CN115028587A - Preparation process of benzimidazole derivative intermediate - Google Patents
Preparation process of benzimidazole derivative intermediate Download PDFInfo
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- CN115028587A CN115028587A CN202210718752.6A CN202210718752A CN115028587A CN 115028587 A CN115028587 A CN 115028587A CN 202210718752 A CN202210718752 A CN 202210718752A CN 115028587 A CN115028587 A CN 115028587A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0006—Controlling or regulating processes
- B01J19/0013—Controlling the temperature of the process
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
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Abstract
The application relates to the technical field of chemical pharmacy, and particularly discloses a preparation process of a benzimidazole derivative intermediate. A preparation process of a benzimidazole derivative intermediate comprises the following steps:
(ii) a In the synthesis route, the synthesis of the compound II, the compound III, the compound IV, the compound V and the compound IV is carried out in a reaction kettle, the reaction kettle comprises a reaction kettle body, a stirring mechanism, a temperature regulating mechanism, an evaporation mechanism and a reflux mechanism, wherein the stirring mechanism is used for mixing and stirring materials in the reaction kettle body, the temperature regulating mechanism is used for regulating and controlling the temperature of the reaction kettle body, and the evaporation mechanism is used for assisting in evaporating the solventAnd the reflux mechanism is used for realizing reflux reaction. The benzimidazole derivative intermediate synthesized by the method has high yield and purity, and the reaction kettle is matched with the synthesis process.
Description
Technical Field
The application relates to the technical field of chemical pharmacy, in particular to a preparation process of a benzimidazole derivative intermediate.
Background
The most widely used benzimidazole drugs are antiparasitic drugs, such as mebendazole and albendazole, which are commonly used in life, and after the drugs are taken, parasites in vivo can be rapidly excreted out of the body. In addition, many benzimidazole derivatives have recently been reported to have excellent anti-gastric ulcer efficacy, and research into targeting has been gradually conducted.
The 3-benzyl-7-hydroxy-2-methyl-3H-benzimidazole-5-carboxylic acid is a key intermediate of a new anti-gastric ulcer drug, but the research on the synthesis production of the 3-benzyl-7-hydroxy-2-methyl-3H-benzimidazole-5-carboxylic acid is less at present, and the purity and yield of the product obtained by the present synthesis method are lower. In addition, in the synthesis process of 3-benzyl-7-hydroxy-2-methyl-3H-benzimidazole-5-carboxylic acid, the regulation and control of the temperature are more, the temperature of a plurality of reaction stages is different, and in the synthesis process, partial stages need to react in a reflux state, and the operation of evaporating the solvent is needed. The common reaction kettle can not meet the reaction requirements, so that a plurality of devices need to be converted in the synthesis process of the 3-benzyl-7-hydroxy-2-methyl-3H-benzimidazole-5-carboxylic acid, the operation is troublesome, and the production efficiency is low; meanwhile, material loss is easily generated in the process of transferring materials, so that the yield of products is easily low.
Disclosure of Invention
In order to improve the purity and yield of the synthesized benzimidazole derivative intermediate and provide a reaction kettle matched with the preparation process, the application provides a preparation process of the benzimidazole derivative intermediate.
The application provides a preparation process of a benzimidazole derivative intermediate, which adopts the following technical scheme:
a preparation process of a benzimidazole derivative intermediate comprises the following steps:
in the synthesis route, the synthesis of a compound II, a compound III, a compound IV and a compound II is carried out in a reaction kettle, the reaction kettle comprises a reaction kettle body, a stirring mechanism, a temperature regulating mechanism, an evaporating mechanism and a reflux mechanism, the temperature regulating mechanism comprises a flow dividing component, a circulating component and a temperature sensing component, an interlayer is arranged on the peripheral wall of the reaction kettle body, the flow dividing component comprises a flow dividing plate, and the flow dividing plate is spirally arranged in the interlayer, namely a spiral channel is formed in the interlayer; the reaction kettle body is provided with an upper circulation port and a lower circulation port, the upper circulation port and the lower circulation port are both communicated with the interior of the interlayer, the upper circulation port is positioned above the flow distribution plate, the lower circulation port is positioned below the flow distribution plate, the circulation component comprises a circulation pump, and the circulation pump introduces a cold and heat source into the interlayer from one side of the lower circulation port and flows out from one side of the upper circulation port; the temperature sensing component comprises a temperature sensor and a display screen, the temperature sensor and the display screen are both arranged on the reaction kettle body, and the temperature sensor transmits a sensed real-time temperature signal to the display screen for display; the stirring mechanism is used for mixing and stirring materials in the reaction kettle body, the steaming mechanism is used for steaming a solvent in a reaction system, and the reflux mechanism is used for realizing reflux in reflux reaction.
By adopting the technical scheme, the synthesis operation of the synthesis route is simpler, and the purity and yield of the synthesized benzimidazole derivative intermediate are higher. In addition, the reaction kettle integrating the stirring mechanism, the temperature regulating mechanism, the steaming mechanism and the reflux mechanism is relatively matched with the synthesis process, so that each synthesis stage can be carried out in the same device, the material loss caused by material transfer is reduced, the product yield is improved, and the production efficiency is higher.
