CN115978796B - Synthesis method of substituted nitrogen-containing quinazolinone compounds - Google Patents
Synthesis method of substituted nitrogen-containing quinazolinone compounds Download PDFInfo
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Abstract
一种取代含氮喹唑啉酮类化合物的合成方法，其利用一种加强型加热套以实施，以反‑3（3‑吡啶基）烯丙酸、2‑(7‑氮杂苯并三氮唑)‑N,N,N',N'‑四甲基脲六氟磷酸酯和2‑氨基苯甲酸乙酯为原料；最终得到产物(E)‑3‑(4‑氯苄基)‑2‑(2‑(吡啶‑3‑基)乙烯基)喹唑啉‑4(3H)‑酮。
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
The invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to a synthesis method of a substituted nitrogen-containing quinazolinone compound.
Background
The method for synthesizing the substituted nitrogen-containing quinazolinone compound, wherein quinazolinone and derivatives thereof are important compounds, have stronger biological activity and can be applied to the field of medicines, but the specific compound (E) -3- (4-chlorobenzyl) -2- (2- (pyridine-3-yl) vinyl) quinazolin-4 (3H) -one and the method disclosed by the application are rarely applied as medical intermediates or are disclosed in literature or data. Due to the characteristics of the molecule, a unique synthetic route and a unique higher yield problem, the method cannot be popularized to the synthesis of other similar structures.
Because of the nature of the molecule, this method cannot be generalized to the synthesis of other similar structures. This is determined by the originality of the preparation process, the higher yields and the irreproducibility of the shorter reaction times, which are obtained from numerous experiments, other routes being essentially incapable of higher yields or acceptable reaction times. In particular, the practical problem of the temperature control of the present application is not noted, and the same or similar method as the present application is not adopted to make the improvement on the apparatus.
Furthermore, the prior art has the problem that, firstly, the preparation of (E) -3- (4-chlorobenzyl) -2- (2- (pyridin-3-yl) vinyl) quinazolin-4 (3H) -one is relatively low in yield, and the person skilled in the art who has found or asked it now gives yields not higher than 10% and generally has waste which is relatively difficult to handle.
Secondly, the method of the application is the same as the preparation method of a plurality of substances, and the method needs to be heated for a long time, in the process, the common heating means can hardly ensure that the temperature is consistent, especially in winter or when the wind is large, the temperature of the system is often difficult to keep consistent with the temperature set by a heating device or a heating sleeve (four-mouth bottle or other glassware with large area exposed in the air), and the yield is obviously adversely affected through a plurality of comparison experiments. However, the prior art does not pay attention to the defect, and the blanket is used at most, or the heat preservation pad is used for simply preserving heat, but firstly, the heat preservation effect is insufficient, and secondly, the bottle body possibly needs to be stirred vigorously, and the requirement of stirring the bottle body for a long time cannot be met by simply taking a heat preservation measure.
Disclosure of Invention
The first object of the present application is to solve two specific problems in the prior art, namely, the problem of how to obtain (E) -3- (4-chlorobenzyl) -2- (2- (pyridin-3-yl) vinyl) quinazolin-4 (3H) -one by a few steps with high yield starting from trans-3 (3-pyridyl) allyl acid, and the problem of high yield, less waste and easy treatment, and the scheme of the present application perfectly solves the problem, and secondly, how to maintain stable temperature for a long period of time very effectively in the face of each step, avoiding the adverse effect of temperature change, which is solved in the present application.
The invention discloses a reinforced heating sleeve which is characterized by comprising a lower fixed sleeve and an upper movable sleeve.
The lower fixing sleeve comprises a lower heating sleeve, a shell, a foot, a control circuit, a control panel and a power supply part.
The upper movable sleeve comprises an upper heating sleeve, a lining and an outer lining, wherein the upper heating sleeve, the lining and the outer lining are provided with side walls and upper edges.
The lower heating sleeve and the upper heating sleeve are respectively connected with a control circuit, are independently powered and controlled by the control circuit, and are integrally controlled in temperature by a control panel.
