A process for the preparation of encephentide

Abstract

The application discloses a preparation method of a dual PDE3 / 4 inhibitor, ensefentine. The preparation method comprises the following steps: firstly, carrying out a sizuki coupling reaction on initial raw materials, a compound shown in formula 1 and a compound shown in formula 2, to obtain a compound shown in formula 3; secondly, carrying out intramolecular cyclization on the compound shown in formula 3 to obtain a compound shown in formula 4; thirdly, converting a carbonyl group into a compound shown in formula 5 by using POCl3; fourthly, carrying out an alkylation reaction on the compound shown in formula 5 and a compound shown in formula 6 to obtain a compound shown in formula 7; and finally, carrying out a substitution reaction on an acylimine of the compound shown in formula 7 and a compound shown in formula 8 to obtain the product, ensefentine. The raw materials are easy to obtain, the operation method is simple, the product yield is high, and the method is suitable for batch production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, in particular, to a preparation method of ensifentrine. BACKGROUND

[0002] On June 26, 2024, the U.S. FDA approved Ohtuvayre (ensifentrine, Chinese name: ensifentrine) of Verona Pharma for marketing, which is used for the maintenance treatment of adult chronic obstructive pulmonary disease (COPD). Ensifentrine is the first inhaled product with a novel mechanism of action in more than 20 years, providing a new treatment option for COPD patients. Ensifentrine is a dual-target inhibitor targeting phosphodiesterase-3 (PDE3) and phosphodiesterase-4 (PDE4) developed by Verona, with an affinity for PDE3 that is 3440 times that of PDE4. As a dual PDE3 / 4 inhibitor, ensifentrine can provide both bronchodilation and anti-inflammatory effects, significantly improving the respiratory function and quality of life of patients; in addition, as an aerosol inhalation preparation, it helps to avoid gastrointestinal-related side effects. As a new mechanism drug in the field of COPD, the overall safety of ensifentrine is good, and more patients in the placebo group stop taking the drug due to side effects. More side effects of ensifentrine than the placebo group include hypertension, back pain, nasopharyngitis, etc.

[0003] The chemical structural formula of ensifentrine is shown as formula I:

[0004]

[0005] However, the current preparation method of ensifentrine still needs to be improved. SUMMARY

[0006] The present application aims to at least solve one of the technical problems in the related art. To this end, one object of the present application is to provide a preparation method of a compound of formula I, ensifentrine. Compared with the prior art, the preparation method of the present application obtains a compound of formula 3 by subjecting the initial raw material compound of formula 1 and the compound of formula 2 to a sizuki coupling reaction, obtains a compound of formula 4 by intramolecular cyclization, converts the carbonyl group to halide (compound of formula 5) by using POCl3, and then obtains a compound of formula 7 by subjecting the compound of formula 6 to an alkylation reaction, wherein the acylimine of the compound of formula 7 is subjected to a substitution reaction with the compound of formula 8 to obtain the product, ensifentrine.

[0007] In one aspect of the present application, the present application provides a preparation method of a compound of formula I, ensifentrine. According to an embodiment of the present application, the preparation method comprises:

[0008] (1) contacting a compound shown as formula 1 with a compound shown as formula 2, potassium carbonate, tetrakis(triphenylphosphine)palladium, to obtain a compound shown as formula 3;

[0009] (2) contacting the compound shown as formula 3 with trifluoroacetic anhydride (TFAA), to obtain a compound shown as formula 4;

[0010] (3) contacting the compound shown as formula 4 with phosphorus oxychloride, to obtain a compound shown as formula 5;

[0011] (4) contacting the compound shown as formula 5 with a compound shown as formula 6, to obtain a compound shown as formula 7;

[0012] (5) contacting the compound shown as formula 7 with a compound shown as formula 8, potassium phosphate, iodide, to obtain the compound shown as formula I, encainide,

[0013]

[0014] wherein the iodide is at least one selected from sodium iodide, or potassium iodide.

[0015] The inventor finds that, by using the preparation method, with the compound shown as formula 1 and the compound shown as formula 2, potassium carbonate, tetrakis(triphenylphosphine)palladium as starting materials, the target product encainide can be successfully synthesized by 5 steps of reaction.

[0016] The term "contacting" used herein should be interpreted broadly, which can be any way that can make at least two reactants chemically react, for example, the two reactants can be mixed under appropriate conditions. If necessary, the reactants to be contacted can be mixed under stirring, and thus the type of stirring is not particularly limited, for example, it can be mechanical stirring, i.e. stirring under the action of mechanical force.

[0017] In this document, the terms "first", "second", "third", etc. are used only for descriptive purposes and are not to be construed as indicating or implying relative importance or an indicated number of technical features. Thus, features defined with "first", "second" can explicitly or implicitly include one or more of the features. In the description of the present application, the meaning of "a plurality of" is two or more, unless otherwise specifically limited.

[0018] According to the embodiments of the present application, the above-mentioned method for preparing the compound shown as formula 3, the compound shown as formula 4, the compound shown as formula 5, the compound shown as formula 7, the compound shown as formula I can further have at least one of the following additional technical features:

[0019] According to embodiments of the present application, the chemical reactions described in the present application can be carried out according to any method known in the art. The source of the raw materials of the compound of formula 3, the compound of formula 4, the compound of formula 5, the compound of formula 7, and the compound of formula I is not particularly limited, which can be prepared by using any known method, or obtained commercially. For example, the compound of formula 1 has a cas of: 681431-18-5.