Meanwhile, the spiral splitter plate is arranged on the interlayer in the reaction kettle body, the spiral channel is formed in the interlayer, the circulation path of the cold and heat source in the interlayer is lengthened, the splitter plate is also one of temperature conduction media, the contact area of the cold and heat source and the inner wall of the interlayer is increased, the contact time is prolonged, and the temperature control sensitivity is improved.
In addition, the temperature sensor monitors the temperature of the reaction kettle body in real time and transmits a temperature signal to the display screen in real time, so that the temperature of the reaction kettle body is monitored in real time, and workers can conveniently regulate and control the circulation rate of a cold and heat source according to the real-time temperature; the temperature regulation and control of the reaction kettle body are more timely and accurate, the required temperature of the synthesis reaction is effectively supported, and the positive significance of a certain degree on the product yield and the purity is achieved.
Preferably, a heat insulation layer is arranged on the outer peripheral wall of the reaction kettle body, and the temperature sensor is arranged between the heat insulation layer and the reaction kettle body.
Through adopting above-mentioned technical scheme, the heat preservation helps reducing the temperature interference of ambient temperature to the reation kettle body for the temperature regulation and control of reation kettle body is comparatively stable. And the temperature sensor is positioned between the heat-insulating layer and the reaction kettle body, so that the temperature measurement accuracy of the temperature sensor is improved.
As preferred, evaporate mechanism including retrieving jar, outlet duct, cooling tube, drainage plate and cooling device, the outlet duct sets up on the top of reation kettle body and communicates with each other with reation kettle body is inside, the one end of reation kettle body is kept away from at the outlet duct to the cooling tube intercommunication, just the cooling tube sets up from being close to one side downward sloping of outlet duct towards one side of keeping away from the outlet duct, retrieve jar and reation kettle body and place side by side, the one end that the outlet duct was kept away from to the cooling tube communicates with each other with retrieving the jar, the drainage plate sets up on the inside pipe wall of cooling tube, just the setting of drainage plate orientation outlet duct one side tilt up from the cooling tube one side, just there is the clearance between the inside pipe wall of drainage plate and outlet duct, cooling device is used for cooling the cooling tube.
Through adopting above-mentioned technical scheme, when evaporating the solvent, volatile solvent leaves the reation kettle body through the outlet duct and gets into in the cooling tube, because the cooling tube downward sloping sets up, in the cooling tube reliquefied solvent gets into the recovery jar along the cooling tube, helps reducing the condition of the solvent backward flow to the outlet duct after reliquefying. And meanwhile, a drainage plate inclined towards one side of the cooling pipe is further arranged at the junction of the cooling pipe and the air outlet pipe, so that the condition of backflow of the solvent after re-liquefaction is further reduced. Meanwhile, the distilled solvent is collected through the recovery tank, so that air pollution is reduced, and the recovered solvent can be reused after purification, thereby being beneficial to reducing the cost.
Preferably, the backflow mechanism comprises a backflow pipe and a condensing device, the backflow pipe is arranged on the top end wall of the reaction kettle body, the backflow pipe is communicated with the inside of the reaction kettle body, the top end of the backflow pipe is in a closed state, and the condensing device is used for cooling the backflow pipe.
Through adopting above-mentioned technical scheme to condensing equipment cools off the back flow, and the back flow top is sealed, makes this internal material of reation kettle liquefy in the back flow tube again after the gasification, realizes the reflux reaction promptly.
Preferably, the return pipe is used as an air outlet pipe, and a valve is arranged on the air outlet pipe and below the position where the air outlet pipe is communicated with the cooling pipe, namely, the cooling pipe is communicated with one end of the return pipe, which is far away from the reaction kettle body.
By adopting the technical scheme, the return pipe is used as the air outlet pipe, and the corresponding working mode can be selected by controlling the opening and closing of the valve at the stage of solvent evaporation or reflux reaction. Meanwhile, the steaming mechanism and the reflux mechanism are integrated together, so that the operation is convenient.
Preferably, the synthesis of the compound (c) is as follows: at the temperature of minus 15 plus or minus 2 ℃ to minus 10 plus or minus 2 ℃, chloroethyl ester is added into a mixture of acetonitrile and methanol; stirring and reacting for 10-12 h, evaporating the solvent, and then sequentially performing extraction, filtration, washing and drying to obtain a compound II.
By adopting the technical scheme, chloroethyl ester, acetonitrile and methanol are mixed at the temperature of minus 15 +/-2 ℃ to minus 10 +/-2 ℃, and the stirring reaction time is controlled to be 10-12 h; after the solvent is evaporated, the steps of extraction, filtration, washing and drying are carried out in sequence, and the obtained compound (II) has high yield and purity and is simple to operate.
Preferably, the compound (c) is synthesized by the following steps: adding a compound II into a mixture of benzylamine and methanol at the temperature of-10 +/-2 ℃ to-6 +/-2 ℃, primarily mixing, heating to 2-5 ℃, stirring and preserving heat for 2-3 hours, evaporating a solvent, and sequentially performing extraction, filtration, washing and drying to obtain the compound III.
