CN115591495A - System and method for continuously preparing medical intermediate 2-hydroxy-5-nitropyridine by using microreactor - Google Patents
System and method for continuously preparing medical intermediate 2-hydroxy-5-nitropyridine by using microreactor Download PDFInfo
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- XKWSQIMYNVLGBO-UHFFFAOYSA-N 5-nitro-1h-pyridin-2-one Chemical compound OC1=CC=C([N+]([O-])=O)C=N1 XKWSQIMYNVLGBO-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 34
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims abstract description 68
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 58
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000000243 solution Substances 0.000 claims abstract description 32
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 29
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 19
- 239000007864 aqueous solution Substances 0.000 claims abstract description 18
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 17
- 238000003756 stirring Methods 0.000 claims abstract description 14
- 238000006396 nitration reaction Methods 0.000 claims abstract description 8
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 239000000463 material Substances 0.000 claims description 23
- 239000011593 sulfur Substances 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 238000012856 packing Methods 0.000 claims description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000945 filler Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 239000011521 glass Substances 0.000 claims description 3
- 239000012450 pharmaceutical intermediate Substances 0.000 claims description 3
- 229910001220 stainless steel Inorganic materials 0.000 claims description 3
- 239000010935 stainless steel Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- HLTDBMHJSBSAOM-UHFFFAOYSA-N 2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CC=N1 HLTDBMHJSBSAOM-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 17
- UGSBCCAHDVCHGI-UHFFFAOYSA-N 5-nitropyridin-2-amine Chemical compound NC1=CC=C([N+]([O-])=O)C=N1 UGSBCCAHDVCHGI-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract 1
- 239000002994 raw material Substances 0.000 description 13
- 238000012546 transfer Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 9
- 238000007086 side reaction Methods 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000010924 continuous production Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000003507 refrigerant Substances 0.000 description 2
- 229910000619 316 stainless steel Inorganic materials 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- PFRUBEOIWWEFOL-UHFFFAOYSA-N [N].[S] Chemical compound [N].[S] PFRUBEOIWWEFOL-UHFFFAOYSA-N 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000013021 overheating Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0006—Controlling or regulating processes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0006—Controlling or regulating processes
- B01J19/0013—Controlling the temperature of the process
-
- 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
- B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0053—Details of the reactor
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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- B01J2219/00004—Scale aspects
- B01J2219/00011—Laboratory-scale plants
- B01J2219/00013—Miniplants
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- Pyridine Compounds (AREA)
Abstract
Description
技术领域technical field
本发明属于化工生产技术领域，具体涉及一种制备2-羟基-5-硝基吡啶的装备和使用方法。The invention belongs to the technical field of chemical production, and in particular relates to equipment and a method for preparing 2-hydroxy-5-nitropyridine.
背景技术Background technique
2-羟基-5-硝基吡啶可作为医药、农药、染料中间体，用于合成多种吡啶化合物。目前报道的2-羟基-5-硝基吡啶合成方法主要是2-氨基吡啶为原料，在间歇釜内较低温度下向浓硫酸中加入2-氨基吡啶搅拌溶解，然后在低于30℃下缓慢滴加硝硫混酸，然后升温，在50℃左右搅拌反应5h，然后在低温下控温0～10℃滴加亚硝酸钠水溶液，结晶分离得到2-羟基-5-硝基吡啶。上述工艺反应时间很长，产率低。2-Hydroxy-5-nitropyridine can be used as an intermediate in medicine, pesticide, and dye to synthesize various pyridine compounds. The currently reported 2-hydroxy-5-nitropyridine synthesis method mainly uses 2-aminopyridine as a raw material. Add 2-aminopyridine to concentrated sulfuric acid at a lower temperature in a batch kettle to stir and dissolve, and then dissolve it at a temperature lower than 30°C. Slowly add nitric acid mixed acid dropwise, then heat up, stir and react at about 50°C for 5h, then add sodium nitrite aqueous solution dropwise at low temperature at 0-10°C, crystallize and separate to obtain 2-hydroxy-5-nitropyridine. Above-mentioned technique reaction time is very long, and productive rate is low.
硝化反应是一个强放热过程，传统的间歇式制备过程常常伴随“热点”，一方面导致的安全问题；另一方面，由于局部温度过高，容易发生副反应，导致原料转化率低；同时工艺过程复杂、流程长、效率低及生产成本高。The nitration reaction is a strong exothermic process. The traditional batch preparation process is often accompanied by "hot spots", which lead to safety problems on the one hand; The process is complicated, the process is long, the efficiency is low and the production cost is high.