The upper heating sleeve and the lower heating sleeve are both provided with netlike alloy wires, the netlike alloy wires are wrapped by alkali-free glass fibers and are shaped in vacuum by aluminum silicate cotton, the lower heating sleeve is hemispherical, the outer wall of the upper heating sleeve, the outer lining and the inner lining are cylindrical side walls, the upper ends of the upper heating sleeve, the outer lining and the inner lining extend inwards to form annular upper edges, one sides of the upper heating sleeve, the outer lining and the inner lining are provided with openings, the inner lining and the outer lining are teflon material layers with the thickness of 3-8mm and are netlike hollow, and connecting wires of the upper heating sleeve and a control circuit are positioned outside the upper heating sleeve.
A synthesis method of a substituted nitrogen-containing quinazolinone compound, namely a synthesis method of (E) -3- (4-chlorobenzyl) -2- (2- (pyridin-3-yl) vinyl) quinazoline-4 (3H) -ketone, which is implemented by using a reinforced heating jacket, and comprises the steps of (1) dissolving trans-3 (3-pyridyl) allyl acid, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate and ethyl 2-aminobenzoate in an N, N-dimethylformamide solution (200-250 mL) in a mass ratio of 2:3:3, wherein the trans-3 (3-pyridyl) allyl acid is not more than 10g; slowly adding triethylamine with the amount twice of that of trans-3 (3-pyridyl) allyl acid, placing the lower part of the four-mouth bottle after mixing in a lower heating jacket, opening an upper heating jacket, transversely sleeving the upper part of the four-mouth bottle, closing the opening, controlling heating to 25 ℃ by a control panel, keeping the reaction for not less than 12 hours, concentrating to obtain a crude product after TLC determines that the reaction is complete, extracting three times by 300mL of ethyl acetate each time, washing once by not less than 600mL of water, washing 3 times by not less than 300mL of saturated saline, drying by 10g of anhydrous magnesium sulfate for 30min, filtering and spinning, passing through a column by 100-200 mesh silica gel wet method by not less than 100g of petroleum ether to ethyl acetate=50:1, intermediate A (E) -ethyl 2- (3- (pyridin-3-yl) acrylamido) benzoate was obtained as a pale yellow solid.
(2) Dissolving 30-40mmol of intermediate A in not less than 120ml of tetrahydrofuran, treating with aqueous solution containing 3eq of sodium hydroxide to a volume of not less than 80ml, placing in a four-mouth bottle, placing the lower part of the mixed four-mouth bottle in a lower heating jacket, opening an opening of an upper heating jacket, transversely sleeving the upper part of the four-mouth bottle, closing the opening, controlling heating by a control panel to keep the temperature at 60 ℃ and keeping the reaction for not less than 2 hours, removing a heating device after the TLC determines that the reaction is complete, cooling the mixture to room temperature, concentrating the mixture, adjusting the pH value to 6 with dilute hydrochloric acid while stirring to form white precipitate, stirring for at least 5 minutes, filtering the white precipitate, washing 3 times with not less than 80ml of pure water, merging and drying to obtain intermediate B (E) -2- (3- (pyridin-3-yl) acrylamide) benzoic acid in a white solid form.
(3) 10-20Mmol of intermediate B is taken, the mixture is mixed and dissolved in not less than 100mL of dichloromethane according to the ratio of the intermediate B to the mass of the carbot condensing agent to the chlorobenzylamine of 2:3:3, then 3 parts of N, N-diisopropylethylamine is gradually added, the mixture is placed in a four-port bottle, the lower part of the mixed four-port bottle is placed in a lower heating sleeve, the opening of an upper heating sleeve is opened, the mixture is transversely sleeved on the upper part of the four-port bottle, the opening is closed, heating is controlled by a control panel to be kept at 25 ℃ and stirring reaction is kept for not less than 12 hours, after the TLC determines that the reaction is complete, heating equipment is removed, the mixture is concentrated to obtain crude products, 100mL of dichloromethane is extracted twice each time, 100mL of saline is used for washing the organic phase three times, 10g of anhydrous magnesium sulfate is dried for 30min, filtration and spin-drying are carried out, 100-200 meshes of silica gel are used for column chromatography, petroleum ether/ethyl acetate=50:1, and intermediate C in a light yellow solid form (((E) -N- (4-chlorobenzyl) -3- (3-benzamide) is obtained by wet method).
