.9 mmol), heat to reflux, react for 4 h. After the reaction is completed, add water dropwise (50 mL * 2) to the reaction vessel, stir, let it stand and separate layers, collect the organic phase, add anhydrous sodium sulfate, stir to dry, centrifuge and separate, collect the organic phase, and concentrate the organic phase to obtain the solid of intermediate I.

[0043] (2) The solid was dried under vacuum at 45 °C; the dried intermediate I solid was added to a high-pressure reactor, 40 mL of ethanol was added, urea (2.9 g, M = 60.06, 49.1 mmol) was added, stirred, heated to 100 °C, and the pressure in the reactor was maintained at 0.4 MPa; after the reaction was completed, the temperature was lowered for crystallization, and centrifuged to obtain a solid.

[0044] (3) The solid obtained in (2) above was added to a 250 mL flask, 40 mL of isopropanol was added, heated to dissolve clear, stirred for 1 h, the temperature was lowered for crystallization to 20 °C, centrifuged, and the solid was collected to obtain the product encefinetine, with a two-step yield of 67.5% and a purity of 99.2%.

[0045] Example 6

[0046] (1) SM (8.0 g, M = 391, 20.4 mmol) was added to a 250 mL three-necked flask, dimethylfuran (50 mL) was added, stirred to dissolve, potassium acetate (2.0 g, M = 98.1, 20.4 mmol) was added, cyclohexylamine (1.8 g, M = 43.07, 42.9 mmol) was slowly added, heated to reflux, reacted for 4 h, after the reaction was completed, water (50 mL * 2) was added dropwise to the reaction vessel, stirred, allowed to stand for liquid separation, the organic phase was collected, anhydrous sodium sulfate was added, stirred and dried, centrifuged, the organic phase was collected, and the organic phase was concentrated to obtain intermediate I solid.

[0047] (2) The solid was dried under vacuum at 45 °C; the dried intermediate I solid was added to a high-pressure reactor, 40 mL of ethanol was added, urea (2.5 g, M = 60.06, 40.8 mmol) was added, stirred, heated to 100 °C, and the pressure in the reactor was maintained at 0.4 MPa; after the reaction was completed, the temperature was lowered for crystallization, and centrifuged to obtain a solid.

[0048] (3) The solid obtained in (2) above was added to a 250 mL flask, 40 mL of methanol was added, heated to dissolve clear, stirred for 1 h, the temperature was lowered for crystallization to 20 °C, centrifuged, and the solid was collected to obtain the product encefinetine, with a two-step yield of 66.8% and a purity of 99.0%.

[0049] Comparative Example 1

[0050] (1) SM (8.0 g, M = 391, 20.4 mmol) was added to a 250 mL three-necked flask, dimethylfuran (50 mL) was added, stirred to dissolve, potassium acetate (1.8 g, M = 98.1, 18.4 mmol) was added, cyclohexylamine (0.9 g, M = 43.07, 20.4 mmol) was slowly added, heated to reflux, reacted for 4 h, after the reaction was completed, water (50 mL * 2) was added dropwise to the reaction vessel, stirred, allowed to stand for liquid separation, the organic phase was collected, anhydrous sodium sulfate was added, stirred and dried, centrifuged, the organic phase was collected, and the organic phase was concentrated to obtain intermediate I solid.

[0051] (2) The solid was dried under vacuum at 45°C; the dried solid intermediate I was added to a high-pressure reactor, 40 mL of ethanol and urea (1.9 g, M = 60.06, 30.6 mmol) were added, the mixture was stirred, and the mixture was heated to 100°C while maintaining the pressure in the reactor at 0.4 MPa; after the reaction was completed, the mixture was cooled and crystallized, and centrifuged to obtain a solid.

[0052] (3) The solid obtained in the above (2) was added to a 250 mL flask, and 40 mL of methanol was added. The mixture was heated until it became clear, stirred for 1 h, cooled to 20° C. for crystallization, and centrifuged. The solid was collected to obtain the product Ensefentin. The two-step yield was 60.4% and the purity was 98.2%.

