Synthesis method of substituted nitrogen-containing quinazolinone compounds

Abstract

A method for synthesizing a substituted nitrogen-containing quinazolinone compound is implemented by using a reinforced heating jacket, using trans-3(3-pyridyl)allylic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and ethyl 2-aminobenzoate as raw materials; and finally obtaining the product (E)-3-(4-chlorobenzyl)-2-(2-(pyridin-3-yl)vinyl)quinazolin-4(3H)-one.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of pharmaceutical intermediates, and in particular to a method for synthesizing substituted nitrogen-containing quinazolinone compounds. Background Art

[0002] A method for synthesizing substituted nitrogen-containing quinazolinone compounds. Quinazolinone and its derivatives are an important class of compounds with strong biological activity and can be used in the field of medicine. However, the specific compound (E)-3-(4-chlorobenzyl)-2-(2-(pyridin-3-yl)vinyl)quinazolin-4(3H)-one and the method mentioned in the present application are rarely used as pharmaceutical intermediates, or have been disclosed in literature or data. Due to the characteristics of the molecule, the unique synthesis route, and the unique high yield problem, the method cannot be extended to the synthesis of other similar structures.

[0003] Due to the characteristics of the molecule, this method cannot be extended to the synthesis of other similar structures. This is determined by the originality of the preparation method obtained through countless experiments, the high yield and the non-replicability of the short reaction time. Other routes basically cannot have a high yield or an acceptable reaction time. In particular, the actual problem of temperature control in the present application was not taken into account, and the same or similar method as the present application was not adopted to improve the device.

[0004] In addition, the prior art still has the following problems: first, the method for preparing (E)-3-(4-chlorobenzyl)-2-(2-(pyridin-3-yl)vinyl)quinazoline-4(3H)-one has a low yield; currently, none of the persons in the field we have found or consulted have given a yield higher than 10%, and generally, there are wastes that are difficult to handle.

[0005] Second, the present method, like many preparation methods of this substance, requires heating for a long time. In this process, it is difficult to ensure that the temperature remains consistent with general heating means, especially in winter or when the wind is strong. The temperature of the system is often difficult to maintain consistent with the temperature set by the heating device or heating jacket (four-necked bottles or other glassware, with a large area exposed to the air). After many comparative experiments, we found that this actually has a significant adverse effect on the yield. However, the prior art does not pay attention to this defect. At most, blankets or insulation pads are used to simply keep warm. However, first, the insulation effect is not enough, and second, because the bottle may need to be vigorously stirred, such a simple insulation measure cannot meet the needs of the bottle for long-term stirring reaction. Summary of the invention

[0006] The first purpose of the present invention is to solve two specific problems in the prior art. The first is how to obtain (E)-3-(4-chlorobenzyl)-2-(2-(pyridin-3-yl)vinyl)quinazolin-4(3H)-one from trans-3(3-pyridyl)allylic acid through a few steps with high yield, and the yield is high, the waste is small and it is easy to handle. The present application perfectly solves this problem. The second is how to effectively maintain a stable temperature for a long time to avoid the adverse effects of temperature changes in each step that requires long-term heating reaction. This has been solved in the present application.

[0007] The present invention claims protection for a reinforced heating sleeve, characterized in that it comprises a lower fixed sleeve and an upper movable sleeve.

[0008] The lower fixing sleeve comprises a lower heating sleeve, an outer shell, a base, a control circuit, a control panel and a power supply unit.

[0009] The upper movable sleeve comprises an upper heating sleeve, an inner lining and an outer lining; the upper heating sleeve, the inner lining and the outer lining are all provided with side walls and an upper edge.

[0010] The lower heating jacket and the upper heating jacket are respectively connected to the control circuit, are independently powered and controlled by the control circuit, and are integrally temperature controlled by the control panel.

[0011] Both the upper heating sleeve and the lower heating sleeve are equipped with mesh alloy wires, which are wrapped with alkali-free glass fiber and vacuum-formed with aluminum silicate wool; the lower heating sleeve is hemispherical, and the upper heating sleeve, outer lining and inner lining are all in the following shapes: the outer wall is a cylindrical side wall, and the upper end extends inward to form a circular upper edge; one side of the upper heating sleeve, outer lining and inner lining has an opening; the inner lining and outer lining are Teflon material layers with a thickness of 3-8mm, and are both mesh-shaped and hollow; the connecting line between the upper heating sleeve and the control circuit is located on the outside of the upper heating sleeve.