相对于常规间歇釜，微反应器具有传热传质系数高，混合性能好，温度容易控制和过程安全可控等优点。微反应器有着极好的传热和传质能力，可以实现物料的均匀混合和反应热的高效传递。正是利用微反应器高效的传质传热特性，实现2-氨基吡啶硝化生成2-氨基-5-硝基吡啶，进而与亚硝酸钠发生重氮化反应、水解反应过程的热量快速传递，减少副反应的发生，提高过程安全性和选择性。采用微反应器制备2-羟基-5-硝基吡啶，为解决间歇釜制备过程存在的问题供新的方法和手段。Compared with conventional batch kettles, microreactors have the advantages of high heat and mass transfer coefficient, good mixing performance, easy temperature control and safe and controllable process. The microreactor has excellent heat and mass transfer capabilities, which can achieve uniform mixing of materials and efficient transfer of reaction heat. It is precisely by utilizing the efficient mass and heat transfer characteristics of the microreactor to realize the nitration of 2-aminopyridine to generate 2-amino-5-nitropyridine, and then undergo diazotization reaction with sodium nitrite and rapid heat transfer during the hydrolysis reaction. Reduce the occurrence of side reactions, improve process safety and selectivity. The preparation of 2-hydroxy-5-nitropyridine by using a microreactor provides a new method and means for solving the problems existing in the preparation process of batch kettles.
发明内容Contents of the invention
为了解决工业上使用间歇釜生产2-羟基-5-硝基吡啶，该过程副反应多、反应时间长，过程容易形成热点造成飞温，带来安全性问题。微反应器的传质传热效率比釜式反应器高出1～3个数量级，能够迅速带走反应产生的热量，从而降低事故发生的概率。针对上述间歇釜制备2-羟基-5-硝基吡啶过程中存在的问题，本发明提出了一种利用微反应器连续制备2-羟基-5-硝基吡啶的系统，利用微反应器高效混合能力和优秀的传质传热性能，能够强化反应的传质传热过程，同时微反应器和搅拌釜组合提高了生产效率，显著减少了反应器的体积和反应时间，提高反应选择性和过程安全性，减少了副反应的发生。与传统的间歇式制备相比，该方法可以实现2-羟基-5-硝基吡啶连续化生产，原料转化率高，副反应少，产品收率达到53％(优选为65％)以上，具有重要的商业价值。In order to solve the problem of industrial production of 2-hydroxy-5-nitropyridine using batch kettles, there are many side reactions and long reaction time in the process, and hot spots are easily formed in the process to cause overheating, which brings safety problems. The mass transfer and heat transfer efficiency of the microreactor is 1 to 3 orders of magnitude higher than that of the tank reactor, which can quickly take away the heat generated by the reaction, thereby reducing the probability of accidents. Aiming at the problems existing in the process of preparing 2-hydroxy-5-nitropyridine in the above-mentioned batch kettle, the present invention proposes a system for continuously preparing 2-hydroxy-5-nitropyridine using a microreactor, which utilizes the microreactor to efficiently mix The ability and excellent mass and heat transfer performance can strengthen the mass and heat transfer process of the reaction. At the same time, the combination of the microreactor and the stirred tank improves the production efficiency, significantly reduces the volume of the reactor and the reaction time, and improves the reaction selectivity and process. Safety, reducing the occurrence of side reactions. Compared with the traditional batch preparation, the method can realize the continuous production of 2-hydroxy-5-nitropyridine, the conversion rate of raw materials is high, the side reaction is less, and the product yield reaches more than 53% (preferably 65%). important commercial value.
一方面，本发明提供了一种利用套管式微反应器内连续制备医药中间体2-羟基-5-硝基吡啶的系统，包括六个套管式微反应器，六个套管式微反应器之间通过管道串联，每个套管式微反应器内置换热器，最后一个套管式反应器和搅拌釜(收集釜)连接。On the one hand, the present invention provides a system for continuously preparing the pharmaceutical intermediate 2-hydroxyl-5-nitropyridine in a sleeve-type microreactor, including six sleeve-type microreactors, one of the six sleeve-type microreactors The space is connected in series through pipelines, each jacketed microreactor has a built-in heat exchanger, and the last jacketed reactor is connected with a stirred tank (collecting tank).
