CN111925299A - Continuous flow method for synthesizing 3-methyl-4-butyryl-5-nitrobenzoic acid methyl ester and reaction device thereof - Google Patents
Continuous flow method for synthesizing 3-methyl-4-butyryl-5-nitrobenzoic acid methyl ester and reaction device thereof Download PDFInfo
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 113
- 238000000034 method Methods 0.000 title claims abstract description 28
- SDKUVEBBPWMBCQ-UHFFFAOYSA-N methyl 4-butanoyl-3-methyl-5-nitrobenzoate Chemical compound CC=1C=C(C(=O)OC)C=C(C=1C(CCC)=O)[N+](=O)[O-] SDKUVEBBPWMBCQ-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 91
- 239000007788 liquid Substances 0.000 claims abstract description 72
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 61
- 239000002253 acid Substances 0.000 claims abstract description 47
- 238000010791 quenching Methods 0.000 claims abstract description 46
- 239000012074 organic phase Substances 0.000 claims abstract description 32
- 238000006396 nitration reaction Methods 0.000 claims abstract description 27
- 239000000047 product Substances 0.000 claims abstract description 19
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 17
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229940095102 methyl benzoate Drugs 0.000 claims abstract description 16
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 13
- 230000035484 reaction time Effects 0.000 claims abstract description 9
- 238000003860 storage Methods 0.000 claims description 103
- 239000000243 solution Substances 0.000 claims description 50
- 230000000171 quenching effect Effects 0.000 claims description 44
- 239000003795 chemical substances by application Substances 0.000 claims description 34
- 239000004065 semiconductor Substances 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- IGCBUUTXGYCQAI-UHFFFAOYSA-N methyl 4-(butanoylamino)-3-methyl-5-nitrobenzoate Chemical compound CCCC(=O)NC1=C(C)C=C(C(=O)OC)C=C1[N+]([O-])=O IGCBUUTXGYCQAI-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 19
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 14
- RZMQQYDXKPDLJH-UHFFFAOYSA-N methyl 4-(butanoylamino)-3-methylbenzoate Chemical compound CCCC(=O)NC1=CC=C(C(=O)OC)C=C1C RZMQQYDXKPDLJH-UHFFFAOYSA-N 0.000 claims description 14
- 239000011259 mixed solution Substances 0.000 claims description 13
- 239000004809 Teflon Substances 0.000 claims description 12
- 229920006362 Teflon® Polymers 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 9
- 238000000926 separation method Methods 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 6
- 230000003472 neutralizing effect Effects 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 238000005112 continuous flow technique Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000002274 desiccant Substances 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 16
- 239000000463 material Substances 0.000 abstract description 13
- 239000006227 byproduct Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 239000002910 solid waste Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000008346 aqueous phase Substances 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 12
- 239000005457 ice water Substances 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 2
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
- F17D—PIPE-LINE SYSTEMS; PIPE-LINES
- F17D1/00—Pipe-line systems
- F17D1/08—Pipe-line systems for liquids or viscous products
- F17D1/14—Conveying liquids or viscous products by pumping
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
- F17D—PIPE-LINE SYSTEMS; PIPE-LINES
- F17D3/00—Arrangements for supervising or controlling working operations
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- General Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Water Supply & Treatment (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a continuous flow method for synthesizing 3-methyl-4-butyryl-5-nitrobenzoic acid methyl ester and a reaction device thereof, which take 3-methyl-4-butyryl methyl benzoate as a raw material, mixed acid (nitric acid and sulfuric acid) as a nitration reagent, continuously input the materials into a high-efficiency mixer through a metering pump, mix the materials, enter a temperature-controlled pipeline reactor for nitration reaction, quench reaction liquid in the pipeline reactor after the reaction is finished, then continuously separate liquid, and obtain an organic phase which is neutralized, dried, concentrated and recrystallized to obtain a pure product of the 3-methyl-4-butyryl-5-nitrobenzoic acid methyl ester. The continuous flow nitration mixed acid has small consumption, short reaction time, high conversion rate, less byproducts and less solid waste, and accords with the green chemical concept; the continuous flow synthesis method has the advantages of good safety, convenient intelligent control, high reaction and post-treatment efficiency and the like, and has industrial production application value.
Description
Technical Field
The invention discloses a continuous flow method for synthesizing 3-methyl-4-butyryl-5-nitrobenzoic acid methyl ester and a reaction device thereof.
Background
The 3-methyl-4-butyryl-5-nitrobenzoic acid methyl ester is an important intermediate for synthesizing the antihypertensive drug telmisartan, and the synthesis method is usually to take 3-methyl-4-butyryl methyl benzoate as a raw material and prepare the compound by nitration of mixed acid.
In the prior art, the synthesis of 3-methyl-4-butyryl-5-nitrobenzoic acid methyl ester is generally carried out by taking 3-methyl-4-butyryl methyl benzoate as a raw material and carrying out a kettle type nitration reaction with excessive mixed acid (for example, Chinese patent applications CN103319415 and CN 104610161). The traditional batch kettle type nitration reaction has many disadvantages: firstly, because fuming nitric acid and concentrated sulfuric acid are generally used in the traditional mixed acid nitration, a large amount of heat can be released in the nitration reaction process, and safety accidents are easily caused if the temperature is not well controlled; secondly, the kettle type nitration can cause multiple nitration reactions due to long reaction time, thereby affecting the product quality and causing potential safety hazards.
Continuous Flow Chemical Reaction (Flow Chemical Reaction) is a Chemical Reaction that occurs in a microchannel reactor, tubular reactor, or compact tank reactor by pumping two or more different gaseous, liquid, or semi-solid reactants through a Flow pump at a given Flow rate. The continuous flow reaction greatly shortens the reaction time by changing the heat transfer and mass transfer modes of the reaction, thereby improving the reaction efficiency. Meanwhile, the reaction risk is greatly reduced due to the small liquid holdup of the continuous flow reactor. Continuous flow synthesis can efficiently link main reaction and post-treatment, thereby saving time, space and labor, finally reducing production cost and improving production efficiency and safety.
Disclosure of Invention
Aiming at the problems of high nitration risk, long reaction time, many byproducts and the like in the prior art, the invention aims to provide a high-efficiency and safe continuous flow method for synthesizing 3-methyl-4-butyryl-5-nitrobenzoic acid methyl ester and a reaction device thereof.