[0012] A method for synthesizing a substituted nitrogen-containing quinazolinone compound, namely, a method for synthesizing (E)-3-(4-chlorobenzyl)-2-(2-(pyridin-3-yl)vinyl)quinazolin-4(3H)-one, which is implemented by using a reinforced heating jacket, and the steps are: (1) dissolving trans-3(3-pyridyl)allylic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and ethyl 2-aminobenzoate in a molar ratio of 2:3:3 in an N,N-dimethylformamide solution (200-250 mL), wherein the amount of trans-3(3-pyridyl)allylic acid does not exceed 10 g; slowly adding triethylamine in an amount twice the amount of the trans-3(3-pyridyl)allylic acid, and mixing the mixed tetraethylamine. The lower part of the four-necked flask is placed in the lower heating jacket, and the opening of the upper heating jacket is opened, and the four-necked flask is horizontally covered with the upper part, and the opening is closed; the heating is controlled by the control panel to maintain at 25° C., and the reaction is maintained for not less than 12 hours. When TLC determines that the reaction is complete, the crude product is concentrated to obtain the crude product, which is extracted three times with 300 mL of ethyl acetate each time, and then washed once with not less than 600 ml of water, and then washed three times with not less than 300 mL of saturated brine, dried with 10 g of anhydrous magnesium sulfate for 30 minutes, filtered and spin-dried, and wet-columned with not less than 100 g of 100-200 mesh silica gel, with the ratio of petroleum ether to ethyl acetate being 50:1, to obtain intermediate A in the form of a light yellow solid: (E)-2-(3-(pyridin-3-yl)acrylamide)benzoic acid ethyl ester.

[0013] (2) Take 30-40 mmol of intermediate A, dissolve it in not less than 120 ml of tetrahydrofuran, and treat it with an aqueous solution containing 3 eq of sodium hydroxide in a volume of not less than 80 ml, put it in a four-necked bottle, put the lower part of the mixed four-necked bottle in the lower heating jacket, and open the opening of the upper heating jacket, put it horizontally on the upper part of the four-necked bottle, and close the opening; control the heating to maintain 60° C. through the control panel, and keep the reaction for not less than 2 hours. When TLC determines that the reaction is complete, remove the heating equipment, cool the mixture to room temperature and concentrate it, adjust the pH value to 6 with dilute hydrochloric acid while stirring, and after a white precipitate is formed, stir for at least 5 minutes, filter it, and wash it 3 times with not less than 80 ml of pure water, combine it and dry it to obtain intermediate B in the form of a white solid: (E)-2-(3-(pyridin-3-yl)acrylamide)benzoic acid.

[0014] (3) Take 10-20 mmol of intermediate B, mix and dissolve them in not less than 100 mL of dichloromethane according to the ratio of intermediate B: Carter condensation agent: p-chlorobenzylamine of 2:3:3, then gradually add 3 parts of N,N-diisopropylethylamine, put them in a four-necked bottle, put the lower part of the mixed four-necked bottle in the lower heating jacket, open the opening of the upper heating jacket, put it horizontally on the upper part of the four-necked bottle, and close the opening; control the heating to maintain at 25° C. through the control panel, and keep the stirring reaction for not less than 12h, when TLC determined that the reaction was complete, the heating equipment was removed and the crude product was concentrated. The product was extracted twice with 100mL of dichloromethane each time, and the organic phase was washed three times with 100mL of brine each time. It was dried over 10g of anhydrous magnesium sulfate for 30min, filtered and spin-dried, and passed through a column with not less than 50g of 100-200 mesh silica gel by wet method, and petroleum ether / ethyl acetate = 50:1 to obtain intermediate C in the form of a light yellow solid: ((E)-N-(4-chlorobenzyl)-2-(3-(pyridin-3-yl)acrylamide)benzamide.

