CN114950318B - Production process of imidazole monoester - Google Patents
Production process of imidazole monoester Download PDFInfo
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- CN114950318B CN114950318B CN202210600147.9A CN202210600147A CN114950318B CN 114950318 B CN114950318 B CN 114950318B CN 202210600147 A CN202210600147 A CN 202210600147A CN 114950318 B CN114950318 B CN 114950318B
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- methylation
- imidazole
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- reaction
- temperature control
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title claims abstract description 153
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 16
- 238000007069 methylation reaction Methods 0.000 claims abstract description 170
- 230000011987 methylation Effects 0.000 claims abstract description 127
- 238000006243 chemical reaction Methods 0.000 claims abstract description 65
- 238000004821 distillation Methods 0.000 claims abstract description 60
- 239000007788 liquid Substances 0.000 claims abstract description 31
- 239000007787 solid Substances 0.000 claims abstract description 23
- -1 imidazole diester Chemical class 0.000 claims abstract description 17
- 238000001914 filtration Methods 0.000 claims abstract description 15
- 238000005886 esterification reaction Methods 0.000 claims abstract description 10
- 239000011541 reaction mixture Substances 0.000 claims abstract description 7
- 238000007670 refining Methods 0.000 claims abstract description 6
- ZUUNZDIGHGJBAR-UHFFFAOYSA-N 1h-imidazole-2,5-dicarboxylic acid Chemical compound OC(=O)C1=CNC(C(O)=O)=N1 ZUUNZDIGHGJBAR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000007791 liquid phase Substances 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000004744 fabric Substances 0.000 claims description 20
- 238000007599 discharging Methods 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- 238000009826 distribution Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- 239000002826 coolant Substances 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- 230000018044 dehydration Effects 0.000 claims description 5
- 238000006297 dehydration reaction Methods 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 7
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract 1
- 230000001276 controlling effect Effects 0.000 description 9
- 239000010410 layer Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229920001971 elastomer Polymers 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000005480 Olmesartan Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 5
- 229960005117 olmesartan Drugs 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical group BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 238000003825 pressing Methods 0.000 description 3
- 239000003507 refrigerant Substances 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000005253 cladding Methods 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229940102396 methyl bromide Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- NAXQLKYVZISHEZ-UHFFFAOYSA-N OC(C)(C)C=1N=C(N(C1C(=O)OC)C1=C(C=CC=C1)C1=NN=NN1)CCC Chemical compound OC(C)(C)C=1N=C(N(C1C(=O)OC)C1=C(C=CC=C1)C1=NN=NN1)CCC NAXQLKYVZISHEZ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000498 cooling water Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- KZBJJAFGNMRRHN-UHFFFAOYSA-N ethyl 5-(2-hydroxypropan-2-yl)-2-propyl-1h-imidazole-4-carboxylate Chemical compound CCCC1=NC(C(=O)OCC)=C(C(C)(C)O)N1 KZBJJAFGNMRRHN-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000007769 metal material Substances 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/18—Stationary reactors having moving elements inside
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D29/00—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor
- B01D29/01—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor with flat filtering elements
- B01D29/03—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor with flat filtering elements self-supporting
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D29/00—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor
- B01D29/01—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor with flat filtering elements
- B01D29/05—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor with flat filtering elements supported
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D29/00—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor
- B01D29/50—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor with multiple filtering elements, characterised by their mutual disposition
- B01D29/56—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor with multiple filtering elements, characterised by their mutual disposition in series connection
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D3/00—Distillation or related exchange processes in which liquids are contacted with gaseous media, e.g. stripping
- B01D3/02—Distillation or related exchange processes in which liquids are contacted with gaseous media, e.g. stripping in boilers or stills
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D36/00—Filter circuits or combinations of filters with other separating devices
- B01D36/003—Filters in combination with devices for the removal of liquids
-
- 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
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0053—Details of the reactor
-
- 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
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0053—Details of the reactor
- B01J19/0066—Stirrers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Vaporization, Distillation, Condensation, Sublimation, And Cold Traps (AREA)
Abstract
The application relates to the field of preparation of pharmaceutical intermediates, and particularly discloses a production process of imidazole monoester, which comprises the steps of taking imidazole dicarboxylic acid as a raw material, obtaining imidazole diester through esterification reaction, and preparing the imidazole diester through methylation reaction and refining steps; the methylation reaction system comprises a reaction kettle for methylation, a connecting pipe, a distillation kettle for methylation and a filter assembly connected to the connecting pipe, wherein the filter assembly comprises a filter plate and a collecting box; the inner cavity of the collecting box is communicated with the distilling kettle for methylation, the filtering plate separates the inner cavity of the collecting box to form a solid cavity and a liquid cavity, and after the reaction mixture is filtered by the filtering plate, the liquid phase enters the distilling kettle for methylation. The imidazole monoester methylation reaction is matched with a methylation reaction system, so that the transfer times of a reaction mixture are reduced, the transfer is convenient, and the production efficiency of the imidazole monoester is improved.
Description
Technical Field
The application relates to the technical field of olmesartan intermediate preparation, in particular to a production process of imidazole monoester.