By adopting the technical scheme, the preliminary mixing temperature is controlled to be-10 +/-2 ℃ to-6 +/-2 ℃, the temperature is adjusted to 2-5 ℃ after the preliminary mixing for reaction for 2-3 h, and the steps of extraction, filtration, washing and drying are sequentially carried out after the solvent is evaporated, so that the obtained compound has high yield and purity, and the operation is simple.
Preferably, the synthesis step of the compound (iv) is as follows: adding triethylamine into a mixture of a compound III, isopropanol and 2-bromomalonaldehyde, heating to 80-85 ℃, refluxing and preserving heat for 11-12 h, evaporating a solvent, and then sequentially performing extraction, drying, filtering, washing and concentration steps to obtain the compound IV.
By adopting the technical scheme, the reaction temperature is controlled to be 80-85 ℃, the temperature is kept for 11-12 h in a reflux state, and the steps of extracting, filtering, washing and drying are sequentially carried out after the solvent is evaporated, so that the obtained compound has high yield and purity, and the operation is simple.
Preferably, the compound (c) is synthesized by the following steps: adding sodium ethoxide into ethanol under the protection of inert gas, adding diethyl succinate, heating to 50-60 ℃, adding a compound IV, stirring, keeping the temperature for 2-3 h, evaporating the solvent, and sequentially performing extraction, filtration, washing, reduced pressure concentration and vacuum drying to obtain a compound V.
By adopting the technical scheme, the reaction temperature is controlled to be 50-60 ℃, the stirring and heat preservation are carried out for 2-3 h, the steps of extracting, filtering, washing and drying are carried out in sequence after the solvent is evaporated, the obtained compound has high yield and purity, and the operation is simple.
Preferably, the synthesis steps of the compound (c) are as follows: mixing the compound (c) with acetonitrile, heating to 80-85 ℃, adding acetic anhydride, stirring and preserving heat for 2-3 hours, adding methanol into the residue after solvent is evaporated, continuing adding methanol after decompression and concentration, cooling to-2-0 ℃, adding a sodium hydroxide solution, heating to 80-85 ℃, refluxing and preserving heat for 2-3 hours, cooling to 20-25 ℃, adding deionized water for dilution, adjusting the pH to 4.0-4.5, and sequentially filtering, washing and drying to obtain the compound (c), namely the benzimidazole derivative intermediate.
By adopting the technical scheme, the raw materials are selected and the reaction parameters are controlled, so that the obtained compound has high yield and purity, and the operation is simple.
In summary, the present application has the following beneficial effects:
1. the application provides a specific synthetic route for synthesizing the intermediate of the benzimidazole derivative, the yield and the purity of the intermediate of the benzimidazole derivative obtained by synthesizing the synthetic route are high, and the operation is simple; in addition, the reaction kettle integrating the stirring mechanism, the temperature regulating mechanism, the steaming mechanism and the reflux mechanism is further provided, and the process of the synthesis route is matched, so that each reaction stage can be carried out in the reaction kettle, the operation of transferring materials to corresponding devices in different reaction stages is reduced, the production efficiency is improved, the material loss in the transferring process is reduced, and the positive significance is realized for improving the product yield.
2. This application sets into spiral helicine flow distribution plate through further in the intermediate layer of reation kettle body, forms helical coiled passage in the inside of intermediate layer, when letting in cold and hot source for the area of contact of cold and hot source and intermediate layer inner wall is bigger and contact time is longer, thereby helps improving control by temperature change sensitivity.
3. The evaporation and recovery of the solvent are realized by matching the air outlet pipe, the cooling pipe and the cooling device, and the cooling pipe is inclined downwards towards one side of the recovery tank, so that the reflux condition of the re-liquefied solvent is reduced; and a drainage plate which inclines downwards towards one side of the cooling pipe is arranged on one side of the cooling pipe close to the air outlet pipe, so that the reflux condition of the re-liquefied solvent is further reduced.
Drawings
FIG. 1 is a schematic view of the structure of a reaction vessel in example 1 of the present application.
FIG. 2 is a sectional view of a sandwich structure in a reaction vessel used in example 1 of the present application.
Fig. 3 is an enlarged view at a in fig. 2.
Fig. 4 is an enlarged view at B in fig. 2.
Description of the reference numerals: 1. a reaction kettle; 2. a reaction kettle body; 21. a heat-insulating layer; 22. a feed inlet; 23. a feed opening; 24. an interlayer; 25. an upper circulation port; 26. a lower circulation port; 3. a stirring mechanism; 31. a drive motor; 32. a stirring paddle; 4. a temperature regulating mechanism; 41. a flow dividing member; 411. a splitter plate; 42. a circulating member; 421. a circulation pump; 43. a temperature sensing component; 431. a temperature sensor; 432. a display screen; 5. a steaming-out mechanism; 51. a recovery tank; 52. an air outlet pipe; 53. a cooling tube; 54. a drainage plate; 55. a cooling device; 6. a reflux mechanism; 61. a return pipe; 62. a condensing unit; 7. a condenser tube; 8. a valve; 9. a helical channel.
