A preparation method of enasidenib bulk drug

Abstract

The application discloses a preparation method of enciferstat bulk drug and belongs to the field of drug synthesis. 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one (SM) is used as a raw material, and the raw material is reacted with cyclohexylamine under alkaline conditions, and the reaction is washed with water, dried, and concentrated to obtain an intermediate I; the intermediate I is reacted with urea under pressurized heating conditions to prepare an enciferstat drug molecule, the two-step yield is more than 67%, and the purity is more than 99%, the method has a simple operation process, the product is easy to purify, the yield is high, the product purity is high, and a new method for preparing enciferstat bulk drug is provided.

Description

TECHNICAL FIELD

[0001] The present application relates to the synthesis of Ensifentrine, and belongs to the technical field of drug synthesis. BACKGROUND

[0002] Ensifentrine is a new drug molecule, mainly used for the treatment of chronic obstructive pulmonary disease (COPD) and other respiratory diseases. As a dual-acting drug, it exhibits potential efficacy and clinical value by inhibiting lung inflammation and improving airway patency. In recent years, Ensifentrine has attracted widespread attention in the pharmaceutical field.

[0003]

[0004] In the patent published by Spago et al. in 2018, 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a] isoquinolin-4-one is used as the starting material, and reacts with bromoacetonitrile under basic conditions to form intermediate a1. The cyano group of intermediate a1 is reduced to form intermediate a2 under the condition of Raney nickel / H2, and then reacts with potassium cyanate to finally obtain the target product. This route has high product purity, but the steps are complicated, and bromoacetonitrile is expensive. The product is not easy to control during hydrogenation reduction, which is not conducive to industrial production. The synthesis route is as follows:

[0005]

[0006] Another reaction route under this patent is to use 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, and react 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. This route has high product 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 safe and reliable production, low cost, economic and green, simple synthesis route. SUMMARY

[0009] The present application aims at the deficiency of the prior art, and provides a synthesis method of encainide raw medicine, which is: taking SM as a raw material, reacting with cyclohexylamine under alkaline condition, carrying out water washing, drying, and concentrating to obtain intermediate I; and reacting intermediate I with urea under pressurized heating condition to prepare encainide medicine molecule.

[0010] (1) adding SM into a reactor, adding an organic solvent, stirring and dissolving, adding a base, slowly adding cyclohexylamine, stirring, heating to reflux; after the reaction is completed, adding water dropwise into the reaction container, stirring, standing and separating, collecting the organic phase, adding a drying agent, stirring and drying, centrifugally separating, collecting the organic phase liquid, and concentrating to obtain intermediate I solid.

[0011] (2) adding the dried intermediate I solid into a high-pressure reaction kettle, adding ethanol and urea, stirring, and pressurized heating; after the reaction is completed, cooling and crystallizing, centrifugally separating, and collecting the solid.

[0012] (3) adding the solid obtained in the above (2) into a container, adding a solvent, stirring, cooling and crystallizing, centrifuging, collecting the solid, and obtaining the product encainide.

[0013] The base in step (1) is one or two of sodium acetate, lithium carbonate, cesium carbonate, sodium carbonate, sodium ethoxide, and potassium tert-butoxide, preferably potassium carbonate, and the adding amount is a molar ratio of SM:base = 1:1.2-1:2; the adding amount of cyclohexylamine is SM:cyclohexylamine = 1:1.2-1:2.3, preferably SM:base = 1:1.5 and SM:cyclohexylamine = 1:1.4; the adding 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, and dimethyl furan, preferably THF, and the adding amount is 4-8 times the mass of SM, preferably 5 times the mass of SM; the solvent in step (3) is one or more of isopropyl alcohol, acetone, and methanol, and the adding amount is 5-10 times the mass of SM, preferably 6 times the mass of SM.

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

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

[0017] In the original route, there are problems such as high price of bromoacetonitrile, uncontrollable hydrogenation reduction product, and cyanide by-product, therefore, the cheaper cyclohexylamine is used, and urea is used to replace potassium cyanate.

