Preparation method of ensafetine

Abstract

The invention discloses a preparation method of ensafenetine, 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 chloroethylamine hydrochloride under an alkaline condition to prepare an intermediate 1; the intermediate 1 reacts with methyl carbamate to prepare Ensifentraine drug molecules, the two-step yield is 65% or above, and 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 ensefentin raw material medicine.

Description

Technical Field

[0001] The present invention specifically relates to a preparation method of Ensefentin, and belongs to the technical field of drug synthesis. Background Art

[0002] Ensifentrine is an innovative drug molecule with a unique structure that has been shown to be highly effective in treating chronic obstructive pulmonary disease (COPD) and other related respiratory diseases. As a dual-action drug, ensifentrine not only effectively suppresses inflammatory responses in the lungs but also improves airway patency, significantly alleviating symptoms and improving lung function. This dual action holds great potential for clinical treatment, particularly in the management of COPD, where ensifentrine is considered an important therapeutic option.

[0003]

[0004] The development of Ensifentrine not only brings new hope for the treatment of COPD but also provides an innovative direction for drug development for the pharmaceutical industry. With the in-depth development of related research and the continued progress of clinical trials, Ensifentrine is expected to become an important drug for the treatment of respiratory diseases in the future and contribute to improving the quality of life of millions of COPD patients worldwide.

[0005] In 2018, patent CN109641891A published by Spago et al. proposed a synthetic route using 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. In this process, the raw material first reacts with bromoacetonitrile under alkaline conditions to produce intermediate a1. Intermediate a1 is then converted to intermediate a2 by reducing the cyano group using hydrogen in the presence of a Raney nickel catalyst; this is then reacted with potassium cyanate to ultimately obtain the target product. While this synthetic route can provide a high-purity product, it presents certain challenges. First, the reaction steps are relatively cumbersome, and the operating conditions of each step require precise control to ensure the quality of the final product. Second, the high cost of bromoacetonitrile as a reaction raw material affects the economic viability of the entire reaction process. In addition, the hydrogenation reduction step involves a complex catalytic reaction, and the controllability of the product is poor. Especially in industrial production, it may face problems such as low product yield and low purity. These problems make this method not very ideal for large-scale production. The synthetic route is as follows:

[0006]

[0007] In another reaction pathway under this patent, 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. First, it is reacted with 2-(2-bromoethyl)isoindoline-1,3-dione under the catalysis of potassium carbonate and sodium iodide to synthesize intermediate b1; the obtained intermediate b1 is reacted with hydrazine hydrate in a mixed solvent of chloroform and ethanol to produce intermediate b2; intermediate b2 is then reacted with potassium cyanate to finally obtain the desired target product. Although this route can effectively obtain products with higher purity, its atom utilization rate is low and chloroform is used as a solvent, which increases the complexity and disadvantages of production to a certain extent. The synthetic route is as follows:

[0008]

[0009] To improve the feasibility of industrial production, optimization of the reaction route could be considered. For example, exploring alternative, cheaper raw materials or optimizing the amount of bromoacetonitrile used could reduce unnecessary costs. Furthermore, by studying the use of different catalysts, it may be possible to improve the selectivity of the hydrogenation reduction step, enhancing the controllability and yield of the product. Furthermore, finding simpler steps or more efficient reaction conditions could significantly enhance the application prospects of this route in industrial production. Summary of the Invention

[0010] The present invention addresses the deficiencies in the prior art and proposes a method for synthesizing Ensifentrine, which comprises: using 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one (SM) as a raw material, reacting it with chloroethylamine hydrochloride under alkaline conditions to prepare an intermediate 1; and reacting the intermediate 1 with methyl carbamate to prepare the Ensifentrine drug molecule. To solve the above problems, the present invention provides the following technical solutions:

[0011] (1) SM was added to reactor 1, solvent 1 was added, stirred to dissolve, the temperature was lowered, a base was added, chloroethylamine hydrochloride was slowly added, and the mixture was stirred. After the reaction was completed, water was added to the reaction vessel, the mixture was stirred, centrifuged, and the solid was collected. The solid was dried under forced air at 45°C to obtain intermediate 1 solid.