(4) Taking 0.9-1.1g of intermediate C, taking a four-mouth bottle, mixing the intermediate C with not less than 30mL of acetonitrile and 10mL of water, adding 6.7eq of iodine and 9.0eq of hexamethyldisiloxane of the intermediate C a small number of times, placing the lower part of the four-mouth bottle after mixing in a lower heating jacket, opening an opening of an upper heating jacket, transversely sleeving the upper part of the four-mouth bottle, closing the opening, controlling heating to be kept at 25 ℃ through a control panel, keeping stirring for reaction for not less than 12 hours, blowing nitrogen to dry the mixture after the TLC determines that the reaction is complete, not less than 1 hour, dissolving and separating an aqueous phase and an organic phase by ethyl acetate, adding a sodium thiosulfate solution into the aqueous phase for extraction, extracting the organic phase twice by 100mL of ethyl acetate, washing three times by 100mL of saline, combining all the organic phases, drying by 10g of anhydrous magnesium sulfate for 30min, filtering and spin-drying, passing through a wet method column with not less than 50g of 100-200 meshes of ethyl acetate, and obtaining white solid after the TLC determines that the reaction is complete, the mixture is dried by blowing nitrogen for not less than 1 hour.
Post-treatment purification by liquid chromatography with 65% 2-amino-3-chloro-1, 4-naphthoquinone/0.1% trifluoroacetic acid, adjusting the pH of the resulting solid to 8 with sodium bicarbonate solution, dissolving with sufficient dichloromethane, drying and concentrating to give the compound (E) -3- (4-chlorobenzyl) -2- (2- (pyridin-3-yl) vinyl) quinazolin-4 (3H) -one as a pale yellow solid.
Compared with the prior art, the application has the advantages that firstly, the upper part of the four-mouth bottle is exposed to the air for a long time, the system temperature is often unstable (particularly in winter, the upper half part of the four-mouth bottle is exposed to the air and is unstable and is often obviously lower than the set temperature, such as the set temperature of 90 ℃, the actual temperature fluctuates between 90 ℃ and 82 ℃ and obviously adversely affects the productivity by comparison), the soft heating sleeve is arranged at the upper part of the heating sleeve, the problem is perfectly solved, the additional soft heating sleeve is easy to apply, and the system reaction at the required temperature can be effectively ensured. 2. The preparation method is good, the raw materials are easy to obtain, the steps are short, no special complicated mechanism exists, the yield is extremely high, and the yield can reach about 15.9 percent stably, which is also superior to the similar technology in the prior art. The prior art generally gives very low yields of the product or is too complicated to be comparable to the present application.
Compared with the preparation method of similar substances, the method has the advantages that the utilization rate of raw materials in each step is very high, industrial production is realized with great value, the method is finely designed, the synthesis is effectively realized, the yield is higher, the average yield is more than 15%, the method has certain industrial production value and great economic value, the method reflects extremely strong application conception and creativity through careful design of an additional heating sleeve, good preparation effect is obtained, no similar public information is available for reference in the prior art, and the scheme has originality.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
Fig. 1 is a schematic front view of a heating jacket.
Fig. 2 is a schematic view of the structure of the upper heating jacket.
FIG. 3 is a schematic diagram of the synthesis step.
FIG. 4 is a nuclear magnetic resonance diagram of the final product.
The device comprises a lower fixed sleeve, an upper movable sleeve, a lower heating sleeve, a 12, a shell, a 13, a foot, a 14, a control circuit, a 15, a control panel, a 16, a power supply part, a 21, an upper heating sleeve, a 22, a lining, a 23, an outer lining and an opening.
Detailed Description
The preferred embodiments of the present invention will be described in detail below with reference to 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 clear and defining the scope of the present invention.