The invention aims at providing a reaction device for synthesizing 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester through pipeline synthesis, which is characterized by mainly comprising a fuming nitric acid liquid storage tank 1, a concentrated sulfuric acid liquid storage tank 2, a 3-methyl-4-butyryl methyl benzoate liquid storage tank 8, a quencher liquid storage tank 15, a first pipeline reactor 6, a second pipeline reactor 12, a liquid separating tank 19 and a receiving tank; the outlet of each liquid storage tank is connected with a pipeline through a metering pump; outlets of the fuming nitric acid liquid storage tank 1 and the concentrated sulfuric acid liquid storage tank 2 are connected with an inlet of a first efficient mixer 4, and an outlet of the first efficient mixer 4 is connected with an inlet of a first pipeline reactor 6; an outlet of the first pipeline reactor 6 and an outlet of the 3-methyl-4-butyryl methyl benzoate liquid storage tank are connected with an inlet of the second high-efficiency mixer 11; the outlet of the second high-efficiency mixer 11 is connected with the inlet of a second pipeline reactor 12; the second pipeline reactor 12 and the quenching agent liquid storage tank 15 are connected with the inlet of a third high-efficiency mixer 17; the outlet of the third efficient mixer 17 is connected with a liquid separating tank 19, and the upper part and the lower part of the liquid separating tank 19 are respectively connected with a first receiving tank 22 and a second receiving tank 23.
Further, the first pipeline reactor 6 and the second pipeline reactor 12 are continuous flow pipeline reactors, the length of the pipeline is 25-200m, the diameter of the pipeline is 0.5-40mm, and the pipeline is made of Teflon tubes or quartz glass tubes.
Further, the first pipeline reactor 6 and the second pipeline reactor 12 are respectively arranged in a semiconductor temperature control box, and the temperature range is controlled to be 0-100 ℃.
The reaction device for synthesizing the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester by pipelining adopts pipelining to carry out nitration reaction and quenching. The device has the advantages of scientific and reasonable design, good safety, convenient intelligent control, short reaction time, high post-treatment efficiency and industrial production application value.
A second object of the present invention is to provide a continuous flow process for the synthesis of methyl 3-methyl-4-butanoyl-5-nitrobenzoate, characterized in that a reaction apparatus according to any one of claims 1 to 3 is used, comprising the steps of:
(1) fuming nitric acid is stored in a fuming nitric acid liquid storage tank 1, concentrated sulfuric acid is stored in a concentrated sulfuric acid liquid storage tank 2, 3-methyl-4-butyryl methyl benzoate shown in a formula (I) is dissolved in an organic solvent A and stored in a liquid storage tank 8, and a quenching agent is stored in a quenching agent liquid storage tank 15;
(2) adjusting the pipeline temperature of the first pipeline reactor 6 and the second pipeline reactor 12 to 5-70 ℃;
(3) starting metering pumps of the fuming nitric acid liquid storage tank 1 and the concentrated sulfuric acid liquid storage tank 2, feeding a sample into the first efficient mixer 4, and continuously flowing the mixed solution into the first pipeline reactor 6;
(4) when the mixed acid effluent is about to enter the second high-efficiency mixer 11, starting a metering pump of a 3-methyl-4-butyryl methyl benzoate liquid storage tank 8, feeding a sample into the second high-efficiency mixer 11, and allowing the mixed reaction liquid to enter a second tubular reactor 12 for nitration reaction;
(5) when the nitration reaction liquid is about to reach the third high-efficiency mixer 17, a metering pump connected with the quenching agent liquid storage tank 15 is started, and the nitration reaction liquid and the quenching agent are mixed by the third high-efficiency mixer 17 and then enter a liquid separation tank 19;
(6) the organic phase and the water phase respectively flow into a first receiving tank 22 and a second receiving tank 23 with throttle valves after being separated by a liquid separating tank 19;
(7) neutralizing, drying and concentrating the organic phase collected in the receiving tank to obtain a solid crude product;
(8) recrystallizing the solid crude product by using an organic solvent B to obtain a product 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester shown in a formula (II), wherein the reaction equation is as follows:
further, the concentration of the fuming nitric acid in the step (1) is 95-98%, the concentration of the concentrated sulfuric acid is 50-98%, the organic solvent A is dichloromethane, chloroform, 1, 2-dichloroethane or ethyl acetate, the concentration of the solution of the organic solvent A is 0.1-3.0mol/L, the quenching agent is water, and the temperature of the quenching agent is 0-15 ℃.
Further, the temperature of the mixture of fuming nitric acid and concentrated sulfuric acid in the step (3) is controlled to be 5-45 ℃.
Further, in the step (4), the molar ratio of the methyl 3-methyl-4-butyramidobenzoate to the nitric acid and the sulfuric acid is 1:1.5:0.5-1:9.0:3.5, the nitration reaction temperature is 5-40 ℃, and the reaction time is 1-30 min.
Further, the volume ratio of the nitration reaction liquid and the quenching agent in the step (5) is 1:0.8-1: 5.0.
Further, the neutralizing agent used in the step (7) is an aqueous solution of sodium carbonate, sodium bicarbonate, sodium phosphate, potassium phosphate or sodium monohydrogen phosphate, the concentration of which is 10-30%; the drying agent is anhydrous sodium sulfate, anhydrous calcium chloride or anhydrous magnesium sulfate.
Further, the organic solvent B in the step (8) is a mixed solution of petroleum ether and ethyl acetate (volume ratio is 30:1-1:10), a mixed solution of acetone and water (volume ratio is 40:1-1:10), a mixed solution of methanol and water (volume ratio is 40:1-1:10), a mixed solution of ethanol and water (volume ratio is 40:1-1:10) and a mixed solution of tetrahydrofuran and water (volume ratio is 40:1-1: 20).
The method takes 3-methyl-4-butyryl methyl benzoate as a raw material, mixed acid (nitric acid and sulfuric acid) as a nitration reagent, the materials are continuously input into a high-efficiency mixer through a metering pump to be mixed and then enter a temperature-controlled pipeline reactor to carry out nitration reaction, after the reaction is finished, reaction liquid is quenched in the pipeline reactor, then continuous liquid separation is carried out, and the obtained organic phase is neutralized, dried, concentrated and recrystallized to obtain a pure product of 3-methyl-4-butyryl-5-nitrobenzoic acid methyl ester. The continuous flow nitration mixed acid has small consumption, short reaction time, high conversion rate, less byproducts and less solid waste, and accords with the green chemical concept; the continuous flow synthesis method has the advantages of good safety, convenient intelligent control, high reaction and post-treatment efficiency and the like, and has industrial production application value.