[0012] (2) Add the dried solid intermediate 1 to reactor 2, add methanol and methyl carbamate, stir, and heat to react; after the reaction is completed, cool and crystallize, centrifuge and collect the solid.

[0013] (3) The solid obtained in the above (2) was added to a container, and solvent 3 was added. The temperature was raised with stirring, the temperature was lowered for crystallization, and the solid was collected by centrifugation to obtain the product Ensefentin.

[0014] The base in step (1) is one or two of cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium acetate, lithium carbonate, sodium carbonate, sodium ethoxide, preferably cesium carbonate, and the addition amount is SM: base = 1:2.2 to 1:4, preferably SM: base = 1:2.3; the addition amount of chloroethylamine hydrochloride is SM: chloroethylamine hydrochloride = 1:1.1 to 1:1.5, preferably SM: chloroethylamine hydrochloride = 1:1.2; the addition amount of methyl carbamate in step (2) is SM: methyl carbamate = 1:1.2 to 1:2, preferably SM: methyl carbamate = 1:1.3.

[0015] The solvent in step (1) is one or two of DMF, DMSO, NMP, DMA, and DMAC, preferably DMF, and the amount added is 5 to 10 times the mass of SM, preferably 5 times the amount of solvent; the solvent in step (3) is one or two of isopropanol, acetone, acetonitrile, and ethyl acetate, and the amount added is 3 to 8 times the mass of SM, preferably 4 times the amount of solvent.

[0016] The reaction time of step (1) is 2 to 3 hours, and the reaction temperature is 20 to 40° C., preferably 20 to 30° C.; the reaction time of step (2) is 4 to 6 hours, and the reaction temperature is 30 to 50° C., preferably 40 to 50° C.

[0017] The temperature of step (3) is 60-80° C., the stirring time after heating is 2-3 h, the cooling rate is 15° C. / h, and the stirring time after cooling is 0.5-1 h.

[0018] The original synthetic route has several potential limiting factors, mainly including the high price of bromoacetonitrile, poor controllability of the product in the hydrogenation-reduction step, and the possible generation of cyanide byproducts during the reaction. These issues not only affect the economic efficiency of the reaction, but may also pose certain challenges to the environment and industrial production. To overcome these problems, some optimization and alternative measures can be considered. First, the high price of bromoacetonitrile increases the cost of the original route, so it is possible to consider using cheaper alternative raw materials. In this process, chloroethylamine hydrochloride has been proposed as a viable alternative. Chloroethylamine hydrochloride not only has a lower cost, but also can provide similar chemical reactivity in the reaction, thereby improving the economic efficiency of the entire synthetic route. Secondly, the product controllability of the hydrogenation-reduction step is poor and may result in lower yields and impurities. To improve this, optimization of reaction conditions is key. However, in terms of alternatives, methyl carbamate has been proposed as an alternative to potassium cyanate. Methyl carbamate not only provides a similar amination effect, but is also milder than potassium cyanate, reducing the formation of cyanide by-products, thereby helping to improve product purity and reaction selectivity while reducing environmental risks.

[0019] By replacing bromoacetonitrile with chloroethylamine hydrochloride and potassium cyanate with methyl carbamate, not only can raw material costs be effectively reduced, but the controllability and safety of the reaction can also be improved, making the synthetic route more feasible for industrial production. These improvements help to increase atom utilization, reduce byproduct formation, and optimize the reaction process, thereby improving overall production efficiency and environmental protection.

[0020] The beneficial effects of the present invention are:

[0021] (1) The present invention has excellent reaction safety and stability, and low raw material cost, which can significantly reduce the overall cost in the production process and effectively reduce energy consumption, thereby improving the economic benefits of production.