所述六个套管式微反应器沿物料的流向方向依次为第一级微反应器、第二级微反应器、第三级微反应器、第四级微反应器、第五级微反应器和第六级微反应器，所述第六级微反应器和搅拌釜连接；The six sleeve-type microreactors are followed by the first-stage microreactor, the second-stage microreactor, the third-stage microreactor, the fourth-stage microreactor, and the fifth-stage microreactor along the flow direction of the material. With the sixth stage microreactor, the sixth stage microreactor is connected with the stirred tank;
所述微反应器为套管式微通道反应器。The microreactor is a casing microchannel reactor.
优选地，所述第一级微反应器、第二级微反应器、第五级微反应器为内径4～6mm，管长50～60cm，内管体积6.5～8.5ml的套管式微反应器，其内部装填孔隙率为85～97％的填料，实际反应体积6～7.5ml；所述第三级微反应器、第四级反应器、第六级反应器为内径4～6mm，管长60～75cm，内管体积8～11ml的套管式微反应器，内部装填孔隙率为85～97％的填料，实际反应体积8～10ml。Preferably, the first-stage microreactor, the second-stage microreactor, and the fifth-stage microreactor are sleeve-type microreactors with an inner diameter of 4-6mm, a tube length of 50-60cm, and an inner tube volume of 6.5-8.5ml , its internal packing porosity is 85～97% filler, and actual reaction volume is 6～7.5ml; The described third-stage microreactor, fourth-stage reactor, sixth-stage reactor are internal diameter 4～6mm, tube length 60 ~ 75cm,
优选地，所述填料为金属丝网填料，例如不锈钢丝网填料。Preferably, the packing is wire mesh packing, such as stainless steel mesh packing.
优选地，所述套管式微反应器的内管为反应管、外管为换热器。Preferably, the inner tube of the jacketed microreactor is a reaction tube, and the outer tube is a heat exchanger.
优选地，不同级套管式微反应器之间通过内径2～4mm，每段长度10～50cm的管道连接。Preferably, the sleeve-type microreactors at different levels are connected by pipes with an inner diameter of 2-4 mm and a length of each section of 10-50 cm.
优选地，所述收集釜为一般夹套式玻璃釜或不锈钢釜，通过外接冷媒控制釜内温度。Preferably, the collection kettle is a general jacketed glass kettle or a stainless steel kettle, and the temperature inside the kettle is controlled by an external refrigerant.
另一方面，本发明提供了一种利用上述系统制备2-羟基-5-硝基吡啶的方法，在第一级微反应器内2-氨基吡啶的浓硫酸溶液和硝硫混酸混合，发生硝化反应，形成反应液后继续在第二级微反应器、第三级微反应器、第四级微反应器和第五级微反应器内混合、发生硝化反应生成2-氨基-5-硝基吡啶，硝化反应完全后，在第六级微反应器内与亚硝酸钠水溶液混合，发生重氮化和水解反应生成2-羟基-5-硝基吡啶，最后反应完全后的物料进入搅拌釜，物料在搅拌釜内进一步降温、用氨水中和、析晶，过滤得到产品2-羟基-5-硝基吡啶。On the other hand, the present invention provides a kind of method utilizing above-mentioned system to prepare 2-hydroxy-5-nitropyridine, the concentrated sulfuric acid solution of 2-aminopyridine is mixed with nitric sulfur mixed acid in the first-stage microreactor, and nitration occurs Reaction, after forming the reaction solution, continue to mix in the second-stage microreactor, third-stage microreactor, fourth-stage microreactor and fifth-stage microreactor, and nitration reaction occurs to generate 2-amino-5-nitro Pyridine, after the nitration reaction is complete, is mixed with sodium nitrite aqueous solution in the sixth-stage micro-reactor, and undergoes diazotization and hydrolysis reactions to generate 2-hydroxy-5-nitropyridine, and finally the material after the complete reaction enters the stirring tank. The material is further cooled in the stirred tank, neutralized with ammonia water, crystallized, and filtered to obtain the product 2-hydroxy-5-nitropyridine.
优选的，所述微反应器反应温度控制在10℃～80℃。Preferably, the reaction temperature of the microreactor is controlled at 10°C to 80°C.