Detailed Description
The present application will be described in further detail with reference to the accompanying FIGS. 1 to 4, examples and comparative examples, and all of the starting materials referred to in the present application are commercially available.
Examples
Example 1
A preparation process of a benzimidazole derivative intermediate is disclosed, and the synthetic route of the benzimidazole derivative intermediate is as follows:
the specific synthesis steps are as follows:
synthesis of compound (S1): controlling the temperature of the reaction kettle to be minus 12 +/-2 ℃, then adding 41.6g of acetonitrile and 64.5g of methanol, stirring and mixing uniformly, and slowly adding 78.9g of chloroethyl ester under stirring; then controlling the temperature of the reaction kettle to be 0 ℃, and stirring and preserving heat for 11 hours; then controlling the temperature of the reaction kettle to be 30 +/-2 ℃, distilling out the solvent, adding 253.3g of acetone into the distillation residue, stirring to obtain a suspension, and stirring and preserving the temperature of the suspension for 2 hours at the temperature of 3 +/-2 ℃; then, under the condition of nitrogen, filtering and separating suspension, washing by using 68.5g of acetone, and then carrying out vacuum drying for 5 hours at the temperature of 40 +/-2 ℃ to obtain a white powder compound (II);
synthesis of Compound (S2): 78.4g of benzylamine and 641.4g of methanol were added to the reaction vessel with stirring; controlling the temperature of the reaction kettle to be minus 8 +/-2 ℃, adding 80.2g of compound II, and stirring for 3 hours at the temperature of 3 ℃; IPC inspection is carried out in the reaction process, and when the benzylamine spot disappears on the thin-layer chromatographic plate, the reaction is stopped; evaporating the solvent at the temperature of 40 plus or minus 2 ℃; and 310.7g of acetone were added to the residue to obtain a suspension; stirring the obtained suspension for 5 hours at the temperature of 25 +/-2 ℃; the suspension is separated by filtration and washed with 65.2g of acetone; drying the obtained compound for 12h in vacuum at the temperature of 40 +/-2 ℃ to obtain a white powdery compound (c);
synthesis of compound S3 (iv): adding 121.6g of compound (c) and 90.4g of 2-bromomalonaldehyde into a reaction kettle, adding 355.2g of isopropanol, stirring and mixing to form suspension; then, 121.2g of triethylamine is slowly added into the suspension, the temperature is heated to 80 ℃, and the reflux and heat preservation are carried out for 12 hours; IPC detection is carried out in the reaction process, and the reaction is finished when the spots of the compound III disappear on a thin-layer chromatographic plate; evaporating the solvent at 50 +/-2 ℃, adding 1202.1g of dichloromethane and 903.9g of deionized water into the residue under the stirring state, separating the organic phase, adding 42.7g of sodium sulfate for separation and drying, washing with 147.8g of dichloromethane after filtration, and concentrating the filtrate under reduced pressure at the temperature of 40 +/-2 ℃ to obtain a brown compound (r);
synthesis of compound (S4): adding 250.4g of ethanol into a reaction kettle in a nitrogen environment, then slowly adding 53.3g of sodium ethoxide, and stirring for 1 h; adding 131.4g of diethyl succinate, heating to 55 ℃, slowly adding 107.9g of compound (r) into 255.4g of ethanol to obtain a mixed solution, controlling the adding time of the solution to be 3 hours, and then continuously stirring for 2.5 hours; the solvent was then distilled off at 50. + -. 2 ℃ and 1435.1g of dichloromethane and 1079.0g of deionized water were added to the distillation residue, the pH was adjusted to 5.0 using hydrochloric acid and stirring was carried out for 1 h; the organic phase was separated, 54.0g of sodium sulfate was added to the organic phase, separated and dried, and then filtered and washed with 173.7g of dichloromethane; concentrating the filtrate at 40 + -2 deg.C under reduced pressure, adding 434.3g methyl ethyl ketone into the residue, and concentrating at 40 + -2 deg.C under reduced pressure; to this residue, 1086g of methyl ethyl ketone was further added to form a suspension, which was stirred at 25 ± 2 ℃ for 3 h; filtering to separate suspension, vacuum drying the obtained compound with 173.7g methyl ethyl ketone at 40 + -2 deg.C for 12h to obtain light yellow to light brown powder;
synthesis of compound (S5): adding 61.9g of compound and 243.4g of acetonitrile into a reaction kettle, uniformly mixing and stirring, heating to 82 ℃, then slowly adding 53.9g of acetic anhydride, stirring for 1 hour, and keeping the temperature for 2 hours; then evaporating the solvent at 50 +/-2 ℃ to remove the anhydride in the mixture; then 98.1g of methanol was added to the distillation residue and concentrated under reduced pressure at 50. + -. 2 ℃ to give a residue; 526.4g of methanol are added to the concentrated residue and stirred to give a suspension which is cooled to 0 ℃ and 37.7g of sodium hydroxide solution are slowly added at this temperature, the reaction mixture is heated to 82 ℃ and heated under reflux for 2 h; the reaction mixture was cooled to 20 ℃; stirring and adding 664.6g of deionized water, adjusting the pH to 4.0 by using acetic acid, and stirring for 3h at the stirring speed of 90 rpm; filtering to separate suspension, washing with 105.3g methanol and 132.9g deionized water, and drying in a hot air drier at 45 +/-2 deg.c for 12 hr to obtain yellow to brown powdered compound, 3-benzyl-7-hydroxy-2-methyl-3H-benzimidazole-5-carboxylic acid.