Background
Olmesartan (Olmesartan) chemical name: 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [ 2' - (tetrazol-5-yl) phenyl ] methylimidazole-5-carboxylic acid, a novel angiotensin ii receptor inhibitor developed by japan three co-ltd, has the following structural formula:
。
4- (1-hydroxy-1-methylethyl) -2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (one of the imidazole monoesters) is a key intermediate for the preparation of olmesartan, and has the chemical structural formula:
。
the invention patent application with the application publication number of CN111170946A discloses a synthesis method of an olmesartan intermediate, and the technical scheme is as follows: tartaric acid is used as a raw material, and the compound is prepared through cyclization reaction, esterification reaction and methylation reaction; wherein the methylation reaction comprises the steps of:
Sequentially adding a first organic solvent, magnesium chips and an initiator into a Grignard preparation kettle, heating to 55-60 ℃ under the condition of nitrogen substitution and protection, starting to slowly introduce monohalomethane gas, keeping the temperature, continuing to introduce chloromethane gas until the magnesium chips are almost completely consumed, continuing to stir for about 1 hour, opening cooling water, cooling the reaction liquid to room temperature, and pressing into a methylation kettle for standby;
Step 2, cooling the Grignard solution in the methylation kettle to 0 ℃, starting to dropwise add the tetrahydrofuran solution of the imidazole diethyl ester, keeping the temperature for 3 hours after 5 hours, preparing an ammonium chloride aqueous solution in the hydrolysis kettle, putting the reaction solution in the hydrolysis kettle, hydrolyzing at the temperature of less than 10 ℃, keeping the temperature for 1 hour after 3 hours of discharging, and continuing to keep the temperature for 3 hours;
And 3, standing for layering, extracting a water layer by using tetrahydrofuran, combining an organic layer, washing by using saturated brine, layering, decoloring by using active carbon of the organic layer, and performing filter pressing to obtain a filtrate.
For the related art, the inventor considers that the methylation reaction is performed in the above manner, and generally, the reaction mixture needs to be placed in a grignard preparation kettle and then transferred to a hydrolysis kettle, and then a plurality of containers are needed in the steps of extraction, layering filtration and the like, so that the number of times that the reaction mixture needs to be transferred in the production process of the imidazole monoester is large, and the production efficiency is affected.
Disclosure of Invention
In order to improve the production efficiency of imidazole monoester, the application provides a production process of imidazole monoester.
The application provides a production process of imidazole monoester, which adopts the following technical scheme:
The imidazole monoester producing process with imidazole dicarboxylic acid as material includes esterification to obtain imidazole diester, methylation and refining to obtain imidazole diester, and the methylation includes the following steps:
S1, adding toluene, tetrahydrofuran, magnesium chips and iodine into a reaction kettle for methylation, and introducing monohalomethane into the reaction kettle for methylation to prepare a format reagent;
s2, dropwise adding toluene solution of imidazole diester into a reaction kettle for methylation, and stirring for reaction;
s3, after the reaction is finished, adding dilute hydrochloric acid into a reaction kettle for methylation, standing for layering, removing a water layer, adding anhydrous sodium sulfate for dehydration, filtering, and distilling to obtain an imidazole monoester crude product;
The device comprises a methylation reaction system, a first valve and a second valve, wherein the methylation reaction system comprises a reaction kettle for methylation, a connecting pipe, a distillation kettle for methylation and a filter assembly connected to the connecting pipe, the end part of the connecting pipe, which is close to the reaction kettle for methylation, is provided with the first valve, the filter assembly comprises a filter plate and a collecting box, one end of the connecting pipe is connected with the bottom of the reaction kettle for methylation, and the other end of the connecting pipe is connected with the top of the distillation kettle for methylation; the inner cavity of the collecting box is communicated with the distilling kettle for methylation, the filtering plate separates the inner cavity of the collecting box to form a solid cavity and a liquid cavity, the solid cavity is communicated with the reaction kettle for methylation, the liquid cavity is communicated with the distilling kettle for methylation, and after the reaction mixture is filtered by the filtering plate, the liquid phase enters the distilling kettle for methylation;
The bottom of the reaction kettle for methylation is connected with a water outlet pipe, and the end part of the water outlet pipe, which is close to the reaction kettle for methylation, is connected with a second valve; the top of the reaction kettle for methylation is connected with a water inlet pipe, and a third valve is connected to the water inlet pipe;
The top of the distillation kettle for methylation is connected with a distillation pipe for steam circulation;
the methylation reaction system further comprises a first temperature control component for controlling the temperature of the reaction kettle for methylation and a second temperature control component for controlling the temperature of the distillation kettle for methylation.
By adopting the technical scheme, toluene is adopted as a solvent to prepare toluene solution of imidazole diester in methylation reaction, the toluene volatility is low, the toluene price is cheaper than tetrahydrofuran, the toluene selling price is about 7 yuan/kg, and the tetrahydrofuran selling price is about 30 yuan/kg, so that the production cost is greatly reduced, and meanwhile, the toluene solution can be recovered for secondary use by subsequent distillation, so that the resource is saved; toluene is not easy to be miscible with water, and a simplified process flow is not required to be washed by saturated brine; after the pH is regulated by adding hydrochloric acid, excessive hydrochloric acid can be volatilized and removed by heating, so that the imidazole monoester is not easy to pollute, and the purity of the imidazole monoester is higher;
When the methylation reaction process is matched with a methylation reaction system, methylation reaction is carried out in a reaction kettle for methylation, after the reaction is finished, a third valve is opened, dilute hydrochloric acid enters the reaction kettle for methylation from a water inlet pipe to quench the reaction, and meanwhile, the pH value is adjusted; then, standing for layering, wherein the lower layer is a water layer, the upper layer is an organic layer, the second valve is opened to drain water, then the second valve is closed, anhydrous sodium sulfate is added into the reaction kettle for methylation for dehydration, then the second valve is opened, organic layer and sodium sulfate solid enter a connecting pipe and are filtered by a filter plate, liquid flows into the distillation kettle for methylation, and the solid is positioned in a collecting box. Heating and distilling in a distilling kettle for methylation, discharging steam from a distilling pipe, recycling distilled tetrahydrofuran and toluene, wherein residues in the distilling kettle for methylation are imidazole monoester crude products, and a first temperature control assembly and a second temperature control assembly are used for controlling the temperature in a reaction kettle for methylation and the distilling kettle for methylation, so that the preparation of format reagents is convenient, and the methylation reaction and the distillation in the distilling kettle for methylation are carried out; according to the scheme, the methylation reaction is carried out without converting a plurality of containers, only one transfer is needed, and the organic layer can be filtered and transferred through the connecting pipe and the first valve, so that the transfer is convenient, and the production efficiency of the imidazole monoester is improved.
