Methods of synthesizing avanafil, intermediates, and uses thereof

Abstract

The present application relates to a method for synthesizing avanafil and an intermediate and use thereof. The method comprises the step of mixing a dissolving system containing 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide and tetrabutylammonium bromide into iodobenzene diacetate at a first temperature condition for reaction. Through the step, the intermediate prepared by the method has high purity, less by-products of over-oxidation, and can greatly reduce the impurity content of the final product avanafil, so as to improve the product quality of avanafil.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of Avanafil, in particular to a method for synthesizing Avanafil and an intermediate and use thereof. BACKGROUND

[0002] Avanafil (cas: 330784-47-9) is an orally fast-acting high-selectivity phosphodiesterase-5 (PDE-5) inhibitor, which has the advantages of the fastest onset and the smallest side effects among similar drugs, and is used for treating male erectile dysfunction.

[0003] At present, a general synthesis method of Avanafil is as follows Figure 1 The key step is to oxidize the thioether to obtain Avanafil intermediate a (4-[(3-chloro-4-methoxybenzyl) amino]-2-methanesulfinyl-N-(pyrimidin-2-ylmethyl) pyrimidine-5-carboxamide). The reaction selectivity and the impurities generated in the reaction of the key step will greatly affect the purity and quality control of the finally prepared Avanafil. Therefore, it has great industrial value to develop an oxidation method with mild conditions, high reaction selectivity and easy post-treatment purification to obtain high-purity Avanafil intermediate a.

[0004] At present, the preparation method of Avanafil intermediate a mainly uses meta-chloroperoxybenzoic acid (m-CPBA) as an oxidant, and the related descriptions are described in domestic and foreign patents WO2015177807A1, EP2886540A1, CN103833736A and CN104059025B. The main disadvantages are:

[0005] (1) The oxidation activity of meta-chloroperoxybenzoic acid is relatively high, although the dropwise addition is often used, but the reaction control is still difficult, the reaction selectivity is poor, and the thioether is easily over-oxidized to sulfone (such as Figure 7 as shown in 4-[(3-chloro-4-methoxybenzyl) amino]-2-methanesulfonyl-N-(pyrimidin-2-ylmethyl) pyrimidine-5-carboxamide);

[0006] (2) The Avanafil intermediate a in the patent is not purified directly for the next step reaction, which is not conducive to the quality control of the Avanafil intermediate a in industrial mass production, and will ultimately affect the purity and impurity control of the generated Avanafil raw material medicine;

[0007] (3) Meta-chloroperoxybenzoic acid is a controlled chemical, and its oxidation activity is relatively high. If the reaction residue is not treated in time, it will cause production danger, and there are often safety hazards in industrial mass production;

[0008] (4) The side reaction is more, and it is easy to generate nitrogen oxide impurities. These nitrogen oxide impurities are potential genotoxic impurities, and the structure is similar to avanafil. Simple post-treatment and recrystallization operations are difficult to remove the impurities;

[0009] In addition, the patent CN103833736A also describes a method for preparing an avanafil intermediate a using sodium hypochlorite as an oxidizing agent. In this method, a solid sodium hypochlorite is used. However, the solid sodium hypochlorite is less used in industrial production due to its poor stability and explosive nature. Therefore, the industrial value of this method is not great. SUMMARY

[0010] Therefore, the present application provides a method for synthesizing an avanafil intermediate and its use, so as to at least partially solve one of the above problems.

[0011] One of the objects of the present application is to provide a method for synthesizing an avanafil intermediate. The avanafil intermediate is 4-[(3-chloro-4-methoxybenzyl)amino]-2-methanesulfinyl-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide. The method comprises: mixing a dissolving system containing 4-[(3-chloro-4-methoxybenzyl)amino]-2-methanesulfinyl-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide and tetrabutylammonium bromide into diiodobenzene dicarboxylic acid at a first temperature condition to react.

[0012] Specifically, the molar ratio of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methanesulfinyl-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide and tetrabutylammonium bromide in the dissolving system is 1:(0.02-1).

[0013] Specifically, the molar ratio of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methanesulfinyl-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide and tetrabutylammonium bromide in the dissolving system is selected from 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09 or 1:0.1.

[0014] Specifically, the solvent in the dissolving system is selected from at least two of dichloromethane, ethyl acetate, methyl tert-butyl ether, methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone or water.

