CN117582909B - System and method for continuously producing 5-isosorbide mononitrate - Google Patents
System and method for continuously producing 5-isosorbide mononitrate Download PDFInfo
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- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 title claims abstract description 54
- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000006386 neutralization reaction Methods 0.000 claims abstract description 171
- 238000006243 chemical reaction Methods 0.000 claims abstract description 169
- 239000007788 liquid Substances 0.000 claims abstract description 150
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 100
- 238000000605 extraction Methods 0.000 claims abstract description 79
- 238000010791 quenching Methods 0.000 claims abstract description 71
- 238000000926 separation method Methods 0.000 claims abstract description 66
- 230000000171 quenching effect Effects 0.000 claims abstract description 63
- 238000002425 crystallisation Methods 0.000 claims abstract description 50
- 230000008025 crystallization Effects 0.000 claims abstract description 50
- 239000000126 substance Substances 0.000 claims abstract description 17
- 239000000047 product Substances 0.000 claims description 157
- 239000012074 organic phase Substances 0.000 claims description 119
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 87
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 78
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 75
- 239000007795 chemical reaction product Substances 0.000 claims description 64
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 58
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 50
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 41
- 239000000706 filtrate Substances 0.000 claims description 39
- 239000012266 salt solution Substances 0.000 claims description 36
- 239000002994 raw material Substances 0.000 claims description 35
- 239000008346 aqueous phase Substances 0.000 claims description 34
- KLDXJTOLSGUMSJ-JGWLITMVSA-N Isosorbide Chemical compound O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 KLDXJTOLSGUMSJ-JGWLITMVSA-N 0.000 claims description 30
- 239000003513 alkali Substances 0.000 claims description 30
- 229960002479 isosorbide Drugs 0.000 claims description 30
- 229910017604 nitric acid Inorganic materials 0.000 claims description 29
- 230000001546 nitrifying effect Effects 0.000 claims description 29
- 239000003153 chemical reaction reagent Substances 0.000 claims description 26
- 229960003827 isosorbide mononitrate Drugs 0.000 claims description 23
- 238000006396 nitration reaction Methods 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 16
- 239000012467 final product Substances 0.000 claims description 15
- 230000001105 regulatory effect Effects 0.000 claims description 15
- 238000005886 esterification reaction Methods 0.000 claims description 14
- 238000012544 monitoring process Methods 0.000 claims description 14
- 230000035484 reaction time Effects 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 13
- 239000012452 mother liquor Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 239000011259 mixed solution Substances 0.000 claims description 11
- 238000012806 monitoring device Methods 0.000 claims description 11
- 238000010924 continuous production Methods 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 239000012071 phase Substances 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 229960000201 isosorbide dinitrate Drugs 0.000 claims description 7
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 239000012265 solid product Substances 0.000 claims description 5
- 239000012141 concentrate Substances 0.000 claims description 4
- 239000011552 falling film Substances 0.000 claims description 4
- 239000007791 liquid phase Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 4
- 230000003068 static effect Effects 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 2
- 239000000523 sample Substances 0.000 claims 2
- 239000003518 caustics Substances 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 230000001276 controlling effect Effects 0.000 description 25
- 235000019441 ethanol Nutrition 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 239000000463 material Substances 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 239000007787 solid Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000010923 batch production Methods 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 241000208011 Digitalis Species 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- -1 polytetrafluoroethylene Polymers 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- 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
-
- 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
- B01J19/0006—Controlling or regulating processes
-
- 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
- B01J19/0086—Processes carried out with a view to control or to change the pH-value; Applications of buffer salts; Neutralisation reactions
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a system and a method for continuously producing 5-isosorbide mononitrate, and relates to the technical field of chemical industry. The system comprises a first continuous reaction unit, a second continuous reaction unit, a continuous quenching unit, a first continuous neutralization unit, a continuous solid-liquid separation unit, a first continuous extraction unit, a first continuous concentration unit, a sodium salt crystallization unit, a second continuous neutralization unit, a continuous liquid separation unit, a second continuous extraction unit, a second continuous concentration unit and a finished product crystallization unit; the system can continuously produce the 5-isosorbide mononitrate, has higher yield and purity of the product, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of chemical industry, in particular to a system and a method for continuously producing 5-isosorbide mononitrate.
Background
The 5-isosorbide mononitrate is mainly used for the long-term treatment and prevention of coronary heart disease and angina pectoris; can also be used in combination with digitalis and/or diuretics to treat chronic congestive heart failure.
At present, three routes for industrially synthesizing the 5-isosorbide mononitrate are as follows: indirect nitration, direct nitration, and selective reduction. The indirect nitration method has long synthetic process route, the partial method needs to adopt a catalyst, so that the cost is high, the nitration condition is difficult to control, the generated byproducts are difficult to remove, the product is difficult to purify, and the reaction yield is low. The safety risk of the direct nitration method reaction and the post-treatment is high. The disadvantage of the selective reduction method is that the selective reduction is not thorough, and the cost of the selective reducing agent and the catalyst is high, resulting in excessive cost. The main stream industrialized production route still adopts a direct nitration method, and is mainly based on the advantages of short route, low cost, simple operation and the like of the direct nitration method.
Disclosure of Invention
The invention mainly aims to provide a system and a method for continuously producing 5-isosorbide mononitrate, which are used for solving the problem that the prior art is difficult to produce the 5-isosorbide mononitrate with high purity efficiently, with low cost and safely.
In order to achieve the above object, according to a first aspect of the present invention, there is provided a system for continuously producing isosorbide-5-mononitrate, the system comprising:
A first continuous reaction unit having a nitric acid inlet, an acetic anhydride inlet, and a nitrifying reagent outlet, the first continuous reaction unit being for continuously performing a nitrifying reaction of nitric acid and acetic anhydride to generate a nitrifying reagent;
the second continuous reaction unit is provided with a nitrifying reagent inlet, a reaction raw material inlet and a liquid outlet to be quenched; the nitrifying reagent inlet is connected with the nitrifying reagent outlet, and the second continuous reaction unit is used for continuously carrying out esterification reaction on the reaction raw materials to obtain liquid to be quenched; the reaction raw material comprises isosorbide;
the continuous quenching unit is provided with a to-be-quenched liquid inlet, a quencher inlet and a quenched product outlet, the to-be-quenched liquid inlet is connected with the to-be-quenched liquid outlet, and the continuous quenching unit is used for carrying out continuous quenching treatment on the to-be-quenched liquid to obtain a quenched product;
the first continuous neutralization unit is used for continuously carrying out neutralization reaction on the quenching product to obtain a first neutralization reaction product;
the continuous solid-liquid separation unit is used for carrying out continuous solid-liquid separation on the first neutralization reaction product to obtain filtrate;
The first continuous extraction unit is used for continuously extracting the filtrate to obtain a first organic phase;
the first continuous concentration unit is provided with a first organic phase inlet, a first concentrated product outlet and a first fraction outlet, the first organic phase inlet is connected with the first organic phase outlet, and the first continuous concentration unit is used for continuously concentrating the first organic phase to obtain a first concentrated product;
the sodium salt crystallization unit is provided with a first concentrated product inlet, a water inlet, a second liquid alkali inlet, a sodium salt outlet and a sodium salt mother liquor outlet, the first concentrated product inlet is connected with the first concentrated product outlet, and the sodium salt crystallization unit is used for continuously crystallizing the first concentrated product to obtain sodium salt;
the second continuous neutralization unit is provided with a sodium salt solution inlet, an acid inlet and a second neutralization reaction product outlet, the sodium salt solution inlet is connected with a sodium salt solution tank, the sodium salt solution tank is connected with the sodium salt outlet, and the second continuous neutralization unit is used for continuous neutralization reaction of the sodium salt solution to obtain a second neutralization reaction product;
The continuous liquid separation unit is used for continuously separating the second neutralization reaction product to continuously separate a second organic phase and a second aqueous phase;
the second continuous extraction unit is used for continuously extracting the second aqueous phase to obtain a third organic phase;
the second continuous concentration unit is provided with a second organic phase inlet, a third organic phase inlet, a second concentrated product outlet and a second fraction outlet, the second organic phase inlet is connected with the second organic phase outlet, the third organic phase inlet is connected with the third organic phase outlet, and the second continuous concentration unit is used for continuously concentrating the second organic phase and the third organic phase to obtain a second concentrated product;
and the finished product crystallization unit is provided with a second concentrated product inlet, a finished product mother liquor outlet and a finished product outlet, wherein the second concentrated product inlet is connected with the second concentrated product outlet, and the finished product crystallization unit is used for crystallizing the second concentrated product to obtain the 5-isosorbide mononitrate.