Optionally, the filter plate is obliquely arranged, a discharge hole is formed in the side wall of the collecting box connected with the bottom end of the filter plate, and the filter plate is inclined towards the direction close to the discharge hole; the collecting box is provided with a discharging cover for closing the discharging hole, and the discharging hole is communicated with the solid cavity.
Through adopting above-mentioned technical scheme, the discharge gate is located the collection box lateral wall of being connected with the filter bottom, and discharge gate and solid chamber intercommunication, makes the discharge cap open the back, conveniently clears up the filter residue in the solid intracavity, and the filter inclines towards the direction that is close to the discharge gate, makes the filter have certain guide effect to the filter residue, makes things convenient for the filter residue to drop from the discharge gate, simultaneously, because the filter slope, makes the liquid phase see through the filter plate more easily and flow into the liquid intracavity along the filter, improves filtration rate.
Optionally, the filter plate comprises a support plate and filter cloth, the filter cloth wraps one side of the support plate facing the solid cavity, and the filter cloth also wraps the circumferential edge of the support plate; the support plate is provided with liquid-permeable holes, the inner wall of the collecting box is provided with a limiting ring groove, and the support plate tightly clamps the circumferential edge of the filter cloth in the limiting ring groove.
Through adopting above-mentioned technical scheme, the backup pad supports the filter cloth, and the backup pad is with filter cloth circumference border chucking in spacing annular, makes backup pad and filter cloth easy dismounting, makes things convenient for the change of filter cloth.
Optionally, a plurality of accepting plates are fixed with one side of backup pad towards the solid chamber, accepting plate tip is fixed with the backup pad, accepting plate tip extends towards the direction of keeping away from the backup pad.
Through adopting above-mentioned technical scheme, because anhydrous sodium sulfate powder absorbs water and forms sodium sulfate decahydrate crystal and become the piece, the board of accepting supports the piece, reduces the area of contact of piece and filter cloth, makes the filter be difficult for sheltering from by the piece, makes the filter keep better filter effect.
Optionally, the plurality of the board that accepts is parallel to each other and the interval sets up, the length direction of the board that accepts is the same with the incline direction along the backup pad.
Through adopting above-mentioned technical scheme, accept the board and be difficult for hindering filter residue from the discharge gate unloading, make the unloading convenient.
Optionally, the first temperature control subassembly includes first temperature control cover and first temperature control pipe, first temperature control cover is inside to be offered and is used for leading to the first clamp chamber of heating medium or refrigerant, first temperature control pipe intercommunication first clamp chamber, first temperature control cover cladding is in the reation kettle outer wall for the methylation.
Through adopting above-mentioned technical scheme, first accuse temperature cover cladding is in the reation kettle outer wall for methylation, lets in refrigerant or heat medium through first accuse temperature Guan Xiangdi a double-layered intracavity, makes convenient accurate control of temperature, and the temperature is comparatively stable.
Optionally, a vacuum pump for vacuumizing the methylation distillation kettle is connected to the distillation pipe.
Through adopting above-mentioned technical scheme, the vacuum pump evacuation makes during the filtration, and the filter is convenient to see through to the filtrate, improves the filter effect, and carries out reduced pressure distillation during the distillation, reduces the boiling point of toluene and tetrahydrofuran to reduce the required temperature of heat medium, practice thrift heat energy.
Optionally, be connected with the liquid separating pipe on the circumferential inner wall at the reaction kettle top for methylation, liquid separating pipe intercommunication inlet tube, it has a plurality of liquid separating mouths to distribute on the liquid separating pipe lateral wall, liquid separating mouths are towards the reaction kettle inner wall for methylation.
Through adopting above-mentioned technical scheme, a plurality of liquid dividing mouths make dilute hydrochloric acid spray on the reation kettle inner wall for the methylation, wash away the reactant to the reation kettle bottom for the methylation, make things convenient for follow-up operation.
Optionally, the methylation reaction system further comprises a driving assembly for driving the top of the methylation distillation kettle downwards, the driving assembly comprises a base, a driving motor and a gear assembly, two coaxially arranged rotating pipes are rotatably connected to the base, the two rotating pipes are connected with two sides of the top of the methylation distillation kettle, one rotating pipe is coaxially and rotatably connected with the end part of the connecting pipe, and the other rotating pipe is coaxially and rotatably connected with the end part of the distillation pipe;
the gear assembly comprises a driving gear and a driven gear, a mounting cavity for accommodating the gear assembly is formed in the base, the driven gear is coaxially fixed with one of the rotating pipes, the driving motor is fixed on the base, the driving gear and a motor shaft of the driving motor are coaxially fixed, and the driving gear and the driven gear are meshed.