[0020] According to embodiments of the present application, in step (1), the contacting manner of the compound of formula 1, the compound of formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium is not particularly limited. Thus, the efficiency of the contacting reaction of the compound of formula 1, the compound of formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 3 by using the method can be further improved.

[0021] According to embodiments of the present application, in step (1), the following steps are included: the compound of formula 1, the compound of formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium are added into anhydrous dioxane at room temperature, nitrogen is replaced, and the reaction is heated at 95-101°C for 3 hours and 45 minutes to 4 hours and 15 minutes. After the reaction solution is cooled to room temperature, it is filtered with diatomite, washed with water, extracted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to distill off the solvent, the concentrate is purified by silica gel column chromatography with a mixed solvent of dichloromethane / methanol, and the compound of formula 3 is obtained. Thus, the efficiency of the contacting reaction of the compound of formula 1, the compound of formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 3 by using the method can be further improved.

[0022] According to embodiments of the present application, in step (1), the molar ratio of the compound of formula 1, the compound of formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium is 1:(1.0-1.1):(2.5-4.5):(0.05-0.15), and preferably the molar ratio of the compound of formula 1, the compound of formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium is 1:1.02:3.0:0.1. Thus, the efficiency of preparing the compound of formula 3 by using the method can be further improved.

[0023] According to embodiments of the present application, in step (1), the volume ratio of dichloromethane / methanol in the mixed solvent of dichloromethane / methanol is (8-12):1, and preferably the volume ratio of dichloromethane / methanol in the mixed solvent of dichloromethane / methanol is 10:1.

[0024] According to embodiments of the present application, in step (1), it is preferred to heat at 98-101°C for 4 hours.

[0025] According to one embodiment of the present application, in step (1), the following steps are included: at room temperature, the compound of formula 1 (22.60 g, 0.1 mol), the compound of formula 2 (19.48 g, 0.102 mol), potassium carbonate (41.46 g, 0.3 mol) and tetrakis(triphenylphosphine)palladium (11.56 g, 0.01 mol) are added into anhydrous dioxane (260 mL), nitrogen is replaced and the reaction is heated at 98-102°C for 4 hours, after the reaction solution is cooled to room temperature, it is filtered with diatomite, 200 mL of water is added for washing, 200 mL of ethyl acetate is added for extraction, the organic phase is washed with 200 mL of saturated brine, dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to distill off the solvent, the concentrate is purified by silica gel column chromatography with a mixture of dichloromethane / methanol (10:1 by volume) as the eluent to obtain the compound of formula 3, the yield is 25.08 g, the yield is 85.8%.

[0026] According to one embodiment of the present application, in step (2), the contacting manner of the compound of formula 3 with trifluoroacetic anhydride is not particularly limited. Thus, the contacting reaction efficiency of the compound of formula 3 with trifluoroacetic anhydride can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 4 by using the method can be further improved.

[0027] According to one embodiment of the present application, in step (2), the following steps are included: at 0°C, trifluoroacetic anhydride (TFAA) is added into a dichloromethane solution containing the compound of formula 3, the reaction is stirred at room temperature for 0.5 hours, after the reaction is completed, the post-treatment is performed, the reaction solution is quenched with ice water at 0°C, after the organic phase is separated, it is washed with saturated sodium bicarbonate solution, after the organic phase is separated, it is washed with saturated brine, dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to distill off the solvent, the concentrate is purified by silica gel column chromatography with a mixture of petroleum ether / ethyl acetate (3:1 by volume) as the eluent to obtain the compound of formula 4. Thus, the contacting reaction efficiency of the compound of formula 3 with trifluoroacetic anhydride can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 4 by using the method can be further improved.

[0028] According to one embodiment of the present application, in step (2), the molar ratio of the compound of formula 3 to trifluoroacetic anhydride is 1:(1.3-2.0), preferably the molar ratio of the compound of formula 3 to trifluoroacetic anhydride is 1:1.5. Thus, the efficiency of preparing the compound of formula 4 by using the method can be further improved.

[0029] According to one specific embodiment of the present application, in step (2), the following steps are included: at 0°C, trifluoroacetic anhydride (25.87g, 123.17mmol) is added to a dichloromethane solution (240mL) containing the compound shown in formula 3 (24.0g, 82.11mmol), the reaction is stirred at room temperature for 0.5 hours, after the reaction is completed, the reaction solution is quenched by adding ice water (50mL) at 0°C, after the organic layer is separated, 200mL of saturated sodium bicarbonate solution is added for washing, after the organic phase is separated, 100mL of saturated brine is added for washing, the mixture is dried over anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to distill off the solvent, the concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 3:1, and the compound shown in formula 4 is obtained in an amount of 20.29g with a yield of 90.1%.

[0030] According to an embodiment of the present application, in step (3), the contacting manner of the compound shown in formula 4 with phosphorus oxychloride is not particularly limited. Thus, the efficiency of the contacting reaction of the compound shown in formula 4 with phosphorus oxychloride can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound shown in formula 5 by using the method can be further improved.