[0022] (2) The process design of the present invention can significantly reduce the generation of waste, waste gas and wastewater, reduce resource consumption, and have less negative impact on the environment. It is in line with the concepts of green chemistry and sustainable development and has high environmental protection.

[0023] (3) The reaction has high atomic utilization and reaction efficiency, which can significantly increase the yield of the target product while ensuring sufficient reaction and minimize the waste of raw materials. This advantage enables the process to improve economic benefits while helping to make more effective use of limited resources.

[0024] (4) The reaction process of the present invention is simple and easy to operate, and the yield and purity of the product during the production process are high (the two-step yield reaches over 65%, and the purity can reach over 99%; compared with the original route yield of 40%). This feature not only ensures the quality of the final product, but also provides reliable technical support for industrial production, and has great potential for scale-up application and promotion prospects. DETAILED DESCRIPTION

[0025] In order to further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

[0026]

[0027] Example 1

[0028] (1) SM (8.0 g, M = 391, 20.4 mmol) was added to a 250 mL three-necked flask, and DMF (40 mL) was added and stirred to dissolve. Cesium carbonate (8.6 g, M = 325.8, 61.3 mmol) was added and the temperature was lowered to -5 to 5°C. Ethyl chloride (2.8 g, M = 115.9, 24.5 mmol) was slowly added and then heated to 25°C and stirred for 2 h. After the reaction was completed, water (160 mL) was added to the reaction vessel, stirred, centrifuged, and the solid was collected and dried under air at 45°C to obtain 6.2 g of the solid intermediate 1 with a yield of 69.7%.

[0029] 1 HNMR(400MHz,DMSO-d6)δ6.78(s,1H),6.74(s,1H),6.71(s,1H),6.64(s,IH),5.35(s,1H),4.26-4.23(m,2H),3.76( s,3H),3.59(s,3H),3.45-3.42(m,2H),2.84-2.81(m,2H),2.45-2.42(m,2H),1.99(s,6H),1.83(s,3H),1.49(s,2H).

[0030] LC-MS (ESI): m / z = 435.5 [M+H] + .

[0031] (2) The dried solid intermediate 1 was added to a 250 mL three-necked flask, and 40 mL of methanol was added. The mixture was stirred and methyl carbamate (2.3 g, M = 75.07, 30.6 mmol) was added. The mixture was heated to 50°C for 4 h. After the reaction was completed, the temperature was lowered to 20°C for crystallization, and the solid was collected by centrifugation.

[0032] (3) The solid obtained in step (2) was added to a 250 mL flask, and 30 mL of acetonitrile was added. The mixture was heated to 80°C to dissolve the solution, cooled to crystallize, and centrifuged to collect the solid to obtain 6.6 g of the product Ensefentin with a yield of 97.0% and a purity of 99.1%.

[0033] 1 HNMR(400MHz,DMSO-d6)δ6.78(s,1H),6.74(s,1H),6.71(s,1H),6.64(s,IH),5.92(s,1H),5.35(s,1H),5.27(s,2H),4.26- 4.23(m,2H),3.92-3.89(m,2H),3.76(s,3H),3.59(s,3H),3.45-3.42(m,2H),2.84-2.81(m,2H),1.99(s,6H),1.83(s,3H).

[0034] LC-MS (ESI): m / z = 478.5 [M+H] + .

[0035] Example 2

[0036] (1) SM (8.0 g, M = 391, 20.4 mmol) was added to a 250 mL three-necked flask, DMSO (40 mL) was added, and the mixture was stirred to dissolve. Lithium carbonate (3.5 g, M = 73.9, 47 mmol) was added, and chloroethylamine hydrochloride (2.8 g, M = 115.9, 24.5 mmol) was slowly added. The mixture was then heated to 25°C and stirred for 2 h. After the reaction was completed, water (160 mL) was added to the reaction vessel, stirred, and centrifuged to collect the solid. The solid was dried under air at 45°C to obtain 6.1 g of the intermediate 1 solid with a yield of 68.6%.