Through adopting above-mentioned technical scheme, drive assembly drives the stills top down for the methylation, makes things convenient for taking out of imidazole monoester crude, also makes things convenient for the cleaning stills for the methylation simultaneously. The axis of the rotating pipe is the rotating shaft of the distilling still for methylation, and the driving gear is driven by the driving motor to rotate, so that the driven gear and the distilling still for methylation rotate, and the top of the distilling still for methylation is inclined downwards. The connecting pipe and the distillation pipe are rotatably connected to the rotating pipe, so that the distillation kettle for methylation can be conveniently rotated.
Optionally, the second temperature control subassembly includes second accuse temperature cover and second accuse temperature pipe, the second clamp chamber that is used for leading to heating medium or refrigerant is offered to second accuse temperature cover inside, second accuse temperature pipe intercommunication second clamp chamber, the bottom of reaction kettle for the methylation is located to second accuse temperature cover, second accuse temperature cover slides and sets up on the base, the slip direction of second accuse temperature cover is the direction of keeping away from or being close to the distillation kettle for the methylation, second accuse temperature pipe includes end connection's bellows and stereoplasm pipe, the bellows connection second accuse temperature cover, the flexible direction of bellows is the same with the slip direction of second accuse temperature cover.
Through adopting above-mentioned technical scheme, when the still for methylation needs to rotate, second accuse temperature cover slides to keeping away from the still for methylation department, need not to take the second accuse temperature cover when making the still for methylation rotate, reduces the quality of the still for methylation, makes things convenient for motor drive to rotate with the still for methylation. The hard pipe and the corrugated pipe are made of hard materials, and the corrugated pipe enables the second temperature control sleeve to slide conveniently, and is long in service life, high-temperature resistant and not easy to damage.
In summary, the application has the following beneficial effects:
1. The imidazole monoester methylation reaction is matched with a methylation reaction system, so that the transfer times of a reaction mixture are reduced, the transfer is convenient, and the production efficiency of the imidazole monoester is improved;
2. The support plate, the receiving plate and the filter cloth are arranged, so that the filtering efficiency is better;
3. through setting up base, driving motor, gear assembly and connecting pipe, make the stills ejection of compact for methylation convenient.
Drawings
FIG. 1 is a schematic diagram of the overall structure of a methylation reaction system of an example;
FIG. 2 is a schematic view of the structure of a filter assembly of an embodiment;
FIG. 3 is a cross-sectional view taken along line A-A of FIG. 2;
fig. 4 is an enlarged view at B of fig. 3;
FIG. 5 is a cross-sectional view of a reaction vessel for methylation;
FIG. 6 is a cross-sectional view of a distillation still for methylation;
Reference numerals: 1. a reaction kettle for methylation; 11. a water inlet pipe; 111. a third valve; 12. a liquid separating pipe; 121. a liquid separating port; 13. a water outlet pipe; 131. a second valve; 2. a distillation still for methylation; 21. a distillation tube; 211. a fourth valve; 212. a vacuum pump; 3. a connecting pipe; 31. a first valve; 4. a filter assembly; 41. a filter plate; 411. a support plate; 4111. a liquid-permeable hole; 412. a receiving plate; 413. a filter cloth; 42. a collection box; 421. a solid cavity; 422. a liquid chamber; 423. a limit ring groove; 424. a discharge port; 425. a first rotation shaft; 426. a discharge cover; 427. sealing ring grooves; 428. a rubber ring; 429. a limit bar; 4291. a second rotation shaft; 5. a first temperature control assembly; 51. a first temperature control jacket; 511. a first clamping cavity; 52. a first temperature control tube; 6. a drive assembly; 61. a base; 611. a support base; 612. a rotary tube; 613. a mounting cavity; 62. a driving motor; 63. a gear assembly; 631. a drive gear; 632. a driven gear; 7. a second temperature control assembly; 71. a second temperature control sleeve; 711. a second clamping cavity; 72. a second temperature control tube; 721. a bellows; 722. a hard tube; 8. a slide block; 81. and a sliding groove.
Detailed Description
The application is described in further detail below with reference to the examples and figures 1-6.
The embodiment of the application discloses a production process of imidazole monoester, which takes imidazole dicarboxylic acid as a raw material, obtains imidazole diester through esterification reaction, and is prepared through methylation reaction and refining step of the imidazole diester, wherein the equations of the esterification reaction and the methylation reaction are as follows:
Esterification reaction:
。
methylation reaction:
。
The specific steps of the esterification reaction are as follows: pumping 1500kg of ethanol into an esterification reaction kettle, adding 200kg of imidazole dicarboxylic acid at the temperature of 0-5 ℃, dropwise adding 240kg of thionyl chloride, refluxing and preserving heat for 8 hours until the reaction is complete, and distilling under reduced pressure to recover ethanol; adding 1200kg of water and 10kg of activated carbon into the reactant, preserving heat for 30min, stirring for decoloration, performing filter pressing, putting filtrate into a crystallization kettle, adjusting pH to 7.2 with sodium bicarbonate aqueous solution, cooling to 0 ℃, crystallizing, centrifugally separating solid and liquid, and vacuum drying the solid at 50 ℃ for 12h to obtain 240kg of imidazole diester.