[0018] The present application has the following advantages:

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

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

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

[0022] (4) The present reaction is simple to operate, the yield of the obtained product is high, and the purity is high (the two-step yield is more than 67%, and the purity is more than 99%; compared with the prior art, the yield is 40%), and has good industrial amplification prospect. DETAILED DESCRIPTION

[0023] In order to further understand the present application, the preferred embodiments of the present application are described below in combination with examples, but it should be understood that these descriptions are only for further illustrating the features and advantages of the present application, and are not limitations of the claims of the present application.

[0024]

[0025] Example 1

[0026] (1) SM (8.0 g, M = 391, 20.4 mmol) was added to a 250 mL three-necked flask, THF (40 mL) was added, stirred and dissolved, lithium carbonate (1.8 g, M = 73.89, 24.5 mmol) was added, cyclohexylamine (1.0 g, M = 43.07, 24.5 mmol) was slowly added, heated to reflux, reacted for 4 h, after the reaction was completed, water (50 mL*2) was added to the reaction vessel, stirred, and separated into layers, the organic phase was collected, anhydrous sodium sulfate was added, stirred and dried, centrifuged and separated, and the organic phase was collected and concentrated to obtain solid intermediate I.

[0027] (2) The solid was vacuum dried at 45℃; the dried solid intermediate I was added to a high-pressure reaction kettle, 40 mL of ethanol was added, urea (1.8 g, M = 60.06, 30.6 mmol) was added, stirred, heated to 100℃, and the pressure in the kettle was kept at 0.2 MPa; after the reaction was completed, the temperature was lowered to crystallize, centrifuged and separated to obtain a solid.

[0028] (3) The solid obtained in the above (2) was added to a 250 mL flask, 40 mL of methanol was added, heated to dissolve, stirred for 1 h, cooled to 20 °C, centrifuged, and the solid was collected to obtain the product encainide, with a two-step yield of 67.7% and a purity of 99.3%.

[0029] Example 2

[0030] (1) SM (8.0 g, M = 391, 20.4 mmol) was added to a 250 mL three-necked flask, THF (50 mL) was added, stirred to dissolve, cesium carbonate (9.9 g, M = 325.82, 30.6 mmol) was added, cyclohexylamine (1.3 g, M = 43.07, 30.6 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, and the layers were separated by standing, 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 the intermediate I solid.

[0031] (2) The solid was vacuum dried at 45 °C; the dried intermediate I solid was added to a high-pressure reaction kettle, 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 kettle was kept at 0.3 MPa; after the reaction was completed, the product was crystallized by cooling, centrifuged, and the solid was obtained.

[0032] (3) The solid obtained in the above (2) was added to a 250 mL flask, 40 mL of methanol was added, heated to dissolve, stirred for 1 h, cooled to 20 °C, centrifuged, and the solid was collected to obtain the product encainide, with a two-step yield of 67.7% and a purity of 99.3%.

[0033] Example 3

[0034] (1) SM (12.0 g, M = 391, 30.6 mmol) was added to a 250 mL three-necked flask, THF (60 mL) was added, stirred to dissolve, lithium carbonate (2.9 g, M = 73.89, 39.8 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, and the layers were separated by standing, 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 the intermediate I solid.

[0035] (2) The solid was vacuum dried at 45 °C; the dried intermediate I solid was added to a high-pressure reaction kettle, 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 kettle was kept at 0.3 MPa; after the reaction was completed, the product was crystallized by cooling, centrifuged, and the solid was obtained.

[0036] (3) The solid obtained in the above (2) was added to a 250 mL flask, 60 mL of isopropyl alcohol was added, heated to dissolve, stirred for 1 h, cooled to crystallize, to 20 °C, centrifuged, and the solid was collected to obtain the product encainide, with a two-step yield of 67.2% and a purity of 99.1%.

[0037] Example 4

[0038] (1) SM (8.0 g, M = 391, 20.4 mmol) was added to a 250 mL three-necked flask, dimethyl furan (50 mL) was added, stirred to dissolve, lithium carbonate (3.1 g, M = 73.89, 40.8 mmol) was added, and cycloethylamine (1.8 g, M = 43.07, 42.9 mmol) was slowly added. Heating was carried out to reflux, and the reaction was carried out for 4 h. After the reaction was completed, water (50 mL*2) was added dropwise to the reaction container, stirred, and the layers were separated by standing. 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 the intermediate I solid.