[0031] According to an embodiment of the present application, in step (3), the following steps are included: at room temperature, the compound shown in formula 4 is added to phosphorus oxychloride, the reaction is stirred to be heated to a reflux state for 3 hours, after the reaction solution is cooled to room temperature, it is concentrated under reduced pressure, when a small amount of mixture remains, an appropriate amount of ice water is added, rapid stirring is performed, saturated NaOH solution is added dropwise until pH=10, the solid is filtered, the filter cake is washed with ice water, and the compound shown in formula 5 is obtained after drying. Thus, the efficiency of the contacting reaction of the compound shown in formula 4 with phosphorus oxychloride can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound shown in formula 5 by using the method can be further improved.

[0032] According to an embodiment of the present application, in step (3), the weight ratio of the compound shown in formula 4 to phosphorus oxychloride is 1:(5-10), and preferably the weight ratio of the compound shown in formula 4 to phosphorus oxychloride is 1:6.3. Thus, the efficiency of preparing the compound shown in formula 5 by using the method can be further improved.

[0033] According to one specific embodiment of the present application, in step (3), the following steps are included: at room temperature, the compound shown in formula 4 (19.0g, 69.27mmol) is added to phosphorus oxychloride (120mL), the reaction is stirred to be heated to a reflux state for 3 hours, after the reaction solution is cooled to room temperature, it is concentrated under reduced pressure, when a small amount of mixture (about 30mL) remains, an appropriate amount of ice water is added, rapid stirring is performed, saturated NaOH solution is added dropwise until pH=10, the solid is filtered, the filter cake is washed with ice water (50mL), and the compound shown in formula 5 is obtained after drying in an amount of 13.40g with a yield of 66.1%.

[0034] According to an embodiment of the present application, in step (4), the contacting manner of the compound of formula 5 with the compound of formula 6 is not particularly limited. Thus, the contacting reaction efficiency of the compound of formula 5 with the compound of formula 6 can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 7 by using the method can be further improved.

[0035] According to an embodiment of the present application, in step (4), the contacting manner of the compound of formula 5 with the compound of formula 6 is not particularly limited. Thus, the contacting reaction efficiency of the compound of formula 5 with the compound of formula 6 can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 7 by using the method can be further improved.

[0036] According to an embodiment of the present application, in step (4), the molar ratio of the compound of formula 5 to the compound of formula 6 is 1: (2.5-4.0), and preferably the molar ratio of the compound of formula 5 to the compound of formula 6 is 1:3.0. Thus, the efficiency of preparing the compound of formula 7 by using the method can be further improved.

[0037] According to an embodiment of the present application, in step (4), the short-chain alcohol A is at least one selected from isopropyl alcohol or ethanol.

[0038] According to an embodiment of the present application, in step (4), preferably, the stirring reaction is performed for 3 hours and 15 minutes.

[0039] According to an embodiment of the present application, in step (4), the contacting manner of the compound of formula 5 with the compound of formula 6 is not particularly limited. Thus, the contacting reaction efficiency of the compound of formula 5 with the compound of formula 6 can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 7 by using the method can be further improved.

[0040] According to an embodiment of the present application, in step (5), the contacting manner of the compound of formula 7 with the compound of formula 8, potassium phosphate, and iodide is not particularly limited. Thus, the contacting reaction efficiency of the compound of formula 7 with the compound of formula 8, potassium phosphate, and iodide can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula I by using the method can be further improved.

[0041] According to an embodiment of the present application, in step (5), the following steps are included: at room temperature, the compound of formula 7, the compound of formula 8, potassium phosphate and iodide are mixed in dry 2-butanone, the reaction solution is heated to keep refluxing under nitrogen atmosphere, the reaction is stirred for 17-20 hours, after the reaction is completed, the reaction solution is cooled to room temperature, then filtered with diatomite, the filter cake is washed with dichloromethane, dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to distill off the solvent, the concentrate is purified by silica gel column chromatography with dichloromethane / methanol mixed solvent to obtain the compound of formula I, i.e. encainide. In this way, the efficiency of the contact reaction of the compound of formula 7 with the compound of formula 8, potassium phosphate and iodide can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula I, i.e. encainide, by using the method can be further improved.

[0042] According to an embodiment of the present application, in step (5), the molar ratio of the compound of formula 7 to the compound of formula 8, potassium phosphate and iodide is 1:(2.0-4.0):(4.0-6.0):(2.0-4.0), preferably the molar ratio of the compound of formula 7 to the compound of formula 8, potassium phosphate and iodide is 1:3.0:5.0:3.0. In this way, the efficiency of preparing the compound of formula I by using the method can be further improved.

[0043] According to an embodiment of the present application, in step (5), the iodide is at least one selected from sodium iodide or potassium iodide, preferably the iodide is selected from sodium iodide.

[0044] According to an embodiment of the present application, in step (5), the volume ratio of dichloromethane to methanol in the dichloromethane / methanol mixed solvent is (15-25):1, preferably the volume ratio of dichloromethane to methanol is 20:1.

[0045] According to an embodiment of the present application, in step (5), the reaction is preferably stirred for 18 hours.