The specific steps of the methylation reaction are as follows:
Referring to fig. 1, S1, preparation of a formative reagent: 200kg of toluene, 500kg of tetrahydrofuran, 50kg of magnesium chips and 0.2kg of iodine are added into a reaction kettle 1 for methylation, the mixture is heated to 55 ℃, and under the protection of nitrogen, methyl halide is introduced, wherein the methyl halide is methyl bromide or methyl chloride, 200kg of methyl bromide is introduced in the examples, and the mixture is stirred for 2 hours after the introduction is finished, so as to prepare a Grignard reagent;
S2, methylation reaction is carried out: 240kg of imidazole diester obtained by the esterification reaction is dissolved in 720kg of toluene to prepare toluene solution of imidazole diester, the content in the reaction kettle 1 for methylation is cooled to 0 ℃, the toluene solution of imidazole diester is dropwise added for 6h, and the mixture is stirred for 3h after the dropwise addition is completed;
S3, separating an imidazole monoester crude product: after the step S2 is completed, 260kg of 30wt% dilute hydrochloric acid and 1750kg of water are added into the reaction kettle 1 for methylation, stirring, standing and layering are carried out, a water layer is removed, 20kg of anhydrous sodium sulfate is added into an organic layer for dehydration, then filtration and reduced pressure distillation are carried out, toluene and tetrahydrofuran are recovered, and 220kg of crude imidazole monoester is obtained.
The refining steps are as follows: 220kg of crude imidazole monoester is added into a refining kettle, 400kg of isopropyl ether is added, the mixture is heated to 60 ℃ for dissolution, then cooled for crystallization, and is centrifuged, and vacuum drying is carried out for 24 hours at 50 ℃ to obtain 200kg of imidazole monoester, and the purity of the imidazole monoester is 99% through detection.
Referring to fig. 1, the process for producing an imidazole monoester further includes a methylation reaction system used in conjunction with the methylation reaction step. The methylation reaction system comprises a reaction kettle 1 for methylation, a distillation kettle 2 for methylation, a connecting pipe 3 and a filtering component 4 connected to the connecting pipe 3.
Referring to fig. 1, the bottom of the reaction kettle 1 for methylation has a higher level than the top of the distillation kettle 2 for methylation, and one end of the connecting pipe 3 is connected to the bottom of the reaction kettle 1 for methylation, and the other end is connected to the top of the distillation kettle 2 for methylation.
Referring to fig. 1, a first valve 31 is connected to the end of the connecting pipe 3 near the methylation reaction kettle 1, and the first valve 31 may be a butterfly valve or a ball valve, in the embodiment, a butterfly valve is selected.
Referring to fig. 1, the filter assembly 4 is connected to a side of the first valve 31 near the methylating still 2.
Referring to fig. 2 and 3, the filter assembly 4 includes a filter plate 41 and a collection box 42, the filter plate 41 partitions the inner cavity of the collection box 42 into a solid cavity 421 and a liquid cavity 422, and the solid cavity 421 is located above the liquid cavity 422.
Referring to fig. 1 and 3, the reaction vessel 1 for methylation communicates with the solid chamber 421, and the distillation vessel 2 for methylation communicates with the liquid chamber 422.
Referring to fig. 3 and 4, the filter plate 41 includes a support plate 411, a receiving plate 412 and a filter cloth 413, wherein a plurality of liquid permeable holes 4111 are distributed on the support plate 411, the end of the receiving plate 412 in the width direction is fixed on one side of the support plate 411 facing the solid cavity 421, a plurality of receiving plates 412 are parallel to each other and are arranged at intervals, and the interval between adjacent receiving plates 412 is 2-3cm. The filter cloth 413 covers the side of the bearing plate 412 and the supporting plate 411 located in the solid cavity 421, and the filter cloth 413 wraps the circumferential edge of the supporting plate 411.
Referring to fig. 3 and 4, a limiting ring groove 423 into which the filter plate 41 is clamped is formed in the inner wall of the collecting box 42, when the supporting plate 411 is clamped in the limiting ring groove 423, the circumferential edge of the filter cloth 413 is pressed in the limiting ring groove 423 by the end part of the supporting plate 411, and the filter cloth 413 has certain deformability, so that the filter plate 41 is clamped in the limiting ring groove 423 in an interference fit manner, and fixation is realized.
Referring to fig. 3 and 4, the supporting plate 411 is obliquely arranged in the collecting box 42, and a discharging hole 424 for discharging the filter residues is formed in the side wall of the collecting box 42 connected with the end part with the lowest position of the supporting plate 411. The length direction of the receiving plate 412 is the same as the inclination direction of the support plate 411.
Referring to fig. 3 and 4, a discharge cover 426 for controlling the opening and closing of the discharge port 424 is rotatably connected to the collection box 42 by providing a first rotation shaft 425. The first rotating shaft 425 is connected above the discharge port 424, the axis of the first rotating shaft 425 is horizontal and parallel to the plate surface of the supporting plate 411, and the discharge cover 426 is far away from or attached to the outer wall of the collecting box 42 after rotating and seals the discharge port 424.
Referring to fig. 3, the collecting box 42 is provided with a discharge port 424, and a seal ring groove 427 is provided on the outer side wall, and the seal ring groove 427 extends along the circumferential direction of the discharge port 424. A rubber ring 428 is fixed in the sealing ring groove 427, the rubber ring 428 protrudes out of the sealing ring groove 427, and one side of the rubber ring 428 away from the sealing ring groove 427 is used for abutting against the discharging cover 426 to seal the discharging hole 424.