Example 1
The reinforced heating sleeve is characterized by comprising a lower fixed sleeve 1 and an upper movable sleeve 2, wherein the lower fixed sleeve comprises a lower heating sleeve 11, a shell 12, a foot 13, a control circuit 14, a control panel 15 and a power supply part 16, the upper movable sleeve 2 comprises an upper heating sleeve 21, a lining 22 and an outer lining 23, the upper heating sleeve 21, the lining 22 and the outer lining 23 are respectively provided with side walls and upper edges, and the lower heating sleeve and the upper heating sleeve are respectively connected with the control circuit, are independently powered and controlled by the control circuit and are integrally controlled by the control panel. The arrangement of the lower heating sleeve is similar to that of a common heating sleeve, but the arrangement of the upper movable sleeve is original, and a commercial product is not found, so that the upper heating sleeve and the lower heating sleeve are self-made, and the metal wires of the upper heating sleeve and the lower heating sleeve can be connected in parallel in terms of a control circuit and connected into the control circuit, but the actual temperature control condition of the circuit is different from that of the original temperature control circuit, and the circuit needs to be recalibrated and marked. It is also possible to use two control circuits separately for the lower heating jacket, but in this way the output power is actually doubled, taking care of the power matching of the supply part. The heating jacket can be 220v or 380 v. The temperature control of the upper heating sleeve and the lower heating sleeve is subjected to multiple comparison and correction.
The upper heating sleeve and the lower heating sleeve are both provided with netlike alloy wires, the netlike alloy wires are wrapped by alkali-free glass fibers and are vacuum-shaped by aluminum silicate cotton, the lower heating sleeve is hemispherical, the upper heating sleeve, the outer lining and the inner lining are all cylindrical side walls, the upper ends of the upper heating sleeve, the outer lining and the inner lining extend inwards to form annular upper edges, one sides of the upper heating sleeve, the outer lining and the inner lining are provided with openings, the inner lining and the outer lining are Teflon material layers with the thickness of 3-8mm and are netlike hollow, and connecting wires of the upper heating sleeve and the control circuit are positioned outside the upper heating sleeve. The bottle body is arranged in a cylindrical shape, and compared, the pattern is more favorable for maintaining the temperature, and a hot air layer is formed between the upper part of the bottle body and the upper heating sleeve, so that the bottle body is more favorable for maintaining the temperature.
The wrapping of the heating jacket is similar to the prior art, but the prior art for selecting the inner lining and the outer lining does not see, the plastic products of Teflon or other Teflon systems are better, the plastic products are resistant to a certain high temperature (no influence below 260 ℃), the heating jacket is moderate in hardness, the heating jacket can be kept in a certain shape after being supported from the outside and the inside, and the opening part can be opened, so that the upper part of the four-mouth bottle can be conveniently wrapped from the side, and the material is a very suitable material, which is a targeted material after the functional conception is carried out. Other fluorine-containing plastics can be selected as long as the conditions are met that no peculiar smell or obvious volatile substances are generated after heating, no obvious softening and deformation are generated below 250 ℃, and the strength can be maintained even if the fluorine-containing plastics are heated for a long time at 100-180 ℃.
As shown in fig. 1-2, the lower heating jacket is a hemisphere, while the upper jacket is a part of a cylinder (circular in the center cut out from the top) and has an opening on one side, which allows the body to be inserted due to its flexibility as a whole while the teflon shell remains in shape. The upper heating sleeve and the lower heating sleeve can share a control circuit, or the control circuit can be two parts connected in parallel to respectively control the upper heating sleeve and the lower heating sleeve, and an opening can be formed on the outer wall of the lower heating sleeve and used for leading out a circuit comprising a control wire and a power wire and connected with the upper heating sleeve. The coupling relationship is shown in fig. 2, with both the outer liner and the inner liner being shaped similarly to the heating jacket to facilitate support of the heating jacket. In order to facilitate the heat dissipation, the outer liner and the inner liner are designed to be net-shaped, so that the heat dissipation is facilitated, as shown in fig. 2.