[0037] LC-MS (ESI): m / z = 435.5 [M+H] + .

[0038] (2) The dried solid intermediate 1 was added to a 250 mL three-necked flask, 40 mL of methanol was added, and the mixture was stirred. Methyl carbamate (2.0 g, M = 75.07, 26.6 mmol) was added and heated to 45 ° C for 4 h. After the reaction was completed, the temperature was lowered to 20 ° C for crystallization, and the solid was collected by centrifugation.

[0039] (3) The solid obtained in (2) above was added to a 250 mL flask, and 40 mL of ethyl acetate was added. The mixture was heated to 77°C to dissolve the solution, cooled to crystallize, and centrifuged to collect the solid to obtain 6.5 g of the product Ensefentin, with a yield of 96.9% and a purity of 99.0%.

[0040] 1 HNMR(400MHz,CD3OD)δ6.78(s,1H),6.74(s,1H),6.71(s,1H),6.64(s,IH),5.35(s,1H),4.26-4.23(m,2H),3 .92-3.89(m,2H),3.76(s,3H),3.59(s,3H),3.45-3.42(m,2H),2.84-2.81(m,2H),1.99(s,6H),1.83(s,3H).

[0041] LC-MS (ESI): m / z = 478.5 [M+H] + .

[0042] Example 3

[0043] (1) SM (8.0 g, M = 391, 20.4 mmol) was added to a 250 mL three-necked flask, NMP (40 mL) was added, and the mixture was stirred to dissolve. Potassium tert-butoxide (6.8 g, M = 112.2, 61.3 mmol) was added, and the temperature was lowered to -5 to 5°C. Ethyl chloride (2.8 g, M = 115.9, 24.5 mmol) was slowly added, and the mixture was heated to 25°C and stirred for 2 h. After the reaction was completed, water (160 mL) was added to the reaction vessel, stirred, and centrifuged to collect the solid. The solid was dried under air at 45°C to obtain 6.1 g of the intermediate 1 solid with a yield of 68.6%.

[0044] LC-MS (ESI): m / z = 435.5 [M+H] + .

[0045] (2) The dried solid intermediate 1 was added to a 250 mL three-necked flask, 40 mL of methanol was added, and the mixture was stirred. Methyl carbamate (2.5 g, M = 75.07, 32.7 mmol) was added and heated to 45 ° C for 4 h. After the reaction was completed, the temperature was lowered to 20 ° C for crystallization, and the solid was collected by centrifugation.

[0046] (3) The solid obtained in (2) above was added to a 250 mL flask, 50 mL of isopropanol was added, and the mixture was heated to 80°C to dissolve. The mixture was cooled to crystallize and centrifuged to collect the solid to obtain 6.46 g of the product Ensefentin, with a yield of 96.5% and a purity of 99.2%.

[0047] 1 HNMR(400MHz,CD3OD)δ6.78(s,1H),6.74(s,1H),6.71(s,1H),6.64(s,IH),5.35(s,1H),4.26-4.23(m,2H),3 .92-3.89(m,2H),3.76(s,3H),3.59(s,3H),3.45-3.42(m,2H),2.84-2.81(m,2H),1.99(s,6H),1.83(s,3H).

[0048] LC-MS (ESI): m / z = 478.5 [M+H] + .

[0049] Example 4

[0050] (1) SM (8.0 g, M = 391, 20.4 mmol) was added to a 250 mL three-necked flask, and DMF (40 mL) was added and stirred to dissolve. Potassium carbonate (8.5 g, M = 138.2, 61.3 mmol) was added and the temperature was lowered to -5 to 5°C. Ethyl chloride (4.3 g, M = 115.9, 36.8 mmol) was slowly added and then heated to 25°C and stirred for 2 h. After the reaction was completed, water (160 mL) was added to the reaction vessel, stirred, centrifuged, and the solid was collected and dried under air at 45°C to obtain 6.3 g of Intermediate 1 solid with a yield of 70.8%.