Referring to fig. 2 and 3, the outer wall of the collecting box 42 provided with the discharge port 424 is rotatably connected with a limiting bar 429 by providing a second rotation shaft 4291, the length direction of the second rotation shaft 4291 is horizontal, and the length direction of the second rotation shaft 4291 is perpendicular to the length direction of the first rotation shaft 425. The length direction of the limiting strip 429 is perpendicular to the length direction of the second rotating shaft 4291, the end part of the limiting strip 429, which is far away from the rotating shaft, rotates to the side, which is far away from the discharge hole 424, of the discharge cover 426, so that the limiting strip 429 presses the discharge cover 426 on the rubber ring 428, and the discharge hole 424 is sealed. When the limiting bar 429 rotates to be separated from the discharging cover 426, the discharging cover 426 can rotate towards a direction away from the discharging hole 424, so that discharging is realized at the discharging hole 424.
Referring to fig. 1, a water inlet pipe 11 through which dilute hydrochloric acid and water enter the methylation reaction kettle 1 is connected to the top of the methylation reaction kettle 1, and a third valve 111 is connected to the water inlet pipe 11, wherein the third valve 111 is a ball valve.
Referring to fig. 5, a liquid distribution pipe 12 is fixed to the inner wall of the top of the reaction kettle 1 for methylation, the liquid distribution pipe 12 is communicated with a water inlet pipe 11, a plurality of liquid distribution openings 121 are distributed on the liquid distribution pipe 12, and the liquid distribution openings 121 face the inner wall of the reaction kettle 1 for methylation, so that water can flush the inner wall of the reaction kettle 1 for methylation.
Referring to fig. 5, the bottom of the reaction kettle 1 for methylation is connected with a water outlet pipe 13, the end of the water outlet pipe 13, which is close to the reaction kettle 1 for methylation, is connected with a second valve 131 for controlling the on-off of the water storage pipe, and the second valve 131 can be a ball valve or a butterfly valve, and in the embodiment, a butterfly valve is selected.
Referring to fig. 5, the methylation reaction system further includes a first temperature control assembly 5 for controlling the temperature of the reaction kettle 1 for methylation, the first temperature control assembly 5 includes a first temperature control sleeve 51 and two first temperature control pipes 52, the first temperature control sleeve 51 is cylindrical, and the first temperature control sleeve 51 is sleeved at the bottom end of the reaction kettle 1 for methylation. The first temperature control sleeve 51 is internally provided with a first clamping cavity 511, the first clamping cavity 511 is communicated with two first temperature control pipes 52, one first temperature control pipe 52 is used for allowing a cooling medium or a heating medium to enter the first clamping cavity 511, and the other first temperature control pipe 52 is used for allowing the cooling medium or the heating medium to be discharged out of the first clamping cavity 511.
Referring to fig. 1, a distillation tube 21 is connected to the top of the methylation distillation still 2, a fourth valve 211 is connected to the distillation tube 21, the fourth valve 211 is a ball valve, and a vacuum pump 212 for evacuating the inner cavity of the methylation distillation still 2 is also connected to the distillation tube 21.
Referring to fig. 6, the methylation reaction system further comprises a driving assembly 6 for driving the top of the methylation distillation still 2 to flip downward, wherein the driving assembly 6 comprises a base 61, a driving motor 62 and a gear assembly 63. The base 61 includes two supporting seats 611, and two rotating pipes 612 are rotatably connected to one side of the two supporting seats 611, where the axes of the two rotating pipes 612 coincide. The ends of the two rotating pipes 612 that are close to each other are fixed to the top of the methylation distillation still 2. The end of the connecting pipe 3 close to the methylation distillation still 2 is coaxially and rotatably connected to the rotary pipe 612, and the end of the distillation pipe 21 close to the methylation distillation still 2 is coaxially and rotatably connected to the other rotary pipe 612.
Referring to fig. 6, a mounting chamber 613 for accommodating the gear assembly 63 is formed in the support seat 611 adjacent to the distillation tube 21, and a rotation tube 612 connected to the distillation tube 21 penetrates the mounting chamber 613. The gear assembly 63 includes a driving gear 631 and a driven gear 632, the driven gear 632 and a rotation pipe 612 connected to the distillation pipe 21 are coaxially fixed, the driving motor 62 is fixed to the support base 611, a motor shaft of the driving motor 62 extends into the mounting chamber 613, the motor shaft of the driving motor 62 and the driving gear 631 are coaxially fixed, and the driving gear 631 and the driven gear 632 are engaged. When the driving motor 62 drives the driving gear 631 to rotate, the driven gear 632 can rotate and drive the rotation tube 612 and the reaction vessel to rotate.
Referring to fig. 6, the methylation reaction system further includes a second temperature control assembly 7 for controlling the temperature of the methylation distillation still 2, the second temperature control assembly 7 includes a second temperature control sleeve 71 and two second temperature control pipes 72, the second temperature control sleeve 71 is located between two supporting seats 611, sliding blocks 8 are fixed on two side walls of the second temperature control sleeve 71, and sliding grooves 81 for sliding the sliding blocks 8 are formed on two side walls of the supporting seats 611, which are close to each other. The second temperature control jacket 71 slides in a direction away from or toward the bottom of the methylation still 2 so that the methylation still 2 can be separated from the second temperature control jacket 71 or the methylation still 2 can enter the second temperature control jacket 71.
Referring to fig. 6, the sliding block 8 is made of rubber, has a certain deformation capability, and also has a certain supporting force, and the inner wall of the sliding groove 81 is fixed with the sliding block 8 in an interference fit manner, so that the sliding block 8 is not easy to slide in the sliding groove 81 under the action of external force due to the friction force of the sliding groove 81 to the sliding block 8.