Further, the system further comprises:
the first online pH monitoring device is connected with the first continuous neutralization unit and is used for online monitoring the pH value of the reaction system in the first continuous neutralization unit; the second online pH monitoring device is connected with the second continuous neutralization unit and is used for online monitoring the pH value of the reaction system in the second continuous neutralization unit; and/or
The second organic phase inlet and the third organic phase inlet are the same inlet or two inlets.
Further, the first continuous reaction unit and the second continuous reaction unit are each independently one of a static mixer, a microchannel mixer, a stirring mixer, a jet mixer, a tubular reactor, a continuous columnar stirring reactor, and a continuous kettle reactor; and/or
The continuous quenching unit, the first continuous neutralization unit and the second continuous neutralization unit are continuous stirring reactors; and/or
The continuous solid-liquid separation unit is one of a horizontal decanter centrifuge, a disc centrifuge and a flat plate decanter centrifuge; and/or
The first continuous extraction unit and the second continuous extraction unit are one of a centrifugal extractor, a continuous extraction column and a rotary disk extractor; and/or
The first continuous concentration unit and the second continuous concentration unit are continuous falling film concentration devices; and/or
The continuous liquid separation unit is one of a liquid-liquid phase separator and an extraction liquid separation column.
According to a second aspect of the present invention there is provided a process for the continuous production of isosorbide-5-mononitrate using the system described above, the process comprising the steps of:
s1, adding nitric acid into acetic anhydride to perform nitration reaction to obtain a nitration reagent; dissolving isosorbide in acetic acid to obtain a raw material solution;
s2, adding a nitrifying reagent into the raw material solution to perform esterification reaction to obtain a liquid to be quenched;
s3, adding a quenching agent into the liquid to be quenched to obtain a quenched product;
s4, adding liquid alkali into the quenched product, and adjusting the pH value to 6.2-6.7 to obtain a first neutralization reaction product;
s5, filtering the first neutralization reaction product to obtain an isosorbide dinitrate solid product and a filtrate;
s6, adding a first extractant into the filtrate to obtain a first organic phase;
s7, concentrating the first organic phase to obtain a first concentrated product;
s8, adding water and liquid alkali into the first concentrated product for crystallization, and filtering to obtain sodium salt and sodium salt mother liquor;
s9, dissolving sodium salt in a mixed solution of water and ethyl acetate to obtain a sodium salt solution; adding acid into the sodium salt solution, and regulating the pH value to 6.2-6.7 to obtain a second neutralization reaction product;
S10, separating a second neutralization reaction product to obtain a second aqueous phase and a second organic phase;
s11, adding a second extractant into the second aqueous phase, and extracting to obtain a third organic phase;
s12, mixing the second organic phase and the third organic phase, and concentrating to obtain a second concentrated product;
s13, adding the second concentrated product into the mixed solution of n-heptane and ethanol, adding active carbon after dissolving, refluxing, filtering, cooling and crystallizing to obtain the 5-isosorbide mononitrate.
Further, the nitric acid is concentrated nitric acid, the quenching agent is water, the first extractant and the second extractant are ethyl acetate, and the ethanol is absolute ethanol.
Further, the mass ratio of n-heptane to ethanol is (3-6): (1-2); and/or the reaction time of nitric acid and acetic anhydride in the first continuous reaction unit is 5-15min; and/or the reaction time of the raw material solution and the nitrifying agent in the second continuous reaction unit is 4-10min.
Further, the quenching time of the liquid to be quenched in the continuous quenching unit is 60-240s; and/or
The neutralization reaction time of the quenching product in the first continuous neutralization unit is 10-60min; and/or
The separation time of the first neutralization reaction product in the continuous solid-liquid separation unit is 5-30min; and/or
The extraction time of the filtrate in the first continuous extraction unit is 10-45min; and/or
The concentration time of the first organic phase in the first continuous concentration unit is 15-90min; and/or
The reaction time of the sodium salt solution in the second continuous neutralization unit is 10-45min; and/or
The liquid separation time of the second neutralization reaction product in the continuous liquid separation unit is 10-45min; and/or
The extraction time of the second water phase in the second continuous extraction unit is 10-45min; and/or
The concentration time of the mixture of the second organic phase and the third organic phase in the second continuous concentration unit is 15-60min.
Further, the nitric acid is fuming nitric acid, and when the flow rate of the fuming nitric acid into the first continuous reaction unit is 10-30 kg/h:
the flow rate of the acetic anhydride introduced into the first continuous reaction unit is 25-60kg/h;
in the raw material solution, the volume ratio of acetic acid to isosorbide is (1-5): 1; the flow rate of the raw material solution into the second continuous reaction unit is 100-300kg/h;
the flow rate of the quenching agent introduced into the continuous quenching unit is 100-300kg/h;
the flow of the liquid caustic soda introduced into the first continuous neutralization unit is regulated in real time according to the first online pH detection device;
the output flow rate of the filtrate in the continuous solid-liquid separation unit is 500-1100kg/h;
The flow rate of the first extractant added into the first continuous extraction unit is 200-800kg/h, and the output flow rate of the first organic phase in the first continuous extraction unit is 250-850kg/h;
transferring the first concentrated product in the first continuous concentrating unit into a sodium salt crystallizing unit, introducing water and liquid alkali into the sodium salt crystallizing unit, wherein the mass ratio of the first concentrated product, the water and the liquid alkali introduced into the sodium salt crystallizing unit is (4.5-9): (9-18): (20-40);
in the sodium salt solution, the mass ratio of the sodium salt to the water to the ethyl acetate is (6-12): (4.5-9): (15-30); the flow rate of the sodium salt solution added into the second continuous neutralization unit is 150-450kg/h, and the flow rate of the acid added into the second continuous neutralization unit is regulated in real time according to a second online pH monitoring device;
the output flow of the second water phase in the continuous liquid separation unit is 20-150kg/h, and the output flow of the second organic phase is 100-350kg/h;
the flow rate of the second extractant introduced into the second continuous extraction unit is 100-300kg/h, and the output flow rate of the third organic phase in the second continuous extraction unit is 100-450kg/h;
the mass ratio of the second concentrated product, n-heptane and ethanol in the finished product crystallization unit is (2-4): (3-6): (1-2);
The sum of the respective feed flow rates of the first continuous reaction unit, the second continuous reaction unit, the continuous quenching unit, the first continuous neutralization unit, the continuous solid-liquid separation unit, the first continuous extraction unit, the first continuous concentration unit, the second continuous neutralization unit, the continuous liquid separation unit, the second continuous extraction unit and the second continuous concentration unit is the same as the sum of the discharge flow rates.
Further, HNO in the first continuous reaction unit 3 The ratio of the amount of the substance to acetic anhydride is (1-1.5): (1-2); HNO introduced into the first continuous reaction unit 3 The ratio of the amount of the substance to the amount of the substance of isosorbide fed into the second continuous reaction unit is (1 to 1.5): (1-1.1), the reaction temperature of nitric acid and acetic anhydride is 5-20 ℃; and/or
The temperature of the esterification reaction in the second continuous reaction unit is 5-20 ℃; and/or
The reaction temperature in the first continuous neutralization unit and the second continuous neutralization unit is 10-25 ℃; and/or
The crystallization temperature in the sodium salt crystallization unit is 0-5 ℃, and the crystallization time is 1-3h; and/or
The crystallization temperature in the finished product crystallization unit is 0-5 ℃, and the crystallization time is 8-12h.
Further, HNO in the first continuous reaction unit 3 The ratio of the amount of the substance to acetic anhydride is (1-1.1): (1.3-1.5); HNO introduced into the first continuous reaction unit 3 The ratio of the amount of the substance to the amount of the substance of isosorbide fed into the second continuous reaction unit is (1-1.1): (1-1.1); and/or
The volume ratio of acetic acid to isosorbide in the raw material solution is (2-5): 1, a step of; and/or
The reaction temperature in the first continuous reaction unit is 10-15 ℃, and the reaction temperature in the second continuous reaction unit is 10-15 ℃.
By adopting the technical scheme of the invention, the continuous production of the 5-isosorbide mononitrate is realized by adopting the first continuous reaction unit, the second continuous reaction unit, the continuous quenching unit, the first continuous neutralization unit, the continuous solid-liquid separation unit, the first continuous extraction unit, the first continuous concentration unit, the sodium salt crystallization unit, the second continuous neutralization unit, the continuous liquid separation unit, the second continuous extraction unit, the second continuous concentration unit and the finished product crystallization unit, the safety risk in the production process can be reduced by continuously quenching after the reaction is finished, the quenching liquid can be continuously neutralized by continuous neutralization, the neutralization heat generated in unit time is lower, the influence on the reaction process is smaller, and too much byproducts are not generated; the system can improve the purity and the production efficiency of the 5-isosorbide mononitrate, can realize automatic control of equipment, reduces personnel operation, has higher production safety, and has smaller occupied area compared with batch production equipment and lower cost compared with continuous production equipment.