[0015] (4) Take 0.9-1.1 g of intermediate C, take a four-necked bottle, use not less than 30 mL of acetonitrile and 10 mL of water to mix the intermediate C, and add 6.7 eq of iodine and 9.0 eq of hexamethyldisiloxane of the intermediate C in small amounts and multiple times, put the lower part of the mixed four-necked bottle in the lower heating jacket, open the opening of the upper heating jacket, put it horizontally on the upper part of the four-necked bottle, and close the opening; control the heating to maintain at 25° C. through the control panel, and keep stirring the reaction for not less than 12 hours. After TLC confirmed that the reaction was complete, nitrogen was blown in to dry the mixture for no less than 1 h, the aqueous phase and the organic phase were dissolved with ethyl acetate and separated, the aqueous phase was extracted with sodium thiosulfate solution, the organic phase was extracted twice with 100 mL of ethyl acetate, and washed three times with 100 mL of brine, all organic phases were combined, dried over 10 g of anhydrous magnesium sulfate for 30 min, filtered and spin-dried, and wet-columned with no less than 50 g of 100-200 mesh silica gel, petroleum ether / ethyl acetate = 50:1, to obtain a white solid.

[0016] Post-treatment: Purify with a liquid chromatography column containing 65% 2-amino-3-chloro-1,4-naphthoquinone / 0.1% trifluoroacetic acid, adjust the pH value of the obtained solid to 8 with sodium bicarbonate solution, dissolve with sufficient dichloromethane, dry and concentrate to obtain a light yellow solid compound (E)-3-(4-chlorobenzyl)-2-(2-(pyridin-3-yl)vinyl)quinazoline-4(3H)-one.

[0017] Compared with the prior art, the advantages of the present invention are: 1. For long-term heating, the upper part of the four-necked bottle is exposed to the air, which often leads to unstable system temperature (especially in winter, we use a thermal imager to monitor for a long time and find that the upper part of the four-necked bottle is exposed to the air, the temperature is unstable, and the temperature is often significantly lower than the set temperature. For example, when the setting is 90°C, the actual temperature fluctuates between 90-82°C. After comparison, it has a significant adverse effect on the yield). A soft heating jacket is set on the upper part of the heating jacket, which perfectly solves this problem. The additional soft heating jacket is easy to apply and can effectively ensure that the system reacts at the required temperature. There is no similar complete setting in the prior art. 2. The preparation method itself is good, the raw materials are easy to obtain, the steps are short, there is no particularly complex mechanism, and the yield is extremely high, which can stably reach about 15.9%, which is also better than similar technologies in the prior art. The product obtained in the prior art generally has a very low yield, or the process is too complicated, which is not comparable to the present application.

[0018] There is no report on the preparation of this product in the prior art. Compared with the preparation methods of similar substances, the steps of the method of this application are meticulously designed, and the raw material utilization rate in each step is very high, which has great value for industrial production. Through the meticulous design of the method of the present invention, not only the synthesis is effectively achieved, but also the yield is high, averaging more than 15%, which has certain industrial production value and great economic value. The application embodies a strong inventive concept and creativity through the careful design of the additional heating jacket, and achieves good preparation results. There is no similar public information in the prior art for reference, and the scheme of the present invention is original. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0020] Figure 1 This is a schematic diagram of the front view of the heating jacket.

[0021] Figure 2 It is a schematic diagram of the structure of the upper heating jacket.

[0022] Figure 3 It is a schematic diagram of the synthesis steps.

[0023] Figure 4 This is the NMR image of the final product.

[0024] Figure numerals: 1, lower fixed sleeve, 2, upper movable sleeve, 11, lower heating sleeve, 12, outer shell, 13, base, 14, control circuit, 15, control panel, 16, power supply unit, 21, upper heating sleeve, 22, lining, 23, outer lining; 24, opening. DETAILED DESCRIPTION

[0025] The preferred embodiments of the present invention are described in detail below in conjunction with the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0026] Example 1