[0051] LC-MS (ESI): m / z = 435.5 [M+H] + .

[0052] (2) The dried solid intermediate 1 was added to a 250 mL three-necked flask, 50 mL of methanol was added, and the mixture was stirred. Methyl carbamate (2.3 g, M = 75.07, 30.6 mmol) was added and heated to 45 ° C for 4 h. After the reaction was completed, the temperature was lowered to 20 ° C for crystallization, and the solid was collected by centrifugation.

[0053] (3) The solid obtained in step (2) was added to a 250 mL flask, and 50 mL of acetone was added. The mixture was heated to 70°C to dissolve the mixture, cooled to crystallize, and centrifuged to collect the solid to obtain 6.65 g of the product Ensefentin, with a yield of 96.0% and a purity of 99.4%.

[0054] 1 HNMR(400MHz,CD3OD)δ6.78(s,1H),6.74(s,1H),6.71(s,1H),6.64(s,IH),5.35(s,1H),4.26-4.23(m,2H),3 .92-3.89(m,2H),3.76(s,3H),3.59(s,3H),3.45-3.42(m,2H),2.84-2.81(m,2H),1.99(s,6H),1.83(s,3H).

[0055] LC-MS (ESI): m / z = 478.5 [M+H] + .

[0056] Example 5

[0057] (1) SM (8.0 g, M = 391, 20.4 mmol) was added to a 500 mL three-necked flask, DMA (50 mL) was added, and the mixture was stirred to dissolve. Potassium acetate (5.0 g, M = 98.1, 51.1 mmol) was added, and the temperature was lowered to -5 to 5°C. Ethyl chloride (4.3 g, M = 115.9, 36.8 mmol) was slowly added, and the mixture was heated to 30°C and stirred for 2 h. After the reaction was completed, water (160 mL) was added to the reaction vessel, stirred, and centrifuged. The solid was collected and dried under air at 45°C to obtain 6.1 g of Intermediate 1 as a solid, with a yield of 68.6%.

[0058] LC-MS (ESI): m / z = 435.5 [M+H] + .

[0059] (2) The dried solid intermediate 1 was added to a 250 mL three-necked flask, 50 mL of methanol was added, and the mixture was stirred. Methyl carbamate (2.3 g, M = 75.07, 30.6 mmol) was added and heated to 45 ° C for 4 h. After the reaction was completed, the temperature was lowered to 20 ° C for crystallization, and the solid was collected by centrifugation.

[0060] (3) The solid obtained in step (2) was added to a 250 mL flask, and 50 mL of acetonitrile was added. The mixture was heated to 80°C to dissolve the solution, cooled to crystallize, and centrifuged to collect the solid to obtain 6.57 g of the product Ensefentin, with a yield of 98.0% and a purity of 98.9%.

[0061] 1 HNMR(400MHz,CD3OD)δ6.78(s,1H),6.74(s,1H),6.71(s,1H),6.64(s,IH),5.35(s,1H),4.26-4.23(m,2H),3 .92-3.89(m,2H),3.76(s,3H),3.59(s,3H),3.45-3.42(m,2H),2.84-2.81(m,2H),1.99(s,6H),1.83(s,3H).

[0062] LC-MS (ESI): m / z = 478.5 [M+H] + .

[0063] Example 6

[0064] (1) SM (8.0 g, M = 391, 20.4 mmol) was added to a 1 L three-necked flask, and DMF (40 mL) was added and stirred to dissolve. Potassium acetate (8.0 g, M = 98.1, 81.8 mmol) was added and the temperature was lowered to -5 to 5°C. Ethyl chloride (4.3 g, M = 115.9, 36.8 mmol) was slowly added and then heated to 30°C and stirred for 2 h. After the reaction was completed, water (160 mL) was added to the reaction vessel, stirred, centrifuged, and the solid was collected. The solid was dried under air at 45°C to obtain 6.2 g of the intermediate 1 solid with a yield of 69.7%.