[0053] Comparative Example 2

[0054] (1) SM (4 g, 10 mmol), 2-(2-bromoethyl)isoindolin-1,3-one (6.9 g, 33 mmol), potassium carbonate (3.7 g, 27 mmol) and sodium iodide (4.1 g, 27 mmol) were sequentially dissolved in dry acetonitrile (20 mL), protected by nitrogen, and refluxed for 8 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was washed with dichloromethane and the filtrate was decompressed to obtain the target product.

[0055] (2) The solid obtained above was dissolved in chloroform (10 mL) and ethanol (10 mL), and hydrazine hydrate (2 g, 80 wt%) was added, stirred evenly, and reacted at room temperature for 24 h. After the reaction was completed, the mixture was filtered, and the filtrate was distilled under reduced pressure to obtain a solid.

[0056] (3) The above solid was dissolved in water (20 mL), 1N hydrochloric acid (1 mL) was added, and the mixture was stirred evenly. The temperature was then raised to 80°C, and an aqueous solution (10 mL) of potassium cyanate (810 mg, 10 mmol) was added dropwise to the system. After the addition was completed, the reaction was continued for 2 h. The mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a residue. The residue was separated by column chromatography to obtain solid ensefentin, with a three-step yield of 40% and a purity of 97.9%.

[0057] Although the above describes the specific implementation of the present invention in combination with the embodiments, it is not intended to limit the implementation of the present invention. For those skilled in the art, various modifications or variations that can be made by those skilled in the art on the basis of the technical solution of the present invention without creative work are still within the protection scope of the present invention.

Claims

1. A method for preparing an ensefentin bulk drug, characterized in that: The preparation method comprises: reacting SM raw material with cycloethylamine under alkaline conditions, washing, drying and concentrating the reaction to obtain intermediate I; reacting intermediate I with urea under pressurized heating conditions to prepare encefantine drug molecules, and the reaction equation is: The specific steps are as follows: (1) Add SM to a reactor, add an organic solvent, stir to dissolve, add a base, slowly add cycloethylamine, stir, and heat to reflux; after the reaction is completed, drip water into the reaction container, stir, stand and separate, collect the organic phase, add a desiccant, stir to dry, centrifuge, collect the organic phase liquid, and concentrate to obtain intermediate I; (2) adding the dried intermediate I to a high-pressure reactor, adding ethanol and urea, stirring, pressurizing and heating; after the reaction is completed, cooling and crystallizing, centrifuging and collecting the solid; (3) The solid obtained in the above (2) is added into a container, a solvent is added, the temperature is raised with stirring, the temperature is lowered for crystallization, and the solid is collected by centrifugation to obtain the product Ensefentin.

2. The method for preparing the Ensefentin API as claimed in claim 1, wherein: The base in step (1) is one or two of sodium acetate, lithium carbonate, cesium carbonate, sodium carbonate, sodium ethoxide, and potassium tert-butoxide, wherein the molar ratio of the SM raw material to the base is 1:1.2 to 1:2, and the molar ratio of the SM to cycloethylamine is 1:1.2 to 1:2.3; the molar ratio of SM to urea in step (2) is 1:1.3 to 1:

3.

3. The method for preparing the Ensefentin API as claimed in claim 1, characterized in that: The organic solvent of step (1) is one or more of THF, tert-methyl ether, dioxane, and dimethylfuran, and the amount of organic solvent added is 4 to 8 times the mass of SM; the solvent of step (3) is one or more of isopropanol, acetone, and methanol, and the amount of solvent added is 5 to 10 times the mass of SM.

4. The method for preparing the Ensefentin API as claimed in claim 1, characterized in that: The reaction time of step (1) is 4 to 6 hours, and the reaction temperature is 60 to 110° C.; the reaction time of step (2) is 4 to 6 hours, and the reaction temperature is 80 to 100° C., and the pressure is 0.2 to 0.4 MPa.

5. The method for preparing the Ensefentin API as claimed in claim 1, characterized in that: The temperature of step (3) is 70-80°C, the stirring time after heating is 2-3h, the cooling rate is 10°C / h, and the stirring time after cooling is 0.5-1h.

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