Example 2
A synthesis method of a substituted nitrogen-containing quinazolinone compound, namely a synthesis method of (E) -3- (4-chlorobenzyl) -2- (2- (pyridin-3-yl) vinyl) quinazolin-4 (3H) -one, which is implemented by using a reinforced heating jacket, and comprises the following steps:
(1) The trans-3 (3-pyridyl) allyl acid, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate and ethyl 2-aminobenzoate in the mass ratios of 2:3:3 were dissolved in 200mL of N, N-dimethylformamide solution at 8.5g,57mmol,32.5g,85.5mmol and 14.12g,85.5mmol, respectively;
Slowly adding triethylamine, 11.53g,114mmol, placing the lower part of the four-mouth bottle after mixing in a lower heating jacket, opening an opening of an upper heating jacket, transversely sleeving the upper part of the four-mouth bottle, closing the opening, controlling heating by a control panel to keep the temperature at 25 ℃ and keeping the reaction for not less than 12 hours, concentrating to obtain a crude product after the TLC determines that the reaction is complete, extracting three times by 300mL of ethyl acetate each time, washing once by 600mL of water, washing 3 times by not less than 300mL of saturated saline, drying by 10g of anhydrous magnesium sulfate for 30min, filtering and spin-drying, passing a column by a 100-200 mesh silica gel wet method, petroleum ether to ethyl acetate=50:1, and obtaining an intermediate A (E) -2- (3- (pyridin-3-yl) acrylamide) ethyl benzoate in a light yellow solid form, and 8.9g, wherein the yield of the step 1 is 52%.
(2) 30Mmol of intermediate A,8.9g, dissolved in 120ml of tetrahydrofuran, treated with an aqueous solution containing 3eq of sodium hydroxide (3.6 g,90 mmol) and having a volume of not less than 80ml, placed in a four-necked flask, the lower part of the four-necked flask after mixing was placed in a lower heating jacket, the opening of the upper heating jacket was opened, the upper part of the four-necked flask was transversely covered and the opening was closed, heating was maintained at 60℃by a control panel and the reaction was maintained for not less than 2 hours, after the completion of the TLC determination, the heating apparatus was removed, the mixture was cooled to room temperature and concentrated, the next was adjusted to pH 6 with dilute hydrochloric acid while stirring, after forming a white precipitate, stirred for at least 10 minutes, filtered and washed 3 times with 80ml of pure water, and combined and dried to give intermediate B (E) -2- (3- (pyridin-3-yl) acrylamido) benzoic acid as a white solid, 5.7g, yield 71%.
(3) 10-20Mmol of intermediate B is taken, according to the ratio of the intermediate B to the mass of the carbot condensing agent to the chlorobenzylamine being 2:3:3, 2.68g,10mmol,6.6g,15mmol,2.12g and 15mmol are respectively mixed and dissolved in 100mL of dichloromethane, 1.9g and 15mmol of N, N-diisopropylethylamine are gradually added, the mixture is placed in a four-mouth bottle, the lower part of the four-mouth bottle is placed in a lower heating jacket, the opening of the upper heating jacket is opened, the mixture is transversely sleeved at the upper part of the four-mouth bottle, and the opening is closed, heating is controlled to be kept at 25 ℃ by a control panel, stirring reaction is kept for not less than 12 hours, after the TLC determines that the reaction is complete, the heating equipment is removed, the mixture is concentrated to obtain crude products, 100mL of dichloromethane is used for extraction twice each time, 100mL of dichloromethane is used for washing the organic phase three times, anhydrous magnesium sulfate is dried for 30min, filtration and spin-drying is carried out, 100-200 g of 100-200 meshes of ethyl acetate is used, the mixture is used for obtaining ethyl acetate (50-50 g, ethyl acetate, 50-ethyl acetate=1:9-4-benzoyl chloride (1-3-benzoyl amide) (2-1-3-benzyl-1% of solid, 1:9%).