[0027] A reinforced heating sleeve, characterized in that: it includes a lower fixed sleeve 1 and an upper movable sleeve 2; the lower fixed sleeve includes a lower heating sleeve 11, an outer shell 12, a foot 13, a control circuit 14, a control panel 15 and a power supply unit 16; the upper movable sleeve 2 includes an upper heating sleeve 21 and an inner lining 22 and an outer lining 23; the upper heating sleeve 21 and the inner lining 22 and the outer lining 23 are all provided with side walls and upper edges; the lower heating sleeve and the upper heating sleeve are respectively connected to the control circuit, and are independently powered and controlled by the control circuit, and the temperature is controlled integrally by the control panel. The setting of the lower heating sleeve here is similar to that of the general heating sleeve, but the setting of the upper movable sleeve is original, and we did not find any commercially available products, so it is self-made. In terms of the control circuit, the metal wires of the upper heating sleeve and the lower heating sleeve can be connected in parallel and connected to a control circuit, but the actual temperature control of this circuit is different from the original one, and needs to be recalibrated and marked. It is also possible to use two control circuits separately with the lower heating sleeve, but in this way, the output power is actually doubled, and attention should be paid to the power matching of the power supply part. The heating jacket can be 220v or 380v. The temperature control of the upper and lower heating jackets has been compared and calibrated many times.

[0028] Furthermore, both the upper heating sleeve and the lower heating sleeve are provided with mesh alloy wires, which are wrapped with alkali-free glass fiber and vacuum-shaped with aluminum silicate wool; the lower heating sleeve is hemispherical, and the upper heating sleeve, outer lining, and inner lining are all in the following shapes: the outer wall is a cylindrical side wall, and the upper end extends inward to form a circular upper edge; one side of the upper heating sleeve, outer lining, and inner lining are all open; the inner lining and outer lining are 3-8mm thick Teflon material layers, and are both mesh-shaped and hollowed out; the connection line between the upper heating sleeve and the control circuit is located on the outside of the upper heating sleeve. It is set to be cylindrical here. After comparison, this style is more conducive to maintaining temperature, and a hot air layer is formed between the upper part of the bottle body and the upper heating sleeve, which is more conducive to maintaining temperature.

[0029] The wrapping of the heating sleeve is similar to the existing technology, but the selection of the inner lining and the outer lining here is not seen in the existing technology. It is better to choose Teflon or other Teflon system plastic products, which can withstand a certain high temperature (no effect below 260℃), and have moderate hardness and softness. After supporting the heating sleeve from the outside and inside, it can keep a certain shape and open the opening to facilitate wrapping the upper part of the four-mouth bottle from the side. It is a very suitable material. This is a targeted material selection after we first carry out functional conception. Other fluorine-containing plastics can also be selected as long as they meet the following conditions: no odor after heating, or obvious volatile substances, no obvious softening or deformation below 250℃, and can maintain strength even if heated for a long time at 100-180℃.

[0030] like Figure 1-2 As shown, the lower heating jacket is a hemispherical shape, while the upper heating jacket is a part of a cylinder (the center circle is cut off at the top) and has an opening on one side. Since the whole has a certain degree of flexibility, the bottle body can be inserted into it, and the Teflon shell can maintain its shape. The upper and lower heating jackets can share a control circuit, or the control circuit can be two parts connected in parallel to control the upper and lower heating jackets respectively. There can be an opening on the outer wall of the lower heating jacket for leading out a circuit containing a control line and a power line to connect with the upper heating jacket. Figure 2 The combination relationship is shown in FIG. 1 . The outer lining and the inner lining are similar in shape to the heating jacket to facilitate the support of the heating jacket. In order to facilitate the dissipation of heat, the outer lining and the inner lining are designed in a mesh shape to facilitate the dissipation of heat. Figure 2 shown.

[0031] Example 2

[0032] A method for synthesizing a substituted nitrogen-containing quinazolinone compound, namely, a method for synthesizing (E)-3-(4-chlorobenzyl)-2-(2-(pyridin-3-yl)vinyl)quinazolin-4(3H)-one, which is implemented using a reinforced heating jacket, and the steps are:

[0033] (1) 8.5 g, 57 mmol, 32.5 g, 85.5 mmol, and 14.12 g, 85.5 mmol of trans-3(3-pyridyl)allylic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and ethyl 2-aminobenzoate in a molar ratio of 2:3:3 were dissolved in 200 mL of N,N-dimethylformamide solution;