Referring to fig. 6, a second clamping chamber 711 is provided in the second temperature control jacket 71, and both second temperature control pipes 72 are communicated with the second clamping chamber 711. One of the second temperature control pipes 72 is used for allowing a cooling medium or a heating medium to enter the clamping cavity, and the other second temperature control pipe 72 is used for allowing the cooling medium or the heating medium to exit the clamping cavity.
Referring to fig. 6, the second temperature controlling pipe 72 includes a bellows 721 and a hard pipe 722, the bellows 721 and the hard pipe 722 are both made of metal materials, the bellows 721 is capable of shrinking, the shrinking direction of the bellows 721 is a vertical direction, and the shrinking direction of the bellows 721 is the same as the sliding direction of the second temperature controlling jacket 71.
Referring to fig. 5 and 6, the methylation reaction vessel 1 and the methylation distillation vessel 2 are each provided with a stirring paddle for stirring the material in the vessel and a stirring motor for driving the stirring paddle to rotate.
The implementation principle of the production process of the imidazole monoester in the embodiment of the application is as follows: the methylation reaction flow is used by matching with a methylation reaction system, so that a plurality of containers are not required to be replaced in the methylation reaction process. When the reaction is carried out in the reaction kettle 1 for methylation, water and dilute hydrochloric acid are added through the water inlet pipe 11 for quenching reaction after the reaction is completed, a water layer at the bottom is discharged through the water outlet pipe 13 after layering, anhydrous sodium sulfate is added into the collecting layer for dehydration, the anhydrous sodium sulfate is filtered through the first connecting pipe 3 and the filtering component 4, the vacuum pump 212 is started for suction through the filtering, the filtering efficiency is quickened, filter residues can be discharged from the discharge port 424, filtrate enters the distillation kettle 2 for methylation along the connecting pipe 3, the filtrate is heated and distilled through the second temperature control component 7, the vacuum pump 212 is vacuumized during distillation to reduce the boiling points of solvent toluene and tetrahydrofuran, and the toluene and the tetrahydrofuran can be recycled, so that the method is energy-saving and environment-friendly. After vacuumizing and drying, the crude imidazole monoester is positioned at the bottom of the distillation kettle 2 for methylation, the kettle cover of the distillation kettle 2 for methylation is opened, the distillation kettle 2 for methylation is driven to rotate by a driving motor 62, the top of the distillation kettle 2 for methylation is turned downwards, and the material discharging and the cleaning of the distillation kettle 2 for methylation are facilitated.
The present embodiment is only for explanation of the present application and is not to be construed as limiting the present application, and modifications to the present embodiment, which may not creatively contribute to the present application as required by those skilled in the art after reading the present specification, are all protected by patent laws within the scope of claims of the present application.
Claims (10)
1. The process for producing the imidazole monoester is characterized in that imidazole dicarboxylic acid is used as a raw material, imidazole diester is obtained through esterification reaction, and the imidazole diester is prepared through methylation reaction and refining, wherein the methylation reaction comprises the following steps:
S1, adding toluene, tetrahydrofuran, magnesium chips and iodine into a reaction kettle (1) for methylation, and introducing monohalomethane into the reaction kettle (1) for methylation to prepare a format reagent;
s2, dropwise adding toluene solution of imidazole diester into the reaction kettle (1) for methylation, and stirring for reaction;
s3, after the reaction is finished, adding dilute hydrochloric acid into a reaction kettle (1) for methylation, standing for layering, removing a water layer, adding anhydrous sodium sulfate for dehydration, filtering, and distilling to obtain an imidazole monoester crude product;
The device comprises a methylation reaction system, and is characterized by further comprising a reaction kettle (1) for methylation, a connecting pipe (3), a distillation kettle (2) for methylation and a filter assembly (4) connected to the connecting pipe (3), wherein a first valve (31) is arranged at the end part of the connecting pipe (3) close to the reaction kettle (1) for methylation, the filter assembly (4) comprises a filter plate (41) and a collecting box (42), one end of the connecting pipe (3) is connected with the bottom of the reaction kettle (1) for methylation, and the other end of the connecting pipe is connected with the top of the distillation kettle (2) for methylation; the inner cavity of the collecting box (42) is communicated with the distilling kettle (2) for methylation, the inner cavity of the collecting box (42) is divided by the filter plate (41) to form a solid cavity (421) and a liquid cavity (422), the solid cavity (421) is communicated with the distilling kettle (1) for methylation, the liquid cavity (422) is communicated with the distilling kettle (2) for methylation, and after the reaction mixture is filtered by the filter plate (41), a liquid phase enters the distilling kettle (2) for methylation;
The bottom of the reaction kettle (1) for methylation is connected with a water outlet pipe (13), and the end part of the water outlet pipe (13) close to the reaction kettle (1) for methylation is connected with a second valve (131); the top of the reaction kettle (1) for methylation is connected with a water inlet pipe (11), and the water inlet pipe (11) is connected with a third valve (111);
The top of the distillation kettle (2) for methylation is connected with a distillation pipe (21) for circulating steam;
The methylation reaction system also comprises a first temperature control component (5) for controlling the temperature of the reaction kettle (1) for methylation and a second temperature control component (7) for controlling the temperature of the distillation kettle (2) for methylation.