[0015] In particular, the molar ratio of the 4-[(3-chloro-4-methoxybenzyl)amino]-2- methylthio-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide to the iodobenzene diacetate is 1 : (1.0-2.0). For example, the molar ratio of the 4-[(3-chloro-4- methoxybenzyl)amino]-2-methylthio-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide to the iodobenzene diacetate is selected from 1 : 1.01, 1 : 1.02, 1 : 1.03, 1 : 1.04, 1 : 1.05, 1 : 1.06, 1 : 1.07, 1 : 1.08, 1 : 1.09, 1 : 1.1, 1 : 1.11, 1 : 1.12, 1 : 1.13, 1 : 1.14, 1 : 1.15, 1 : 1.16, 1 : 1.17, 1 : 1.18, 1 : 1.19, 1 : 1.20, 1 : 1.21, 1 : 1.22, 1 : 1.23, 1 : 1.24, 1 : 1.25, 1 : 1.26, 1 : 1.27, 1 : 1.28, 1 : 1.29, 1 : 1.30, 1 : 1.31, 1 : 1.32, 1 : 1.33, 1 : 1.34, 1 : 1.35, 1 : 1.36, 1 : 1.37, 1 : 1.38, 1 : 1.39, 1 : 1.40, 1 : 1.41, 1 : 1.42, 1 : 1.43, 1 : 1.44, 1 : 1.45, 1 : 1.46, 1 : 1.47, 1 : 1.48, 1 : 1.49, 1 : 1.50, 1 : 1.51, 1 : 1.52, 1 : 1.53, 1 : 1.54, 1 : 1.55, 1 : 1.56, 1 : 1.57, 1 : 1.58, 1 : 1.59, 1 : 1.60, 1 : 1.61, 1 : 1.62, 1 : 1.63, 1 : 1.64, 1 : 1.65, 1 : 1.66, 1 : 1.67, 1 : 1.68, 1 : 1.69, 1 : 1.70, 1 : 1.71, 1 : 1.72, 1 : 1.73, 1 : 1.74, 1 : 1.75, 1 : 1.76, 1 : 1.77, 1 : 1.78, 1 : 1.79, 1 : 1.80, 1 : 1.81, 1 : 1.82, 1 : 1.83, 1 : 1.84, 1 : 1.85, 1 : 1.86, 1 : 1.87, 1 : 1.88, 1 : 1.89, 1 : 1.90, 1 : 1.91, 1 : 1.92, 1 : 1.93, 1 : 1.94, 1 : 1.95, 1 : 1.96, 1 : 1.97, 1 : 1.98, 1 : 1.99, or 1 : 2.

[0016] Specifically, the first temperature condition is selected from -10-10℃, -9-9℃, -8-8℃, -7-7℃, -6-6℃, -5-5℃, -4-4℃, -3-3℃, -2-2℃, -1-1℃, -1-10℃, -2-10℃, -3-10℃, -4-102℃, -5-10℃, -6-10℃, -7-10℃, -8-10℃, -9-10℃, -10-0℃, -10-1℃, -10-2℃, -10-3℃, -10-4℃, -10-5℃, -10-6℃, -10-7℃, -10-8℃, -10-9℃, -10℃, -9℃, -8℃, -7℃, -6℃, -5℃, -4℃, -3℃, -2℃, -1℃ or 0℃.

[0017] Specifically, the method further comprises the steps of: quenching the reaction using an aqueous sodium sulfite solution; and purifying the quenched reaction product to obtain the avanafil intermediate.

[0018] Specifically, the concentration of the aqueous sodium sulfite solution is 5%-20%. For example, the concentration of the aqueous sodium sulfite solution is 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%.

[0019] Specifically, the step of purifying comprises: extracting the quenched reaction product to obtain an organic phase; washing the organic phase with water, concentrating to dryness and recrystallizing.

[0020] Specifically, the quenching is performed at 6-18h of the reaction.

[0021] Specifically, the step of extracting the quenched reaction product comprises: extracting the quenched reaction product with dichloromethane after standing.

[0022] Specifically, the recrystallization is performed using acetone.

[0023] Specifically, the recrystallization is performed using tetrahydrofuran.

[0024] Specifically, for the solid concentrated to dryness, acetone is used, and the temperature is raised (30-60℃) to reflux for 0.5h, and then the temperature is lowered (-10-10℃) to crystallize for 2h, and then filtered and dried.