Compared with the prior art, the continuous flow method for synthesizing the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester has the following innovation and advantages that: the process reduces the dosage of nitric acid and sulfuric acid, and reduces three wastes; the reaction time is shortened, the reaction and production efficiency is improved, the side reaction is reduced, and the process safety is improved.
Drawings
FIG. 1 is a schematic diagram of a device dedicated to continuous flow synthesis of 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester.
In the figure: 1-fuming nitric acid liquid storage tank, 2-concentrated sulfuric acid liquid storage tank, 3-first metering pump, 4-first high-efficiency blending device, 5-second metering pump, 6-first pipeline reactor, 7-first semiconductor temperature control box, 8-3-methyl-4-butyryl methyl benzoate liquid storage tank, 9-third metering pump, 10-first temperature measuring instrument, 11-second high-efficiency blending device, 12-second pipeline reactor, 13-second semiconductor temperature control box, 14-second temperature measuring instrument, 15-quenching agent liquid storage tank, 16-fourth metering pump, 17-third high-efficiency blending device, 18-third temperature measuring instrument, 19-liquid separation tank, 20-first throttling valve, 21-first throttling valve, 22-first receiving tank and 23-second receiving tank.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.
The structure of the special reaction device used in the embodiment is shown in fig. 1, and mainly comprises a fuming nitric acid liquid storage tank 1 (an outlet is provided with a first metering pump 3), a concentrated sulfuric acid liquid storage tank 2 (an outlet is provided with a first metering pump 5), a 3-methyl-4-butyryl methyl benzoate liquid storage tank 8 (an outlet is provided with a first metering pump 9), a quencher liquid storage tank 15 (an outlet is provided with a first metering pump 16), a first pipeline reactor 6, a second pipeline reactor 12, a liquid separation tank 19 and a receiving tank. The first pipeline reactor 6 and the second pipeline reactor 12 are respectively arranged in the first semiconductor temperature control box 7 and the second semiconductor temperature control box 13, and the temperature range is controlled to be 0-100 ℃.
The outlet of each liquid storage tank is connected with a pipeline through a metering pump; outlets of the fuming nitric acid liquid storage tank 1 and the concentrated sulfuric acid liquid storage tank 2 are connected with an inlet of a first efficient mixer 4, and an outlet of the first efficient mixer 4 is connected with an inlet of a first pipeline reactor 6; an outlet of the first pipeline reactor 6 and an outlet of the 3-methyl-4-butyryl methyl benzoate liquid storage tank are connected with an inlet of the second high-efficiency mixer 11; the outlet of the second high-efficiency mixer 11 is connected with the inlet of a second pipeline reactor 12; the second pipeline reactor 12 and the quenching agent liquid storage tank 15 are connected with the inlet of a third high-efficiency mixer 17; the outlet of the third efficient mixer 17 is connected with a liquid separating tank 19, and the upper part and the lower part of the liquid separating tank 19 are respectively connected with a first receiving tank 22 and a second receiving tank 23.
A first temperature measuring instrument 10 is arranged on a pipeline between the first pipeline reactor 6 and the second high-efficiency mixer 11; a second temperature measuring instrument 14 is arranged on a pipeline between the second pipeline reactor 12 and the third efficient mixer 17; and a third temperature measuring instrument 18 is arranged on a pipeline between the third high-efficiency blending machines 17 and a pipeline between the liquid separating tanks 19.
A continuous flow process for the synthesis of methyl 3-methyl-4-butyramido-5-nitrobenzoate comprising the steps of:
(1) fuming nitric acid is stored in a fuming nitric acid liquid storage tank 1, concentrated sulfuric acid is stored in a concentrated sulfuric acid liquid storage tank 2, 3-methyl-4-butyryl methyl benzoate shown in a formula (I) is dissolved in an organic solvent A and stored in a liquid storage tank 8, and a quenching agent is stored in a quenching agent liquid storage tank 15;
(2) opening a first semiconductor temperature control box 10 and a second semiconductor temperature control box 13, and adjusting the temperature of the pipeline to 5-70 ℃;
(3) starting a first metering pump 3 connected with a fuming nitric acid liquid storage tank 1, starting a second metering pump 5 connected with a concentrated sulfuric acid liquid storage tank 2, injecting a sample into a first high-efficiency mixer 4, continuously flowing the mixed solution into a first pipeline reactor 6, and monitoring the temperature of the mixed acid effluent through a first temperature measuring instrument 10;
(4) when the mixed acid effluent is about to enter a second high-efficiency mixer 11, starting a third metering pump 9 connected with a liquid storage tank 8, feeding a sample into the second high-efficiency mixer 11, and allowing the mixed reaction liquid to enter a second tubular reactor 12 for nitration reaction;
(5) when the nitration reaction liquid is about to reach the third high-efficiency blending device 17, a fourth metering pump 16 connected with a quenching agent storage tank 15 is started, and the reaction liquid and the quenching agent are mixed by the third high-efficiency blending device 17 and then enter a liquid separation tank 19;
(6) the organic phase and the water phase respectively flow into a first receiving tank 22 and a second receiving tank 23 with throttle valves after being separated by a liquid separating tank;
(7) neutralizing, drying and concentrating the organic phase collected in the receiving tank to obtain a solid crude product;
(8) recrystallizing the solid crude product by using an organic solvent B to obtain a product 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester shown in a formula (II), wherein the reaction equation is as follows:
example 1:
the structure of the special reaction device used in this example is shown in fig. 1, the length of the reactor pipeline is 20m, the diameter is 3mm, and the pipeline material is teflon pipe.
Firstly, opening a precooling pipeline of a first semiconductor temperature control box 7, setting the temperature at 10 ℃, and opening a second semiconductor temperature control box 13, setting the temperature at 25 ℃; next, a sufficient amount of fuming nitric acid was stored in a fuming nitric acid storage tank 1, a sufficient amount of 98% sulfuric acid was stored in a concentrated sulfuric acid storage tank 2, 23.5 g (0.1mol) of methyl 3-methyl-4-butanamidobenzoate was dissolved in 200mL of methylene chloride and then stored in a storage tank 8, and a sufficient amount of ice water at 5 ℃ was stored in a quencher storage tank 15.