[0034] Slowly add triethylamine, 11.53 g, 114 mmol, place the lower part of the mixed four-necked flask in the lower heating jacket, open the opening of the upper heating jacket, cover the upper part of the four-necked flask horizontally, and close the opening; control the heating to maintain at 25° C. through the control panel, and keep the reaction for not less than 12 h. When TLC determines that the reaction is complete, concentrate to obtain a crude product, extract three times with 300 mL of ethyl acetate each time, wash once with 600 ml of water, and then wash 3 times with not less than 300 mL of saturated brine, dry with 10 g of anhydrous magnesium sulfate for 30 min, filter and spin dry, and pass through a column with not less than 100 g of 100-200 mesh silica gel wet method, with petroleum ether to ethyl acetate = 50:1, to obtain intermediate A in the form of a light yellow solid: (E)-2-(3-(pyridin-3-yl)acrylamide)benzoic acid ethyl ester; 8.9 g, step 1 yield 52%.

[0035] (2) Take 30mmol of intermediate A, 8.9g, dissolve it in 120ml of tetrahydrofuran, and treat it with an aqueous solution containing 3eq of sodium hydroxide (3.6g, 90mmol) in a volume of not less than 80ml, put it in a four-necked bottle, put the lower part of the mixed four-necked bottle in the lower heating jacket, and open the opening of the upper heating jacket, put it horizontally on the upper part of the four-necked bottle, and close the opening; control the heating to maintain 60°C through the control panel, and keep the reaction for not less than 2h. When TLC determines that the reaction is complete, remove the heating equipment, cool the mixture to room temperature and concentrate it, adjust the pH value to 6 with dilute hydrochloric acid while stirring, and after a white precipitate is formed, stir for at least 10 minutes, filter it, and wash it 3 times with 80ml of pure water, combine and dry it to obtain intermediate B in the form of a white solid: (E)-2-(3-(pyridin-3-yl)acrylamide)benzoic acid; 5.7g, yield 71%.

[0036] (3) Take 10-20 mmol of intermediate B, and mix and dissolve them in 100 mL of dichloromethane according to the ratio of the amount of intermediate B: Carter condensation agent: p-chlorobenzylamine of 2:3:3, then gradually add 1.9 g, 15 mmol of N, N-diisopropylethylamine, put them in a four-necked bottle, put the lower part of the mixed four-necked bottle in the lower heating jacket, open the opening of the upper heating jacket, put it horizontally on the upper part of the four-necked bottle, and close the opening; control the heating and keeping temperature by the control panel. The mixture was maintained at 25°C and stirred for at least 12 hours. When TLC confirmed that the reaction was complete, the heating equipment was removed and the crude product was concentrated. The crude product was extracted twice with 100 mL of dichloromethane each time, and the organic phase was washed three times with 100 mL of brine each time. The product was dried over 10 g of anhydrous magnesium sulfate for 30 minutes, filtered and dried by spin drying. The product was passed through a column with at least 50 g of 100-200 mesh silica gel by wet method, and petroleum ether / ethyl acetate = 50:1 to obtain intermediate C in the form of a light yellow solid: ((E)-N-(4-chlorobenzyl)-2-(3-(pyridin-3-yl)acrylamide)benzamide; 1.9 g, yield 48%.

[0037] (4) Take 1 g of intermediate C, take a four-necked bottle, use not less than 30 mL of acetonitrile and 10 mL of water to mix the intermediate C, and add 6.7 eq of iodine and 9.0 eq of hexamethyldisiloxane (iodine 6.7 g, 17.1 mmol, 6.7 eq, hexamethyldisiloxane, 3.7 g, 20.95 mmol, 9.0 eq) of the intermediate C in small amounts and multiple times, put the lower part of the mixed four-necked bottle in the lower heating jacket, open the opening of the upper heating jacket, put it horizontally on the upper part of the four-necked bottle, and close the opening; control the addition by the control panel The heat was maintained at 25°C, and the stirring reaction was maintained for no less than 12 hours. When TLC determined that the reaction was complete, nitrogen was blown in to dry the mixture for no less than 1 hour. The aqueous phase and the organic phase were dissolved and separated with ethyl acetate. The aqueous phase was extracted with sodium thiosulfate solution. The organic phase was extracted twice with 100 mL of ethyl acetate and washed three times with 100 mL of brine. All organic phases were combined, dried with 10 g of anhydrous magnesium sulfate for 30 minutes, filtered and spin-dried, and wet-coated with no less than 50 g of 100-200 mesh silica gel, petroleum ether / ethyl acetate = 50:1, to obtain a white solid;