[0025] Specifically, the solid evaporated to dryness is continuously mixed with tetrahydrofuran, the temperature is raised (30-70℃) to reflux for 0.5h, and then the temperature is lowered (-10-10℃) to crystallize for 2h, and then filtered and dried.

[0026] The method for synthesizing avanafil also provided by the present application comprises the following steps: mixing 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide and tetrabutylammonium bromide in a dissolving system at a first temperature, and then adding iodobenzene diacetate to perform a first reaction; after quenching the first reaction, the obtained reaction product is extracted to obtain an organic phase; adding triethylamine and L-proline to the organic phase at a second temperature to perform a second reaction, and thus the avanafil is obtained.

[0027] The method for synthesizing an intermediate of avanafil also provided by the present application has the use in preparing the intermediate of avanafil or the avanafil.

[0028] The method for synthesizing an intermediate of avanafil provided by the present application uses tetrabutylammonium bromide as a catalyst to catalyze the preparation of the intermediate a of avanafil. Since the reaction process can be controlled by the tetrabutylammonium bromide, the reaction does not need to be added dropwise, and the reaction selectivity provided by the method is good, and the occurrence rate of over-oxidation of the thioether is reduced.

[0029] In addition, the reaction product provided by the method only needs to be simply recrystallized and purified, and thus a white powder of the intermediate a of avanafil with high purity can be obtained, and the quality control of the intermediate a of avanafil can be conveniently performed, which is also beneficial to the quality control and impurity control of the subsequent avanafil bulk drug.

[0030] In addition, the reaction condition of the method is mild, the operation is simple, the yield of the intermediate a of avanafil is high, the purity is high, and the method has a good industrialization prospect in the preparation of the intermediate of avanafil or the avanafil.

[0031] In addition, the method uses iodobenzene diacetate as an oxidant. The iodobenzene diacetate is stable in property, easy to store, low in safety risk, and small in toxicity. Compared with the oxidants such as sodium hypochlorite (easy to decompose), meta-chloroperoxybenzoic acid (a regulated chemical), and hydrogen peroxide (a regulated chemical) reported in the previous patents, the production safety and convenience are greatly improved. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 The synthesis route map of the intermediate a of avanafil and the avanafil provided by the prior art is shown.

[0033] Figure 2 The mass spectrum of the intermediate a of avanafil synthesized in Example 1 is shown.

[0034] Figure 3 The HPLC detection spectrum of the product of the intermediate a of avanafil synthesized in Example 1 is shown.

[0035] Figure 4 The HPLC detection spectrum of the product of the avanafil synthesized in Example 1 is shown.

[0036] Figure 5 HPLC detection spectrum of the product of the intermediate a of avanafil synthesized in Example 2.

[0037] Figure 6 HPLC detection spectrum of the product of the intermediate a of avanafil synthesized in Comparative Example 8.

[0038] Figure 7 Schematic diagram of the over-oxidation of a sulfide to a sulfone (4-[(3-chloro-4-methoxybenzyl)amino]-2-methanesulfonyl-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide). DETAILED DESCRIPTION

[0039] In order to make the objects, technical solutions and advantages of the present application clearer, the present application will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and not used to limit the present application. The reagents not described in detail in the present application are all conventional reagents and can be obtained from commercial channels; the methods not described in detail are all conventional experimental methods and can be known from the prior art.

[0040] The present application provides a method for synthesizing an intermediate of avanafil and the use thereof. The present inventors have found through a large number of experiments that the reaction can occur when tetrabutylammonium bromide (TBAB) is used, and the reaction does not occur without the addition of tetrabutylammonium bromide. In addition, the reaction also does not substantially occur when other catalysts (such as benzyltriethylammonium chloride (TEBA), tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride) are used instead.