优选的，首先原料液的配制，包括的浓硫酸溶液和硝硫混酸以及亚硝酸钠水溶液的配制，2-氨基吡啶的浓硫酸溶液的质量浓度为5wt％～20wt％，优选为10wt％；硝硫混酸溶液中，发烟硝酸和浓硫酸摩尔比为1:1～5，优选硝酸和硫酸的摩尔比为1:2；亚硝酸钠水溶液的浓度10wt％～40wt％，优选为25％；2-氨基吡啶与亚硝酸钠的摩尔比在1:1.05～1.25，优选摩尔比为1:1.15。Preferably, at first the preparation of raw material liquid, the preparation of the concentrated sulfuric acid solution that comprises and nitric sulfur mixed acid and sodium nitrite aqueous solution, the mass concentration of the concentrated sulfuric acid solution of 2-aminopyridine is 5wt%～20wt%, is preferably 10wt%; Nitrate In the sulfur mixed acid solution, the molar ratio of fuming nitric acid and concentrated sulfuric acid is 1:1～5, preferably the molar ratio of nitric acid and sulfuric acid is 1:2; the concentration of sodium nitrite aqueous solution is 10wt%～40wt%, preferably 25%; 2 - The molar ratio of aminopyridine to sodium nitrite is 1:1.05-1.25, preferably 1:1.15.
优选地，所述2-氨基吡啶的浓硫酸溶液的流速为4.5～5.5ml/min，所述硝硫混酸的流速为1.2～1.6ml/min；所述亚硝酸钠水溶液的流速为2.4～3.2ml/min。Preferably, the flow rate of the concentrated sulfuric acid solution of 2-aminopyridine is 4.5-5.5ml/min, the flow rate of the nitric-sulfur mixed acid is 1.2-1.6ml/min; the flow rate of the sodium nitrite aqueous solution is 2.4-3.2 ml/min.
优选的，将2-氨基吡啶的浓硫酸溶液和混酸在第一级反应器和第二级反应器内混合反应，2-氨基吡啶和硝酸的摩尔比为1:1.0～1.15；第一级反应器和第二级反应器两个反应器的温度为10℃～60℃，优选反应温度为30℃。Preferably, the concentrated sulfuric acid solution of 2-aminopyridine and the mixed acid are mixed and reacted in the first-stage reactor and the second-stage reactor, and the molar ratio of 2-aminopyridine and nitric acid is 1:1.0～1.15; the first-stage reaction The temperature of the reactor and the second-stage reactor is 10°C to 60°C, and the preferred reaction temperature is 30°C.
优选的，中混合反应液在第三级微反应器和第四级微反应器4内重排反应，反应温度为50℃～80℃，优选反应温度为60℃。Preferably, the mixed reaction solution is rearranged in the third-stage microreactor and the fourth-stage microreactor 4, and the reaction temperature is 50°C to 80°C, preferably 60°C.
将亚硝酸钠水溶液与反应液在第六级微反应器内混合反应，2-氨基吡啶与亚硝酸钠的摩尔比在1:1.05～1.25，优选摩尔比为1:1.15；第五级反应器和第六级反应器的温度为20～50℃，优选反应温度为40℃。The sodium nitrite aqueous solution and the reaction liquid are mixed and reacted in the sixth-stage microreactor. The molar ratio of 2-aminopyridine to sodium nitrite is 1:1.05-1.25, preferably 1:1.15; the fifth-stage reactor The temperature of the reactor and the sixth stage reactor is 20-50°C, preferably the reaction temperature is 40°C.
优选的，所述反应物料在微反应器内的总停留时间为4～8min，优选总停留时间为6min。Preferably, the total residence time of the reaction materials in the microreactor is 4-8 minutes, preferably 6 minutes.
优选的，收集釜中用氨水调节pH为5～6，析晶温度为0～15℃，优选析晶温度5℃。Preferably, ammonia water is used in the collection tank to adjust the pH to 5-6, and the crystallization temperature is 0-15°C, preferably 5°C.