2. The process for producing an imidazole monoester according to claim 1, wherein: the filter plate (41) is obliquely arranged, a discharge hole (424) is formed in the side wall of a collecting box (42) connected with the bottom end of the filter plate (41), and the filter plate (41) is inclined towards the direction close to the discharge hole (424); the collecting box (42) is provided with a discharging cover (426) for closing a discharging hole (424), and the discharging hole (424) is communicated with the solid cavity (421).
3. The process for producing an imidazole monoester according to claim 2, wherein: the filter plate (41) comprises a support plate (411) and filter cloth (413), wherein the filter cloth (413) wraps one side of the support plate (411) facing the solid cavity (421), and the filter cloth (413) also wraps the circumferential edge of the support plate (411); liquid-permeable holes (4111) are distributed in the supporting plate (411), limiting ring grooves (423) are formed in the inner wall of the collecting box (42), and the circumferential edges of the filter cloth (413) are clamped in the limiting ring grooves (423) by the supporting plate (411).
4. A process for the production of an imidazole monoester according to claim 3, characterized in that: one side of the supporting plate (411) facing the solid cavity (421) is fixed with a plurality of bearing plates (412), the end parts of the bearing plates (412) are fixed with the supporting plate (411), and the end parts of the bearing plates (412) extend in the direction away from the supporting plate (411).
5. The process for producing an imidazole monoester according to claim 4, wherein: the plurality of bearing plates (412) are arranged in parallel and at intervals, and the length direction of the bearing plates (412) is the same as the inclination direction along the supporting plate (411).
6. The process for producing an imidazole monoester according to claim 1, wherein: the first temperature control assembly (5) comprises a first temperature control sleeve (51) and a first temperature control tube (52), a first clamping cavity (511) for communicating a heating medium or a cooling medium is formed in the first temperature control sleeve (51), the first temperature control tube (52) is communicated with the first clamping cavity (511), and the first temperature control sleeve (51) is coated on the outer wall of the reaction kettle (1) for methylation.
7. The process for producing an imidazole monoester according to claim 1, wherein: the distillation tube (21) is connected with a vacuum pump (212) for vacuumizing the methylation distillation kettle (2).
8. The process for producing an imidazole monoester according to claim 1, wherein: the reaction kettle for methylation (1) is characterized in that a liquid distribution pipe (12) is connected to the circumferential inner wall of the top of the reaction kettle for methylation (1), the liquid distribution pipe (12) is communicated with a water inlet pipe (11), a plurality of liquid distribution ports (121) are distributed on the side wall of the liquid distribution pipe (12), and the liquid distribution ports (121) face the inner wall of the reaction kettle for methylation (1).
9. The process for producing an imidazole monoester according to claim 1, wherein: the methylation reaction system further comprises a driving assembly (6) for driving the top of the methylation distillation kettle (2) downwards, the driving assembly (6) comprises a base (61), a driving motor (62) and a gear assembly (63), two coaxially arranged rotating pipes (612) are rotatably connected to the base (61), the two rotating pipes (612) are connected with two sides of the top of the methylation distillation kettle (2), one rotating pipe (612) is coaxially and rotatably connected with the end part of the connecting pipe (3), and the other rotating pipe (612) is coaxially and rotatably connected with the end part of the distillation pipe (21);
The gear assembly (63) comprises a driving gear (631) and a driven gear (632), a mounting cavity (613) for accommodating the gear assembly (63) is formed in the base (61), the driven gear (632) is coaxially fixed with one of the rotating pipes (612), the driving motor (62) is fixed on the base (61), the driving gear (631) and a motor shaft of the driving motor (62) are coaxially fixed, and the driving gear (631) and the driven gear (632) are meshed.
10. The process for producing an imidazole monoester according to claim 9, wherein: the second temperature control assembly (7) comprises a second temperature control sleeve (71) and a second temperature control tube (72), a second clamping cavity (711) used for communicating a heating medium or a cooling medium is formed in the second temperature control sleeve (71), the second temperature control tube (72) is communicated with the second clamping cavity (711), the second temperature control sleeve (71) is sleeved at the bottom of the reaction kettle (1) for methylation, the second temperature control sleeve (71) is arranged on the base (61) in a sliding mode, the sliding direction of the second temperature control sleeve (71) is the direction away from or close to the distillation kettle (2) for methylation, the second temperature control tube (72) comprises a corrugated tube (721) and a hard tube (722) which are connected with the end portion, and the extending direction of the corrugated tube (721) is the same as the sliding direction of the second temperature control sleeve (71).
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| CN102101844A (en) * | 2009-12-18 | 2011-06-22 | 上海信凯生物医药科技有限公司 | Preparation method of 2-propyl-4-[(1-hydroxy-1-methyl) ethyl]-1H-imidazole-5-carboxylic acid ethyl ester |
| CN101798300A (en) * | 2010-02-23 | 2010-08-11 | 陈志龙 | N-phenylindole methyl substituted bis-benzimidazole derivative and application thereof in reducing blood pressure and the like |
| CN102649779A (en) * | 2012-04-20 | 2012-08-29 | 山东鲁药制药有限公司 | Synthesis method for medicine intermediate 1-methyl-3-phenylpiperazine |
| CN103319529A (en) * | 2013-07-17 | 2013-09-25 | 山东潍坊润丰化工有限公司 | Synthetic method of diethyl methyl-phosphonite and glufosinate-ammonium |
| CN103626771A (en) * | 2013-11-22 | 2014-03-12 | 安徽悦康凯悦制药有限公司 | Process for preparing doripenem |
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