[0041] In the reaction process, the active oxidizing species can be bromine positive ions with oxidizing property formed by tetrabutylammonium bromide and iodobenzene diacetate or a high-valence bromine complex similar to NBS, which is converted back to bromine negative ions after participating in the sulfide oxidation process, completing the catalytic cycle. In addition, by controlling the catalytic amount of tetrabutylammonium bromide, the concentration of the active oxidizing species formed by tetrabutylammonium bromide and iodobenzene diacetate can be controlled, thereby selectively generating a sulfoxide, reducing the occurrence of side reactions, and reducing the generation rate of sulfone (4-[(3-chloro-4-methoxybenzyl)amino]-2-methanesulfonyl-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide). In addition, the oxidizing property of the active oxidizing species formed by tetrabutylammonium bromide and iodobenzene diacetate is relatively mild, which is also convenient for controlling the reaction. Figure 7

[0042] ​Based on this, the application discloses a method for synthesizing an avanafil intermediate. The avanafil intermediate is 4-[(3-chloro-4-methoxybenzyl)amino]-2-methanesulfinyl-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide. The method comprises: mixing a dissolving system containing 4-[(3-chloro-4-methoxybenzyl)amino]-2-methanesulfinyl-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide and tetrabutylammonium bromide with iodobenzene diacetate at a first temperature condition to perform a reaction.

[0043] The method for synthesizing the avanafil intermediate is characterized in that: by mixing tetrabutylammonium bromide and iodobenzene diacetate in the reaction system containing 4-[(3-chloro-4-methoxybenzyl)amino]-2-methanesulfinyl-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, the tetrabutylammonium bromide and the iodobenzene diacetate form a mild oxidizing active oxidizing species, so that the reaction process can be controlled, the sulfoxide can be synthesized with high selectivity, and the side reactions and impurity generation are reduced.

[0044] Therefore, the following specific examples are used for illustration, but do not constitute a limitation to the application.

[0045] Example 1

[0046] 1. Preparation of the avanafil intermediate a

[0047] 430.91g (1mol) of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methanesulfinyl-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide and 16.12g (0.05mol) of tetrabutylammonium bromide are dissolved in 4L of dichloromethane, 3.2L of N,N-dimethylformamide and 80mL of purified water, then the refrigeration and stirring are started, the temperature of the reaction liquid is reduced to about 0℃, 405.14g (1.25mol) of iodobenzene diacetate is added, and stirring is performed for 12h. After the reaction is completed, 10% sodium sulfite aqueous solution is added to quench the reaction and stirring is performed for 15min, then the stirring is stopped, the water phase is separated after static layering, and the water phase is extracted with dichloromethane. After stirring for 15min, the organic phase is separated and combined with the aforementioned organic phase. The combined organic phase is washed with purified water and saturated brine, concentrated and rotary dried to obtain white solid. 3L of acetone is added to the obtained white solid, warmed to reflux for 0.5h, then crystallized at low temperature for two hours, filtered and dried. 2L of tetrahydrofuran is added to the dried solid powder, warmed to reflux for 0.5h, then crystallized at low temperature for two hours, filtered and dried to obtain 352g of white crystalline powder.

[0048] The white crystalline powder is the avanafil intermediate a (4-[(3-chloro-4-methoxybenzyl)amino]-2-methanesulfinyl-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide). As Figure 2The MS was detected as [M+Na] + The yield was 74.61% and the purity was 99.39% (see Figure 3 , retention time 31.656 min, purity in terms of peak area percentage in Figure 3 ). The yield calculation formula was 100% x M1 x a / M2.

[0049] M1 is the molar mass of the product of this step. a is the purity of the avanafil intermediate a in this step. M2 is the molar mass of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide.

[0050] 1 H NMR: 9.26 (s, 1H), 8.82 (d, J = 6.0 Hz, 3H), 8.50 (s, 1H), 7.42 (t, J = 5.2 Hz, 2H), 7.28 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 4.60 (d, J = 6.0 Hz, 2H), 4.52 (d, J = 5.8 Hz, 2H), 3.78 (s, 3H), 2.46 (s, 3H). MS (m / z): 447.0. Elemental analysis: calculated: C 51.06, H 4.29, Cl 7.93, N 18.80, O 10.74, S 7.17; found: C 51.06, H 4.28, Cl 7.92, N 18.82, O 10.73, S 7.18.