Drawings
FIG. 1 is a system for continuously producing isosorbide-5-mononitrate according to the invention;
FIG. 2 is a liquid chromatogram of the product after the end of the nitration reaction of example 1;
FIG. 3 is a liquid chromatogram of the product after the completion of the nitration reaction of comparative example 1;
FIG. 4 is a liquid chromatogram of the final product of example 1;
FIG. 5 is an infrared absorption spectrum of the final product of example 1.
Detailed Description
It should be noted that, in the case of no conflict, the embodiments and features in the embodiments may be combined with each other. The present invention will be described in detail with reference to examples.
As described in the background of the invention, the prior art has the problem that high-purity 5-isosorbide mononitrate cannot be produced industrially efficiently, at low cost and safely. In order to solve the above problems, in an exemplary embodiment of the present invention, there is provided a system for continuously producing isosorbide-5-mononitrate, the system comprising:
a first continuous reaction unit 10 having a nitric acid inlet, an acetic anhydride inlet, and a nitrifying agent outlet, the first continuous reaction unit 10 being for continuously performing a nitrifying reaction of nitric acid and acetic anhydride to produce a nitrifying agent;
a second continuous reaction unit 20 having a nitrifying agent inlet, a reaction raw material inlet, and a liquid to be quenched outlet; the nitrifying reagent inlet is connected with the nitrifying reagent outlet, and the second continuous reaction unit 20 is used for continuously carrying out esterification reaction on the reaction raw materials to obtain liquid to be quenched; the reaction raw material comprises isosorbide;
The continuous quenching unit 30 is provided with a to-be-quenched liquid inlet, a quencher inlet and a quenched product outlet, the to-be-quenched liquid inlet is connected with the to-be-quenched liquid outlet, and the continuous quenching unit 30 is used for carrying out continuous quenching treatment on the to-be-quenched liquid so as to prevent or reduce the generation of byproducts and obtain a quenched product;
a first continuous neutralization unit 40 having a quench product inlet, a first liquid base inlet, and a first neutralization reaction product outlet, the quench product inlet being connected to the quench product outlet, the first continuous neutralization unit 40 being configured to continuously neutralize the quench product to obtain a first neutralization reaction product;
a continuous solid-liquid separation unit 50 having a first neutralization reaction product inlet, a solid product outlet and a filtrate outlet, the first neutralization reaction product inlet being connected to the first neutralization reaction product outlet, the continuous solid-liquid separation unit 50 being for performing continuous solid-liquid separation on the first neutralization reaction product to obtain a filtrate;
a first continuous extraction unit 60 having a filtrate inlet, a first extractant inlet, a first organic phase outlet, and a first aqueous phase outlet, the filtrate inlet being connected to the filtrate outlet, the first continuous extraction unit 60 being for continuously extracting the filtrate to obtain a first organic phase;
A first continuous concentration unit 70 having a first organic phase inlet, a first concentrated product outlet, and a first fraction outlet, the first organic phase inlet being connected to the first organic phase outlet, the first continuous concentration unit 70 being configured to continuously concentrate the first organic phase to obtain a first concentrated product;
a sodium salt crystallization unit 80 having a first concentrated product inlet, a water inlet, a second liquid caustic soda inlet, a sodium salt outlet, and a sodium salt mother liquor outlet, the first concentrated product inlet being connected to the first concentrated product outlet, the sodium salt crystallization unit 80 being for continuously crystallizing the first concentrated product to obtain a sodium salt;
a second continuous neutralization unit 90 having a sodium salt solution inlet, an acid inlet, and a second neutralization reaction product outlet, the sodium salt solution inlet being connected to a sodium salt solution tank, the sodium salt solution tank being connected to the sodium salt outlet, the second continuous neutralization unit 90 being configured to continuously neutralize the sodium salt solution to obtain a second neutralization reaction product;
a continuous liquid separation unit 100 having a second neutralization reaction product inlet, a second aqueous phase outlet, and a second organic phase outlet, the second neutralization reaction product inlet being connected to the second neutralization reaction product outlet, the continuous liquid separation unit 100 being configured to continuously separate the second neutralization reaction product into a second organic phase and a second aqueous phase;
A second continuous extraction unit 110 having a second aqueous phase inlet, a second extractant inlet, a third organic phase outlet, and a third aqueous phase outlet, the second aqueous phase inlet being connected to the second aqueous phase outlet, the second continuous extraction unit 110 being configured to continuously extract the second aqueous phase to obtain a third organic phase;
a second continuous concentration unit 120 having a second organic phase inlet, a third organic phase inlet, a second concentrated product outlet, and a second fraction outlet, the second organic phase inlet being connected to the second organic phase outlet, the third organic phase inlet being connected to the third organic phase outlet, the second continuous concentration unit 120 being configured to continuously concentrate the second organic phase and the third organic phase to obtain a second concentrated product;
a final product crystallization unit 130 having a second concentrated product inlet, a final product mother liquor outlet, and a final product outlet, the second concentrated product inlet being connected to the second concentrated product outlet, the final product crystallization unit 130 being configured to crystallize the second concentrated product to obtain isosorbide-5-mononitrate.
The unstable nitrified liquid can be immediately quenched after discharging by utilizing a continuous quenching mode, the safety risk can be reduced by a continuous flow technology, the operation efficiency is improved, and the whole system is automatically controlled, so that the operation of personnel can be reduced; in addition, the continuous neutralization mode is utilized to realize immediate neutralization after discharging of the quenched nitrified liquid, the waiting time is reduced, the system is prevented from being hot, the neutralization heat generated in unit time is small, the heat generated by neutralization can be removed in time through a continuous flow technology, the production safety is high, and the treatment time for producing the same amount of products is short; the product of the continuous neutralization unit can be subjected to solid-liquid separation in a continuous solid-liquid separation mode, so that continuous feeding is realized, and the effect of continuously separating out solids and liquid is achieved; the neutralized filtrate can be immediately separated into a water phase and an organic phase by adopting a continuous extraction mode, so that the extraction operation time is shortened, the extraction efficiency is improved, and the consumption of an extractant is reduced; the organic phase after extraction can be continuously fed and continuously concentrated in a continuous concentration mode, so that the concentration time is greatly shortened, the concentration efficiency is improved, meanwhile, the occupation of continuous production equipment is small, and the cost can be saved.
As a preferred embodiment of the present invention, the system further comprises: the first online pH monitoring device is connected with the first continuous neutralization unit 40 and is used for online monitoring the pH value of the reaction system in the first continuous neutralization unit 40; the second online pH monitoring device is connected with the second continuous neutralization unit 90 and is used for online monitoring the pH value of the reaction system in the second continuous neutralization unit 90; and/or
The second organic phase inlet and the third organic phase inlet are the same inlet or two inlets.
The online pH monitoring device can monitor the pH value of the reaction liquid in the first continuous neutralization unit and the second continuous neutralization unit in real time, so that the adding flow of liquid alkali is adjusted, the reaction process is controlled, and the purity of the reaction product is improved.
Typically, but not by way of limitation, the first continuous reaction unit 10 and the second continuous reaction unit 20 are each independently one of a static mixer, a microchannel mixer, an agitation type mixer, a jet mixer, a tubular reactor, a continuous column agitation reactor, a continuous tank reactor; and/or
The continuous quenching unit 30, the first continuous neutralization unit 40, and the second continuous neutralization unit 90 are continuous stirred reactors; and/or
The continuous solid-liquid separation unit 50 is one of a decanter centrifuge, a disc centrifuge, and a flat plate decanter centrifuge; and/or
The first continuous extraction unit 60 and the second continuous extraction unit 110 are one of a centrifugal extractor, a continuous extraction column, and a rotary disk extractor; and/or
The first continuous concentration unit 70 and the second continuous concentration unit 120 are continuous falling film concentration devices; and/or
The continuous liquid separation unit 100 is one of a liquid-liquid phase separator and an extraction liquid separation column.
Typically, but not limited to, the materials of the static mixer, the micro-channel mixer, the stirring mixer and the jet mixer include but are not limited to one of stainless steel, polytetrafluoroethylene and SiC, and the materials of the tubular reactor, the continuous columnar stirring reactor and the continuous kettle reactor include but are not limited to one of stainless steel, enamel, siC and steel lining anticorrosive materials.
By adopting the device, continuous production can be stably realized, the safety of the system is higher, and the service life is longer.