Referring to fig. 1 and 2, in the above synthesis process, the synthesis of compound (ii), compound (iii), compound (iv), compound (v), and compound (c) is performed in reaction vessel 1. The reaction kettle 1 comprises a reaction kettle body 2, a stirring mechanism 3, a temperature regulating mechanism 4, an evaporating mechanism 5 and a backflow mechanism 6, wherein a heat insulation layer 21 is fixedly connected to the outer peripheral wall of the reaction kettle body 2, a feed inlet 22 is formed in the top end wall of the reaction kettle body 2, and a feed outlet 23 is formed in the peripheral wall, close to the bottom end, of the reaction kettle body 2; the temperature regulating mechanism 4 comprises a flow dividing component 41, a circulating component 42 and a temperature sensing component 43, and an interlayer 24 is arranged on the peripheral wall of the reaction kettle body 2; the shunting part 41 comprises a shunting plate 411, and the shunting plate 411 is fixedly connected inside the interlayer 24 in a spiral shape, namely a spiral channel 9 is formed inside the interlayer 24.
Referring to fig. 1 and 2, an upper circulation port 25 and a lower circulation port 26 are formed in the reaction kettle body 2, the upper circulation port 25 and the lower circulation port 26 are both communicated with the interior of the interlayer 24, the upper circulation port 25 is located above the flow distribution plate 411, and the lower circulation port 26 is located below the flow distribution plate 411. The circulating means 42 includes a circulating pump 421, and the circulating pump 421 supplies a cold source into the intermediate layer 24 from the lower circulating port 26 side and flows out from the upper circulating port 25 side.
Referring to fig. 1, 2 and 3, the temperature sensing part 43 includes a temperature sensor 431 and a display screen 432, the temperature sensor 431 is fixedly connected between the heat insulating layer 21 and the outer peripheral wall of the reaction kettle body 2, the display screen 432 is fixedly connected on the outer peripheral wall of the reaction kettle body 2 and extends out of the heat insulating layer 21, and the temperature sensor 431 transmits the sensed real-time temperature signal to the display screen 432 for display.
Referring to fig. 1 and 2, the stirring mechanism 3 is used for mixing and stirring materials in the reaction kettle body 2, and specifically includes a driving motor 31 and a stirring paddle 32, the driving motor 31 is fixedly connected to the top end wall of the reaction kettle body 2, and the stirring paddle 32 is fixedly connected to the driving end of the driving motor 31 and extends into the reaction kettle body 2.
Referring to fig. 1, 2 and 4, the steaming mechanism 5 includes a recovery tank 51, an outlet pipe 52, a cooling pipe 53, a flow guide plate 54 and a cooling device 55, the outlet pipe 52 is fixedly connected to the top end of the reaction kettle body 2 and is communicated with the inside of the reaction kettle body 2, the cooling pipe 53 is communicated with the top end of the outlet pipe 52, and the cooling pipe 53 is arranged from one side close to the outlet pipe 52 to one side far away from the outlet pipe 52 in a downward inclination manner. The recycling tank 51 is arranged in parallel with the reaction kettle body 2, one end of the cooling pipe 53, which is far away from the air outlet pipe 52, is communicated with the recycling tank 51, and a discharging port is arranged on the recycling tank 51, which is close to the bottom end. The flow guiding plate 54 is fixedly connected to the inner wall of the tube at the junction of the cooling tube 53 and the outlet tube 52, the flow guiding plate 54 is inclined upward from one side of the cooling tube 53 to one side of the outlet tube 52, and a gap is formed between the flow guiding plate 54 and the inner wall of the outlet tube 52. The cooling device 55 is used for cooling the cooling pipe 53, the cooling device 55 is a condensation pipe 7, and the condensation pipe 7 is sleeved on the outer wall of the cooling pipe 53; meanwhile, the air outlet pipe 52 can be opened and closed through the valve 8.
Referring to fig. 1, 2 and 4, the reflux mechanism 6 includes a reflux pipe 61 and a condensing unit 62, the reflux pipe 61 is fixedly connected to the top end wall of the reaction vessel body 2, the reflux pipe 61 is communicated with the inside of the reaction vessel body 2, and the top end of the reflux pipe 61 is in a closed state. The condensing unit 62 is used for cooling the return pipe 61, the condensing unit 62 is also a condensing pipe 7, and the condensing pipe 7 is sleeved on the outer wall of the return pipe 61.