[0051] 2. Preparation of avanafil

[0052] The 352 g of white crystalline powder was dissolved in 3 L of dichloromethane, and then the refrigeration and stirring were started, and after the temperature of the reaction solution was lowered to 0°C, 200 ml of triethylamine was added, and then the dichloromethane solution of L-prolinol was added dropwise. After the dropwise addition was completed, the refrigeration was turned off, and the stirring was performed at room temperature for 8 h. After the reaction was completed, the saturated ammonium chloride solution was added for washing, and then the 1 N diluted hydrochloric acid was added for extraction, and the aqueous phase was separated. The aqueous phase was slowly added with the aqueous sodium hydroxide solution to adjust the pH to 7 to 8, and then the dichloromethane was added for extraction, and the organic phase was separated. The organic phase was heated to reflux, a small amount of activated carbon was added, and after refluxing for 0.5 h, it was filtered while hot, the filtrate was evaporated, and recrystallized from ethanol to obtain 337 g of a white solid. Finally, the white solid was recrystallized from a mixed solvent of ethanol / ethyl acetate to obtain 307 g of a pure white solid, which was avanafil, and the yield was 85.02% and the purity was 100% (see Figure 4 , retention time 31.656 min, purity in terms of peak area percentage in

[0053] The yield calculation formula is 100% x M3 x b / M1 x a. M3 is the molar mass of the reaction product of this step. b is the purity of avanafil in the reaction product of this step.

[0054] Example 2

[0055] The 430.91 g (1 mol) of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N- (pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 32.24 g (0.1 mol) of tetrabutylammonium bromide were dissolved in a mixed solvent of 4 L of dichloromethane, 3.2 L of N,N-dimethylformamide and 80 ml of purified water, and then the refrigeration and stirring were started. When the temperature of the reaction solution was lowered to about 0°C, 648.22 g (2 mol) of iodobenzene diacetate was added, and stirring was performed for 12 h. After the completion of the reaction, 10% sodium sulfite aqueous solution was added to quench the reaction and stirring was performed for 15 min, and then the stirring was stopped, and after the separation of the layers by standing, the water phase was separated. The water phase was extracted with dichloromethane, and after stirring for 15 min, the organic phase was separated and combined with the previously obtained organic phase. The combined organic phase was washed with purified water and saturated brine, and after concentration and drying, a white solid was obtained. To the obtained white solid, 3 L of acetone was added, and the temperature was raised to reflux for 0.5 h, and then the temperature was lowered to crystallize for 2 h, and then the solid was filtered and dried. To the obtained solid powder, 2 L of tetrahydrofuran was added, and the temperature was raised to reflux for 0.5 h, and then the temperature was lowered to crystallize for 2 h, and then the solid was filtered and dried, and 347 g of white crystalline powder was obtained, which was 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylsulfinyl-N- (pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, an intermediate of avanafil. It was found that the yield was 72.74%, and the purity was 98.30% (see Figure 5 , retention time 31.625 min, purity in terms of peak area percentage in Figure 5 ). Figure 5 The fraction having a retention time of 42.023 min in

[0056] Preparation of avanafil intermediate a

[0057] The 430.91 g (1 mol) of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N- (pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 11.39 g (0.05 mol) of benzyltriethylammonium chloride is dissolved in 4 L of dichloromethane, 3.2 L of N,N- dimethylformamide and 80 ml of purified water, and then the refrigeration and stirring are started, and when the temperature of the reaction solution is lowered to about 0°C, 405.14 g (1.25 mol) of iodobenzene diacetate is added, and after stirring for 12 h, 10% sodium sulfite aqueous solution is added to quench the reaction and stirred for 15 min, and then the stirring is stopped, and after the separation of the layers is completed, the water phase is separated. The water phase is extracted with dichloromethane, and the combined organic phase is washed with purified water and saturated brine, and after concentration and drying, no white solid is obtained, indicating that the reaction does not produce avanafil intermediate a.

[0058] Preparation of avanafil intermediate a

[0059] The 430.91 g (1 mol) of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N- (pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 11.39 g (0.05 mol) of benzyltriethylammonium chloride is dissolved in 4 L of dichloromethane, 3.2 L of N,N- dimethylformamide and 80 ml of purified water, and then the refrigeration and stirring are started, and when the temperature of the reaction solution is lowered to about 0°C, 405.14 g (1.25 mol) of iodobenzene diacetate is added, and after stirring for 12 h, 10% sodium sulfite aqueous solution is added to quench the reaction and stirred for 15 min, and then the stirring is stopped, and after the separation of the layers is completed, the water phase is separated. The water phase is extracted with dichloromethane, and the combined organic phase is washed with purified water and saturated brine, and after concentration and drying, no white solid is obtained, indicating that the reaction does not produce avanafil intermediate a.