[0046] According to an embodiment of the present application, in step (5), the following steps are included: at room temperature, the compound of formula 7 (10.0 g, 25.55 mmol), the compound of formula 8 (12.80 g, 76.64 mmol), potassium phosphate (27.11 g, 127.73 mmol) and sodium iodide (11.49 g, 76.64 mmol) are mixed in dry 2-butanone (300 mL), the reaction solution is heated to keep refluxing under nitrogen atmosphere, the reaction is stirred for 18 hours, after the reaction is completed, the reaction solution is cooled to room temperature, then filtered with diatomite, the filter cake is washed with dichloromethane (100 mL), dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to distill off the solvent, the concentrate is purified by silica gel column chromatography with dichloromethane / methanol mixed solvent in a volume ratio of 20:1 to obtain the compound of formula I, i.e. encainide, in an amount of 9.44 g, with a yield of 77.4% and an HPLC purity of 99.6%.

[0047] According to the specific embodiments of the present application, the synthesis route of the compound of formula I, encafenentide, can be as follows:

[0048]

[0049] Compared with the prior art, the preparation method of encafenentide described in the present application has at least the following beneficial effects:

[0050] 1. Compared with the prior art, the beneficial effect of the preparation method described in the present application is that the initial raw materials, the compound of formula 1 and the compound of formula 2, are subjected to a sizuki coupling reaction to obtain the compound of formula 3, an intramolecular cyclization is performed to obtain the compound of formula 4, POCl3 is used to convert the carbonyl group into a halide (the compound of formula 5), and then an alkylating reaction is performed with the compound of formula 6 to obtain the compound of formula 7, wherein the acylimine of the compound of formula 7 is subjected to a substitution reaction with brominated urea to obtain the product, encafenentide.

[0051] 2. Compared with the prior art method, the present application has the following significant advantages: (1) In WO2012037782, when a compound with a hydroxyl group is faced, the hydroxyl group is first protected and then subjected to a substitution reaction. In the present application, a boronic acid compound is selected as the starting material, and a sizuki reaction is performed with the compound, so that a high reaction yield can be obtained without the need for protection and deprotection of the hydroxyl group, thereby reducing the two-step reaction of protection and deprotection of the hydroxyl group. (2) In WO2023109802, the compound of formula 7 is reacted with 2-(2-bromoethyl)iso-indole-1,3-dione to obtain a compound that is easy to remove, then hydrazine hydrate is added to obtain an amine group, and potassium chlorate is added to obtain the final product (urea). In the present application, the compound of formula 7 is directly reacted with halogenated urea to obtain the final product, thereby shortening the two-step reaction and simplifying the reaction operation. (3) The raw material selected in the present application is easy to obtain, the operation method is simple, the product yield is high, and the present application is suitable for batch production. DETAILED DESCRIPTION

[0052] The embodiments of the present application are described in detail below. The embodiments described below are exemplary and are only used to explain the present application and cannot be understood as a limitation of the present application. If the specific techniques or conditions are not specified in the embodiments, the techniques or conditions described in the literature in the art or according to the product instructions are used. If the reagents or instruments are not specified by the manufacturer, they are all conventional products that can be obtained by purchase.

[0053] Example 1 Synthesis of the compound of formula 3

[0054] To a solution of compound of formula 1 (22.60 g, 0.1 mol), compound of formula 2 (19.48 g, 0.102 mol), potassium carbonate (41.46 g, 0.3 mol) and tetrakis(triphenylphosphine) palladium (11.56 g, 0.01 mol) in dry dioxane (260 mL) was added at room temperature, purged with nitrogen and heated at 98 °C to 101 °C for 4 h. The reaction mixture was cooled to room temperature, filtered through celite, washed with 200 mL of water, extracted with 200 mL of ethyl acetate, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the solvent was distilled off. The residue was purified by column chromatography using 10:1 mixture of dichloromethane / methanol as an eluent to obtain compound of formula 3 in 25.08 g, 85.8% yield.

[0055] LC-MS (APCI): m / z = 293.1 (M+1) + .

[0056] Synthesis of compound of formula 3 as per example 2

[0057] To a solution of compound of formula 1 (22.60 g, 0.1 mol), compound of formula 2 (19.10 g, 0.1 mol), potassium carbonate (34.55 g, 0.25 mol) and tetrakis(triphenylphosphine) palladium (5.78 g, 0.005 mol) in dry dioxane (260 mL) was added at room temperature, purged with nitrogen and heated at 95 °C to 98 °C for 3 h 45 min. The reaction mixture was cooled to room temperature, filtered through celite, washed with 200 mL of water, extracted with 200 mL of ethyl acetate, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the solvent was distilled off. The residue was purified by column chromatography using 8:1 mixture of dichloromethane / methanol as an eluent to obtain compound of formula 3 in 23.88 g, 81.7% yield.

[0058] Synthesis of compound of formula 3 as per example 3

[0059] To a solution of compound of formula 1 (22.60 g, 0.1 mol), compound of formula 2 (20.01 g, 0.11 mol), potassium carbonate (62.19 g, 0.45 mol) and tetrakis(triphenylphosphine)palladium (17.34 g, 0.015 mol) in dry dioxane (260 mL) was added at room temperature, purged with nitrogen and heated at 98 °C to 101 °C for 4 hours and 15 minutes. The reaction mixture was cooled to room temperature and filtered through celite. To the filtrate was added 200 mL of water and stirred for 10 minutes. The organic layer was separated and washed with 200 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using 12:1 mixture of dichloromethane and methanol as eluent to give compound of formula 3. Yield: 24.84 g, 85.0 %.