In another exemplary embodiment of the present invention, there is provided a method for continuously producing isosorbide-5-mononitrate, which realizes continuous production of isosorbide-5-mononitrate by using the above-mentioned system, comprising the steps of:
S1, adding nitric acid into acetic anhydride to perform nitration reaction to obtain a nitration reagent; dissolving isosorbide in acetic acid to obtain a raw material solution;
s2, adding a nitrifying reagent into the raw material solution to perform esterification reaction to obtain a liquid to be quenched;
s3, adding a quenching agent into the liquid to be quenched to obtain a quenched product;
s4, adding liquid alkali into the quenched product, and adjusting the pH value to 6.2-6.7 to obtain a first neutralization reaction product;
s5, filtering the first neutralization reaction product to obtain an isosorbide dinitrate solid product and a filtrate;
s6, adding a first extractant into the filtrate to obtain a first organic phase;
s7, concentrating the first organic phase to obtain a first concentrated product;
s8, adding water and liquid alkali into the first concentrated product for crystallization, and filtering to obtain sodium salt and sodium salt mother liquor;
s9, dissolving sodium salt in a mixed solution of water and ethyl acetate to obtain a sodium salt solution; adding acid into the sodium salt solution, and regulating the pH value to 6.2-6.7 to obtain a second neutralization reaction product;
s10, separating a second neutralization reaction product to obtain a second aqueous phase and a second organic phase;
s11, adding a second extractant into the second aqueous phase, and extracting to obtain a third organic phase;
S12, mixing the second organic phase and the third organic phase, and concentrating to obtain a second concentrated product;
s13, adding the second concentrated product into the mixed solution of n-heptane and ethanol, adding active carbon after dissolving, refluxing, filtering, cooling and crystallizing to obtain the 5-isosorbide mononitrate.
By adopting the system, the high-purity 5-isosorbide mononitrate can be prepared by continuous production, the production process is safe, the cost is low, the yield is high, and the system is suitable for industrial application. In addition, the solvent is selected during crystallization, the active carbon is a material for adsorbing impurities commonly used, and the mixed solution of n-heptane and ethanol is used as the solvent for crystallization, so that the yield of the product can be improved under the condition of not affecting the purity of the product.
In a preferred embodiment of the present invention, the nitric acid is concentrated nitric acid, the quencher is water, the extractant is ethyl acetate, the ethanol is absolute ethanol, and the components are selected so that the reactions can be sufficiently performed at a low cost.
As a preferred embodiment of the present invention, the mass ratio of n-heptane to ethanol is (3-6): (1-2) the purity and yield of isosorbide-5-mononitrate can be better balanced when the ratio is satisfied. In addition, the reaction time of nitric acid and acetic anhydride in the first continuous reaction unit 10 is 5 to 15 minutes; and/or the reaction time of the raw material solution and the nitrifying agent in the second continuous reaction unit 20 is 4 to 10 minutes. The time of the nitration reaction and the esterification reaction has great influence on the yield and the purity of the product, and the method for continuously introducing the raw materials and continuously reacting can effectively improve the yield and the purity of the product by controlling the reaction time within the range.
As a preferred embodiment of the present invention, the quenching time of the liquid to be quenched in the continuous quenching unit 30 is 60 to 240s; and/or
The neutralization reaction time of the quenched product in the first continuous neutralization unit 40 is 10 to 60 minutes; and/or
The separation time of the first neutralization reaction product in the continuous solid-liquid separation unit 50 is 5-30min; and/or
The extraction time of the filtrate in the first continuous extraction unit 60 is 10-45min; and/or
The concentration time of the first organic phase in the first continuous concentration unit 70 is 15-90min; and/or
The reaction time of the sodium salt solution in the second continuous neutralization unit 90 is 10 to 45 minutes; and/or
The liquid separation time of the second neutralization reaction product in the continuous liquid separation unit 100 is 10-45min; and/or
The extraction time of the second aqueous phase in the second continuous extraction unit 110 is 10-45min; and/or
The concentration time of the mixture of the second organic phase and the third organic phase in the second continuous concentration unit 120 is 15 to 60 minutes.
The purity and yield of the product 5-isosorbide mononitrate can be further improved by controlling the time of the reaction materials in each reaction unit to fall within the above range.
As a preferred embodiment of the present invention, the nitric acid is fuming nitric acid, when the flow rate of fuming nitric acid into the first continuous reaction unit 10 is 10-30 kg/h:
the flow rate of the acetic anhydride introduced into the first continuous reaction unit 10 is 25-60kg/h;
in the raw material solution, the volume ratio of acetic acid to isosorbide is (1-5): 1; the flow rate of the raw material solution into the second continuous reaction unit 20 is 100-300kg/h;
the flow rate of the quenching agent into the continuous quenching unit 30 is 100-300kg/h;
the flow rate of the caustic soda liquid introduced into the first continuous neutralization unit 40 is adjusted in real time according to the first online pH monitoring device;
the output flow rate of the filtrate in the continuous solid-liquid separation unit 50 is 500-1100kg/h;
The flow rate of the first extractant added into the first continuous extraction unit 60 is 200-800kg/h, and the output flow rate of the first organic phase in the first continuous extraction unit 60 is 250-850kg/h;
transferring the first concentrated product in the first continuous concentrating unit 70 to a sodium salt crystallizing unit 80, introducing water and liquid alkali into the sodium salt crystallizing unit 80, wherein the mass ratio of the first concentrated product, water and liquid alkali introduced into the sodium salt crystallizing unit 80 is (4.5-9): (9-18): (20-40);
in the sodium salt solution, the mass ratio of the sodium salt to the water to the ethyl acetate is (6-12): (4.5-9): (15-30); the flow rate of the sodium salt solution added into the second continuous neutralization unit 90 is 150-450kg/h, and the flow rate of the acid added into the second continuous neutralization unit 90 is regulated in real time according to a second online pH monitoring device;
the output flow rate of the second water phase in the continuous liquid separation unit 100 is 20-150kg/h, and the output flow rate of the second organic phase is 100-350kg/h;
the flow rate of the second extractant introduced into the second continuous extraction unit 110 is 100-300kg/h, and the output flow rate of the third organic phase in the second continuous extraction unit 110 is 100-450kg/h;
the mass ratio of the second concentrated product, n-heptane, ethanol in the final crystallization unit 130 is (2-4): (3-6): (1-2).
The sum of the feed flow rates and the discharge flow rate of the first continuous reaction unit 10, the second continuous reaction unit 20, the continuous quenching unit 30, the first continuous neutralization unit 40, the continuous solid-liquid separation unit 50, the first continuous extraction unit 60, the first continuous concentration unit 70, the second continuous neutralization unit 90, the continuous liquid separation unit 100, the second continuous extraction unit 110, and the second continuous concentration unit 120 are the same. In addition, fuming nitric acid can be replaced by other concentrated nitric acid, and the flow rate of fuming nitric acid can be adjusted according to the requirement.
The flow and the concentration of each component are limited, so that the reaction can be continuously carried out, the production efficiency is improved as much as possible, and the product is ensured to have higher purity.
As a preferred embodiment of the present invention, the ratio of the amounts of nitric acid to acetic anhydride in the first continuous reaction unit 10 is (1-1.5): (1-2); the ratio of the amount of nitric acid material fed into the first continuous reaction unit 10 to the amount of isosorbide material fed into the second continuous reaction unit 20 is (1-1.5): (1-1.1), the reaction temperature of nitric acid and acetic anhydride is 5-20 ℃; and/or
The temperature of the esterification reaction in the second continuous reaction unit 20 is 5-20 ℃; and/or
The reaction temperature in the first continuous neutralization unit 40 and the second continuous neutralization unit 90 is 10 to 25 ℃; and/or
The crystallization temperature in the sodium salt crystallization unit 80 is 0-5 ℃ and the crystallization time is 1-3h; and/or
The crystallization temperature in the final crystallization unit 130 is 0-5 deg.c and the crystallization time is 8-12h.
The above limitation of the reaction conditions is beneficial to further improving the production efficiency and the yield and purity of the product.
As a preferred embodiment of the present invention, the ratio of the amounts of nitric acid to acetic anhydride in the first continuous reaction unit 10 is (1-1.1): (1.3-1.5); the ratio of the amount of nitric acid material fed into the first continuous reaction unit 10 to the amount of isosorbide material fed into the second continuous reaction unit 20 is (1-1.1): (1-1.1); and/or
The volume ratio of acetic acid to isosorbide in the raw material solution is (2-5): 1, a step of; and/or
The reaction temperature in the first continuous reaction unit 10 is 10-15 deg.c and the reaction temperature in the second continuous reaction unit 20 is 10-15 deg.c.
The above limitation of the reaction conditions can save the cost and improve the production efficiency without obviously affecting the yield and purity of the product.
The present application is described in further detail below in conjunction with specific embodiments, which should not be construed as limiting the scope of the claims.
In the embodiment, the first continuous reaction unit and the second continuous reaction unit are respectively a micro-channel mixer and a tubular reactor, the first continuous neutralization unit and the second continuous neutralization unit are continuous stirring reactors, the continuous solid-liquid separation unit is a horizontal screw centrifuge, the first continuous extraction unit and the second continuous extraction unit are centrifugal extractors, the first continuous concentration unit and the second continuous concentration unit are continuous falling film concentration devices, and the continuous liquid separation unit is a liquid-liquid phase separator.