[0060] Preparation of avanafil intermediate a

[0061] The 430.91 g (1 mol) of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N- (pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 11.39 g (0.05 mol) of benzyltriethylammonium chloride is dissolved in 4 L of dichloromethane, 3.2 L of N,N- dimethylformamide and 80 ml of purified water, and then the refrigeration and stirring are started, and when the temperature of the reaction solution is lowered to about 0°C, 405.14 g (1.25 mol) of iodobenzene diacetate is added, and after stirring for 12 h, 10% sodium sulfite aqueous solution is added to quench the reaction and stirred for 15 min, and then the stirring is stopped, and after the separation of the layers is completed, the water phase is separated. The water phase is extracted with dichloromethane, and the combined organic phase is washed with purified water and saturated brine, and after concentration and drying, no white solid is obtained, indicating that the reaction does not produce avanafil intermediate a.

[0062] Preparation of avanafil intermediate a

[0063] The 430.91 g (1 mol) of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N- (pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 16.98 g (0.05 mol) tetrabutylammonium hydrogen sulfate is dissolved in a mixed solvent of 4 L of dichloromethane, 3.2 L of N,N-dimethylformamide and 80 ml of purified water, then the refrigeration and stirring are started, the temperature of the reaction solution is lowered to about 0°C, 405.14 g (1.25 mol) of iodobenzene diacetate is added, stirring is carried out for 12 h, then 10% sodium sulfite aqueous solution is added to quench the reaction and stirring is carried out for 15 min, then the stirring is stopped, the water phase is separated after the layers are separated, the water phase is extracted with dichloromethane, the organic phases are combined, purified water and saturated brine are used for washing, after concentration and rotary evaporation, there is no white solid, which indicates that the reaction does not obtain avanafil intermediate a.

[0064] Preparation of avanafil intermediate a

[0065] The 430.91 g (1 mol) of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N- (pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 20.21 g (0.05 mol) of trioctylmethylammonium chloride is dissolved in a mixed solvent of 4 L of dichloromethane, 3.2 L of N,N-dimethylformamide and 80 ml of purified water, then the refrigeration and stirring are started, the temperature of the reaction solution is lowered to about 0°C, 405.14 g (1.25 mol) of iodobenzene diacetate is added, stirring is carried out for 12 h, then 10% sodium sulfite aqueous solution is added to quench the reaction and stirring is carried out for 15 min, then the stirring is stopped, the water phase is separated after the layers are separated, the water phase is extracted with dichloromethane, the organic phases are combined, purified water and saturated brine are used for washing, after concentration and rotary evaporation, there is no white solid, which indicates that the reaction does not obtain avanafil intermediate a.

[0066] Preparation of avanafil intermediate a

[0067] The 430.91 g (1 mol) of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N- (pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 13.19 g (0.05 mol) of dodecyltrimethylammonium chloride is dissolved in a mixed solvent of 4 L of dichloromethane, 3.2 L of N,N-dimethylformamide and 80 ml of purified water, then the refrigeration and stirring are started, the temperature of the reaction solution is lowered to about 0°C, 405.14 g (1.25 mol) of iodobenzene diacetate is added, stirring is carried out for 12 h, then 10% sodium sulfite aqueous solution is added to quench the reaction and stirring is carried out for 15 min, then the stirring is stopped, the water phase is separated after the layers are separated, the water phase is extracted with dichloromethane, the organic phases are combined, purified water and saturated brine are used for washing, after concentration and rotary evaporation, there is no white solid, which indicates that the reaction does not obtain avanafil intermediate a.

[0068] Preparation of avanafil intermediate a

[0069] The 430.91 g (1 mol) of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N- (pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 14.60 g (0.05 mol) of tetradecyltrimethylammonium chloride were dissolved in a mixed solvent of 4 L of dichloromethane, 3.2 L of N,N-dimethylformamide and 80 ml of purified water, and then the refrigeration and stirring were started. When the temperature of the reaction solution was lowered to about 0°C, 405.14 g (1.25 mol) of iodobenzene diacetate was added, and after stirring for 12 h, 10% sodium sulfite aqueous solution was added to quench the reaction and stirred for 15 min, and then the stirring was stopped, and after the layers were separated, the water phase was separated. The water phase was extracted with dichloromethane, and the combined organic phase was washed with purified water and saturated brine, and after concentration and drying, no white solid was obtained, indicating that the intermediate a of avanafil was not obtained.