[0060] Synthesis of compound of formula 3 of comparative example 1

[0061] To a solution of compound of formula 1 (22.60 g, 0.1 mol), compound of formula 2 (24.83 g, 0.13 mol), potassium carbonate (27.64 g, 0.2 mol) and tetrakis(triphenylphosphine)palladium (2.89 g, 0.0025 mol) in dry dioxane (260 mL) was added at room temperature, purged with nitrogen and heated at 90 °C for 5 hours. The reaction mixture was cooled to room temperature and filtered through celite. To the filtrate was added 200 mL of water and stirred for 10 minutes. The organic layer was separated and washed with 200 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using 5:1 mixture of dichloromethane and methanol as eluent to give compound of formula 3. Yield: 23.18 g, 79.3 %.

[0062] Synthesis of compound of formula 4 of example 4

[0063] To a solution of compound of formula 3 (24.0 g, 82.11 mmol) in dichloromethane (240 mL) was added trifluoroacetic anhydride (25.87 g, 123.17 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was quenched with ice cold water (50 mL) at 0 °C. The organic layer was separated and washed with 200 mL of saturated sodium bicarbonate solution. The organic layer was separated and washed with 100 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using 3:1 mixture of petroleum ether and ethyl acetate as eluent to give compound of formula 4. Yield: 20.29 g, 90.1 %.

[0064] LC-MS (APCI): m / z = 275.1 (M+1) + .

[0065] Example 5 Synthesis of compound of formula 4

[0066] Trifluoroacetic anhydride (22.42 g, 106.74 mmol) was added to a solution of compound of formula 3 (24.0 g, 82.11 mmol) in dichloromethane (240 mL) at 0 °C and the reaction was stirred at room temperature for 0.5 h. After completion of the reaction, the reaction mixture was quenched with ice water (50 mL) at 0 °C and the organic layer was separated. The organic layer was washed with saturated sodium bicarbonate solution (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using 3:1 petroleum ether / ethyl acetate as the eluent to obtain compound of formula 4 (19.89 g, 88.3% yield).

[0067] Example 6 Synthesis of compound of formula 4

[0068] Trifluoroacetic anhydride (34.49 g, 123.17 mmol) was added to a solution of compound of formula 3 (24.0 g, 82.11 mmol) in dichloromethane (240 mL) at 0 °C and the reaction was stirred at room temperature for 0.5 h. After completion of the reaction, the reaction mixture was quenched with ice water (50 mL) at 0 °C and the organic layer was separated. The organic layer was washed with saturated sodium bicarbonate solution (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using 3:1 petroleum ether / ethyl acetate as the eluent to obtain compound of formula 4 (20.16 g, 89.5% yield).

[0069] Example 7 Synthesis of compound of formula 5

[0070] Phosphorus oxychloride (120 mL) was added to compound of formula 4 (19.0 g, 69.27 mmol) at room temperature and the reaction was stirred at reflux for 3 h. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. When the residue was about 30 mL, ice water was added to the residue with rapid stirring. Saturated NaOH solution was added dropwise to the mixture until the pH was 10. The solid was filtered and washed with ice water (50 mL). The solid was dried to obtain compound of formula 5 (13.40 g, 66.1% yield).

[0071] LC-MS (APCI): m / z = 293.1 (M+1) + .

[0072] Example 8 Synthesis of compound of formula 5

[0073] To phosphorous oxychloride (240 mL) was added compound of formula 4 (24.0 g, 87.50 mmol) at room temperature and stirred to reflux for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue (about 60 mL) was added ice water and stirred rapidly. Saturated NaOH solution was added drop wise until the pH was 10. The solid was filtered and the filter cake was washed with ice water (60 mL) and dried to obtain compound of formula 5. Yield 16.77 g, 65.6 %.

[0074] Example 9 Synthesis of compound of formula 5

[0075] To phosphorous oxychloride (240 mL) was added compound of formula 4 (24.0 g, 87.50 mmol) at room temperature and stirred to reflux for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue (about 60 mL) was added ice water and stirred rapidly. Saturated NaOH solution was added drop wise until the pH was 10. The solid was filtered and the filter cake was washed with ice water (60 mL) and dried to obtain compound of formula 5. Yield 16.77 g, 65.6 %.

[0076] Comparative Example 2 Synthesis of compound of formula 5

[0077] To phosphorous oxychloride (240 mL) was added compound of formula 4 (24.0 g, 87.50 mmol) at room temperature and stirred to reflux for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue (about 60 mL) was added ice water and stirred rapidly. Saturated NaOH solution was added drop wise until the pH was 10. The solid was filtered and the filter cake was washed with ice water (60 mL) and dried to obtain compound of formula 5. Yield 16.77 g, 65.6 %.

[0078] Example 10 Synthesis of compound of formula 7

[0079] To compound of formula 5 (10.0 g, 34.16 mmol) was added isopropyl alcohol (100 mL) at room temperature and compound of formula 6 (13.86 g, 102.48 mmol) was added. The reaction mixture was stirred to reflux for 3 h 15 min. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ice water (50 mL) and dried to obtain compound of formula 7. Yield 12.40 g, 92.7 %.

[0080] LC-MS (APCI): m / z = 392.2 (M+1) + .