Example 1
An embodiment of the method for continuously producing the 5-isosorbide mononitrate, disclosed by the invention, adopts the system shown in fig. 1 to carry out continuous production, and the method specifically comprises the following steps:
s1 fuming nitric acid (HNO) at a flow rate of 15.4kg/h 3 98% by mass) into a first continuous reaction unit 10, introducing acetic anhydride into the first continuous reaction unit 10 at a flow rate of 36.7kg/h, controlling the reaction temperature of the first continuous reaction unit 10 to be 10 ℃, and continuously performing nitration reaction for 8min to obtain a nitration reagent; HNO (HNO) 3 The ratio of the amount of the substance to acetic anhydride is 1:1.5;
s2, introducing a nitrifying reagent into the second continuous reaction unit 20 at a flow rate of 52.1kg/h, introducing a reaction raw material (acetic acid solution of isosorbide with a volume ratio of acetic acid to isosorbide of 3:1) into the second continuous reaction unit 20 at a flow rate of 145.3kg/h, controlling the reaction temperature of the second continuous reaction unit 20 to be 10 ℃, and continuously carrying out esterification reaction for 6min to obtain a liquid to be quenched; HNO in S1 3 The ratio of the amount of the substance of (2) to the amount of the substance of isosorbide in S2 is 1:1.1;
s3, introducing the liquid to be quenched into the continuous quenching unit 30 at a flow rate of 197.4kg/h, introducing the quenching agent water into the continuous quenching unit 30 at a flow rate of 210kg/h, and continuously quenching for 90S to obtain a quenched product;
s4, introducing the quenching product into the first continuous neutralization unit 40 at a flow rate of 407.4kg/h, regulating the flow rate of liquid alkali in real time through an online pH monitoring system in the first continuous neutralization unit 40, controlling the pH of the neutralization system to be 6.2-6.7, controlling the reaction temperature in the first continuous neutralization unit 40 to be 20 ℃, and continuously reacting for 20min to obtain a first neutralization reaction product;
s5, introducing the first neutralization reaction product into a continuous solid-liquid separation unit 50 at a flow rate of 743kg/h (the flow rate of liquid alkali in S4 is an average value), and continuously carrying out solid-liquid separation for 15min to obtain isosorbide dinitrate solid and filtrate;
s6, introducing filtrate into the first continuous extraction unit 60 at a flow rate of 730kg/h, introducing extractant ethyl acetate into the first continuous extraction unit 60 at a flow rate of 504kg/h, and continuously extracting for 30min to obtain a first organic phase and a first aqueous phase;
s7, introducing the first organic phase into a first continuous concentration unit 70 at a flow rate of 529kg/h, and continuously concentrating for 53min to obtain a first concentrated product;
S8, adding the first concentrated product, water and liquid alkali into a sodium salt crystallization unit 80, stirring and dissolving, then cooling to 5 ℃, crystallizing, and crystallizing for 2 hours to obtain sodium salt and sodium salt mother liquor; the mass ratio of the first concentrated product to water to liquid alkali is 4.5:9:20, a step of;
s9, dissolving sodium salt in a mixed solution of water and ethyl acetate to obtain a sodium salt solution (the mass ratio of the sodium salt to the water to the ethyl acetate is 6:4.5:15), introducing the sodium salt solution into a second continuous neutralization unit 90 at a flow of 252kg/h, regulating the flow of hydrochloric acid in real time through an online pH monitoring system in the second continuous neutralization unit 90, controlling the pH value of the neutralization system to be 6.2-6.7, continuously carrying out neutralization reaction for 15min, and controlling the reaction temperature to be 20 ℃ to obtain a second neutralization reaction product;
s10, introducing a second neutralization reaction product into the continuous liquid separation unit 100 at a flow rate of 252kg/h (the addition amount of hydrochloric acid is negligible), and continuously separating liquid for 15min to obtain a second aqueous phase and a second organic phase;
s11, introducing a second water phase into the second continuous extraction unit 110 at a flow rate of 54.4kg/h, introducing an extractant ethyl acetate into the second continuous extraction unit 110 at a flow rate of 189kg/h, and continuously extracting for 28min to obtain a third organic phase;
S12, introducing a second organic phase into the second continuous concentration unit 120 at a flow rate of 197.6kg/h, introducing a third organic phase into the second continuous concentration unit 120 at a flow rate of 198kg/h, and continuously concentrating for 40min to obtain a second concentrated product;
s13, adding the second concentrated product, n-heptane and absolute ethyl alcohol into a finished product crystallization unit, stirring and dissolving, adding active carbon, refluxing, filtering, cooling filtrate to 5 ℃, crystallizing for 12 hours, and obtaining 5-isosorbide mononitrate; the mass ratio of the second concentrated product, the n-heptane and the absolute ethyl alcohol is 2:3:2.
Example 2
An example of the method for continuously producing isosorbide-5-mononitrate according to the present invention is specifically as follows:
s1, fuming nitric acid (HNO) is added at a flow rate of 10.6kg/h 3 98% by mass percent) is introduced into the first continuous reaction unit 10, acetic anhydride is introduced into the first continuous reaction unit 10 at a flow rate of 25.2kg/h, the reaction temperature of the first continuous reaction unit 10 is controlled to be 12 ℃, and the continuous reaction is carried out for 11.7min, so as to obtain a nitrifying reagent;
s2, introducing a nitrifying reagent into the second continuous reaction unit 20 at a flow rate of 35.8kg/h, introducing a reaction raw material (acetic acid solution of isosorbide with a volume ratio of acetic acid to isosorbide of 3:1) into the second continuous reaction unit 20 at a flow rate of 100kg/h, and controlling the reaction temperature of the second continuous reaction unit 20 to be 12 ℃ for continuous reaction for 8.7min to obtain a liquid to be quenched;
S3, introducing the liquid to be quenched into the continuous quenching unit 30 at a flow rate of 135.8kg/h, introducing the water of the quenching agent into the continuous quenching unit 30 at a flow rate of 144kg/h, and continuously quenching for 130S to obtain a quenched product;
s4, introducing the quenching product into the first continuous neutralization unit 40 at a flow of 279.8kg/h, regulating the flow of liquid alkali in real time through an online pH monitoring system in the first continuous neutralization unit 40, controlling the pH of the neutralization system to be 6.2-6.7, controlling the reaction temperature in the first continuous neutralization unit 40 to be 10 ℃, and continuously reacting for 29min to obtain a first neutralization reaction product;
s5, introducing the first neutralization reaction product into a continuous solid-liquid separation unit 50 at a flow rate of 509kg/h (the flow rate of liquid alkali in S4 is an average value), and continuously carrying out solid-liquid separation for 10min to obtain isosorbide dinitrate solid and filtrate;
s6, introducing filtrate into the first continuous extraction unit 60 at a flow rate of 500kg/h, introducing extractant ethyl acetate into the first continuous extraction unit 60 at a flow rate of 345kg/h, and continuously extracting for 20min to obtain a first organic phase and a first aqueous phase;
s7, introducing the first organic phase into a first continuous concentration unit 70 at a flow rate of 362kg/h, and continuously concentrating for 36min to obtain a first concentrated product;
S8, adding the first concentrated product, water and liquid alkali into a sodium salt crystallization unit 80, stirring and dissolving, then cooling to 3 ℃, crystallizing, and crystallizing for 2 hours to obtain sodium salt and sodium salt mother liquor; the mass ratio of the first concentrated product to water to liquid alkali is 4.5:9:20, a step of;
s9, dissolving sodium salt in a mixed solution of water and ethyl acetate to obtain a sodium salt solution (the mass ratio of the sodium salt to the water to the ethyl acetate is 6:4.5:15), introducing the sodium salt solution into a second continuous neutralization unit 90 at a flow rate of 180kg/h, regulating the flow rate of hydrochloric acid in real time through an online pH monitoring system in the second continuous neutralization unit 90, controlling the pH of the neutralization system to be 6.2-6.7, continuously carrying out a neutralization reaction for 21min, and controlling the reaction temperature to be 10 ℃ to obtain a second neutralization reaction product;
s10, introducing a second neutralization reaction product into the continuous liquid separation unit 100 at a flow rate of 180kg/h, and continuously separating liquid for 21min to obtain a second aqueous phase and a second organic phase;
s11, introducing a second water phase into the second continuous extraction unit 110 at a flow rate of 38.9kg/h, introducing an extractant ethyl acetate into the second continuous extraction unit 110 at a flow rate of 130kg/h, and continuously extracting for 20min to obtain a third organic phase;
s12, introducing a second organic phase into the second continuous concentration unit 120 at a flow rate of 141.1kg/h, introducing a third organic phase into the second continuous concentration unit 120 at a flow rate of 137kg/h, and continuously concentrating for 28min to obtain a second concentrated product;
S13, adding the second concentrated product, n-heptane and absolute ethyl alcohol into a finished product crystallization unit, stirring and dissolving, adding active carbon, refluxing, filtering, cooling filtrate to 3 ℃, crystallizing for 12 hours, and obtaining 5-isosorbide mononitrate; the mass ratio of the second concentrated product, the n-heptane and the absolute ethyl alcohol is 4:6:1.
