CN113968787A - Method for preparing 5-fluoro-4-methyl-2-nitrobenzoic acid - Google Patents
Method for preparing 5-fluoro-4-methyl-2-nitrobenzoic acid Download PDFInfo
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- CN113968787A CN113968787A CN202010728378.9A CN202010728378A CN113968787A CN 113968787 A CN113968787 A CN 113968787A CN 202010728378 A CN202010728378 A CN 202010728378A CN 113968787 A CN113968787 A CN 113968787A
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- 238000000034 method Methods 0.000 title claims abstract description 35
- CFFQWWSEJHPZJD-UHFFFAOYSA-N 5-fluoro-4-methyl-2-nitrobenzoic acid Chemical compound CC1=CC([N+]([O-])=O)=C(C(O)=O)C=C1F CFFQWWSEJHPZJD-UHFFFAOYSA-N 0.000 title claims abstract description 26
- XUQCONCMPCVUDM-UHFFFAOYSA-N 3-fluoro-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C=C1F XUQCONCMPCVUDM-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 238000006396 nitration reaction Methods 0.000 claims abstract description 26
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 75
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 34
- 229910017604 nitric acid Inorganic materials 0.000 claims description 34
- 239000012043 crude product Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- 238000001914 filtration Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 230000000802 nitrating effect Effects 0.000 description 4
- 239000002253 acid Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing 5-fluoro-4-methyl-2-nitrobenzoic acid, belonging to the field of pharmaceutical chemistry. The method comprises the step of carrying out nitration reaction on 3-fluoro-4-methylbenzoic acid and a nitration reagent in a continuous flow reactor to obtain 5-fluoro-4-methyl-2-nitrobenzoic acid. The method provided by the invention adopts continuous flow reaction, can simply, conveniently and safely obtain the target product, and is green and environment-friendly.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, and particularly relates to a method for preparing 5-fluoro-4-methyl-2-nitrobenzoic acid.
Background
5-fluoro-4-methyl-2-nitrobenzoic acid can be used for preparing various medicaments and is an important intermediate compound; the traditional method for preparing the compound is to adopt 3-fluoro-4-methylbenzoic acid to carry out nitration reaction. 3-fluoro-4-methylbenzoic acid and nitration of nitric acid, need to use a large amount of nitric acid and sulfuric acid, the reaction is exothermic many, there are serious potential safety hazards, and in order to control the heat accumulation of reaction, drip nitric acid comparatively slowly, therefore the reaction time is also longer; byproducts are easy to generate, more impurities are generated, the yield of the target product is reduced, and the cost is increased; these are not conducive to industrial scale-up. In addition, the traditional method has large consumption of sulfuric acid, and a large amount of waste acid liquid is generated during post-treatment, so that the treatment is difficult and the environmental pollution is easily caused.
Therefore, a method which is simple in process, high in product purity and yield, low in cost, green and environment-friendly in process and beneficial to industrialization needs to be researched.
Disclosure of Invention
The invention provides a method for preparing 5-fluoro-4-methyl-2-nitrobenzoic acid. The method provided by the invention adopts continuous flow reaction, can simply, conveniently and safely obtain the target product, and has the advantages of short reaction time, high production efficiency, high product purity and yield, less three wastes and environmental protection.
A method of preparing 5-fluoro-4-methyl-2-nitrobenzoic acid comprising: carrying out nitration reaction on the 3-fluoro-4-methylbenzoic acid and a nitration reagent in a continuous flow reactor to obtain 5-fluoro-4-methyl-2-nitrobenzoic acid; wherein the nitration reaction is carried out under continuous flow reaction conditions.
The nitrating agent includes nitric acid.
In some embodiments, a method of making 5-fluoro-4-methyl-2-nitrobenzoic acid comprises: carrying out nitration reaction on 3-fluoro-4-methylbenzoic acid and nitric acid in a continuous flow reactor to obtain 5-fluoro-4-methyl-2-nitrobenzoic acid; wherein the nitration reaction is carried out under continuous flow reaction conditions.
Sulfuric acid may be present or included in the reaction system of the nitration reaction.
In some embodiments, a method of making 5-fluoro-4-methyl-2-nitrobenzoic acid comprises: carrying out nitration reaction on 3-fluoro-4-methylbenzoic acid, nitric acid and sulfuric acid in a continuous flow reactor to obtain 5-fluoro-4-methyl-2-nitrobenzoic acid; wherein the nitration reaction is carried out under continuous flow reaction conditions.
The nitric acid may be at any suitable concentration. In some embodiments, the mass fraction of nitric acid is 65% to 98% for ease of reaction run control. In some embodiments, the mass fraction of nitric acid is 65% to 70%.