[0081] Example 11 Synthesis of compound of formula 7

[0082] To a solution of compound of formula 5 (10.0 g, 34.16 mmol) in isopropanol (100 mL) was added compound of formula 6 (11.55 g, 85.4 mmol) at room temperature and heated to reflux. The reaction was stirred for 3 h. The reaction was monitored by TLC. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ice-cold water (50 mL) and dried to obtain compound of formula 7. The yield was 11.94 g, 89.3 %.

[0083] Example 12: Synthesis of compound of formula 7

[0084] To a solution of compound of formula 5 (10.0 g, 34.16 mmol) in isopropanol (100 mL) was added compound of formula 6 (18.48 g, 136.68 mmol) at room temperature and heated to reflux. The reaction was stirred for 3 h 30 min. The reaction was monitored by TLC. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ice-cold water (50 mL) and dried to obtain compound of formula 7. The yield was 12.22 g, 91.4 %.

[0085] Example 13: Synthesis of compound of formula 7

[0086] To a solution of compound of formula 5 (10.0 g, 34.16 mmol) in isopropanol (100 mL) was added compound of formula 6 (13.86 g, 102.48 mmol) at room temperature and heated to reflux. The reaction was stirred for 3 h 30 min. The reaction was monitored by TLC. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ice-cold water (50 mL) and dried to obtain compound of formula 7. The yield was 12.33 g, 92.2 %.

[0087] Example 14: Preparation of compound of formula I, encafenatine

[0088] To a solution of compound of formula 7 (10.0 g, 25.55 mmol), compound of formula 8 (12.80 g, 76.64 mmol), potassium phosphate (27.11 g, 127.73 mmol) and sodium iodide (11.49 g, 76.64 mmol) in dry 2-butanone (300 mL) was heated to reflux under nitrogen atmosphere. The reaction was stirred for 18 h. The reaction was monitored by TLC. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with dichloromethane (100 mL) and dried over anhydrous sodium sulphate. The filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by column chromatography using 20:1 mixture of dichloromethane / methanol as an eluent to obtain compound of formula I, encafenatine. The yield was 9.44 g, 77.4 %, 99.6 % HPLC purity.

[0089] LC-MS (APCI): m / z = 478.2 (M+1) + .

[0090] 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.97 (s, 6 H) 2.22 (s, 3 H) 2.90 (t, J=5.93 Hz, 2 H) 3.07 - 3.50 (m, 1 H) 3.33 (s, 3 H) 3.62 (s, 3 H) 3.92 (t, J=5.99 Hz, 2 H) 4.18 (t, J=6.72 Hz, 2 H) 5.32 (s, 1 H) 5.45 (br. s., 2 H) 6.11 (t, J=5.75 Hz, 1 H) 6.66 (s, 1 H) 6.86 (s, 2 H) 6.96 (s, 1 H)

[0091] Preparation of compound of formula I, Enasidenib

[0092] To a solution of compound of formula 7 (10.0 g, 25.55 mmol), compound of formula 8 (8.53 g, 51.1 mmol), potassium phosphate (21.69 g, 102.2 mmol) and sodium iodide (7.66 g, 51.1 mmol) in dry 2-butanone (300 mL) was added at room temperature. The reaction mixture was heated to maintain the reflux under nitrogen atmosphere and stirred for 17 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite and the filter cake was washed with dichloromethane (100 mL). The filtrate was dried over anhydrous sodium sulphate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using 15:1 mixture of dichloromethane / methanol as an eluent to obtain compound of formula I, Enasidenib in 9.18 g, 75.2% yield and 99.5% HPLC purity.

[0093] Preparation of compound of formula I, Enasidenib

[0094] To a solution of compound of formula 7 (10.0 g, 25.55 mmol), compound of formula 8 (17.07 g, 102.2 mmol), potassium phosphate (32.54 g, 153.3 mmol) and sodium iodide (15.32 g, 102.2 mmol) in dry 2-butanone (300 mL) was added at room temperature. The reaction mixture was heated to maintain the reflux under nitrogen atmosphere and stirred for 20 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite and the filter cake was washed with dichloromethane (100 mL). The filtrate was dried over anhydrous sodium sulphate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using 25:1 mixture of dichloromethane / methanol as an eluent to obtain compound of formula I, Enasidenib in 9.39 g, 77.0% yield and 99.3% HPLC purity.

[0095] Preparation of compound of formula I, encafenatine

[0096] The compound of formula 7 (10.0 g, 25.55 mmol), the compound of formula 8 (12.8 g, 76.64 mmol), potassium phosphate (27.11 g, 127.73 mmol) and potassium iodide (12.72 g, 76.64 mmol) were dissolved in dry 2-butanone (300 mL) at room temperature. The reaction mixture was heated to maintain reflux under nitrogen atmosphere and stirred for 18 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite and the filter cake was washed with dichloromethane (100 mL). The filtrate was dried over anhydrous sodium sulphate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using 20:1 mixture of dichloromethane / methanol as an eluent to obtain the compound of formula I, encafenatine, in 9.42 g, 77.2% yield and 99.7% HPLC purity.

[0097] Preparation of compound of formula I, encafenatine

[0098] The compound of formula 7 (10.0 g, 25.55 mmol), the compound of formula 8 (4.27 g, 25.55 mmol), potassium phosphate (10.59 g, 76.65 mmol) and sodium iodide (4.98 g, 33.22 mmol) were dissolved in dry 2-butanone (300 mL) at room temperature. The reaction mixture was heated to maintain reflux under nitrogen atmosphere and stirred for 15 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite and the filter cake was washed with dichloromethane (100 mL). The filtrate was dried over anhydrous sodium sulphate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using 10:1 mixture of dichloromethane / methanol as an eluent to obtain the compound of formula I, encafenatine, in 8.99 g, 73.7% yield and 98.6% HPLC purity.