Starting the first metering pump 3 and the second metering pump 5, controlling the flow rate of the two pumps to ensure that the molar equivalent ratio of the nitric acid to the sulfuric acid is 3:1, and controlling the flow rate to ensure that the temperature of the mixed acid flowing out of the first pipeline reactor 6 is kept at about 18 ℃. When the mixed acid is about to reach the second high-efficiency mixer 11, the third metering pump 9 is started, the flow is controlled to ensure that the molar equivalent ratio of the raw materials to the mixed acid is 1:1.5, and the reaction temperature is controlled to be 30-32 ℃. When the reaction solution is about to reach the third high-efficiency mixer 17, the fourth metering pump 16 is started to ensure that the volume ratio of the quenching agent to the reaction solution is 1:1, and the temperature of the quenched reaction solution is measured to be 34-35 ℃. The whole reaction and quenching process took 20 minutes. The reaction solution is collected in a separating tank 19, and a first throttle valve 20 and a second throttle valve 21 are adjusted, and in this example, an aqueous phase is separated from an upper layer of the separating tank into a first receiving tank 22, and an organic phase is collected from a lower layer of the separating tank into a second receiving tank 23. The organic phase is washed by 15 percent sodium carbonate, dried by anhydrous sodium sulfate, and then the solid obtained by concentration is recrystallized by ethanol and water (30:1), and the filter cake is dried to obtain 22.4 g of the pure product of the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, the yield is 80 percent, the melting point is 152-.
Example 2:
the structure of the special reaction device used in this example is shown in fig. 1, the length of the reactor pipeline is 20m, the diameter is 3mm, and the pipeline material is teflon.
Firstly, opening a precooling pipeline of a first semiconductor temperature control box 7, setting the temperature at 10 ℃, and opening a second semiconductor temperature control box 13, setting the temperature at 25 ℃; subsequently, sufficient fuming nitric acid was stored in a fuming nitric acid storage tank 1, sufficient 98% sulfuric acid was stored in a concentrated sulfuric acid storage tank 2, 23.5 g (0.1mol) of methyl 3-methyl-4-butanamidobenzoate was dissolved in 200mL of chloroform and then stored in a storage tank 8, and sufficient ice water at 5 ℃ was stored in a quencher storage tank 15.
Starting the first metering pump 3 and the second metering pump 5, controlling the flow rate of the two pumps to ensure that the molar equivalent ratio of the nitric acid to the sulfuric acid is 3:1, and controlling the flow rate to ensure that the temperature of the mixed acid flowing out of the first pipeline reactor 6 is kept at about 18 ℃. When the mixed acid is about to reach the second mixer 11, the third metering pump 9 is started, the flow is controlled to ensure that the molar equivalent ratio of the raw materials to the mixed acid is 1:1.5, and the reaction temperature is controlled to be 30-32 ℃. When the reaction solution is about to reach the third mixer 17, the fourth metering pump 16 is started to make the volume ratio of the quenching agent to the reaction solution 1:1, and the temperature of the quenched reaction solution is measured to be 34-35 ℃. The whole reaction and quenching process took 20 minutes. The reaction solution is collected in a separating tank 19, and a first throttle valve 20 and a second throttle valve 21 are adjusted, and in this example, an aqueous phase is separated from an upper layer of the separating tank into a first receiving tank 22, and an organic phase is collected from a lower layer of the separating tank into a second receiving tank 23. The organic phase is washed by 15 percent sodium carbonate, dried by anhydrous sodium sulfate, and then the solid obtained by concentration is recrystallized by ethanol and water (30:1), and the filter cake is dried to obtain 23.2 g of the pure product of the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, the yield is 83 percent, the melting point is 152-.
Example 3:
the structure of the special reaction device used in this example is shown in fig. 1, the length of the reactor pipeline is 20m, the diameter is 3mm, and the pipeline material is teflon.
Firstly, opening a precooling pipeline of a first semiconductor temperature control box 7, setting the temperature at 10 ℃, and opening a second semiconductor temperature control box 13, setting the temperature at 25 ℃; next, a sufficient amount of fuming nitric acid was stored in a fuming nitric acid storage tank 1, a sufficient amount of 98% sulfuric acid was stored in a concentrated sulfuric acid storage tank 2, 23.5 g (0.1mol) of methyl 3-methyl-4-butanamidobenzoate was dissolved in 200mL of ethyl acetate and stored in a storage tank 8, and a sufficient amount of ice water at 5 ℃ was stored in a quencher storage tank 15.
Starting the first metering pump 3 and the second metering pump 5, controlling the flow rate of the two pumps to ensure that the molar equivalent ratio of the nitric acid to the sulfuric acid is 3:1, and controlling the flow rate to ensure that the temperature of the mixed acid flowing out of the first pipeline reactor 6 is kept at about 18 ℃. When the mixed acid is about to reach the second mixer 11, the third metering pump 9 is started, the flow is controlled to ensure that the molar equivalent ratio of the raw materials to the mixed acid is 1:1.5, and the reaction temperature is controlled to be 30-32 ℃. When the reaction solution is about to reach the third mixer 17, the fourth metering pump 16 is started to make the volume ratio of the quenching agent to the reaction solution 1:1, and the temperature of the quenched reaction solution is measured to be 34-35 ℃. The whole reaction and quenching process took 22 minutes. The reaction solution is collected in a separating tank 19, and a first throttle valve 20 and a second throttle valve 21 are adjusted, and in this example, an organic phase is separated from an upper layer of the separating tank into a first receiving tank 22, and an aqueous phase is collected from a lower layer of the separating tank into a second receiving tank 23. The organic phase is washed by 15 percent sodium carbonate, dried by anhydrous sodium sulfate, and then the solid obtained by concentration is recrystallized by ethanol and water (30:1), and the filter cake is dried to obtain 21.8 g of the pure product of the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, the yield is 78 percent, the melting point is 152-.
Example 4:
the structure of the special reaction device used in this example is shown in fig. 1, the length of the reactor pipeline is 20m, the diameter is 3mm, and the pipeline material is teflon.
Firstly, opening a precooling pipeline of a first semiconductor temperature control box 7, setting the temperature at 10 ℃, and opening a semiconductor temperature control box 13, setting the temperature at 25 ℃; subsequently, a sufficient amount of fuming nitric acid was stored in a fuming nitric acid storage tank 1, a sufficient amount of 98% sulfuric acid was stored in a concentrated sulfuric acid storage tank 2, 23.5 g (0.1mol) of methyl 3-methyl-4-butanamidobenzoate was dissolved in 200mL of 1, 2-dichloroethane, and then stored in a storage tank 8, and a sufficient amount of ice water at 5 ℃ was stored in a quencher storage tank 15.