Example 3
An example of the method for continuously producing isosorbide-5-mononitrate according to the present invention is specifically as follows:
s1, fuming nitric acid (HNO) is added at a flow rate of 22kg/h 3 98% by mass) into the first continuous reaction unit 10, introducing acetic anhydride into the first continuous reaction unit 10 at a flow rate of 52kg/h, controlling the reaction temperature of the first continuous reaction unit 10 to be 15 ℃, and continuously reacting for 5.6min to obtain a nitrifying reagent;
s2, introducing a nitrifying reagent into the second continuous reaction unit 20 at a flow of 74kg/h, introducing a reaction raw material (acetic acid solution of isosorbide with a volume ratio of acetic acid to isosorbide of 3:1) into the second continuous reaction unit 20 at a flow of 207.5kg/h, and controlling the reaction temperature of the second continuous reaction unit 20 to be 15 ℃ for continuous reaction for 4.2min to obtain a liquid to be quenched;
s3, introducing the liquid to be quenched into the continuous quenching unit 30 at a flow rate of 281.5kg/h, introducing the quenching agent water into the continuous quenching unit 30 at a flow rate of 300kg/h, and continuously quenching for 65S to obtain a quenched product;
S4, introducing the quenching product into the first continuous neutralization unit 40 at a flow rate of 581.5kg/h, regulating the flow rate of liquid alkali in real time through an online pH monitoring system in the first continuous neutralization unit 40, controlling the pH of the neutralization system to be 6.2-6.7, controlling the reaction temperature in the first continuous neutralization unit 40 to be 25 ℃, and continuously reacting for 14min to obtain a first neutralization reaction product;
s5, introducing the first neutralization reaction product into a continuous solid-liquid separation unit 50 at a flow rate of 1062kg/h (the flow rate of liquid alkali in S4 is an average value), and continuously carrying out solid-liquid separation for 21min to obtain isosorbide dinitrate solid and filtrate;
s6, introducing filtrate into the first continuous extraction unit 60 at a flow rate of 1042kg/h, introducing extractant ethyl acetate into the first continuous extraction unit 60 at a flow rate of 720kg/h, and continuously extracting for 42min to obtain a first organic phase and a first aqueous phase;
s7, introducing the first organic phase into a first continuous concentration unit 70 at a flow rate of 755kg/h, and continuously concentrating for 75min to obtain a first concentrated product;
s8, adding the first concentrated product, water and liquid alkali into a sodium salt crystallization unit 80, stirring and dissolving, then cooling to 0 ℃, crystallizing, and crystallizing for 2 hours to obtain sodium salt and sodium salt mother liquor; the mass ratio of the first concentrated product to water to liquid alkali is 4.5:9:20, a step of;
S9, dissolving sodium salt in a mixed solution of water and ethyl acetate to obtain a sodium salt solution (the mass ratio of the sodium salt to the water to the ethyl acetate is 6:4.5:15), introducing the sodium salt solution into a second continuous neutralization unit 90 at a flow rate of 360kg/h, regulating the flow rate of hydrochloric acid in real time through an online pH monitoring system in the second continuous neutralization unit 90, controlling the pH of the neutralization system to be 6.2-6.7, continuously carrying out a neutralization reaction for 11min, and controlling the reaction temperature to be 25 ℃ to obtain a second neutralization reaction product;
s10, introducing a second neutralization reaction product into the continuous liquid separation unit 100 at a flow rate of 360kg/h, and continuously separating liquid for 11min to obtain a second aqueous phase and a second organic phase;
s11, introducing a second water phase into the second continuous extraction unit 110 at a flow rate of 77.6kg/h, introducing an extractant ethyl acetate into the second continuous extraction unit 110 at a flow rate of 270kg/h, and continuously extracting for 41min to obtain a third organic phase;
s12, introducing a second organic phase into the second continuous concentration unit 120 at a flow rate of 282.4kg/h, introducing a third organic phase into the second continuous concentration unit 120 at a flow rate of 284kg/h, and continuously concentrating for 56min to obtain a second concentrated product;
s13, adding the second concentrated product, n-heptane and absolute ethyl alcohol into a finished product crystallization unit, stirring and dissolving, adding active carbon, refluxing, filtering, cooling filtrate to 0 ℃, crystallizing for 12 hours, and obtaining 5-isosorbide mononitrate; the mass ratio of the second concentrated product, the n-heptane and the absolute ethyl alcohol is 3:5:2.
Example 4
In one embodiment of the method for continuously producing isosorbide-5-mononitrate according to the present invention, the difference between the present embodiment and embodiment 1 is that in S13, the mass ratio of the second concentrated product, n-heptane, and absolute ethanol is different, and the mass ratio of the second concentrated product, n-heptane, and absolute ethanol is 2:8:1.
Example 5
In one embodiment of the method for continuously producing isosorbide-5-mononitrate according to the present invention, the difference between the present embodiment and embodiment 1 is that in S13, the mass ratio of the second concentrated product, n-heptane, and absolute ethanol is different, and the mass ratio of the second concentrated product, n-heptane, and absolute ethanol is 3:3:3.
Example 6
In one example of the method for continuously producing isosorbide-5-mononitrate according to the present invention, this example differs from example 1 only in that n-heptane is not used in S13, and the mass ratio of the second concentrated product to absolute ethanol is 2:5.
Example 7
In one example of the method for continuously producing isosorbide-5-mononitrate according to the present invention, this example differs from example 1 only in that in S13, anhydrous ethanol is not used, and the mass ratio of the second concentrated product to n-heptane is 2:5.
Example 8
An example of the method for continuously producing isosorbide-5-mononitrate according to the present invention is specifically as follows:
S1, fuming nitric acid (HNO) is added at a flow rate of 6.6kg/h 3 98% by mass) into a first continuous reaction unit 10, introducing acetic anhydride into the first continuous reaction unit 10 at a flow rate of 15.7kg/h, controlling the reaction temperature of the first continuous reaction unit 10 to be 10 ℃, and continuously reacting for 18.7min to obtain a nitrifying reagent;
s2, introducing a nitrifying reagent into the second continuous reaction unit 20 at a flow rate of 22.3kg/h, introducing a reaction raw material (acetic acid solution of isosorbide with a volume ratio of acetic acid to isosorbide of 3:1) into the second continuous reaction unit 20 at a flow rate of 62.3kg/h, and controlling the reaction temperature of the second continuous reaction unit 20 to be 10 ℃ for continuous reaction for 14min to obtain a liquid to be quenched;
s3, introducing the liquid to be quenched into the continuous quenching unit 30 at a flow rate of 84.6kg/h, introducing the quenching agent water into the continuous quenching unit 30 at a flow rate of 90kg/h, and continuously quenching for 210S to obtain a quenched product;
s4, introducing the quenching product into the first continuous neutralization unit 40 at a flow of 174.6kg/h, regulating the flow of liquid alkali in real time through an online pH monitoring system in the first continuous neutralization unit 40, controlling the pH of the neutralization system to be 6.2-6.7, controlling the reaction temperature in the first continuous neutralization unit 40 to be 20 ℃, and continuously reacting for 47min to obtain a first neutralization reaction product;
S5, introducing the first neutralization reaction product into a continuous solid-liquid separation unit 50 at a flow rate of 318.6kg/h (the flow rate of liquid alkali in S4 is an average value), and continuously carrying out solid-liquid separation for 6.4min to obtain isosorbide dinitrate solid and filtrate;
s6, introducing filtrate into the first continuous extraction unit 60 at a flow rate of 308kg/h, introducing extractant ethyl acetate into the first continuous extraction unit 60 at a flow rate of 216kg/h, and continuously extracting for 12min to obtain a first organic phase and a first aqueous phase;
s7, introducing the first organic phase into a first continuous concentration unit 70 at a flow rate of 219kg/h, and continuously concentrating for 22min to obtain a first concentrated product;
s8, adding the first concentrated product, water and liquid alkali into a sodium salt crystallization unit 80, stirring and dissolving, then cooling to 5 ℃, crystallizing, and crystallizing for 2 hours to obtain sodium salt and sodium salt mother liquor; the mass ratio of the first concentrated product to water to liquid alkali is 4.5:9:20, a step of;
s9, dissolving sodium salt in a mixed solution of water and ethyl acetate to obtain a sodium salt solution (the mass ratio of the sodium salt to the water to the ethyl acetate is 6:4.5:15), introducing the sodium salt solution into a second continuous neutralization unit 90 at a flow rate of 108kg/h, regulating the flow rate of hydrochloric acid in real time through an online pH monitoring system in the second continuous neutralization unit 90, controlling the pH of the neutralization system to be 6.2-6.7, continuously carrying out a neutralization reaction for 35min, and controlling the reaction temperature to be 20 ℃ to obtain a second neutralization reaction product;
S10, introducing a second neutralization reaction product into the continuous liquid separation unit 100 at a flow rate of 108kg/h, and continuously separating liquid for 30min to obtain a second aqueous phase and a second organic phase;
s11, introducing a second water phase into the second continuous extraction unit 110 at a flow rate of 27.5kg/h, introducing an extractant ethyl acetate into the second continuous extraction unit 110 at a flow rate of 81kg/h, and continuously extracting for 14min to obtain a third organic phase;
s12, introducing a second organic phase into the second continuous concentration unit 120 at a flow rate of 80.5kg/h, introducing a third organic phase into the second continuous concentration unit 120 at a flow rate of 83kg/h, and continuously concentrating for 16min to obtain a second concentrated product;
s13, adding the second concentrated product, n-heptane and absolute ethyl alcohol into a finished product crystallization unit, stirring and dissolving, adding active carbon, refluxing, filtering, cooling filtrate to 5 ℃, crystallizing for 12 hours, and obtaining 5-isosorbide mononitrate; the mass ratio of the second concentrated product, the n-heptane and the absolute ethyl alcohol is 2:3:2.