(4) Taking 1g of intermediate C, taking a four-mouth bottle, mixing the intermediate C with not less than 30mL of acetonitrile and 10mL of water, adding 6.7eq of iodine and 9.0eq of hexamethyldisiloxane (6.7 g of iodine, 17.1mmol,6.7eq, hexamethyldisiloxane, 3.7g,20.95mmol,9.0 eq) of the intermediate C a small number of times, placing the lower part of the mixed four-mouth bottle in a lower heating jacket, opening an opening of an upper heating jacket, transversely sleeving the upper part of the four-mouth bottle, closing the opening, controlling heating by a control panel to keep at 25 ℃ and stirring for not less than 12 hours, after TLC determines that the reaction is complete, blowing nitrogen to dry the mixture, not less than 1 hour, dissolving and separating an aqueous phase and an organic phase by ethyl acetate, adding a sodium thiosulfate solution into the aqueous phase, extracting the organic phase twice by 100mL of ethyl acetate, washing three organic phases by 100mL of brine, combining all the organic phases, drying by 10g of anhydrous magnesium sulfate, filtering for not less than 50g of petroleum ether, and obtaining a white solid by wet method of not less than 50 mesh of ethyl acetate;
Post-treatment purification by liquid chromatography with 65% 2-amino-3-chloro-1, 4-naphthoquinone/0.1% trifluoroacetic acid, adjusting the pH of the resulting solid to 8 with sodium bicarbonate solution, dissolving with sufficient dichloromethane, drying and concentrating to give the compound (E) -3- (4-chlorobenzyl) -2- (2- (pyridin-3-yl) vinyl) quinazolin-4 (3H) -one as a pale yellow solid. 900mg, 89.8% yield. The total yield was 15.9%.
Example 3
A synthesis method of a substituted nitrogen-containing quinazolinone compound, namely a synthesis method of (E) -3- (4-chlorobenzyl) -2- (2- (pyridin-3-yl) vinyl) quinazolin-4 (3H) -one, which is implemented by using a reinforced heating jacket, and comprises the following steps:
(1) The amounts of trans-3 (3-pyridyl) propenoic acid, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate and ethyl 2-aminobenzoate in the ratio of 2:3:3 were dissolved in 200mL of N, N-dimethylformamide solution, respectively, 9g,34.41g,14.95 g;
Slowly adding triethylamine, 12.21g, placing the lower part of the mixed four-mouth bottle in a lower heating jacket, opening an opening of an upper heating jacket, transversely sleeving the upper part of the four-mouth bottle, closing the opening, controlling heating to be 25 ℃ through a control panel, keeping the reaction for not less than 14h, concentrating to obtain a crude product after the TLC determines that the reaction is complete, extracting three times with 300mL of ethyl acetate each time, washing with 600mL of water for one time, washing with not less than 300mL of saturated saline solution for 3 times, drying with 10g of anhydrous magnesium sulfate for 30min, filtering and spin-drying, passing through a column with 100-200 meshes of silica gel wet method, wherein petroleum ether is 50:1 compared with ethyl acetate to obtain an intermediate A (E) -2- (3- (pyridin-3-yl) acrylamide) ethyl benzoate in a light yellow solid form, and 9.53g, wherein the yield of the step 1 is 52.58%.
(2) 35Mmol of intermediate A was dissolved in 140ml of tetrahydrofuran and treated with an aqueous solution containing 3eq of sodium hydroxide (4.2 g) of not less than 100ml, placed in a four-necked flask, the lower part of the mixed flask was placed in a lower heating mantle, the opening of the upper heating mantle was opened, the flask was transversely covered on the upper part of the flask and the opening was closed, heating was kept at 60℃by a control panel and the reaction was kept for not less than 3 hours, after the completion of the TLC, the heating apparatus was removed, the mixture was cooled to room temperature and concentrated while stirring, and the pH was adjusted to 6 with dilute hydrochloric acid to form a white precipitate, which was then stirred for at least 15 minutes, filtered, and washed 3 times with 100ml of pure water, and combined and dried to give intermediate B (E) -2- (3- (pyridin-3-yl) acrylamido) benzoic acid in the form of a white solid, 6.69g, yield 71.5%.