[0039] (2) The solid was vacuum dried at 45 °C; the dried intermediate I solid was added to a high-pressure reaction kettle, 60 mL of ethanol was added, urea (3.3 g, M = 60.06, 55.2 mmol) was added, stirred, heated to 100 °C, and the pressure in the kettle was kept at 0.25 MPa. After the reaction was completed, the product was crystallized by cooling, and centrifuged to obtain the solid.

[0040] (3) The solid obtained in the above (2) was added to a 250 mL flask, 60 mL of isopropyl alcohol was added, heated to dissolve, stirred for 1 h, cooled to crystallize, to 20 °C, centrifuged, and the solid was collected to obtain the product encainide, with a two-step yield of 67.2% and a purity of 99.1%.

[0041] Example 5

[0042] (1) SM (8.0 g, M = 391, 20.4 mmol) was added to a 250 mL three-necked flask, dimethyl furan (50 mL) was added, stirred to dissolve, lithium carbonate (3.1 g, M = 73.89, 40.8 mmol) was added, and cycloethylamine (1.8 g, M = 43.07, 42.9 mmol) was slowly added. Heating was carried out to reflux, and the reaction was carried out for 4 h. After the reaction was completed, water (50 mL*2) was added dropwise to the reaction container, stirred, and the layers were separated by standing. 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 the intermediate I solid.

[0043] (2) The solid was vacuum dried at 45°C; the dried solid of intermediate I was added into a high-pressure reaction kettle, 40 mL of ethanol was added, urea (2.9 g, M = 60.06, 49.1 mmol) was added, stirring, heated to 100°C, and the pressure in the kettle was kept at 0.4 MPa; after the reaction was completed, the product was crystallized by cooling, centrifuged, and a solid was obtained.

[0044] (3) The solid obtained in the above (2) was added into a 250 mL flask, 40 mL of isopropyl alcohol was added, heated to dissolve, stirred for 1 h, cooled to 20°C, centrifuged, and the solid was collected to obtain the product encainide, 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 into a 250 mL three-necked flask, dimethyl furan (50 mL) was added, stirred to dissolve, potassium acetate (2.0 g, M = 98.1, 20.4 mmol) was added, and cycloethylamine (1.8 g, M = 43.07, 42.9 mmol) was slowly added, heated to reflux, reacted for 4 h, water (50 mL*2) was added into the reaction container after the reaction was completed, stirred, and the layers were separated by standing, 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 a solid of intermediate I.

[0047] (2) The solid was vacuum dried at 45°C; the dried solid of intermediate I was added into a high-pressure reaction kettle, 40 mL of ethanol was added, urea (2.5 g, M = 60.06, 40.8 mmol) was added, stirring, heated to 100°C, and the pressure in the kettle was kept at 0.4 MPa; after the reaction was completed, the product was crystallized by cooling, centrifuged, and a solid was obtained.

[0048] (3) The solid obtained in the above (2) was added into a 250 mL flask, 40 mL of isopropyl alcohol was added, heated to dissolve, stirred for 1 h, cooled to 20°C, centrifuged, and the solid was collected to obtain the product encainide, with a two-step yield of 67.5% and a purity of 99.2%.

[0049] Comparative Example 1

[0050] (1) SM (8.0 g, M = 391, 20.4 mmol) was added into a 250 mL three-necked flask, dimethyl furan (50 mL) was added, stirred to dissolve, potassium acetate (2.0 g, M = 98.1, 20.4 mmol) was added, and cycloethylamine (1.8 g, M = 43.07, 42.9 mmol) was slowly added, heated to reflux, reacted for 4 h, water (50 mL*2) was added into the reaction container after the reaction was completed, stirred, and the layers were separated by standing, 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 a solid of intermediate I.

[0051] (2) Solid 45℃ vacuum drying; the dried intermediate I solid was added into a high-pressure reaction kettle, 40 mL of ethanol was added, urea (1.9 g, M = 60.06, 30.6 mmol) was added, stirring, heating to 100℃, and keeping the pressure in the kettle at 0.4 MPa; after the reaction was completed, cooling and crystallization, centrifugal separation, and solid was obtained.