[0038] Post-treatment: Purify with a liquid chromatography column of 65% 2-amino-3-chloro-1,4-naphthoquinone / 0.1% trifluoroacetic acid, adjust the pH value of the obtained solid to 8 with sodium bicarbonate solution, dissolve with sufficient dichloromethane, dry and concentrate to obtain a light yellow solid compound (E)-3-(4-chlorobenzyl)-2-(2-(pyridin-3-yl)vinyl)quinazolin-4(3H)-one. 900 mg, yield 89.8%. Total yield 15.9%.

[0039] Example 3

[0040] A method for synthesizing a substituted nitrogen-containing quinazolinone compound, namely, a method for synthesizing (E)-3-(4-chlorobenzyl)-2-(2-(pyridin-3-yl)vinyl)quinazolin-4(3H)-one, which is implemented using a reinforced heating jacket, and the steps are:

[0041] (1) 9 g, 34.41 g, and 14.95 g of trans-3(3-pyridyl)allylic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and ethyl 2-aminobenzoate, respectively, in a molar ratio of 2:3:3, were dissolved in 200 mL of N,N-dimethylformamide solution;

[0042] Slowly add triethylamine, 12.21 g, place the lower part of the mixed four-necked flask in the lower heating jacket, open the opening of the upper heating jacket, cover the upper part of the four-necked flask horizontally, and close the opening; control the heating to maintain at 25° C. through the control panel, and keep the reaction for not less than 14 hours. When TLC determines that the reaction is complete, concentrate to obtain a crude product, extract three times with 300 mL of ethyl acetate each time, wash once with 600 ml of water, and then wash 3 times with not less than 300 mL of saturated brine, dry with 10 g of anhydrous magnesium sulfate for 30 min, filter and spin dry, and pass through a column with not less than 100 g of 100-200 mesh silica gel wet method, with petroleum ether to ethyl acetate = 50:1, to obtain intermediate A in the form of a light yellow solid: (E)-2-(3-(pyridin-3-yl)acrylamide)benzoic acid ethyl ester; 9.53 g, step 1 yield 52.58%.

[0043] (2) Take 35 mmol of intermediate A, dissolve it in 140 ml of tetrahydrofuran, and treat it with an aqueous solution containing 3 eq of sodium hydroxide (4.2 g) in a volume of not less than 100 ml. Put it in a four-necked bottle, put the lower part of the mixed four-necked bottle in the lower heating jacket, and open the opening of the upper heating jacket, put it horizontally on the upper part of the four-necked bottle, and close the opening; control the heating to maintain at 60° C. through the control panel, and keep the reaction for not less than 3 hours. When TLC determines that the reaction is complete, remove the heating equipment, cool the mixture to room temperature and concentrate it. While stirring, adjust the pH value to 6 with dilute hydrochloric acid. After a white precipitate is formed, stir for at least 15 minutes, filter it, and wash it three times with 100 ml of pure water. Combine and dry it to obtain intermediate B in the form of a white solid: (E)-2-(3-(pyridin-3-yl)acrylamide)benzoic acid; 6.69 g, yield 71.5%.

[0044] (3) Take 10-20 mmol of intermediate B, and mix and dissolve them in 110 mL of dichloromethane according to the ratio of the amount of intermediate B: Carter condensation agent: p-chlorobenzylamine of 2:3:3, then gradually add 2.09 g, 16.5 mmol of N,N-diisopropylethylamine, put them in a four-necked bottle, put the lower part of the mixed four-necked bottle in the lower heating jacket, open the opening of the upper heating jacket, put it horizontally on the upper part of the four-necked bottle, and close the opening; through the control panel The heating was controlled to be maintained at 25° C., and the stirring reaction was maintained for no less than 14 h. When TLC determined that the reaction was complete, the heating equipment was removed and the crude product was concentrated. The crude product was extracted twice with 110 mL of dichloromethane each time, and the organic phase was washed three times with 110 mL of brine each time. The product was dried with 11 g of anhydrous magnesium sulfate for 30 min, filtered and spin-dried, and wet-columned with 55 g of 100-200 mesh silica gel. The mixture was filtered with petroleum ether / ethyl acetate = 50:1 to obtain intermediate C in the form of a light yellow solid: ((E)-N-(4-chlorobenzyl)-2-(3-(pyridin-3-yl)acrylamide)benzamide; 2.14 g, yield 49.2%.