上述利用微反应器连续制备2-羟基-5-硝基吡啶的方法，具体包括以下步骤：The above-mentioned method for continuously preparing 2-hydroxyl-5-nitropyridine using a microreactor specifically comprises the following steps:
(1)2-氨基吡啶的浓硫酸溶液的配制：在室温下，将一定量的2-氨基吡啶缓慢加入到浓硫酸中，搅拌使其完全溶解后形成2-氨基吡啶的浓硫酸溶液，作为原料A；其中，2-氨基吡啶的浓硫酸溶液的质量浓度为5wt％～20wt％；(1) Preparation of the concentrated sulfuric acid solution of 2-aminopyridine: at room temperature, slowly add a certain amount of 2-aminopyridine in the concentrated sulfuric acid, stir to form the concentrated sulfuric acid solution of 2-aminopyridine after making it dissolve completely, as Raw material A; wherein, the mass concentration of the concentrated sulfuric acid solution of 2-aminopyridine is 5wt%～20wt%;
(2)硝硫混酸溶液的配制：在室温下，将一定量的发烟硝酸缓慢加入到浓硫酸中，形成硝硫混酸溶液，作为原料B，其中硝酸和硫酸摩尔比为1:2；(2) Preparation of nitric-sulfur mixed acid solution: at room temperature, slowly add a certain amount of fuming nitric acid into concentrated sulfuric acid to form nitric-sulfur mixed acid solution, as raw material B, wherein the molar ratio of nitric acid and sulfuric acid is 1:2;
(3)亚硝酸钠水溶液的配制：在室温下，将一定量的亚硝酸钠加入到水中，搅拌溶解后形成亚硝酸钠水溶液，作为原料C，亚硝酸钠水溶液的质量浓度10wt％～40wt；(3) Preparation of sodium nitrite aqueous solution: at room temperature, a certain amount of sodium nitrite is added to water, after stirring and dissolving, sodium nitrite aqueous solution is formed, as raw material C, the mass concentration of sodium nitrite aqueous solution is 10wt%～40wt;
(4)两股物料A(2-氨基吡啶的浓硫酸溶液)和B(硝硫混酸溶液)经由两台连续输送设备输入到微反应器，在第一级反应器和第二级微反应器内混合、发生硝化反应，并通过微反应器内置的换热器控制该段反应温度在10℃～40℃；反应后的物料进入第三级微反应器和第四级微反应器。(4) Two strands of materials A (concentrated sulfuric acid solution of 2-aminopyridine) and B (nitrogen-sulfur mixed acid solution) are input to the microreactor through two continuous conveying equipment, and the first-stage reactor and the second-stage microreactor Internal mixing and nitration reaction occur, and the reaction temperature of this section is controlled at 10°C to 40°C through the built-in heat exchanger of the microreactor; the reacted material enters the third-stage microreactor and the fourth-stage microreactor.
(5)经第二级微反应器反应后的物料进入第三级微反应器和第四级微反应器，通过微反应器内置的换热器控制该反应器的反应温度在50℃～80℃，反应结束后，进入第五级微反应器和第六级微反应器。(5) The material reacted by the second-stage microreactor enters the third-stage microreactor and the fourth-stage microreactor, and the reaction temperature of the reactor is controlled at 50°C to 80°C by the built-in heat exchanger of the microreactor. ℃, after the reaction is completed, enter the fifth-stage microreactor and the sixth-stage microreactor.
(6)经第四级微反应器反应后的物料进入第五级微反应器和第六级微反应器，物料在第五级微反应器继续混合，直至反应完全，在第六级微反应器内与原料C混合、反应重氮化和水解反应，通过微反应器内置的换热器控制第五级微反应器和第六级微反应器的反应温度在20℃～50℃，反应结束后，进入收集釜。(6) The material reacted by the fourth-stage microreactor enters the fifth-stage microreactor and the sixth-stage microreactor, and the material continues to mix in the fifth-stage microreactor until the reaction is complete, and the sixth-stage micro-reaction Mix with raw material C in the vessel, react diazotization and hydrolysis reaction, control the reaction temperature of the fifth-stage micro-reactor and sixth-stage micro-reactor at 20°C to 50°C through the built-in heat exchanger of the micro-reactor, and the reaction ends After that, enter the collection kettle.
(7)反应完全后的物料进入收集釜，降温至0℃～15℃，用氨水中和，调节pH至5～6析晶，抽滤得到产品2-羟基-5-硝基吡啶。(7) After the reaction is complete, the material enters the collection tank, cools down to 0°C-15°C, neutralizes with ammonia water, adjusts the pH to 5-6 and crystallizes, and suction-filters to obtain the product 2-hydroxy-5-nitropyridine.