The feeding molar ratio of the nitric acid to the 3-fluoro-4-methylbenzoic acid can be 1:1-4: 1. In some embodiments, the molar ratio of the nitric acid to the 3-fluoro-4-methylbenzoic acid is from 1:1 to 2:1, which facilitates reaction operation control and product formation. In some embodiments, the molar ratio of the nitric acid to the 3-fluoro-4-methylbenzoic acid is from 1:1 to 1.6:1, which facilitates reaction operation control and product formation.
In some embodiments, the nitrating agent is a mixed acid of nitric acid and sulfuric acid.
In some embodiments, 3-fluoro-4-methylbenzoic acid is mixed with sulfuric acid and then contacted with nitric acid for nitration.
The sulfuric acid may be at any suitable concentration. In some embodiments, the mass fraction of sulfuric acid may be 97% to 99% for ease of handling control. The amount of sulfuric acid used can be any suitable amount. In some embodiments, the amount of sulfuric acid used is at least that amount which will allow complete dissolution of the 3-fluoro-4-methylbenzoic acid. In some embodiments, the molar ratio of sulfuric acid to 3-fluoro-4-methylbenzoic acid is from 1:1 to 1: 20. In some embodiments, the molar ratio of sulfuric acid to 3-fluoro-4-methylbenzoic acid is from 1:3 to 1: 18. In some embodiments, the molar ratio of sulfuric acid to 3-fluoro-4-methylbenzoic acid is from 1:4 to 1: 15. In some embodiments, the molar ratio of sulfuric acid to 3-fluoro-4-methylbenzoic acid is from 1:5 to 1: 15. In some embodiments, the molar ratio of sulfuric acid to 3-fluoro-4-methylbenzoic acid is from 1:8 to 1: 15. In some embodiments, the molar ratio of sulfuric acid to 3-fluoro-4-methylbenzoic acid is from 1:10 to 1: 15. In some embodiments, the molar ratio of sulfuric acid to 3-fluoro-4-methylbenzoic acid is 1:4, 1:6, 1:9, 1:12, or 1: 15.
The molar ratio of the nitric acid to the sulfuric acid can be 1:4 to 1: 18. In some embodiments, the molar ratio of the nitric acid to the sulfuric acid is 1:10 to 1:15, which is more favorable for controlling the reaction operation.
The reaction temperature of the nitration reaction may be-10 ℃ to 40 ℃. In some embodiments, the nitration reaction is carried out at a reaction temperature of-5 ℃ to facilitate reaction control and formation of the target product.
In the process, the 3-fluoro-4-methylbenzoic acid or/and the nitrating agent may be conveyed into the continuous flow reactor by any suitable conveying means. In some embodiments, 3-fluoro-4-methylbenzoic acid or/and a nitrating agent are continuously fed into a continuous flow reactor using a high pressure tetrafluoro advection pump.
The continuous flow reactor may be any suitable reactor. In some embodiments, the microchannel reactor is used as a continuous flow reactor.
In the method, 3-fluoro-4-methylbenzoic acid and sulfuric acid can be mixed and then conveyed into a continuous flow reactor, and the feed flow rate can be 1ml/min-90 ml/min; preferably 5ml/min to 70ml/min, more preferably 8ml/min to 40 ml/min.
In the method, the feeding flow rate of the nitric acid can be controlled to be 0.1ml/min-50ml/min, preferably 0.5ml/min-30ml/min, and more preferably 2ml/min-10 ml/min.
In some embodiments, in order to facilitate the control of the reaction and the promotion of the formation of the target product, the total flow rate of the feeds of 3-fluoro-4-methylbenzoic acid, sulfuric acid and nitric acid in the process may be 15ml/min to 80ml/min, preferably 20ml/min to 40 ml/min. In some embodiments, a method of making 5-fluoro-4-methyl-2-nitrobenzoic acid comprises: carrying out nitration reaction on 3-fluoro-4-methylbenzoic acid and nitric acid in a continuous flow reactor to obtain 5-fluoro-4-methyl-2-nitrobenzoic acid; wherein the nitration reaction is carried out under continuous flow reaction conditions; sulfuric acid exists in a reaction system of the nitration reaction; the total flow rate of the feeding of the 3-fluoro-4-methylbenzoic acid, the sulfuric acid and the nitric acid is 15ml/min-80 ml/min.
In some embodiments, to facilitate control of the reaction and to promote the formation of the desired product, the residence time of the reaction system formed after contacting 3-fluoro-4-methylbenzoic acid with nitric acid in the continuous flow reactor is in the range of from 20 seconds to 500 seconds, preferably from 30 seconds to 80 seconds.
After the reaction in the continuous flow reactor is finished, a crude product is obtained, and the crude product can be further washed, purified, crystallized and/or pulped and the like to further improve the quality of the crude product. In some embodiments, after the reaction is completed in the continuous flow reactor, crude product is obtained, which is mixed with cold water, crystallized, filtered, and dried to obtain 5-fluoro-4-methyl-2-nitrobenzoic acid product.