The working principle of the reaction vessel 1 in this example is as follows: in the process of using the reaction kettle 1, firstly, the temperature of the reaction kettle body 2 needs to be regulated, and the process of regulating the temperature is as follows: a cold source or a heat source is introduced into the spiral channel 9 through the lower circulation port 26 by using the circulation pump 421, the cold source or the heat source flows in the spiral channel 9 in a spiral upward state until the cold source or the heat source flows out from one side of the upper circulation port 25, and under the condition that the cold source or the heat source is continuously introduced into the circulation pump 421, the circulation of the cold source or the heat source in the spiral channel 9 is realized, and the temperature is regulated at the required temperature. Meanwhile, the cycle rate can be regulated according to the real-time temperature transmitted to the display screen 432 by the temperature sensor 431 in the process, so that the temperature can be controlled within a required range.
After the temperature is regulated and controlled, when the materials need to be stirred, the driving motor 31 drives the stirring paddle 32 to rotate, so that the materials in the reaction kettle body 2 are stirred. When the reflux reaction is performed, condensed water is introduced into the condensing tube 7 on the reflux tube 61, and then the reflux reaction can be performed. And in the process of evaporating the solvent, introducing condensed water into the condensation pipe 7 on the cooling pipe 53, opening the valve 8, introducing the evaporated solvent into the cooling pipe 53 along the gas outlet pipe 52, re-condensing and liquefying in the cooling pipe 53, and finally introducing into the recovery tank 51 along the cooling pipe 53.
The reaction kettle 1 in the embodiment integrates the stirring mechanism 3, the reflux mechanism 6, the steaming mechanism 5 and the temperature regulating mechanism 4, and is matched with the preparation process of the benzimidazole derivative intermediate, so that the operation of replacing devices at different reaction stages is reduced, the material loss is reduced, the production efficiency is improved, and the product yield is improved.
Referring to fig. 1, fig. 2 and fig. 4, in the present embodiment, a return pipe 61 is further used as the outlet pipe 52, and a valve 8 is disposed on the outlet pipe 52 below the position where it communicates with the cooling pipe 53, that is, the cooling pipe 53 communicates with the end of the return pipe 61 away from the reaction kettle body 2.
Example 2
This example is different from example 1 in that, in the synthesis step of the compound of formula (II) S1, the temperature was controlled to-15. + -. 2 ℃ during the mixing of acetonitrile, methanol and chloroethyl ester.
Example 3
This example is different from example 1 in that in the synthesis step of the S1 compound (c), the temperature was controlled to-10 ± 2 ℃ during the mixing of acetonitrile, methanol and chloroethyl ester.
Example 4
This example is different from example 1 in that in the synthesis step of the S1 compound (c), the temperature was controlled to-5 ± 2 ℃ during the mixing of acetonitrile, methanol and chloroethyl ester.
Example 5
This example is different from example 1 in that, in the synthesis step of the compound of formula (II) S1, the temperature was controlled to-20. + -. 2 ℃ during the mixing of acetonitrile, methanol and chloroethyl ester.
Example 6
This example is different from example 1 in that in the synthesis step of the compound S2 (iii), 78.4g of benzylamine and 641.4g of methanol were added to the reaction kettle while stirring; the temperature of the reaction kettle is controlled to be minus 10 +/-2 ℃, 80.2g of compound (II) is added, and then the mixture is stirred for 3 hours at the temperature of 3 ℃.
Example 7
This example is different from example 1 in that in the synthesis step of the compound S2 (iii), 78.4g of benzylamine and 641.4g of methanol were added to the reaction kettle while stirring; controlling the temperature of the reaction kettle to be minus 6 +/-2 ℃, adding 80.2g of compound II, and stirring for 3 hours at the temperature of 3 ℃.
Example 8
This example is different from example 1 in that in the synthesis step of the compound S2 (iii), 78.4g of benzylamine and 641.4g of methanol were added to the reaction kettle while stirring; the temperature of the reaction kettle is controlled to be minus 8 +/-2 ℃, 80.2g of compound (II) is added, and then the mixture is stirred for 3 hours at the temperature of 2 ℃.
Example 9
This example is different from example 1 in that in the synthesis step of the compound (iii) S2, 78.4g benzylamine and 641.4g methanol were added to the reaction kettle under stirring; controlling the temperature of the reaction kettle to be minus 8 +/-2 ℃, adding 80.2g of compound II, and stirring for 3 hours at the temperature of 5 ℃.
Example 10
This example is different from example 1 in that in the synthesis step of the compound S2 (iii), 78.4g of benzylamine and 641.4g of methanol were added to the reaction kettle while stirring; the temperature of the reaction kettle is controlled to be minus 8 +/-2 ℃, 80.2g of compound (II) is added, and then the mixture is stirred for 3 hours at 7 ℃.
Example 11
This example is different from example 1 in that in the synthesis step of the compound (iii) S2, 78.4g benzylamine and 641.4g methanol were added to the reaction kettle under stirring; controlling the temperature of the reaction kettle to be minus 8 +/-2 ℃, adding 80.2g of compound II, and stirring for 3 hours at the temperature of 0 ℃.