[0045] (4) Take 1.1 g of intermediate C, take a four-necked bottle, use 33 mL of acetonitrile and 11 mL of water to mix the intermediate C, and add 6.7 eq of iodine and 9.0 eq of hexamethyldisiloxane (iodine 7.37 g, 18.81 mmol, 6.7 eq, hexamethyldisiloxane, 4.07 g, 23.045 mmol, 9.0 eq) of the intermediate C in small amounts and multiple times, put the lower part of the mixed four-necked bottle in the lower heating jacket, open the opening of the upper heating jacket, put it horizontally on the upper part of the four-necked bottle, and close the opening; control the addition through the control panel The heat was maintained at 25°C, and the stirring reaction was maintained for not less than 16 hours. When TLC determined that the reaction was complete, nitrogen was blown in to dry the mixture for not less than 1.5 hours. The aqueous phase and the organic phase were dissolved with ethyl acetate and separated. The aqueous phase was extracted with sodium thiosulfate solution, and the organic phase was extracted twice with 110 mL of ethyl acetate and washed three times with 110 mL of brine. All organic phases were combined, dried over 10 g of anhydrous magnesium sulfate for 30 minutes, filtered and spin-dried, and wet-columned with not less than 60 g of 100-200 mesh silica gel, petroleum ether / ethyl acetate = 50:1, to obtain a white solid.

[0046] Post-treatment: Purify with a liquid chromatography column of 65% 2-amino-3-chloro-1,4-naphthoquinone / 0.1% trifluoroacetic acid, adjust the pH value of the obtained solid to 7.5 with sodium bicarbonate solution, dissolve with sufficient dichloromethane, dry and concentrate to obtain a light yellow solid compound (E)-3-(4-chlorobenzyl)-2-(2-(pyridin-3-yl)vinyl)quinazolin-4(3H)-one. 1008 mg, yield 91.4%. Total yield 16.9%.

[0047] In addition, multiple tests were conducted using feed amounts and feed ratios similar to those in Example 2-3. It was found that the yield was not lower than 15%, which proves that the yield of the present application is stable.

[0048] In addition, for Examples 2-3, the enhanced heating jacket was not used, and other conditions were the same, and the yield was found to be reduced by at least 3%, which illustrates the significant effect of the device of the present application.

[0049] NMR data of the final product: 1 H NMR (400MHz, DMSO-d6) δ 8.88 (s, 1H), 8.56 (d, J = 4.3Hz, 1H), 8.20 (d, J = 7.9Hz, 1H), 8.15 (d, J = 7.9Hz, 1H), 7.94-7.84 (m, 2H), 7.75 (d, J=8.1Hz, 1H), 7.56 (t, J=7.5Hz, 1H), 7.52-7.43 (m, 2H), 7.39 (d, J=8.4Hz, 2H), 7.32 (d, J=8.4Hz, 2H), 5.65 (s, 2H)ppm.MS: (M-100+H) + :m / z=374.1.

[0050] Preferably, all the above reagents are of chemical purity or above, or are of superior purity. The water is deionized water, preferably double distilled water. The inner lining and outer lining of the above heating jacket are processed by a special Teflon mold. The heating jacket is a mesh alloy wire wrapped by alkali-free glass fiber and vacuum-shaped by aluminum silicate wool.

[0051] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that are not conceived through creative work should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope defined in the claims.