Comparative example 1
Comparative example 1 is a method for batch production of 5-isosorbide mononitrate, which is different from example 1 in that the system for continuous production of 5-isosorbide mononitrate of the present invention is not employed for production, the method employed is a method in which the reaction raw materials are fed into a reaction apparatus in a batch, and the product is transferred to the next apparatus in a batch after the completion of the reaction.
Performance testing
The test conditions of the purity of the reaction system products are shown in table 1, the test conditions of the purity of the final products are shown in table 2, and the test method refers to the pharmacopoeia of 2020 edition of Chinese.
TABLE 1
TABLE 2
The yield was calculated as the ratio between the actual mass of the produced isosorbide-5-mononitrate and the theoretical mass obtained from the amount of the raw material added. The specific yield calculation method comprises the following steps:
yield = product mass x mass fraction of 5-isosorbide mononitrate in product/theoretical yield;
theoretical yield = isosorbide charge/isosorbide molecular weight x 5-isosorbide mononitrate molecular weight.
The test results of the reaction systems of comparative example 1 and example 1 are shown in Table 3, wherein the purity of the reaction system product and the yield of the reaction system product refer to the result of detecting the liquid to be quenched after the esterification reaction.
TABLE 3 Table 3
Note that: the raw materials refer to isosorbide, and the total operation time of the post-treatment unit refers to the time of all post-treatments after the esterification reaction is completed.
As shown by the test results in the table 3, the preparation efficiency of the 5-isosorbide mononitrate prepared by the system can be remarkably improved, and compared with batch production, the yield and purity of the reaction system product can be remarkably improved.
The product yields of the preparation of isosorbide 5-mononitrate and the purity data of isosorbide 5-mononitrate from examples 1 to 7 and comparative example 1 are shown in Table 4.
TABLE 4 Table 4
As can be seen from Table 4, when two solvents of ethanol and n-heptane are selected for recrystallization in step S13, the yield and purity of the product are both high, and when the mass ratio of n-heptane to ethanol satisfies (3-6): in (1-2), the yield and purity of the final product are relatively high. In addition, when the preparation time of the nitrifying reagent is 5-15min and the esterification reaction time is 4-10min, the purity of the final product can reach more than 98.5%.
Fig. 2 is a liquid chromatogram of the product after the end of the nitration reaction of example 1, fig. 3 is a liquid chromatogram of the product after the end of the nitration reaction of comparative example 1, and as can be seen from fig. 2 to 3, the purity of the 5-isosorbide mononitrate prepared in example 1 is significantly higher than that of the 5-isosorbide mononitrate prepared in comparative example 1, and the detection result shows that the purity and yield of the reaction system obtained by the method of example 1 are significantly higher than those of comparative example 1.
FIG. 4 is a liquid chromatogram of the final product of example 1, and FIG. 5 is an infrared absorption spectrum of the final product of example 1. As can be seen from FIG. 4, the final product, 5-isosorbide mononitrate, is extremely pure; as can be seen from FIG. 5, the product prepared was isosorbide 5-mononitrate.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A system for continuously producing isosorbide-5-mononitrate, comprising:
a first continuous reaction unit (10) having a nitric acid inlet, an acetic anhydride inlet, and a nitration reagent outlet, the first continuous reaction unit (10) being for continuously subjecting nitric acid and acetic anhydride to a nitration reaction to produce a nitration reagent;
a second continuous reaction unit (20) having a nitrifying agent inlet, a reaction raw material inlet, and a liquid to be quenched outlet; the nitrifying reagent inlet is connected with the nitrifying reagent outlet, and the second continuous reaction unit (20) is used for continuously carrying out esterification reaction on reaction raw materials to obtain liquid to be quenched; the reaction raw material comprises isosorbide;
the continuous quenching unit (30) is provided with a liquid inlet to be quenched, a quenching agent inlet and a quenching product outlet, the liquid inlet to be quenched is connected with the liquid outlet to be quenched, and the continuous quenching unit (30) is used for carrying out continuous quenching treatment on the liquid to be quenched to obtain a quenching product;
A first continuous neutralization unit (40) having a quench product inlet, a first liquid base inlet, and a first neutralization reaction product outlet, the quench product inlet being connected to the quench product outlet, the first continuous neutralization unit (40) being configured to continuously neutralize the quench product to obtain a first neutralization reaction product;
a continuous solid-liquid separation unit (50) having a first neutralization reaction product inlet, a solid product outlet, and a filtrate outlet, the first neutralization reaction product inlet being connected to the first neutralization reaction product outlet, the continuous solid-liquid separation unit (50) being configured to continuously perform solid-liquid separation on the first neutralization reaction product to obtain a filtrate;
a first continuous extraction unit (60) having a filtrate inlet, a first extractant inlet, a first organic phase outlet and a first aqueous phase outlet, the filtrate inlet being connected to the filtrate outlet, the first continuous extraction unit (60) being for continuously extracting the filtrate to obtain a first organic phase;
a first continuous concentration unit (70) having a first organic phase inlet, a first concentrated product outlet, and a first fraction outlet, the first organic phase inlet being connected to the first organic phase outlet, the first continuous concentration unit (70) being configured to continuously concentrate the first organic phase to obtain a first concentrated product;
A sodium salt crystallization unit (80) having a first concentrated product inlet, a water inlet, a second liquid caustic inlet, a sodium salt outlet, and a sodium salt mother liquor outlet, the first concentrated product inlet being connected to the first concentrated product outlet, the sodium salt crystallization unit (80) being for continuously crystallizing the first concentrated product to obtain a sodium salt;
a second continuous neutralization unit (90) having a sodium salt solution inlet connected to a sodium salt solution tank connected to the sodium salt outlet, an acid inlet, and a second neutralization reaction product outlet, the second continuous neutralization unit (90) being configured to continuously neutralize the sodium salt solution to obtain a second neutralization reaction product;
a continuous liquid separation unit (100) having a second neutralization reaction product inlet, a second aqueous phase outlet, and a second organic phase outlet, the second neutralization reaction product inlet being connected to the second neutralization reaction product outlet, the continuous liquid separation unit (100) being configured to continuously separate the second neutralization reaction product to continuously separate a second organic phase and a second aqueous phase;
a second continuous extraction unit (110) having a second aqueous phase inlet, a second extractant inlet, a third organic phase outlet and a third aqueous phase outlet, the second aqueous phase inlet being connected to the second aqueous phase outlet, the second continuous extraction unit (110) being for continuous extraction of the second aqueous phase to obtain the third organic phase;
A second continuous concentration unit (120) having a second organic phase inlet, a third organic phase inlet, a second concentrated product outlet, and a second fraction outlet, the second organic phase inlet being connected to the second organic phase outlet, the third organic phase inlet being connected to the third organic phase outlet, the second continuous concentration unit (120) being configured to continuously concentrate the second organic phase and the third organic phase to obtain the second concentrated product;
a final product crystallization unit (130) having a second concentrated product inlet, a final product mother liquor outlet and a final product outlet, the second concentrated product inlet being connected to the second concentrated product outlet, the final product crystallization unit (130) being for crystallizing the second concentrated product to obtain the isosorbide-5-mononitrate.