[0099] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "an example", "a specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present application. In the present specification, the illustrative description 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 appropriate manner in any one or more embodiments or examples. In addition, the person skilled in the art can combine and combine the different embodiments or examples described in the present specification and the features of the different embodiments or examples without contradiction.

[0100] Although the embodiments of the present application have been shown and described above, it is understood that the above-described embodiments are exemplary and are not to be construed as limiting the present application, and that changes, modifications, substitutions and variations can be made by those skilled in the art without departing from the scope of the present application.

Claims

1. A process for the preparation of encephaline, characterized in that, Comprising: (1) contacting a compound of Formula 1 with a compound of Formula 2, potassium carbonate, tetrakis(triphenylphosphine)palladium to obtain a compound of Formula 3; (2) contacting the compound of Formula 3 with trifluoroacetic anhydride to obtain a compound of Formula 4; (3) contacting the compound of Formula 4 with phosphorus oxychloride to obtain a compound of Formula 5; (4) contacting the compound of Formula 5 with a compound of Formula 6 to obtain a compound of Formula 7; (5) contacting the compound of Formula 7 with a compound of Formula 8, potassium phosphate, iodide to obtain the compound of Formula I, encainide, ， In step (1), the molar ratio of the compound of Formula 1 to the compound of Formula 2, potassium carbonate, tetrakis(triphenylphosphine)palladium is 1:(1.0-1.1):(2.5-4.5):(0.05-0.15); In step (2), the molar ratio of the compound of Formula 3 to trifluoroacetic anhydride is 1:(1.3-2.0); In step (3), the weight ratio of the compound of Formula 4 to phosphorus oxychloride is 1:(5-10); In step (4), the molar ratio of the compound of Formula 5 to the compound of Formula 6 is 1:(2.5-4.0); In step (5), the molar ratio of the compound of Formula 7 to the compound of Formula 8, potassium phosphate, iodide is 1:(2.0-4.0):(4.0-6.0):(2.0-4.0); In step (5), the iodide is at least one selected from sodium iodide or potassium iodide.

2. The method of claim 1, wherein, In step (1), it comprises the following steps: at room temperature, the compound of Formula 1, the compound of Formula 2, potassium carbonate, and tetrakis(triphenylphosphine)palladium are added to anhydrous dioxane, nitrogen is replaced, and the reaction is heated at 95°C-101°C for 3 hours and 45 minutes-4 hours and 15 minutes, after the reaction solution is cooled to room temperature, it is filtered with diatomite, washed with water, extracted with ethyl acetate, the organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to distill off the solvent, the concentrate is purified by silica gel column chromatography with a mixture of dichloromethane / methanol as the eluent to obtain the compound of Formula 3; In step (2), it comprises the following steps: at 0°C, trifluoroacetic anhydride is added to a dichloromethane solution containing the compound of Formula 3, and the reaction is stirred at room temperature for 0.5 hours, after the reaction is completed, the post-treatment is performed, the reaction solution is quenched with ice water at 0°C, after the organic layer is separated, it is washed with saturated sodium bicarbonate solution, after the organic phase is separated, it is washed with saturated brine, dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to distill off the solvent, the concentrate is purified by silica gel column chromatography with a mixture of petroleum ether / ethyl acetate (volume ratio 3:1) as the eluent to obtain the compound of Formula 4; In step (3), it comprises the following steps: at room temperature, the compound of Formula 4 is added to phosphorus oxychloride, the temperature is stirred to reflux for 3 hours, after the reaction solution is cooled to room temperature, it is concentrated under reduced pressure, when a small amount of mixture remains, an appropriate amount of ice water is added, stirred rapidly, and saturated NaOH solution is added dropwise until pH=10, the solid is filtered, the filter cake is washed with ice water, and dried to obtain the compound of Formula 5; In step (4), the following steps are included: at room temperature, the compound shown as formula 5 is added into short-chain alcohol A, the compound shown as formula 6 is added, then the temperature is increased to reflux, the reaction is stirred for 3 hours to 3 hours and 30 minutes, the reaction is monitored by TLC until it is completed, the reaction solution is cooled to room temperature, filtered, the filter cake is washed with ice water, and dried to obtain the compound shown as formula 7; In step (5), the following steps are included: at room temperature, the compound shown as formula 7, the compound shown as formula 8, potassium phosphate and iodide are mixed in dry 2-butanone, the reaction solution is heated to keep reflux in a nitrogen atmosphere, the reaction is stirred for 17 hours to 20 hours, after the reaction is completed, the temperature is cooled to room temperature, then filtered with diatomite, the filter cake is washed with dichloromethane and dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to evaporate the solvent, the concentrate is purified by silica gel column chromatography with dichloromethane / methanol mixed solvent to obtain the compound shown as formula I, encainide.

3. The method of claim 1, wherein, In step (1), the molar ratio of the compound shown as formula 1, the compound shown as formula 2, potassium carbonate and tetrakis(triphenylphosphine)palladium is 1: 1.02: 3.0: 0.