Claims

1. A method for synthesizing a substituted nitrogen-containing quinazolinone compound, which is carried out by heating with a heating mantle, and the steps are: (1) Dissolve trans-3(3-pyridyl)allylic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and ethyl 2-aminobenzoate in a molar ratio of 2:3:3 in 200-250 mL of N,N-dimethylformamide solution, with the amount of trans-3(3-pyridyl)allylic acid not exceeding 10 g; Slowly add triethylamine in an amount twice the amount of trans-3 (3-pyridyl) allylic acid, place the lower part of the mixed four-necked bottle in a heating jacket, control the heating to maintain at 25°C through the control panel, and keep the reaction for not less than 12 hours. When TLC determines that the reaction is complete, concentrate to obtain a crude product, extract it three times with 300 mL of ethyl acetate each time, wash it once with not less than 600 ml of water, and then wash it three times with not less than 300 mL of saturated brine, dry it with 10 g of anhydrous magnesium sulfate for 30 minutes, filter and spin dry, and pass it through a column with not less than 100 g of 100-200 mesh silica gel wet method, with petroleum ether to ethyl acetate = 50:1, to obtain intermediate A in the form of a light yellow solid: (E)-2-(3-(pyridin-3-yl) acrylamido) benzoic acid ethyl ester; (2) 30-40 mmol of intermediate A was dissolved in not less than 120 ml of tetrahydrofuran, treated with an aqueous solution containing 3 eq of sodium hydroxide in a volume of not less than 80 ml, placed in a four-necked bottle, and the lower part of the mixed four-necked bottle was placed in a heating jacket, and the heating was controlled by the control panel to maintain at 60° C. and the reaction was maintained for not less than 2 hours. When TLC confirmed that the reaction was complete, the heating device was removed, and the mixture was cooled to room temperature and concentrated. While stirring, the pH value was adjusted to 6 with dilute hydrochloric acid. After a white precipitate was formed, it was stirred for at least 5 minutes, filtered, and washed with not less than 80 ml of pure water for 3 times, combined and dried to obtain intermediate B in the form of a white solid: (E)-2-(3-(pyridin-3-yl)acrylamide)benzoic acid; (3) Take 10-20 mmol of intermediate B, mix and dissolve them in not less than 100 mL of dichloromethane according to the molar ratio of intermediate B: carter condensation agent: p-chlorobenzylamine of 2:3:3, then gradually add 3 parts of N,N-diisopropylethylamine, put them in a four-necked bottle, put the lower part of the mixed four-necked bottle in a heating mantle, control the heating to maintain at 25°C through the control panel, and keep stirring for at least 12 hours. When TLC determines that the reaction is complete, , remove the heating equipment, concentrate to obtain a crude product, extract twice with 100 mL of dichloromethane each time, wash the organic phase three times with 100 mL of brine each time, dry with 10 g of anhydrous magnesium sulfate for 30 min, filter and spin dry, wet column with not less than 50 g of 100-200 mesh silica gel, petroleum ether / ethyl acetate = 50:1, and obtain intermediate C in the form of a light yellow solid: ((E)-N-(4-chlorobenzyl)-2-(3-(pyridin-3-yl)acrylamide)benzamide; (4) Take 0.9-1.1 g of intermediate C, take a four-necked bottle, and mix the intermediate C with no less than 30 mL of acetonitrile and 10 mL of water. Add 6.7eq of iodine and 9.0eq of hexamethyldisiloxane of intermediate C in small amounts and multiple times, place the lower part of the mixed four-necked bottle in a heating jacket, control the heating to maintain at 25°C through the control panel, and keep stirring the reaction for no less than 12h. When TLC determines that the reaction is complete, blow nitrogen to dry the mixture for no less than 1h, dissolve and separate the aqueous phase and the organic phase with ethyl acetate, extract the aqueous phase with sodium thiosulfate solution, extract the organic phase twice with 100mL of ethyl acetate, and wash three times with 100mL of brine, combine all organic phases, dry with 10g of anhydrous magnesium sulfate for 30min, filter and spin-dry, and pass through a column with no less than 50g of 100-200 mesh silica gel wet method, petroleum ether / ethyl acetate = 50:1, to obtain a white solid; Post-treatment: Purify with a liquid chromatography column containing 65% 2-amino-3-chloro-1,4-naphthoquinone / 0.1% trifluoroacetic acid, adjust the pH value of the obtained solid to 8 with sodium bicarbonate solution, dissolve with sufficient dichloromethane, dry and concentrate to obtain a light yellow solid compound (E)-3-(4-chlorobenzyl)-2-(2-(pyridin-3-yl)vinyl)quinazoline-4(3H)-one.

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