2. The system of claim 1, wherein the system further comprises:
the first online pH monitoring device is connected with the first continuous neutralization unit (40) and is used for online monitoring the pH value of the reaction system in the first continuous neutralization unit (40); the second online pH monitoring device is connected with the second continuous neutralization unit (90) and is used for online monitoring the pH value of the reaction system in the second continuous neutralization unit (90); and/or
The second organic phase inlet and the third organic phase inlet are the same inlet or two inlets.
3. The system according to claim 1 or 2, wherein the first continuous reaction unit (10) and the second continuous reaction unit (20) are each independently one of a static mixer, a microchannel mixer, a stirring mixer, a jet mixer, a tubular reactor, a continuous column stirring reactor, a continuous tank reactor; and/or
The continuous quenching unit (30), the first continuous neutralization unit (40) and the second continuous neutralization unit (90) are continuously stirred reactors; and/or
The continuous solid-liquid separation unit (50) is one of a decanter centrifuge, a disc centrifuge and a flat plate decanter centrifuge; and/or
The first continuous extraction unit (60) and the second continuous extraction unit (110) are one of a centrifugal extractor, a continuous extraction column and a rotary disk extractor; and/or
The first continuous concentration unit (70) and the second continuous concentration unit (120) are continuous falling film concentration devices; and/or
The continuous liquid separation unit (100) is one of a liquid-liquid phase separator and an extraction liquid separation column.
4. A process for the continuous production of isosorbide-5-mononitrate, characterized in that it utilizes the system of any one of claims 1 to 3 to produce isosorbide-5-mononitrate.
5. The method according to claim 4, characterized in that it comprises the steps of:
s1, adding nitric acid into acetic anhydride to perform nitration reaction to obtain a nitration reagent; dissolving isosorbide in acetic acid to obtain a raw material solution;
s2, adding the nitrifying reagent into the raw material solution to perform esterification reaction to obtain a liquid to be quenched;
s3, adding a quenching agent into the liquid to be quenched to obtain a quenched product;
s4, adding liquid alkali into the quenched product, and adjusting the pH value to 6.2-6.7 to obtain a first neutralization reaction product;
s5, filtering the first neutralization reaction product to obtain an isosorbide dinitrate solid product and a filtrate;
s6, adding a first extractant into the filtrate to obtain a first organic phase;
s7, concentrating the first organic phase to obtain a first concentrated product;
s8, adding water and liquid alkali into the first concentrated product for crystallization, and filtering to obtain sodium salt and sodium salt mother liquor;
s9, dissolving the sodium salt in a mixed solution of water and ethyl acetate to obtain a sodium salt solution; adding acid into the sodium salt solution, and regulating the pH value to 6.2-6.7 to obtain a second neutralization reaction product;
S10, separating the second neutralization reaction product to obtain a second aqueous phase and a second organic phase;
s11, adding a second extractant into the second aqueous phase, and extracting to obtain a third organic phase;
s12, mixing the second organic phase and the third organic phase, and concentrating to obtain a second concentrated product;
and S13, adding the second concentrated product into a mixed solution of n-heptane and ethanol, adding active carbon after dissolving, refluxing, filtering, cooling and crystallizing to obtain the 5-isosorbide mononitrate.
6. The method of claim 5, wherein the step of determining the position of the probe is performed,
the nitric acid is concentrated nitric acid, the quenching agent is water, the first extracting agent and the second extracting agent are ethyl acetate, and the ethanol is absolute ethanol; and/or
In the step S13, the mass ratio of the n-heptane to the ethanol is (3-6): (1-2); and/or
The reaction time of the nitric acid and the acetic anhydride in the first continuous reaction unit (10) is 5-15min; and/or
The reaction time of the raw material solution and the nitrifying agent in the second continuous reaction unit (20) is 4-10min.
7. The method according to claim 5 or 6, wherein,
The quenching time of the liquid to be quenched in the continuous quenching unit (30) is 60-240s; and/or
The neutralization reaction time of the quenching product in the first continuous neutralization unit (40) is 10-60min; and/or
The separation time of the first neutralization reaction product in the continuous solid-liquid separation unit (50) is 5-30min; and/or
The extraction time of the filtrate in the first continuous extraction unit (60) is 10-45min; and/or
The first organic phase is concentrated in the first continuous concentration unit (70) for a period of 15-90 minutes; and/or
The reaction time of the sodium salt solution in the second continuous neutralization unit (90) is 10-45min; and/or
The liquid separation time of the second neutralization reaction product in the continuous liquid separation unit (100) is 10-45min; and/or
The extraction time of the second aqueous phase in the second continuous extraction unit (110) is 10-45min; and/or
The concentration time of the mixture of the second organic phase and the third organic phase in the second continuous concentration unit (120) is 15-60min.
8. The method of claim 7, wherein the step of determining the position of the probe is performed,
the nitric acid is fuming nitric acid, and when the flow rate of the fuming nitric acid into the first continuous reaction unit (10) is 10-30 kg/h:
The flow rate of the acetic anhydride introduced into the first continuous reaction unit (10) is 25-60kg/h;
in the raw material solution, the volume ratio of the acetic acid to the isosorbide is (1-5): 1; the flow rate of the raw material solution into the second continuous reaction unit (20) is 100-300kg/h;
the flow rate of the quenching agent into the continuous quenching unit (30) is 100-300kg/h;
the flow rate of the liquid caustic soda introduced into the first continuous neutralization unit (40) is regulated in real time according to a first online pH detection device;
the output flow rate of the filtrate in the continuous solid-liquid separation unit (50) is 500-1100kg/h;
the flow rate of the first extractant added into the first continuous extraction unit (60) is 200-800kg/h, and the output flow rate of the first organic phase in the first continuous extraction unit (60) is 250-850kg/h;
transferring the first concentrated product in the first continuous concentrating unit (70) to a sodium salt crystallizing unit (80), introducing water and liquid alkali into the sodium salt crystallizing unit (80), wherein the mass ratio of the first concentrated product, the water and the liquid alkali introduced into the sodium salt crystallizing unit (80) is (4.5-9): (9-18): (20-40);
In the sodium salt solution, the mass ratio of the sodium salt to the water to the ethyl acetate is (6-12): (4.5-9): (15-30); the flow rate of the sodium salt solution added into the second continuous neutralization unit (90) is 150-450kg/h, and the flow rate of the acid added into the second continuous neutralization unit (90) is adjusted in real time according to a second online pH monitoring device;
the output flow rate of the second water phase in the continuous liquid separation unit (100) is 20-150kg/h, and the output flow rate of the second organic phase is 100-350kg/h;
the flow rate of the second extractant introduced into the second continuous extraction unit (110) is 100-300kg/h, and the output flow rate of the third organic phase in the second continuous extraction unit (110) is 100-450kg/h;
the mass ratio of the second concentrated product, the n-heptane and the ethanol in the final crystallization unit (130) is (2-4): (3-6): (1-2);
the total of the respective feed flow rates of the first continuous reaction unit (10), the second continuous reaction unit (20), the continuous quenching unit (30), the first continuous neutralization unit (40), the continuous solid-liquid separation unit (50), the first continuous extraction unit (60), the first continuous concentration unit (70), the second continuous neutralization unit (90), the continuous liquid separation unit (100), the second continuous extraction unit (110) and the second continuous concentration unit (120) is the same as the total of the discharge flow rates.
9. The method of claim 8, wherein the step of determining the position of the first electrode is performed,
said firstHNO in a continuous reaction unit (10) 3 The ratio of the amount of the substance to the acetic anhydride is (1-1.5): (1-2); HNO introduced into the first continuous reaction unit (10) 3 The ratio of the amount of substance of (2) to the amount of substance of isosorbide introduced into the second continuous reaction unit (20) is (1-1.5): (1-1.1), the reaction temperature of the nitric acid and the acetic anhydride is 5-20 ℃; and/or
The temperature of the esterification reaction in the second continuous reaction unit (20) is 5-20 ℃; and/or
The reaction temperature in the first continuous neutralization unit (40) and the second continuous neutralization unit (90) is 10-25 ℃; and/or
The crystallization temperature in the sodium salt crystallization unit (80) is 0-5 ℃, and the crystallization time is 1-3h; and/or
The crystallization temperature in the finished product crystallization unit (130) is 0-5 ℃, and the crystallization time is 8-12h.
10. The method according to claim 9, characterized in that HNO in the first continuous reaction unit (10) 3 The ratio of the amount of the substance to the acetic anhydride is (1-1.1): (1.3-1.5); HNO introduced into the first continuous reaction unit (10) 3 The ratio of the amount of substance of (2) to the amount of substance of isosorbide introduced into the second continuous reaction unit (20) is (1-1.1): (1-1.1); and/or
The volume ratio of the acetic acid to the isosorbide in the raw material solution is (2-5): 1, a step of; and/or
The reaction temperature in the first continuous reaction unit (10) is 10-15 ℃, and the reaction temperature in the second continuous reaction unit (20) is 10-15 ℃.
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