Example 12
The difference between this example and example 1 is that triethylamine is added in the synthesis step of the compound (S3), and then the mixture is heated to 85 ℃ and refluxed and kept warm for 12 hours.
Example 13
The difference between this example and example 1 is that triethylamine is added in the synthesis step of the compound (S3), and then the mixture is heated to 70 ℃ and refluxed and kept warm for 12 h.
Example 14
The difference between this example and example 1 is that triethylamine is added in the synthesis step of the compound S3, and then the mixture is heated to 90 ℃ and refluxed and kept warm for 12 hours.
Example 15
The difference between this example and example 1 is that in the synthesis step of compound (S4), diethyl succinate is added and heated to 50 ℃, then the mixed solution obtained by dissolving compound (r) in ethanol is slowly added, the solution addition time is controlled to be 3h, and then stirring is continued for 2.5 h.
Example 16
The difference between this example and example 1 is that in the synthesis step of compound (S4), diethyl succinate is added and heated to 60 ℃, then the mixed solution obtained by dissolving compound (r) in ethanol is slowly added, the solution addition time is controlled to be 3h, and then stirring is continued for 2.5 h.
Example 17
The difference between this example and example 1 is that in the synthesis step of compound (S4), diethyl succinate is added and heated to 40 ℃, then the mixed solution obtained by dissolving compound (r) in ethanol is slowly added, the solution addition time is controlled to be 3h, and then stirring is continued for 2.5 h.
Example 18
The difference between this example and example 1 is that in the synthesis step of compound (S4), diethyl succinate is added and heated to 70 ℃, then the mixed solution obtained by dissolving compound (r) in ethanol is slowly added, the solution addition time is controlled to be 3h, and then stirring is continued for 2.5 h.
Comparative example
Comparative example 1
The comparative example is different from example 1 in that the synthesis of compound (ii), compound (iii), compound (iv), compound (v), and compound (c) was carried out in a common reaction vessel, and the corresponding apparatus was replaced in the reflux stage and the solvent evaporation stage.
Performance detection test method
1. Detecting the purity of the benzimidazole derivative intermediates obtained in examples 1-18 and comparative example 1 by HPLC;
2. the benzimidazole derivative intermediate yields obtained in examples 1 to 18 and comparative example 1 were calculated.
TABLE 1 test data sheet
By checking the data in Table 1 for purity and yield of the product, in combination with example 1 and comparative example
According to the detection result of the ratio 1, firstly, the purity and the yield of the benzimidazole derivative intermediate prepared by the synthetic route provided by the application are high. In addition, compared with a common reaction kettle, the reaction kettle designed by the application also has an evaporation mechanism, a temperature regulation and control mechanism and a reflux mechanism, can reduce the operation of replacing devices at different stages of reaction, and has obvious positive significance on product purity and yield.
According to the detection results of the embodiments 1 to 18, the method is suitable for regulating and controlling the reaction parameters, and the purity and the yield of the prepared benzimidazole derivative intermediate are high.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (10)
1. A preparation process of a benzimidazole derivative intermediate is characterized in that the synthetic route of the benzimidazole derivative intermediate is as follows:
in the synthesis route, the synthesis of a compound II, a compound III, a compound IV, a compound V and a compound IV is carried out in a reaction kettle (1), the reaction kettle (1) comprises a reaction kettle body (2), a stirring mechanism (3), a temperature regulating mechanism (4), an evaporation mechanism (5) and a reflux mechanism (6), the temperature regulating mechanism (4) comprises a flow dividing component (41), a circulating component (42) and a temperature sensing component (43), an interlayer (24) is arranged on the peripheral wall of the reaction kettle body (2), the flow dividing component (41) comprises a flow dividing plate (411), and the flow dividing plate (411) is spirally arranged in the interlayer (24), namely a spiral channel (9) is formed in the interlayer (24); an upper circulation port (25) and a lower circulation port (26) are formed in the reaction kettle body (2), the upper circulation port (25) and the lower circulation port (26) are communicated with the interior of the interlayer (24), the upper circulation port (25) is positioned above the flow distribution plate (411), the lower circulation port (26) is positioned below the flow distribution plate (411), the circulation part (42) comprises a circulation pump (421), and the circulation pump (421) introduces a cold and heat source into the interlayer (24) from one side of the lower circulation port (26) and flows out from one side of the upper circulation port (25); the temperature sensing component (43) comprises a temperature sensor (431) and a display screen (432), the temperature sensor (431) and the display screen (432) are both arranged on the reaction kettle body (2), and the temperature sensor (431) transmits a sensed real-time temperature signal to the display screen (432) for displaying; the stirring mechanism (3) is used for mixing materials in the reaction kettle body (2), the steaming mechanism (5) is used for steaming a solvent in a reaction system, and the reflux mechanism (6) is used for realizing reflux in reflux reaction.
2. The preparation process of the benzimidazole derivative intermediate according to claim 1, wherein an insulating layer (21) is arranged on the outer peripheral wall of the reaction kettle body (2), and the temperature sensor (431) is arranged between the insulating layer (21) and the reaction kettle body (2).