[0070] Preparation of avanafil intermediate a

[0071] Preparation of avanafil intermediate a by m-chloroperoxybenzoic acid method (using the method of CN104059025B):

[0072] 1.0 g of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N-(pyrimidin-2- ylmethyl)pyrimidine-5-carboxamide was dissolved in 10 ml of dichloromethane, and placed in an ice-salt bath, and the stirring was started. When the temperature of the reaction solution was lowered to -10°C, 471 mg of m-chloroperoxybenzoic acid was dissolved in 5 ml of dichloromethane solution and slowly added dropwise to the reaction solution. The addition was completed in 0.5 h, and then 188 mg of m-chloroperoxybenzoic acid was dissolved in 2 ml of dichloromethane and added dropwise to the reaction solution. The temperature was raised to -5 to 0°C, and the reaction was stirred for 0.5 h. Filtration was performed, and the filtrate was washed twice with 30 ml of 5% sodium carbonate solution, and then extracted twice with dichloromethane (30 ml x 2). The organic phase was washed twice with 30 ml of 5% sodium carbonate solution and once with 30 ml of water. After drying with anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain 0.6 g of white solid. As shown in Figure 6 the detection found that the yield was 50.33%, the purity of avanafil intermediate a (31.735 min) was 91.27%, and 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylsulfonyl-N- (pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide (41.990 min) was contained at 3.13%.

[0073] It is found by comparison that the comparative example 1 does not use tetrabutylammonium bromide as a catalyst, the comparative examples 2-7 use benzyl triethylammonium chloride (TEBA), tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, tricaprylylmethylammonium chloride, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride as catalysts in turn, and the results are all not to obtain avanafil intermediate a, thus it is illustrated that the method provided by the embodiment of the application has specificity. The comparative example 8 uses m-chloroperbenzoic acid to prepare the avanafil intermediate a, and 3.13% of by-products generated by over-oxidation are obtained.

[0074] It can be seen that the method provided by the embodiment of the application has high specificity and selectivity, and can selectively synthesize sulfoxide, reduce by-reactions and impurity generation. The method provided by the prior art contains more sulfonyl-based impurities, which is not conducive to the separation and purification of the intermediate a, thus the existing avanafil patents and literatures rarely mention the separation and purification technology of the intermediate a, and basically adopt a simple post-treatment to directly proceed to the next step, which often brings great challenges to the quality control of the industrialized production of avanafil.

[0075] Therefore, the method of the application can effectively avoid the generation of the impurities, and has great technical advantages and good industrialization prospects.

[0076] In the application, tetrabutylammonium bromide which is cheap and easy to obtain is used as a catalyst, and diiodoxybenzene which is stable in property and high in safety is used as an oxidant, so that the catalytic oxidation of the sulfide compound can only generate the sulfoxide intermediate of avanafil, and the by-product of sulfonyl generated by over-oxidation is not generated. After the reaction is completed, the high-purity sulfoxide intermediate can be obtained through simple post-treatment and purification. Compared with the way of not separating and purifying the sulfoxide intermediate in the previous patents, the technical method in the application can better meet the quality control requirements of the intermediate in the industrialized mass production. In summary, the route of the application has good catalytic selectivity, high yield, high purity of the obtained intermediate, simple reaction operation, safety, and can well meet the quality control requirements of the intermediate in the industrialized production of avanafil and the impurity control requirements of the bulk drug, and has good industrialization prospects.

[0077] The above merely describes the preferred embodiments of the application, but the protection scope of the application is not limited to this, and any changes or replacements within the technical range disclosed by the application can be easily thought by those skilled in the art, and should be covered in the protection scope of the application.

Claims

1. A method for synthesizing an avanafil intermediate, wherein the avanafil intermediate is 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylsulfinyl-N-(pyrimidin-2-ylmethyl)pyrimidin-5-carboxamide, the method comprising: A solution containing 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N-(pyrimidin-2-ylmethyl)pyrimidin-5-carboxamide and tetrabutylammonium bromide was mixed with diacetic iodobenzene and reacted under a first temperature condition.

2. The method according to claim 1, wherein, The molar ratio of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N-(pyrimidin-2-ylmethyl)pyrimidin-5-carboxamide and tetrabutylammonium bromide in the solution system is 1:(0.02~0.1).