Starting the first metering pump 3 and the second metering pump 5, controlling the flow rate of the two pumps to ensure that the molar equivalent ratio of the nitric acid to the sulfuric acid is 3:1, and controlling the flow rate to ensure that the temperature of the mixed acid flowing out of the first pipeline reactor 6 is kept at about 18 ℃. When the mixed acid is about to reach the first high-efficiency mixer 11, the third metering pump 9 is started, the flow is controlled to ensure that the molar equivalent ratio of the raw materials to the mixed acid is 1:1.5, and the reaction temperature is controlled to be 30-32 ℃. When the reaction solution is about to reach the third mixer 17, the fourth metering pump 16 is started to make the volume ratio of the quenching agent to the reaction solution 1:1, and the temperature of the quenched reaction solution is measured to be 34-35 ℃. The whole reaction and quenching process took 20 minutes. The reaction solution is collected in a separating tank 19, and a first throttle valve 20 and a second throttle valve 21 are adjusted, and in this example, an aqueous phase is separated from an upper layer of the separating tank into a first receiving tank 22, and an organic phase is collected from a lower layer of the separating tank into a second receiving tank 23. The organic phase is washed by 15 percent sodium carbonate, dried by anhydrous sodium sulfate, and then the solid obtained by concentration is recrystallized by ethanol and water (35:1), and the filter cake is dried to obtain 23.8 g of the pure product of the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, the yield is 85 percent, the melting point is 153-.
Example 5:
the structure of the special reaction device used in this example is shown in fig. 1, the length of the reactor pipeline is 25m, the diameter is 3mm, and the pipeline material is teflon.
Firstly, opening a precooling pipeline of a first semiconductor temperature control box 7, setting the temperature at 10 ℃, and opening a second semiconductor temperature control box 13, setting the temperature at 25 ℃; next, a sufficient amount of fuming nitric acid was stored in a fuming nitric acid storage tank 1, a sufficient amount of 98% sulfuric acid was stored in a concentrated sulfuric acid storage tank 2, 23.5 g (0.1mol) of methyl 3-methyl-4-butanamidobenzoate was dissolved in 200mL of methylene chloride and then stored in a storage tank 8, and a sufficient amount of ice water at 5 ℃ was stored in a quencher storage tank 15.
Starting the first metering pump 3 and the second metering pump 5, controlling the flow rate of the two pumps to ensure that the molar equivalent ratio of the nitric acid to the sulfuric acid is 3:1, and controlling the flow rate to ensure that the temperature of the mixed acid flowing out of the first pipeline reactor 6 is kept at about 15 ℃. When the mixed acid is about to reach the second high-efficiency mixer 11, the third metering pump 9 is started, the flow is controlled to ensure that the molar equivalent ratio of the raw material to the mixed acid is 1:1.8, and the reaction temperature is controlled to be 30-32 ℃. When the reaction solution is about to reach the third high-efficiency mixer 17, the fourth metering pump 16 is started to ensure that the volume ratio of the quenching agent to the reaction solution is 1:1, and the temperature of the quenched reaction solution is measured to be 34-35 ℃. The entire reaction and quenching process took 24 minutes. The reaction solution is collected in a separating tank 19, and a first throttle valve 20 and a second throttle valve 21 are adjusted, and in this example, an aqueous phase is separated from an upper layer of the separating tank into a first receiving tank 22, and an organic phase is collected from a lower layer of the separating tank into a second receiving tank 23. The organic phase is washed by 10 percent sodium carbonate, dried by anhydrous sodium sulfate, and then the solid obtained by concentration is recrystallized by methanol and water (40:1), and the filter cake is dried to obtain 24.1 g of the pure product of the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, the yield is 86 percent, the melting point is 153-.
Example 6:
the structure of the special reaction device used for the implementation is shown in figure 1, the length of a pipeline of the reactor is 25m, the diameter of the pipeline is 3mm, and the pipeline is made of Teflon.
Firstly, opening a precooling pipeline of a first semiconductor temperature control box 7, setting the temperature at 10 ℃, and opening a second semiconductor temperature control box 13, setting the temperature at 25 ℃; subsequently, sufficient fuming nitric acid was stored in a fuming nitric acid storage tank 1, sufficient 98% sulfuric acid was stored in a concentrated sulfuric acid storage tank 2, 23.5 g (0.1mol) of methyl 3-methyl-4-butanamidobenzoate was dissolved in 200mL of chloroform and then stored in a storage tank 8, and sufficient ice water at 5 ℃ was stored in a quencher storage tank 15.
Starting the first metering pump 3 and the second metering pump 5, controlling the flow rate of the two pumps to ensure that the molar equivalent ratio of the nitric acid to the sulfuric acid is 3:1, and controlling the flow rate to ensure that the temperature of the mixed acid flowing out of the first pipeline reactor 6 is kept at about 18 ℃. When the mixed acid is about to reach the second high-efficiency mixer 11, the third metering pump 9 is started, the flow is controlled to ensure that the molar equivalent ratio of the raw materials to the mixed acid is 1:1.8, and the reaction temperature is controlled to be 31-33 ℃. When the reaction solution is about to reach the third high-efficiency mixer 17, the fourth metering pump 16 is started to ensure that the volume ratio of the quenching agent to the reaction solution is 1:1, and the temperature of the quenched reaction solution is measured to be 34-36 ℃. The whole reaction and quenching process took 25 minutes. The reaction solution is collected in a separating tank 19, and a first throttle valve 20 and a second throttle valve 21 are adjusted, and in this example, an aqueous phase is separated from an upper layer of the separating tank into a first receiving tank 22, and an organic phase is collected from a lower layer of the separating tank into a second receiving tank 23. The organic phase is washed by 10 percent sodium carbonate, dried by anhydrous sodium sulfate, and then the solid obtained by concentration is recrystallized by methanol and water (40:1), and the filter cake is dried to obtain 24.1 g of the pure product of the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, the yield is 86 percent, the melting point is 153-.
Example 7:
the structure of the special reaction device used in this example is shown in fig. 1, the length of the reactor pipeline is 25m, the diameter is 3mm, and the pipeline material is teflon.