本发明的有益效果为：(1)本发明采用微反应器实现了2-羟基-5-硝基吡啶用微反应器的连续制备；(2)微反应器体积小，简化了工艺流程，放大容易；(3)相比间歇式反应釜，采用微反应器连续化制备，具有混合效率高，传质传热速率快，反应过程温度可控，产物收率高等优点；(4)反应液可以快速的在反应器内混合反应后流出反应器，缩短了反应液在反应器内的停留时间，避免了由于“热点”带来的副反应发生，提高了产物的选择性；(5)微反应器高效的传质传热特性使得生产过程安全性高，降低了反应过程“热点”造成的安全风险；(6)微反应器内持液量低，相比传统釜式反应器，杜绝了大量物料发生事故的严重性。The beneficial effects of the present invention are: (1) the present invention realizes the continuous preparation of 2-hydroxy-5-nitropyridine using a microreactor; (3) Compared with the batch reactor, the micro-reactor is used for continuous preparation, which has the advantages of high mixing efficiency, fast mass and heat transfer rate, controllable temperature in the reaction process, and high product yield; (4) The reaction solution can be Quickly mix and react in the reactor and then flow out of the reactor, shortening the residence time of the reaction liquid in the reactor, avoiding the occurrence of side reactions caused by "hot spots", and improving the selectivity of the product; (5) Micro-reaction The high-efficiency mass and heat transfer characteristics of the micro-reactor make the production process safe and reduce the safety risk caused by the "hot spots" in the reaction process; (6) The liquid holding capacity in the micro-reactor is low, which eliminates a large number of The severity of the material incident.
从以下实施实例描述中，本发明特征优势显而易见From the description of the following implementation examples, the feature advantages of the present invention are obvious
附图说明Description of drawings
图1、本发明连续制备2-羟基-5-硝基吡啶流程图。Fig. 1, the flow chart of continuous preparation of 2-hydroxyl-5-nitropyridine of the present invention.
图中：1为第一级微反应器，2为第二级微反应器，3为第三级微反应器，4为第四级微反应器，5为第五级微反应器，6为第六级微反应器，7为输料泵，8为搅拌釜。Among the figure: 1 is the first stage microreactor, 2 is the second stage microreactor, 3 is the third stage microreactor, 4 is the fourth stage microreactor, 5 is the fifth stage microreactor, 6 is In the sixth-stage microreactor, 7 is a feeding pump, and 8 is a stirring tank.
具体实施方式detailed description
为了使本领域技术人员更好地理解本发明，以下通过实施例对本发明做进一步说明，但这些实施例并不限制本发明的范围。实施例中所用的试剂等原料均为市售试剂，实施例中所用的技术手段为本领域技术人员所熟知的常规手段。In order to enable those skilled in the art to better understand the present invention, the present invention will be further described below through examples, but these examples do not limit the scope of the present invention. The reagents and other raw materials used in the examples are all commercially available reagents, and the technical means used in the examples are conventional means well known to those skilled in the art.
实施例1微反应器连续制备2-羟基-5-硝基吡啶Embodiment 1 microreactor continuously prepares 2-hydroxyl-5-nitropyridine
如图1所示，一种利用套管式微反应器连续制备医药中间体2-氨基-5-硝基吡啶的系统，包括六个套管式微反应器，六个套管式微反应器之间通过管道串联，每个套管式微反应器内置微换热器，最后一个反应器和搅拌釜连接；所述六个套管式微反应器沿物料的流向方向依次为第一级微反应器1、第二级微反应器2、第三级微反应器3和第四级微反应器4、第五级微反应器5和第六级微反应器6，所述第六级微反应器6和搅拌釜8连接，所述第一级微反应器1连接两台输料泵7，所述第六级微反应器6连接一台输料泵7，所述三台输料泵7均为平流泵；所述六个微反应器均为套管式微通道反应器。所述第一级微反应器1、第二级微反应器2、第五级微反应器5为内径4mm，管长55cm，内管体积6.9ml的套管式微反应器，其内部装填316不锈钢丝网填料，孔隙率95％，实际反应体积6.5ml；所述第三级微反应器3、第四级微反应器4、第六级微反应器6为内径4mm，管长70cm，内管体积8.8ml的套管式微反应器，内部装填金属丝网填料，孔隙率95％，实际反应体积8.4ml。所述套管式微反应器的内管为反应管、外管为换热器。不同级微反应器之间通过内径2mm的塑料软管连接，其长度为25cm。所述搅拌釜6为一般夹套式玻璃釜，通过外接冷媒控制釜内温度。As shown in Figure 1, a system for continuously preparing pharmaceutical intermediates 2-amino-5-nitropyridine using sleeve-type microreactors includes six sleeve-type microreactors, and the six sleeve-type microreactors pass through Pipelines are connected in series, each sleeve-type microreactor has a built-in micro-heat exchanger, and the last reactor is connected to the stirred tank; the six sleeve-type microreactors are sequentially the first-stage microreactor 1, the second-stage microreactor along the flow direction of the material.