3. The method according to claim 1, wherein, The molar ratio of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N-(pyrimidin-2-ylmethyl)pyrimidin-5-carboxamide and tetrabutylammonium bromide in the solution system is selected from 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09 or 1:0.

1.

4. The method according to claim 1, wherein, The solvent in the dissolution system is selected from at least two of dichloromethane, ethyl acetate, methyl tert-butyl ether, methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, and water.

5. The method according to claim 1, wherein the molar ratio of 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N-(pyrimidin-2-ylmethyl)pyrimidin-5-carboxamide to the iodobenzene diacetate is 1:(1.0~2.0).

6. The method according to claim 1, wherein the first temperature condition is selected from -10 to 10°C.

7. The method according to claim 1, wherein the first temperature condition is selected from -9 to 9°C.

8. The method according to claim 1, wherein the first temperature condition is selected from -8 to 8°C.

9. The method according to claim 1, wherein the first temperature condition is selected from -7 to 7°C.

10. The method according to claim 1, wherein the first temperature condition is selected from -6 to 6°C.

11. The method according to claim 1, wherein the first temperature condition is selected from -5 to 5°C.

12. The method according to claim 1, wherein the first temperature condition is selected from -4 to 4°C.

13. The method according to claim 1, wherein the first temperature condition is selected from -3 to 3°C.

14. The method according to claim 1, wherein the first temperature condition is selected from -2 to 2°C.

15. The method according to claim 1, wherein the first temperature condition is selected from -1 to 1°C.

16. The method according to claim 1, wherein the first temperature condition is selected from -1 to 10°C.

17. The method according to claim 1, wherein the first temperature condition is selected from -2 to 10°C.

18. The method according to claim 1, wherein the first temperature condition is selected from -3 to 10°C.

19. The method according to claim 1, wherein the first temperature condition is selected from -4 to 10°C.

20. The method according to claim 1, wherein the first temperature condition is selected from -5 to 10°C.

21. The method according to claim 1, wherein the first temperature condition is selected from -6 to 10°C.

22. The method according to claim 1, wherein the first temperature condition is selected from -7 to 10°C.

23. The method according to claim 1, wherein the first temperature condition is selected from -8 to 10°C.

24. The method according to claim 1, wherein the first temperature condition is selected from -9 to 10°C.

25. The method according to claim 1, wherein the first temperature condition is selected from -10 to 0°C.

26. The method according to claim 1, wherein the first temperature condition is selected from -10 to 1°C.

27. The method according to claim 1, wherein the first temperature condition is selected from -10 to 2°C.

28. The method according to claim 1, wherein the first temperature condition is selected from -10 to 3°C.

29. The method according to claim 1, wherein the first temperature condition is selected from -10 to 4°C.

30. The method according to claim 1, wherein the first temperature condition is selected from -10 to 5°C.

31. The method according to claim 1, wherein the first temperature condition is selected from -10 to 6°C.

32. The method according to claim 1, wherein the first temperature condition is selected from -10 to 7°C.

33. The method according to claim 1, wherein the first temperature condition is selected from -10 to 8°C.

34. The method according to claim 1, wherein the first temperature condition is selected from -10 to 9°C.

35. The method according to claim 1, wherein the first temperature condition is selected from -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C or 0°C.

36. The method according to claim 1, further comprising: The step of quenching the reaction using an aqueous sodium sulfite solution; as well as The step of purifying the quenched reactants to obtain the avanafil intermediate.

37. The method according to claim 36, wherein the concentration of the sodium sulfite aqueous solution is 5% to 20%.

38. The method according to claim 36, wherein the purification step comprises: The quenched reactants were extracted to obtain an organic phase; The organic phase was washed with water, concentrated to dryness, and recrystallized.

39. A method for synthesizing avanafil, comprising: The solution system containing 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthio-N-(pyrimidin-2-ylmethyl)pyrimidin-5-carboxamide and tetrabutylammonium bromide was mixed with diacetic iodobenzene under a first temperature condition to carry out the first reaction; After quenching the first reaction, the resulting reactants were extracted to obtain an organic phase; Triethylamine and L-proline were added to the organic phase, and a second reaction was carried out at a second temperature to obtain avanafil.

40. Use of the method of any one of claims 1 to 38 in the preparation of avanafil.

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