Firstly, opening a precooling pipeline of a first semiconductor temperature control box 7, setting the temperature at 10 ℃, and opening a second semiconductor temperature control box 13, setting the temperature at 25 ℃; next, a sufficient amount of fuming nitric acid was stored in a fuming nitric acid storage tank 1, a sufficient amount of 98% sulfuric acid was stored in a concentrated sulfuric acid storage tank 2, 23.5 g (0.1mol) of methyl 3-methyl-4-butanamidobenzoate was dissolved in 200mL of ethyl acetate and stored in a storage tank 8, and a sufficient amount of ice water at 5 ℃ was stored in a quencher storage tank 15. And starting the first metering pump 3 and the second metering pump 5, controlling the flow rates of the two pumps to ensure that the molar equivalent ratio of the nitric acid to the sulfuric acid is 3:1, and controlling the flow rate to ensure that the temperature of the mixed acid flowing out of the first pipeline reactor 6 is kept at about 18 ℃. When the mixed acid is about to reach the second high-efficiency mixer 11, the third metering pump 9 is started, the flow is controlled to ensure that the molar equivalent ratio of the raw materials to the mixed acid is 1:1.8, and the reaction temperature is controlled to be 31-33 ℃. When the reaction solution is about to reach the third high-efficiency mixer 17, the fourth metering pump 16 is started to ensure that the volume ratio of the quenching agent to the reaction solution is 1:1, and the temperature of the quenched reaction solution is measured to be 34-36 ℃. The whole reaction and quenching process took 25 minutes. The reaction solution is collected in a separating tank 19, and a first throttle valve 20 and a second throttle valve 21 are adjusted, and in this example, an organic phase is separated from an upper layer of the separating tank into a first receiving tank 22, and an aqueous phase is collected from a lower layer of the separating tank into a second receiving tank 23. The organic phase is washed by 10 percent sodium carbonate, dried by anhydrous sodium sulfate, and then the solid obtained by concentration is recrystallized by methanol and water (40:1), and the filter cake is dried to obtain 22.4 g of the pure product of the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, the yield is 80 percent, the melting point is 152-.
Example 8:
the structure of the special reaction device used in this example is shown in fig. 1, the length of the reactor pipeline is 25m, the diameter is 3mm, and the pipeline material is teflon.
Firstly, opening a precooling pipeline of a first semiconductor temperature control box 7, setting the temperature at 10 ℃, and opening a second semiconductor temperature control box 13, setting the temperature at 25 ℃; next, a sufficient amount of fuming nitric acid was stored in a fuming nitric acid storage tank 1, a sufficient amount of 80% sulfuric acid was stored in a concentrated sulfuric acid storage tank 2, 23.5 g (0.1mol) of methyl 3-methyl-4-butanamidobenzoate was dissolved in 200mL of methylene chloride and then stored in a storage tank 8, and a sufficient amount of ice water at 5 ℃ was stored in a quencher storage tank 15. And starting the first metering pump 3 and the second metering pump 5, controlling the flow rates of the two pumps to ensure that the molar equivalent ratio of the nitric acid to the sulfuric acid is 3:1, and controlling the flow rate to ensure that the temperature of the mixed acid flowing out of the first pipeline reactor 6 is kept at about 18 ℃. When the mixed acid is about to reach the second high-efficiency mixer 11, the third metering pump 9 is started, the flow is controlled to ensure that the molar equivalent ratio of the raw materials to the mixed acid is 1:1.8, and the reaction temperature is controlled to be 31-32 ℃. When the reaction solution is about to reach the third mixer 17, the fourth metering pump 16 is started to make the volume ratio of the quenching agent to the reaction solution 1:1, and the temperature of the quenched reaction solution is measured to be 33-35 ℃. The whole reaction and quenching process took 25 minutes. The reaction solution is collected in a separating tank 19, and a first throttle valve 20 and a second throttle valve 21 are adjusted, and in this example, an aqueous phase is separated from an upper layer of the separating tank into a first receiving tank 22, and an organic phase is collected from a lower layer of the separating tank into a second receiving tank 23. The organic phase is washed by 10 percent sodium carbonate, dried by anhydrous sodium sulfate, and then the solid obtained by concentration is recrystallized by methanol and water (40:1), and the filter cake is dried to obtain 21.8 g of the pure product of the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, the yield is 78 percent, the melting point is 153-.
Example 9:
the structure of the special reaction device used in this example is shown in fig. 1, the length of the reactor tube is 25m, the diameter is 4mm, and the tube material is a quartz glass tube.
Firstly, opening a precooling pipeline of a first semiconductor temperature control box 7, setting the temperature at 10 ℃, and opening a second semiconductor temperature control box 13, setting the temperature at 25 ℃; next, a sufficient amount of fuming nitric acid was stored in a fuming nitric acid storage tank 1, a sufficient amount of 98% sulfuric acid was stored in a concentrated sulfuric acid storage tank 2, 23.5 g (0.1mol) of methyl 3-methyl-4-butanamidobenzoate was dissolved in 150mL of methylene chloride and then stored in a storage tank 8, and a sufficient amount of ice water at 5 ℃ was stored in a quencher storage tank 15.
Starting the first metering pump 3 and the second metering pump 5, controlling the flow rate of the two pumps to ensure that the molar equivalent ratio of the nitric acid to the sulfuric acid is 3:1, and controlling the flow rate to ensure that the temperature of the mixed acid flowing out of the first pipeline reactor 6 is kept at about 18 ℃. When the mixed acid is about to reach the second high-efficiency mixer 11, the third metering pump 9 is started, the flow is controlled to ensure that the molar equivalent ratio of the raw materials to the mixed acid is 1:1.5, and the reaction temperature is controlled to be 30-32 ℃. When the reaction solution is about to reach the third high-efficiency mixer 17, the fourth metering pump 16 is started to ensure that the volume ratio of the quenching agent to the reaction solution is 1:1, and the temperature of the quenched reaction solution is measured to be 33-34 ℃. The entire reaction and quenching process took 18 minutes. The reaction solution is collected in a separating tank 19, and a first throttle valve 20 and a second throttle valve 21 are adjusted, and in this example, an aqueous phase is separated from an upper layer of the separating tank into a first receiving tank 22, and an organic phase is collected from a lower layer of the separating tank into a second receiving tank 23. The organic phase is washed by 10 percent sodium carbonate, dried by anhydrous sodium sulfate, and then the solid obtained by concentration is recrystallized by methanol and water (40:1), and the filter cake is dried to obtain 23.2 g of the pure product of the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, the yield is 83 percent, the melting point is 153-.