利用上述微反应器连续制备2-羟基-5-硝基吡啶的方法，具体步骤如下：Utilize above-mentioned microreactor to continuously prepare the method for 2-hydroxyl-5-nitropyridine, concrete steps are as follows:
(1)室温下，先将2-氨基吡啶(0.903mol，85g)分批缓慢加入765g浓硫酸(98wt％)中，搅拌使其完全溶解，得到2-氨基吡啶的浓硫酸溶液，作为原料相A；其中2-氨基吡啶的质量浓度为10wt％。(1) At room temperature, first slowly add 2-aminopyridine (0.903mol, 85g) in batches to 765g of concentrated sulfuric acid (98wt%), stir to dissolve it completely, and obtain the concentrated sulfuric acid solution of 2-aminopyridine as the raw material phase A; wherein the mass concentration of 2-aminopyridine is 10wt%.
(2)室温下，先将硝酸64.3g(1.0mol，98wt％)缓慢加入200g(2.0mol，98wt％)浓硫酸中，搅拌形成硝酸和硫酸摩尔比1:2的硝硫混酸溶液，作为原料相B。(2) At room temperature, slowly add 64.3g (1.0mol, 98wt%) of nitric acid into 200g (2.0mol, 98wt%) of concentrated sulfuric acid, and stir to form a nitric-sulfur mixed acid solution with a molar ratio of nitric acid and sulfuric acid of 1:2, as a raw material Phase B.
(3)室温下，先将亚硝酸钠(0.725mol，50g)缓慢加入150g水中，搅拌完全溶解，得到亚硝酸钠水溶液，作为原料相C；其中亚硝酸钠的质量浓度为25wt％。(3) At room temperature, slowly add sodium nitrite (0.725mol, 50g) into 150g of water, stir and dissolve completely to obtain an aqueous solution of sodium nitrite as raw material phase C; wherein the mass concentration of sodium nitrite is 25wt%.
(4)三股原料相A(5.5ml/min)、B(1.5ml/min)和C(2.8ml/min)通过三台平流泵输入到微通道反应器中，通过外循环水浴控制反应器，两股物料A和B在第一级微反应器1和第二级微反应器2内强烈混合并反应。反应物料进一步进入第三级微反应器3和第四级微反应器4混合并反应，；反应物料再进一步进入第五级微反应器5和第六级微反应器6，反应物料和C在第六级微反应器6内强烈混合并反应；同时，控制第一级微反应器1和第二级微反应器2的反应温度为30℃，控制第三级微反应器3和第四级微反应器4的反应温度为60℃，控制第五级微反应器5和第六级微反应器6的反应温度为40℃。物料在微反应器中总停留时间为6min。反应完全后产物进入收集釜，降温到5℃，搅拌滴加氨水调节pH为5～6，出现大量淡黄色沉淀，抽滤，得到产品2-羟基-5-硝基吡啶。经HPLC分析：原料转化率为99.5％，产品收率80.2％。(4) three strands of raw material phases A (5.5ml/min), B (1.5ml/min) and C (2.8ml/min) are input in the microchannel reactor by three convection pumps, and the reactor is controlled by an external circulating water bath, Two streams of materials A and B are intensively mixed and reacted in the first-stage microreactor 1 and the second-
实施例2-6微反应器连续制备2-羟基-5-硝基吡啶Embodiment 2-6 microreactor continuously prepares 2-hydroxyl-5-nitropyridine
采用与实施例1相同的连续制备2-羟基-5-硝基吡啶的系统和方法。反应过程中，2-氨基吡啶的浓硫酸溶液(5.5ml/min)，混酸(1.5ml/min)，亚硝酸钠水溶液(2.7ml/min)，总的停留时间6min，2-氨基吡啶与硝酸摩尔比为1:1.10，2-氨基吡啶与亚硝酸钠的摩尔比在1:1.12，第三级微反应器3、第四级微反应器4、第五级微反应器5和第六级微反应器6的反应温度不相同，具体结果分别见表1。The same system and method for the continuous preparation of 2-hydroxy-5-nitropyridine as in Example 1 were used. During the reaction, the concentrated sulfuric acid solution (5.5ml/min) of 2-aminopyridine, mixed acid (1.5ml/min), sodium nitrite aqueous solution (2.7ml/min), the total residence time of 6min, 2-aminopyridine and nitric acid The molar ratio is 1:1.10, the molar ratio of 2-aminopyridine to sodium nitrite is 1:1.12, the