3. The preparation process of the benzimidazole derivative intermediate according to claim 1, wherein the steaming-out mechanism (5) comprises a recovery tank (51), an outlet pipe (52), a cooling pipe (53), a flow guiding plate (54) and a cooling device (55), the outlet pipe (52) is arranged at the top end of the reaction kettle body (2) and is communicated with the inside of the reaction kettle body (2), the cooling pipe (53) is communicated with one end of the outlet pipe (52) far away from the reaction kettle body (2), the cooling pipe (53) is arranged from one side close to the outlet pipe (52) to one side far away from the outlet pipe (52) in a downward sloping manner, the recovery tank (51) is arranged in parallel with the reaction kettle body (2), one end of the cooling pipe (53) far away from the outlet pipe (52) is communicated with the recovery tank (51), the flow guiding plate (54) is arranged on the inner wall of the cooling pipe (53), the flow guide plate (54) is arranged from one side of the cooling pipe (53) to one side of the air outlet pipe (52) in an upward inclined mode, a gap exists between the flow guide plate (54) and the inner wall of the air outlet pipe (52), and the cooling device (55) is used for cooling the cooling pipe (53).
4. The preparation process of the benzimidazole derivative intermediate according to claim 3, wherein the reflux mechanism (6) comprises a reflux pipe (61) and a condensing device (62), the reflux pipe (61) is arranged on the top end wall of the reaction kettle body (2), the reflux pipe (61) is communicated with the inside of the reaction kettle body (2), the top end of the reflux pipe (61) is in a closed state, and the condensing device (62) is used for cooling the reflux pipe (61).
5. The preparation process of the benzimidazole derivative intermediate according to claim 4, wherein the return pipe (61) is used as the outlet pipe (52), and a valve (8) is arranged on the outlet pipe (52) below the position where the outlet pipe is communicated with the cooling pipe (53), that is, the cooling pipe (53) is communicated with one end of the return pipe (61) far away from the reaction kettle body (2).
6. The preparation process of the benzimidazole derivative intermediate according to claim 1, wherein the compound (II) is synthesized by the following steps: at the temperature of minus 15 plus or minus 2 ℃ to minus 10 plus or minus 2 ℃, chloroethyl ester is added into a mixture of acetonitrile and methanol; stirring and reacting for 10-12 h, evaporating the solvent, and then sequentially performing extraction, filtration, washing and drying to obtain a compound II.
7. The preparation process of the benzimidazole derivative intermediate according to claim 1, wherein the compound (c) is synthesized by the following steps: adding a compound II into a mixture of benzylamine and methanol at the temperature of-10 +/-2 ℃ to-6 +/-2 ℃, primarily mixing, heating to 2-5 ℃, stirring and preserving heat for 2-3 hours, evaporating a solvent, and sequentially performing extraction, filtration, washing and drying to obtain the compound III.
8. The preparation process of the benzimidazole derivative intermediate according to claim 1, wherein the compound (iv) is synthesized by the following steps: adding triethylamine into a mixture of a compound (III), isopropanol and 2-bromomalonaldehyde, heating to 80-85 ℃, refluxing and preserving heat for 11-12 h, evaporating the solvent, and then sequentially performing extraction, drying, filtering, washing and concentration steps to obtain the compound (IV).
9. The process for preparing the benzimidazole derivative intermediate according to claim 1, wherein the compound (c) is synthesized by the following steps: adding sodium ethoxide into ethanol under the protection of inert gas, adding diethyl succinate, heating to 50-60 ℃, adding a compound IV, stirring, keeping the temperature for 2-3 hours, evaporating the solvent, and sequentially performing extraction, filtration, washing, reduced pressure concentration and vacuum drying to obtain the compound IV.
10. The preparation process of the benzimidazole derivative intermediate according to claim 1, wherein the compound (c) is synthesized by the following steps: mixing the compound fifthly with acetonitrile, heating to 80-85 ℃, adding acetic anhydride, stirring and preserving heat for 2-3 hours, adding methanol into the residue after distilling off the solvent, continuing adding methanol after concentrating under reduced pressure, cooling to-2-0 ℃, adding a sodium hydroxide solution, heating to 80-85 ℃, refluxing and preserving heat for 2-3 hours, cooling to 20-25 ℃, adding deionized water for dilution, adjusting the pH to 4.0-4.5, and sequentially filtering, washing and drying to obtain the compound (the intermediate of the benzimidazole derivative).
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115745838A (en) * | 2022-10-27 | 2023-03-07 | 苏州诚和医药化学有限公司 | Synthetic method of amidine compound and N-benzyl acetamidine hydrochloride |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115745838A (en) * | 2022-10-27 | 2023-03-07 | 苏州诚和医药化学有限公司 | Synthetic method of amidine compound and N-benzyl acetamidine hydrochloride |
| CN115745838B (en) * | 2022-10-27 | 2023-12-22 | 苏州诚和医药化学有限公司 | Method for synthesizing amidine compound and N-benzyl acetamidine hydrochloride |
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