Example 10:
the structure of the special reaction device used in this example is shown in fig. 1, the length of the reactor tube is 25m, the diameter is 4mm, and the tube material is a quartz glass tube.
Firstly, opening a precooling pipeline of a first semiconductor temperature control box 7, setting the temperature at 10 ℃, and opening a second semiconductor temperature control box 13, setting the temperature at 25 ℃; next, a sufficient amount of fuming nitric acid was stored in a fuming nitric acid storage tank 1, a sufficient amount of 98% sulfuric acid was stored in a concentrated sulfuric acid storage tank 2, 23.5 g (0.1mol) of methyl 3-methyl-4-butanamidobenzoate was dissolved in 150mL of ethyl acetate and stored in a storage tank 8, and a sufficient amount of ice water at 5 ℃ was stored in a quencher storage tank 15.
Starting the first metering pump 3 and the second metering pump 5, controlling the flow rate of the two pumps to ensure that the molar equivalent ratio of the nitric acid to the sulfuric acid is 3:1, and controlling the flow rate to ensure that the temperature of the mixed acid flowing out of the first pipeline reactor 6 is kept at about 18 ℃. When the mixed acid is about to reach the second high-efficiency mixer 11, the third metering pump 9 is started, the flow is controlled to ensure that the molar equivalent ratio of the raw materials to the mixed acid is 1:1.5, and the reaction temperature is controlled to be 30-32 ℃. When the reaction solution is about to reach the third high-efficiency mixer 17, the fourth metering pump 16 is started to ensure that the volume ratio of the quenching agent to the reaction solution is 1:1, and the temperature of the quenched reaction solution is measured to be 33-35 ℃. The entire reaction and quenching process took 18 minutes. The reaction solution is collected in a separating tank 19, and a first throttle valve 20 and a second throttle valve 21 are adjusted, and in this example, an organic phase is separated from an upper layer of the separating tank into a first receiving tank 22, and an aqueous phase is collected from a lower layer of the separating tank into a second receiving tank 23. The organic phase is washed by 15 percent sodium carbonate, dried by anhydrous sodium sulfate, and then the solid obtained by concentration is recrystallized by methanol and water (40:1), and the filter cake is dried to obtain 23 g of the pure product of the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, the yield is 82 percent, the melting point is 153-.
Example 11:
the structure of the special reaction device used in the implementation is shown in figure 1, the length of a reactor pipeline is 30m, the diameter of the reactor pipeline is 3mm, and the pipeline is made of Teflon.
Firstly, opening a precooling pipeline of a first semiconductor temperature control box 7, setting the temperature at 10 ℃, and opening a second semiconductor temperature control box 13, setting the temperature at 25 ℃; next, a sufficient amount of fuming nitric acid was stored in a fuming nitric acid storage tank 1, a sufficient amount of 98% sulfuric acid was stored in a concentrated sulfuric acid storage tank 2, 23.5 g (0.1mol) of methyl 3-methyl-4-butanamidobenzoate was dissolved in 100mL of methylene chloride and then stored in a storage tank 8, and a sufficient amount of ice water at 5 ℃ was stored in a quencher storage tank 15.
Starting the first metering pump 3 and the second metering pump 5, controlling the flow rate of the two pumps to ensure that the molar equivalent ratio of the nitric acid to the sulfuric acid is 3:1, and controlling the flow rate to ensure that the temperature of the mixed acid flowing out of the first pipeline reactor 6 is kept at about 18 ℃. When the mixed acid is about to reach the second high-efficiency mixer 11, the third metering pump 9 is started, the flow is controlled to ensure that the molar equivalent ratio of the raw materials to the mixed acid is 1:1.5, and the reaction temperature is controlled to be 30-32 ℃. When the reaction solution is about to reach the third high-efficiency mixer 17, the fourth metering pump 16 is started to ensure that the volume ratio of the quenching agent to the reaction solution is 1:1, and the temperature of the quenched reaction solution is measured to be 33-35 ℃. The entire reaction and quenching process took 18 minutes. The reaction solution is collected in a separating tank 19, and a first throttle valve 20 and a second throttle valve 21 are adjusted, and in this example, an aqueous phase is separated from an upper layer of the separating tank into a first receiving tank 22, and an organic phase is collected from a lower layer of the separating tank into a second receiving tank 23. The organic phase is washed by 10 percent sodium carbonate, dried by anhydrous sodium sulfate, and then the solid obtained by concentration is recrystallized by methanol and water (40:1), and the filter cake is dried to obtain 23 g of the pure product of the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, the yield is 82 percent, the melting point is 153-.
Example 12:
the structure of the special reaction device used in this example is shown in fig. 1, the length of the reactor tube is 30m, the diameter is 3mm, and the tube material is teflon.
Firstly, opening a precooling pipeline of a first semiconductor temperature control box 7, setting the temperature at 10 ℃, and opening a second semiconductor temperature control box 13, setting the temperature at 25 ℃; subsequently, sufficient fuming nitric acid was stored in a fuming nitric acid storage tank 1, sufficient 98% sulfuric acid was stored in a concentrated sulfuric acid storage tank 2, 23.5 g (0.1mol) of methyl 3-methyl-4-butanamidobenzoate was dissolved in 100mL of chloroform and then stored in a storage tank 8, and sufficient ice water at 5 ℃ was stored in a quencher storage tank 15.
Starting the first metering pump 3 and the second metering pump 5, controlling the flow rate of the two pumps to ensure that the molar equivalent ratio of the nitric acid to the sulfuric acid is 3:1, and controlling the flow rate to ensure that the temperature of the mixed acid flowing out of the first pipeline reactor 6 is kept at about 18 ℃. When the mixed acid is about to reach the second high-efficiency mixer 11, the third metering pump 9 is started, the flow is controlled to ensure that the molar equivalent ratio of the raw materials to the mixed acid is 1:1.5, and the reaction temperature is controlled to be 30-32 ℃. When the reaction solution is about to reach the third high-efficiency mixer 17, the fourth metering pump 16 is started to ensure that the volume ratio of the quenching agent to the reaction solution is 1:1, and the temperature of the quenched reaction solution is measured to be 33-35 ℃. The entire reaction and quenching process took 18 minutes. The reaction solution is collected in a separating tank 19, and a first throttle valve 20 and a second throttle valve 21 are adjusted, and in this example, an aqueous phase is separated from an upper layer of the separating tank into a first receiving tank 22, and an organic phase is collected from a lower layer of the separating tank into a second receiving tank 23. The organic phase is washed by 10 percent sodium carbonate, dried by anhydrous sodium sulfate, and then the solid obtained by concentration is recrystallized by ethanol and water (40:1), and the filter cake is dried to obtain 23.5 g of the pure product of the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, the yield is 84 percent, the melting point is 152-.