The temperature of the cold water may be-5 ℃ to 10 ℃.
In some embodiments, a method of making 5-fluoro-4-methyl-2-nitrobenzoic acid comprises: 3-fluoro-4-methylbenzoic acid, nitric acid and sulfuric acid are subjected to nitration reaction in a microchannel reactor at the temperature of-10-40 ℃, a reaction system stays in the microchannel reactor for 20-500 seconds, and a crude product is obtained after the reaction is finished; mixing the crude product with cold water at the temperature of-5-10 ℃, crystallizing, filtering and drying to constant weight to obtain 5-fluoro-4-methyl-2-nitrobenzoic acid; wherein the total flow rate of the feeding of the 3-fluoro-4-methylbenzoic acid, the sulfuric acid and the nitric acid is 15ml/min-80 ml/min.
The method provided by the invention avoids the risks of rapid and large heat release and easy occurrence of safety accidents in the traditional method, is simple, controllable, safe and environment-friendly, has high product purity and yield, and is beneficial to industrial production.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
In the present invention, the expression "compound a" and "compound represented by formula a" means the same compound.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mol means mol, h means hour, min means minute, g means g, and ml means ml.
In the following examples, the molar ratio of nitric acid to 3-fluoro-4-methylbenzoic acid was controlled to be 1:1 to 1.6: 1. Liquid hold-up refers to the amount of liquid held by the microchannel reactor.
Example 1
At room temperature, 3-fluoro-4-methylbenzoic acid (80g) was dissolved in concentrated sulfuric acid (320mL) and cooled to 0. + -. 5 ℃. The temperature in the microchannel was adjusted to 0 ℃. Inputting a sulfuric acid solution of 3-fluoro-4-methylbenzoic acid into a microchannel reactor (with a liquid holdup of 20mL) at a rate of 30mL/min by using a tetrafluoro advection pump, and simultaneously inputting 68% nitric acid into the microchannel reactor at a rate of 2.58 mL/min; the retention time is 36.8 seconds, liquid flows out of a discharge hole, and the purity is 96.1 percent through sampling detection; dropping into ice water, crystallizing while dropping, filtering, and vacuum drying at 50 deg.C to obtain 96.22g of 5-fluoro-4-methyl-2-nitrobenzoic acid with yield of 93.1% and purity of 99.7%.
Example 2
At room temperature, 3-fluoro-4-methylbenzoic acid (100g) was dissolved in concentrated sulfuric acid (400mL) and cooled to 0. + -. 5 ℃. The temperature in the microchannel was adjusted to 0 ℃. Inputting a sulfuric acid solution of 3-fluoro-4-methylbenzoic acid into a microchannel reactor (with a liquid holdup of 20mL) at a rate of 23mL/min by using a tetrafluoro advection pump, and simultaneously inputting 68% nitric acid into the microchannel reactor at a rate of 2.47 mL/min; the retention time is 47.1 seconds, liquid flows out of a discharge hole, and the purity is 96.7 percent through sampling detection; dropwise adding into ice water, crystallizing while dropwise adding, filtering, and vacuum drying at 50 deg.C to obtain 121.18g of 5-fluoro-4-methyl-2-nitrobenzoic acid with yield of 93.8% and purity of 99.6%.
Example 3
At room temperature, 3-fluoro-4-methylbenzoic acid (100g) was dissolved in concentrated sulfuric acid (400mL) and cooled to 10. + -. 5 ℃. The temperature in the microchannel was adjusted to 10 ℃. Inputting a sulfuric acid solution of 3-fluoro-4-methylbenzoic acid into a microchannel reactor (with a liquid holdup of 20mL) at a rate of 20.8mL/min by using a tetrafluoro advection pump, and simultaneously inputting 68% nitric acid into the microchannel reactor at a rate of 2.96 mL/min; the retention time is 50.5 seconds, liquid flows out of a discharge hole, and the purity is 96.3 percent through sampling detection; dropping into ice water, crystallizing while dropping, filtering, and vacuum drying at 50 deg.C to obtain 120.66g of 5-fluoro-4-methyl-2-nitrobenzoic acid with yield of 93.4% and purity of 99.2%.
Example 4
At room temperature, 3-fluoro-4-methylbenzoic acid (100g) was dissolved in concentrated sulfuric acid (400mL) and cooled to 20. + -. 5 ℃. The temperature in the microchannel was adjusted to 20 ℃. Inputting a sulfuric acid solution of 3-fluoro-4-methylbenzoic acid into a microchannel reactor (with a liquid holdup of 20mL) at a rate of 17.7mL/min by using a tetrafluoro advection pump, and simultaneously inputting 68% nitric acid into the microchannel reactor at a rate of 2.66 mL/min; the retention time is 58.9 seconds, liquid flows out of a discharge hole, and the purity is 96.1 percent after sampling and detection; dropwise adding into ice water, crystallizing while dropwise adding, filtering, and vacuum drying at 50 deg.C to obtain 120.28g of 5-fluoro-4-methyl-2-nitrobenzoic acid with yield of 93.1% and purity of 98.9%.