[0065] LC-MS (ESI): m / z = 435.5 [M+H] + .

[0066] (2) The dried solid intermediate 1 was added to a 250 mL three-necked flask, 50 mL of methanol was added, and the mixture was stirred. Methyl carbamate (2.3 g, M = 75.07, 30.6 mmol) was added and heated to 40°C for 6 h. After the reaction was completed, the temperature was lowered to 20°C for crystallization, and the solid was collected by centrifugation.

[0067] (3) The solid obtained in step (2) was added to a 250 mL flask, and 50 mL of ethyl acetate was added. The mixture was heated to 77°C to dissolve the solution, cooled to crystallize, and centrifuged to collect the solid to obtain 6.57 g of the product Ensefentin, with a yield of 96.5% and a purity of 98.5%.

[0068] 1 HNMR(400MHz,CD3OD)δ6.78(s,1H),6.74(s,1H),6.71(s,1H),6.64(s,IH),5.35(s,1H),4.26-4.23(m,2H),3 .92-3.89(m,2H),3.76(s,3H),3.59(s,3H),3.45-3.42(m,2H),2.84-2.81(m,2H),1.99(s,6H),1.83(s,3H).

[0069] LC-MS (ESI): m / z = 478.5 [M+H] + .

[0070] Comparative Example 1

[0071] (1) SM (8.0 g, M = 391, 20.4 mmol) was added to a 500 mL three-necked flask, and DMF (40 mL) was added and stirred to dissolve. Potassium carbonate (5.6 g, M = 138.2, 40.9 mmol) was added and chloroethylamine hydrochloride (2.4 g, M = 115.9, 20.4 mmol) was slowly added. The mixture was then heated to 30°C and stirred for 6 h. When the reaction was almost complete, water (160 mL) was added to the reaction vessel, stirred, and centrifuged to collect the solid. The solid was dried at 45°C under forced air to obtain 5.8 g of the intermediate 1 solid with a yield of 65.2%.

[0072] LC-MS (ESI): m / z = 435.5 [M+H] + .

[0073] (2) The dried solid intermediate 1 was added to a 250 mL three-necked flask, 50 mL of methanol was added, and the mixture was stirred. Methyl carbamate (1.8 g, M = 75.07, 24.5 mmol) was added and heated to 20°C for 6 h. After the reaction was complete, the mixture was centrifuged and the solid was collected.

[0074] (3) The solid obtained in (2) above was added to a 250 mL flask, and 120 mL of ethyl acetate was added. The mixture was heated to 77°C to dissolve the solution, cooled to crystallize, and centrifuged to collect the solid to obtain 5.73 g of the product Ensefentin, with a yield of 90% and a purity of 98.4%.

[0075] 1 HNMR(400MHz,CD3OD)δ6.78(s,1H),6.74(s,1H),6.71(s,1H),6.64(s,IH),5.35(s,1H),4.26-4.23(m,2H),3 .92-3.89(m,2H),3.76(s,3H),3.59(s,3H),3.45-3.42(m,2H),2.84-2.81(m,2H),1.99(s,6H),1.83(s,3H).

[0076] LC-MS (ESI): m / z = 478.5 [M+H] + .

[0077] Comparative Example 2

[0078] (1) SM (4 g, 9 mmol), 2-(2-bromoethyl)isoindolin-1,3-one (6.9 g, 27 mmol), potassium carbonate (3.7 g, 27 mmol), and sodium iodide (4.1 g, 27 mmol) were sequentially dissolved in dry acetonitrile (20 mL) and refluxed under nitrogen for 8 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filter cake was washed with dichloromethane and the filtrate was decompressed to obtain 3.17 g of the target product in a yield of 60.1%.