[0052] (3) The solid obtained in the above (2) was added into a 250 mL flask, 40 mL of methanol was added, heating to dissolve clear, stirring for 1 h, cooling to 20℃, centrifugal separation, and the solid was collected to obtain the product ensifentrine, two-step yield 60.4%, purity 98.2%.

[0053] Comparative Example 2

[0054] (1) SM (4 g, 10 mmol), 2-(2-bromoethyl) isoindoline-1,3-dione (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) under nitrogen protection, and refluxed for 8 hours. After the reaction was completed, it was cooled to room temperature, filtered, the filter cake was washed with dichloromethane, and the filtrate was reduced pressure distilled to obtain the target product.

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

[0056] (3) The solid above was dissolved in water (20 mL), 1N hydrochloric acid (1 mL) was added, stirring was uniform, and then the temperature was raised to 80℃, and a potassium cyanate (810 mg, 10 mmol) aqueous solution (10 mL) was added dropwise to the system, and the dropwise addition was continued for 2 h. After cooling to room temperature, saturated sodium bicarbonate aqueous solution (10 mL) was added, dichloromethane was extracted, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and reduced pressure distilled to obtain a residue, and the residue was separated by column chromatography to obtain ensifentrine solid, three-step yield 40%, purity 97.9%.

[0057] The above describes the specific embodiments of the present application in combination with the examples, but is not a limitation on the embodiments of the present application. Various modifications or variations made by those skilled in the art on the basis of the technical solutions of the present application without creative labor are still within the protection scope of the present application.

Claims

1. A process for the preparation of Enasidenib drug substance, characterized in that, The preparation method is: under alkaline condition, SM raw material is reacted with cyclohexylamine, the reaction is washed with water, dried, concentrated to obtain intermediate I; under pressurized heating condition, intermediate I is reacted with urea to prepare the drug molecule of encainide, and the reaction equation is: The specific operation steps are as follows: (1) SM is added to a reactor, an organic solvent is added, stirring and dissolving, a base is added, cyclohexylamine is slowly added, stirring and heating to reflux; after the reaction is completed, water is added dropwise to the reaction container, stirring, standing and separating, the organic phase is collected, a drying agent is added, stirring and drying, centrifugal separation, the organic phase liquid is collected, and concentrated to obtain intermediate I; (2) After drying, intermediate I is added to a high-pressure reaction kettle, ethanol and urea are added, stirring, pressurized heating; after the reaction is completed, cooling and crystallization, centrifugal separation, and the solid is collected; (3) The solid obtained in the above (2) is added to a container, a solvent is added, heating and stirring, cooling and crystallization, centrifugal separation, and the solid is collected to obtain the product encainide.

2. A process for the preparation of Enasidenib drug substance 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 SM raw material to base is 1:1.2-1:2, and the molar ratio of SM to cyclohexylamine is 1:1.2-1:2.3; in step (2), the molar ratio of SM to urea is 1:1.3-1:

3.

3. A process for the preparation of Enasidenib drug substance as claimed in claim 1 wherein, The organic solvent in step (1) is one or more of THF, methyl tert-butyl ether, dioxane and dimethyl furan, and the amount of the organic solvent added is 4-8 times the mass of SM; the solvent in step (3) is one or more of isopropyl alcohol, acetone and methanol, and the amount of the solvent added is 5-10 times the mass of SM.

4. A process for the preparation of Enasidenib drug substance as claimed in claim 1 wherein, The reaction time in step (1) is 4-6 h, and the reaction temperature is 60-110 DEG C; the reaction time in step (2) is 4-6 h, the reaction temperature is 80-100 DEG C, and the pressure is 0.2-0.4 MPa.

5. A process for the preparation of Enasidenib drug substance as claimed in claim 1 wherein, The temperature in step (3) is 70-80 DEG C, the stirring time after heating is 2-3 h, the cooling rate is 10 DEG C / h, and the stirring time after cooling is 0.5-1 h.

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