(3) 10-20Mmol of intermediate B is taken, according to the ratio of the intermediate B to the mass of the carbot condensing agent to the chlorobenzylamine being 2:3:3, 2.948g,10mmol,7.26g,16.5mmol,2.332g and 16.5mmol respectively, are mixed and dissolved in 110mL of dichloromethane, then 2.09g and 16.5mmol of N, N-diisopropylethylamine are gradually added, the mixture is placed in a four-mouth bottle, the lower part of the four-mouth bottle after mixing is placed in a lower heating jacket, the opening of an upper heating jacket is opened, the opening is transversely sleeved at the upper part of the four-mouth bottle, heating is controlled by a control panel to keep the temperature at 25 ℃ and keep stirring reaction for not less than 14h, after the TLC determines that the reaction is complete, heating equipment is removed, the crude product is obtained by concentrating, 110mL of dichloromethane is extracted twice each time, 110mL of brine is used for washing the organic phase three times, anhydrous magnesium sulfate 11g is dried for 30min, filtration and spin-drying is carried out, and 100 g of ethyl acetate is used for 100-200 mesh ethyl acetate (50-2-ethyl acetate, 2-4-benzyl chloride, 2- (2-ethyl acetate) (2-1:4-benzyl-2-methyl-ethyl acetate, 1) - (+).1.1.1%).
(4) Taking 1.1g of intermediate C, taking a four-necked flask, mixing the intermediate C with 33mL of acetonitrile and 11mL of water, adding 6.7eq of iodine and 9.0eq of hexamethyldisiloxane (7.37 g of iodine, 18.81mmol,6.7eq, hexamethyldisiloxane, 4.07g,23.045mmol,9.0 eq) of intermediate C a small number of times, placing the lower part of the four-necked flask after mixing in a lower heating jacket, opening the opening of the upper heating jacket, transversely covering the upper part of the four-necked flask, closing the opening, controlling heating by a control panel to keep at 25 ℃ and keeping stirring for not less than 16 hours, after the TLC determines that the reaction is complete, blowing nitrogen to dry the mixture, dissolving and separating the aqueous phase and the organic phase with ethyl acetate, adding sodium thiosulfate solution, extracting the organic phase twice with 110mL of ethyl acetate, washing three times with 110mL of brine, combining all the organic phases, drying with 10g of anhydrous sodium thiosulfate, and filtering with not less than 200 g of petroleum ether for not less than 50 g of dry ethyl sulfate, and obtaining a solid of wet method = 100 mesh.
Post-treatment purification by liquid chromatography with 65% 2-amino-3-chloro-1, 4-naphthoquinone/0.1% trifluoroacetic acid, adjusting the pH of the resulting solid to 7.5 with sodium bicarbonate solution, dissolving with sufficient dichloromethane, drying and concentrating to give the compound (E) -3- (4-chlorobenzyl) -2- (2- (pyridin-3-yl) vinyl) quinazolin-4 (3H) -one as a pale yellow solid. 1008mg, 91.4% yield. The total yield was 16.9%.
In addition, a plurality of experiments were conducted by taking the same amounts and proportions as in examples 2 to 3, and it was found that the productivity was not lower than 15%, which confirmed that the productivity of the present application was stable.
In addition, for examples 2-3, the procedure was carried out without the use of a reinforcing heating mantle, and the same conditions were applied, and a decrease in yield of at least 3% was observed. This illustrates the significant effect of the device of the present application.
Nuclear magnetic data of the final product ：1H NMR(400MHz,DMSO-d6)δ8.88(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.
Preferably, all of the aforementioned reagents are of more than chemical purity, or are all of superior purity. The water is deionized water, preferably double distilled water. The inner lining and the outer lining of the heating sleeve are processed by special Teflon molds, the heating sleeve is made of net-shaped alloy wires which are wrapped by alkali-free glass fibers, and aluminum silicate cotton is utilized for vacuum shaping.
The foregoing is merely illustrative of specific embodiments of the present invention, and the scope of the invention is not limited thereto, but any changes or substitutions that do not undergo the inventive effort should be construed as falling within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope defined by the claims.
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