1.

4. The method of claim 2, wherein, In step (1), the volume ratio of dichloromethane / methanol in the dichloromethane / methanol mixed solvent is (8-12):

1.

5. The method of claim 4, wherein, In step (1), the volume ratio of dichloromethane / methanol in the dichloromethane / methanol mixed solvent is 10:

1.

6. The method of claim 2, wherein, In step (1), the reaction is heated at 98°C to 101°C for 4 hours.

7. The method of claim 1, wherein, In step (2), the molar ratio of the compound shown as formula 3 and trifluoroacetic anhydride is 1: 1.

5.

8. The method of claim 1, wherein, In step (3), the weight ratio of the compound shown as formula 4 and phosphorus oxychloride is 1: 6.

3.

9. The method of claim 1, wherein, In step (4), the molar ratio of the compound shown as formula 5 and the compound shown as formula 6 is 1: 3.

0.

10. The method of claim 2, wherein, In step (4), the short-chain alcohol A is at least one selected from isopropyl alcohol or ethanol.

11. The method of claim 2, wherein, In step (4), the stirring reaction time is 3 hours and 15 minutes.

12. The method of claim 1, wherein, In step (5), the molar ratio of the compound shown as formula 7, the compound shown as formula 8, potassium phosphate and iodide is 1: 3.0: 5.0: 3.

0.

13. The method of claim 1, wherein, In step (5), the iodide is sodium iodide.

14. The method of claim 2, wherein, In step (5), the volume ratio of dichloromethane and methanol in the dichloromethane / methanol mixed solvent is (15-25):

1.

15. The method of claim 14, wherein, In step (5), the volume ratio of dichloromethane and methanol is 20:

1.

16. The method of claim 2, wherein, In step (5), the stirring reaction time is 18 hours.

17. The method of claim 1, wherein, In step (1), the following steps are included: 22.60 g of the compound shown in formula 1, 19.48 g of the compound shown in formula 2, 41.46 g of potassium carbonate and 11.56 g of tetrakis(triphenylphosphine)palladium are added into 260 mL of anhydrous dioxane at room temperature, nitrogen is replaced and the reaction is heated at 98°C-102°C for 4 hours, the reaction solution is cooled to room temperature, filtered with diatomite, 200 mL of water is added for washing, 200 mL of ethyl acetate is added for extraction, the organic phase is washed with 200 mL of saturated brine, dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to distill off the solvent, the concentrate is purified by silica gel column chromatography with a mixed solvent of dichloromethane / methanol (10:1 by volume) to obtain the compound shown in formula 3, with a yield of 25.08 g and a yield of 85.8%; In step (2), the following steps are included: 25.87 g of trifluoroacetic anhydride is added into a solution of 24.0 g of the compound shown in formula 3 in 240 mL of dichloromethane at 0°C, the reaction is stirred at room temperature for 0.5 hours, after the reaction is completed, the post-treatment is performed, 50 mL of ice water is added into the reaction solution at 0°C for quenching, the organic phase is separated, 200 mL of saturated sodium bicarbonate solution is added for washing, the organic phase is separated, 100 mL of saturated brine is added for washing, dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to distill off the solvent, the concentrate is purified by silica gel column chromatography with a mixed solvent of petroleum ether / ethyl acetate (3:1 by volume) to obtain the compound shown in formula 4, with a yield of 20.29 g and a yield of 90.1%; In step (3), the following steps are included: 19.0 g of the compound shown in formula 4 is added into 120 mL of phosphorus oxychloride at room temperature, the temperature is increased to reflux state for reaction for 3 hours, the reaction solution is cooled to room temperature, concentrated under reduced pressure, when the remaining amount of the mixture is about 30 mL, appropriate amount of ice water is added, stirred rapidly, saturated NaOH solution is added dropwise until pH=10, the solid is filtered, the filter cake is washed with 50 mL of ice water, dried to obtain the compound shown in formula 5, with a yield of 13.40 g and a yield of 66.1%; In step (4), the following steps are included: 10.0 g of the compound shown in formula 5 is added into 100 mL of isopropyl alcohol at room temperature, 13.86 g of the compound shown in formula 6 is added, then the temperature is increased to reflux state, stirred for reaction for 3 hours and 15 minutes, the reaction is completed according to TLC monitoring, the reaction solution is cooled to room temperature, filtered, the filter cake is washed with 50 mL of ice water, dried to obtain the compound shown in formula 7, with a yield of 12.40 g and a yield of 92.7%; In step (5), the following steps are included: 10.0 g of the compound shown in formula 7, 12.80 g of the compound shown in formula 8, 27.11 g of potassium phosphate and 11.49 g of sodium iodide are dissolved in 300 mL of dry 2-butanone at room temperature, the reaction solution is heated to keep the reflux state in a nitrogen atmosphere, and stirred for 18 hours. After the reaction is completed, it is cooled to room temperature, filtered with diatomite, the filter cake is washed with 100 mL of dichloromethane, dried with anhydrous sodium sulfate, the filtrate is concentrated to distill off the solvent under reduced pressure, and the concentrate is purified by silica gel column chromatography with a dichloromethane / methanol mixed solvent in a volume ratio of 20:1 to obtain the compound encainide shown in formula I, with a yield of 9.44 g, a yield of 77.4%, and an HPLC purity of 99.6%.

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