表1、微通道反应器不同温度对反应的影响Table 1. Effect of different temperatures in microchannel reactor on reaction
实施例7-9微反应器连续制备2-羟基-5-硝基吡啶Embodiment 7-9 microreactor continuously prepares 2-hydroxyl-5-nitropyridine
采用与实施例1相同的连续制备2-羟基-5-硝基吡啶的系统和方法。反应过程中，2-氨基吡啶的浓硫酸溶液(5.5ml/min)，混酸(1.5ml/min)，亚硝酸钠水溶液(2.7ml/min)，总的停留时间6min，2-氨基吡啶与硝酸摩尔比为1:1.10，2-氨基吡啶与亚硝酸钠的摩尔比在1:1.12，第三级微反应器3和第四级微反应器4的反应温度为60℃，第五级微反应器5和第六级微反应器6的反应温度为40℃，套管式微反应器1和2温度不相同，具体结果分别见表2。The same system and method for the continuous preparation of 2-hydroxy-5-nitropyridine as in Example 1 were used. During the reaction, the concentrated sulfuric acid solution (5.5ml/min) of 2-aminopyridine, mixed acid (1.5ml/min), sodium nitrite aqueous solution (2.7ml/min), the total residence time of 6min, 2-aminopyridine and nitric acid The molar ratio is 1:1.10, the molar ratio of 2-aminopyridine to sodium nitrite is 1:1.12, the reaction temperature of the third-
表2、微通道反应器不同温度对反应的影响Table 2. Influence of different temperatures of microchannel reactor on reaction
实施例10-12微反应器连续制备2-羟基-5-硝基吡啶Embodiment 10-12 microreactor continuously prepares 2-hydroxyl-5-nitropyridine
采用与实施例1相同的连续制备2-羟基-5-硝基吡啶的系统和方法。反应过程中，套管式微反应器1和套管式微反应器2温度均为45℃，套管式微反应器3和套管式微反应器4温度均为60℃，套管式微反应器5和套管式微反应器6温度均为40℃，2-氨基吡啶的浓硫酸溶液(5.5ml/min)，硝硫混酸(1.5ml/min)。2-氨基吡啶与硝酸摩尔比为1:1.10，通过调节亚硝酸钠水溶液的进样量来控制2-氨基吡啶和亚硝酸钠的不同摩尔比，具体结果分别见表3。The same system and method for the continuous preparation of 2-hydroxy-5-nitropyridine as in Example 1 were used. During the reaction, the temperatures of the sleeve-type microreactor 1 and the sleeve-
表3、2-羟基-5-硝基吡啶和硝酸不同摩尔比对反应的影响The impact of table 3, 2-hydroxyl-5-nitropyridine and the different molar ratios of nitric acid on the reaction
通过本发明的微反应器连续制备2-羟基-5-硝基吡啶的系统，利用了微反应器高效传质传热特性有效地改善了现有方法中“热点”带来的生产安全问题，提高了产物的选择性和减少了副反应的发生，实现了2-羟基-5-硝基吡啶微反应器连续化生产，具有很高的商业开发价值。The system for continuously preparing 2-hydroxy-5-nitropyridine through the microreactor of the present invention utilizes the high-efficiency mass and heat transfer characteristics of the microreactor to effectively improve the production safety problems caused by "hot spots" in the existing methods, The selectivity of the product is improved, the occurrence of side reactions is reduced, and the continuous production of the 2-hydroxy-5-nitropyridine microreactor is realized, which has high commercial development value.
本领域技术人员可以理解，可对本发明做出一些修改或者调整。这些修改和调整也应当在本发明权利要求限定的范围之内。Those skilled in the art can understand that some modifications or adjustments can be made to the present invention. These modifications and adjustments should also be within the scope defined by the claims of the present invention.
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