Pure product of methyl 3-methyl-4-butanamido-5-nitrobenzoate synthesized by the above example1HNMR data are as follows:1H NMR(500MHz,CDCl3)：8.57(s,1H),8.40(d,J＝1.8Hz,1H),8.10(d,J＝1.4Hz,1H),3.95(s,3H),2.43(t,J＝7.5Hz,2H),2.32(s,3H),1.75(dt,J＝14.8,7.4Hz,2H),1.02(t,J＝7.4Hz,3H)。
Claims (10)
1. the reaction device for synthesizing the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester through pipelining is characterized by mainly comprising a fuming nitric acid liquid storage tank (1), a concentrated sulfuric acid liquid storage tank (2), a 3-methyl-4-butyryl methyl benzoate liquid storage tank (8), a quencher liquid storage tank (15), a first pipeline reactor (6), a second pipeline reactor (12), a liquid separating tank (19) and a receiving tank; the outlet of each liquid storage tank is connected with a pipeline through a metering pump; outlets of the fuming nitric acid liquid storage tank (1) and the concentrated sulfuric acid liquid storage tank (2) are connected with an inlet of a first high-efficiency mixer (4), and an outlet of the first high-efficiency mixer (4) is connected with an inlet of a first pipeline reactor (6); the outlet of the first pipeline reactor (6) and the outlet of the 3-methyl-4-butyryl methyl benzoate liquid storage tank are connected with the inlet of the second high-efficiency mixer (11); the outlet of the second high-efficiency mixer (11) is connected with the inlet of a second pipeline reactor (12); the second pipeline reactor (12) and the quencher liquid storage tank (15) are connected with the inlet of the third high-efficiency mixer (17); the outlet of the third efficient blending device (17) is connected with a liquid separation tank (19), and the upper part and the lower part of the liquid separation tank (19) are respectively connected with a first receiving tank (22) and a second receiving tank (23).
2. The reactor according to claim 1, wherein the first pipe reactor (6) and the second pipe reactor (12) are continuous flow pipe reactors, the length of the pipe is 25-200m, the diameter of the pipe is 0.5-40mm, and the pipe is made of Teflon tube or quartz glass tube.
3. The reactor according to claim 1, wherein the first pipeline reactor (6) and the second pipeline reactor (12) are respectively arranged in a semiconductor temperature control box, and the temperature control range is 0-100 ℃.
4. A continuous flow process for the synthesis of methyl 3-methyl-4-butanoyl-5-nitrobenzoate, characterized in that a reaction apparatus according to any one of claims 1 to 3 is used, comprising the steps of:
(1) fuming nitric acid is stored in a fuming nitric acid storage tank (1), concentrated sulfuric acid is stored in a concentrated sulfuric acid storage tank (2), 3-methyl-4-butyryl methyl benzoate shown in a formula (I) is dissolved in an organic solvent A and stored in a liquid storage tank (8), and a quenching agent is stored in a quenching agent storage tank (15);
(2) adjusting the pipeline temperature of the first pipeline reactor (6) and the second pipeline reactor (12) to 5-70 ℃;
(3) starting metering pumps of the fuming nitric acid liquid storage tank (1) and the concentrated sulfuric acid liquid storage tank (2), feeding a sample into the first efficient mixer (4), and continuously flowing the mixed solution into the first pipeline reactor (6);
(4) when the mixed acid effluent is about to enter a second high-efficiency mixer (11), starting a metering pump of a 3-methyl-4-butyryl methyl benzoate liquid storage tank (8), injecting a sample into the second high-efficiency mixer (11), and allowing the mixed reaction liquid to enter a second tubular reactor (12) for nitration reaction;
(5) when the nitration reaction liquid is about to reach the third high-efficiency blending device (17), a metering pump connected with a quenching agent liquid storage tank (15) is started, and the nitration reaction liquid and the quenching agent are mixed by the third high-efficiency blending device (17) and then enter a liquid separation tank (19);
(6) the organic phase and the water phase are separated by a liquid separation tank (19) and then respectively flow into a first receiving tank (22) and a second receiving tank (23) with throttle valves;
(7) neutralizing, drying and concentrating the organic phase collected in the receiving tank to obtain a solid crude product;
(8) recrystallizing the solid crude product by using an organic solvent B to obtain a product 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester shown in a formula (II), wherein the reaction equation is as follows:
5. the method according to claim 4, wherein the fuming nitric acid concentration in the step (1) is 95-98%, the concentrated sulfuric acid concentration is 50-98%, the organic solvent A is dichloromethane, chloroform, 1, 2-dichloroethane or ethyl acetate, the concentration of the solution of the organic solvent A is 0.1-3.0mol/L, and the quenching agent is water, and the temperature thereof is 0-15 ℃.
6. The process according to claim 4, wherein the temperature of the mixture of fuming nitric acid and concentrated sulfuric acid in the step (3) is controlled to be 5 to 45 ℃.
7. The process according to claim 4, wherein the molar ratio of methyl 3-methyl-4-butyramidobenzoate to nitric acid and sulfuric acid in step (4) is 1:1.5:0.5-1:9.0:3.5, the nitration temperature is 5-40 ℃ and the reaction time is 1-30 min.
8. The process according to claim 4, wherein the volume ratio of the nitration reaction liquid and the quenching agent in the step (5) is 1:0.8 to 1: 5.0.
9. The method according to claim 4, wherein the neutralizing agent used in the step (7) is an aqueous solution of sodium carbonate, sodium bicarbonate, sodium phosphate, potassium phosphate or sodium monohydrogen phosphate, having a concentration of 10-30%; the drying agent is anhydrous sodium sulfate, anhydrous calcium chloride or anhydrous magnesium sulfate.
10. The method according to claim 4, wherein the organic solvent B in the step (8) is a mixed solution of petroleum ether and ethyl acetate (volume ratio of 30:1 to 1:10), a mixed solution of acetone and water (volume ratio of 40:1 to 1:10), a mixed solution of methanol and water (volume ratio of 40:1 to 1:10), a mixed solution of ethanol and water (volume ratio of 40:1 to 1:10), and a mixed solution of tetrahydrofuran and water (volume ratio of 40:1 to 1: 20).
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