Example 5
At room temperature, 3-fluoro-4-methylbenzoic acid (100g) was dissolved in concentrated sulfuric acid (400mL) and cooled to-10. + -. 5 ℃. The temperature in the microchannel was adjusted to-10 ℃. Inputting a sulfuric acid solution of 3-fluoro-4-methylbenzoic acid into a microchannel reactor (with a liquid holdup of 20mL) at a rate of 23.9mL/min by using a tetrafluoro advection pump, simultaneously inputting 68% nitric acid into the microchannel reactor at a rate of 4.11mL/min, starting timing, keeping the time for 42.8 seconds, enabling liquid to flow out of a discharge hole, and sampling and detecting to obtain a product with a purity of 95.7%; dropwise adding into ice water, crystallizing while dropwise adding, filtering, and vacuum drying at 50 deg.C to obtain 119.89g of 5-fluoro-4-methyl-2-nitrobenzoic acid with yield of 92.8% and purity of 99.4%.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. A method of preparing 5-fluoro-4-methyl-2-nitrobenzoic acid comprising: carrying out nitration reaction on 3-fluoro-4-methylbenzoic acid and nitric acid in a continuous flow reactor to obtain 5-fluoro-4-methyl-2-nitrobenzoic acid; wherein the nitration reaction is carried out under continuous flow reaction conditions.
2. The method of claim 1, wherein the mass fraction of the nitric acid is 65% -98%.
3. The method according to claim 1, wherein the reaction system of the nitration reaction comprises sulfuric acid; the feeding molar ratio of the nitric acid to the sulfuric acid is 1:4-1: 18.
4. The process of claim 1, wherein the feed molar ratio of nitric acid to 3-fluoro-4-methylbenzoic acid is from 1:1 to 4: 1.
5. The method of claim 1, wherein the reaction temperature of the nitration reaction is between-10 ℃ and 40 ℃.
6. The process of claim 1 wherein the microchannel reactor is a continuous flow reactor.
7. The process according to any one of claims 1 to 6, wherein 3-fluoro-4-methylbenzoic acid is mixed with sulfuric acid and fed to the continuous flow reactor at a feed flow rate of 1ml/min to 90 ml/min.
8. The method according to any one of claims 1 to 7, wherein the reaction system of the nitration reaction comprises sulfuric acid; the total flow rate of the feeding of the 3-fluoro-4-methylbenzoic acid, the sulfuric acid and the nitric acid is 15ml/min-80 ml/min.
9. The process as claimed in any one of claims 1 to 8, wherein the residence time of the reaction system of the nitration reaction in the continuous flow reactor is between 20 seconds and 500 seconds.
10. The method according to any one of claims 1 to 9, wherein after the nitration reaction is completed, a crude product is obtained, and the crude product is mixed with cold water at a temperature of-5 ℃ to 10 ℃, crystallized, filtered, and dried to a constant weight to obtain 5-fluoro-4-methyl-2-nitrobenzoic acid.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4762844A (en) * | 1984-11-15 | 1988-08-09 | Bayer Aktiengesellschaft | Antibacterially active alkyl-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids |
| CN106565500A (en) * | 2016-10-25 | 2017-04-19 | 黑龙江鑫创生物科技开发有限公司 | Method for synthesizing 2,5-dichloroaniline by micro-channel reactor |
| CN110437144A (en) * | 2018-05-04 | 2019-11-12 | 东莞市东阳光农药研发有限公司 | Quinoline derivatives and its preparation method and application |
-
2020
- 2020-07-24 CN CN202010728378.9A patent/CN113968787A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4762844A (en) * | 1984-11-15 | 1988-08-09 | Bayer Aktiengesellschaft | Antibacterially active alkyl-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids |
| CN106565500A (en) * | 2016-10-25 | 2017-04-19 | 黑龙江鑫创生物科技开发有限公司 | Method for synthesizing 2,5-dichloroaniline by micro-channel reactor |
| CN110437144A (en) * | 2018-05-04 | 2019-11-12 | 东莞市东阳光农药研发有限公司 | Quinoline derivatives and its preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| ATWELL, GRAHAM J. ET AL: "Synthesis and evaluation of 4-substituted analogs of 5-[N, N-bis(2-chloroethyl)amino]-2-nitrobenzamide as bioreductively activated prodrugs using an Escherichia coli nitroreductase", 《ANTI-CANCER DRUG DESIGN》, vol. 11, no. 7, 31 December 1996 (1996-12-31), pages 553 - 567, XP000901664 * |
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