[0079] LC-MS (ESI): m / z = 517.6 [M+H] + .

[0080] (2) The solid obtained above was dissolved in chloroform (10 mL) and ethanol (10 mL), and hydrazine hydrate (2 g, 80 wt%) was added. The mixture was stirred evenly and allowed to react 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 2.2 g of solid, with a yield of 81.1%.

[0081] LC-MS (ESI): m / z = 435.5 [M+H] + .

[0082] (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 complete, the reaction was continued for 2 h. The mixture was cooled to room temperature, and a saturated aqueous sodium bicarbonate solution (10 mL) was added. The mixture was extracted with dichloromethane, and 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 2.0 g of ensefentin solid (yield 83.8% and purity 99%).

[0083] 1 HNMR(400MHz,CD3OD)δ6.78(s,1H),6.74(s,1H),6.71(s,1H),6.64(s,IH),5.35(s,1H),4.26-4.23(m,2H),3 .92-3.89(m,2H),3.76(s,3H),3.59(s,3H),3.45-3.42(m,2H),2.84-2.81(m,2H),1.99(s,6H),1.83(s,3H).

[0084] LC-MS (ESI): m / z = 478.5 [M+H] + .

[0085] Although the above description is based on the specific embodiments of the present invention, it does not limit the embodiments of the present invention. For those skilled in the art, various modifications or variations that can be made on the basis of the technical solution of the present invention without inventive effort are still within the scope of protection of the present invention.

Claims

1. A method for preparing Ensefentin, characterized in that: The preparation method comprises the following steps: using 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one (SM) as a raw material, reacting it with chloroethylamine hydrochloride under alkaline conditions to prepare an intermediate 1; and reacting the intermediate 1 with methyl carbamate to prepare encefantine, and the reaction equation is: The specific steps are as follows: (1) SM was added to reactor 1, solvent 1 was added, stirred to dissolve, the temperature was lowered, a base was added, chloroethylamine hydrochloride was slowly added, and the mixture was stirred. After the reaction was completed, water was added to the reaction vessel, the mixture was stirred, centrifuged, and the solid was collected. The solid was dried under forced air at 45°C to obtain intermediate 1 solid. (2) Add the dried solid intermediate 1 to reactor 2, add methanol and methyl carbamate, stir, and heat to react; after the reaction is completed, cool and crystallize, centrifuge and collect the solid. (3) The solid obtained in the above (2) was added to a container, and solvent 3 was added. The temperature was raised with stirring, the temperature was lowered for crystallization, and the solid was collected by centrifugation to obtain the product Ensefentin.

2. The method for preparing Ensefentin according to claim 1, wherein: The base in step (1) is one or two of cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium acetate, lithium carbonate, sodium carbonate, and sodium ethoxide, and the added amount is SM:base molar ratio = 1:2.2 to 1:4; the added amount of chloroethylamine hydrochloride is SM:chloroethylamine hydrochloride molar ratio = 1:1.1 to 1:1.5; and the added amount of methyl carbamate in step (2) is SM:methyl carbamate molar ratio = 1:1.2 to 1:

2.

3. The method for preparing Ensefentin according to claim 1, wherein: The solvent in step (1) is one or two of DMF, DMSO, NMP, DMA, and DMAC, and the added amount is 5 to 10 times the mass of SM; the solvent in step (3) is one or two of isopropanol, acetone, acetonitrile, and ethyl acetate, and the added amount is 3 to 8 times the mass of SM.

4. The method for preparing Ensefentin according to claim 1, wherein: The reaction time of step (1) is 2 to 3 hours, and the reaction temperature is 20 to 40°C; the reaction time of step (2) is 4 to 6 hours, and the reaction temperature is 30 to 50°C.

5. The method for preparing Ensefentin according to claim 1, wherein: The temperature of step (3) is 60-80°C, the stirring time after heating is 2-3h, the cooling rate is 15°C / h, and the stirring time after cooling is 0.5-1h.

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