CN110078613B - Synthesis method of 2-halogen-5-iodobenzoic acid - Google Patents
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Abstract
The invention discloses a synthetic method of 2-halogen-5-iodobenzoic acid. The method comprises the following steps: the o-halobenzoic acid is further iodinated in an iodinating reagent to obtain the 2-halo-5-iodobenzoic acid. And the post-treatment comprises pouring the reaction solution into a cold reducing aqueous solution for quenching, evaporating the solvent to dryness, recrystallizing and filtering to obtain the product. The method has the advantages of short reaction route, simple operation, environmental protection, safety, economy and wide application prospect.
Description
Technical Field
The invention relates to a preparation method of a chemical intermediate, in particular to a synthesis method of high-quality 2-halogen-5-iodobenzoic acid.
Background
The 2-halogen-5-iodobenzoic acid is an aromatic functional monomer with two different halogens and one carboxyl, can react with different groups by utilizing the activity difference of each group to synthesize compounds substituted by multiple functional groups, and has wide application in the aspects of medical metal organic chemistry and the like. For example: 2-chloro-5-iodobenzoic acid is mainly used for synthesizing the latest hypoglycemic drugs dapagliflozin (BMS-512148), sotagliflozin, Empagliflozin and ertuglifuzin.
The preparation method of 2-halo-5-iodobenzoic acid is reported less, and currently, it is known that Journal of Medicinal Chemistry,5(2006), 1506-glass 1508. synthesis of 2-fluoro-5-iodobenzoic acid is carried out by using o-fluorobenzoic acid as a raw material and NIS/sulfuric acid as an iodinating reagent; CN106748721 uses o-chlorobenzoic acid to synthesize 2-chloro-5-iodobenzoic acid through four-step reaction of nitration, reduction, diazotization and iodination; the leaf fly and the like are synthesized into 2-chloro-5-iodobenzoic acid by taking methyl anthranilate as a raw material through three steps of iodination, sandmeyer reaction and hydrolysis; organic Chemistry,10(2008), 1797-; and the like.
The scheme is analyzed, and the method finds that NIS can obtain products, but has high cost and low economic benefit, and the nitration and diazotization reaction belongs to dangerous reaction, so that the industrial production is not easy to realize, and the reaction steps are long. Although carbon dioxide is used in a green environment, the reaction conditions are harsh, the reaction with butyl lithium is carried out at-70 ℃, the butyl lithium is easy to generate an exothermic reaction when meeting oxygen, a high-concentration (more than 1.0M) butyl lithium solution is easy to rapidly burn when meeting humid air, a solvent in a packaging container is generally a low-boiling-point flammable and explosive liquid, once the liquid expands by heating, the explosion is easy to cause, the product yield is low, and the industrial production is not facilitated.
The related documents are: in CA2735130A1, sodium periodate/potassium iodide/sulfuric acid are used for iodination, and a large amount of sulfuric acid is used in the reaction, so that three wastes are more, the yield is low, and the industrialization is not facilitated. In US2009/0143352A1 and Tetrahedron,60(2004),9113-9119 iodination was performed with sodium periodate/iodine/sulfuric acid, although the substrates differ from the present application. The applicant tried to use the reaction conditions for the synthesis of 2-halo-5-iodobenzoic acid, i.e. using o-halobenzoic acid as the starting material, and adding sodium periodate/iodine to perform the iodination reaction (see example 1), and the results showed that a small amount of product was generated during the reaction, the reaction solution was charcoal black and had more impurities, 3-iodo-2-halo-benzoic acid (a) and 3, 5-diiodo-2-halo-benzoic acid (b) were larger.
In order to achieve the purposes of being green, low in cost and suitable for industrially synthesizing the 2-halogen-5-iodobenzoic acid, the invention provides a green synthesis method for preparing the 2-halogen-5-iodobenzoic acid through multiple attempts.
Disclosure of Invention
The invention provides a synthesis method of 2-halogen-5-iodobenzoic acid, which improves the quality of products and reduces environmental pollution at the same time, so that the production reaction of the products is simple and convenient, the products are environment-friendly, and the products are more suitable for mass production.
A synthetic method of 2-halogen-5-iodobenzoic acid comprises the following steps:
under the action of sulfuric acid, carrying out iodination reaction on o-halobenzoic acid and an iodination reagent in an organic solvent, and carrying out post-treatment after complete reaction to obtain the 2-halo-5-iodobenzoic acid;
the structure of the o-halogenobenzoic acid is shown as the formula (I):
the structure of the 2-halogen-5-iodobenzoic acid is shown as the formula (II):
in the formulas (I) to (II), X is selected from-F, -Cl, -Br or-I.
The reaction route is as follows:
preferably, the iodinating agent consists of an oxidizing agent and iodine.
The kind of the oxidizing agent may have a large influence on the reaction result, and preferably, the oxidizing agent is selected from one or more of potassium periodate, sodium periodate, potassium iodate, sodium iodate, and iodic acid. Wherein the molar ratio of the o-halobenzoic acid to the oxidant to the iodine is 1: 0.1-0.2: 0.5 to 0.6.
Preferably, the mass ratio of the dosage of the o-halobenzoic acid to the dosage of the sulfuric acid is 1: 0.5-50; more preferably, the mass ratio of the dosage of the o-halobenzoic acid to the dosage of the sulfuric acid is 1: 0.5-20.
Preferably, the organic solvent is one or more of dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane.
Preferably, the mass ratio of the o-halobenzoic acid to the solvent is 1: 0.5-50; more preferably, the mass ratio of the o-halobenzoic acid to the solvent is 1: 0.5-20.
Preferably, the post-treatment comprises: and pouring the reaction solution into a cold reducing aqueous solution for quenching, evaporating the solvent to dryness, recrystallizing and filtering to obtain the 2-halogen-5-iodobenzoic acid.
Preferably, the reducing aqueous solution is one or more selected from the group consisting of sodium hypophosphite, sodium bisulfite, sodium dithionite, and sodium thiosulfate aqueous solution.
Preferably, the solvent used for recrystallization is a halogenated hydrocarbon solvent, an alcohol solvent, acetonitrile or an ether solvent.
Preferably, the solvent used for recrystallization is methanol, ethanol, DCM, acetonitrile or MTBE.
Compared with the prior art, the invention has the beneficial effects that:
(1) the method of the invention improves the quality of the product and reduces the environmental pollution at the same time, so that the product production is clean and environment-friendly, and the product is more suitable for mass production.
(2) The solvent adopted by the invention participates in the reaction, so that the iodine atom utilization rate in the iodine reagent is high, the sulfuric acid consumption is low, the three wastes are less, the product yield is high and the economic benefit is high.
Detailed Description
The present invention is further illustrated by the following examples, but the scope of the invention is not limited thereto.
Example 1 (comparative example 1)
Adding 15.6g of o-chlorobenzoic acid into a four-neck flask provided with a thermometer and a stirrer to dissolve in 320.0g of 90% sulfuric acid, adding 3.8g of sodium periodate and 13.0g of iodine into the reaction solution, starting stirring, controlling the reaction temperature to be 25-30 ℃, carrying out heat preservation reaction for 1h, enabling the reaction solution to turn black, pouring the reaction solution into a cold sodium thiosulfate aqueous solution to carry out quenching after the reaction of the raw materials is finished, spin-drying the reaction solution, and filtering to obtain a crude product with the purity of 65%, the content of a is 18% and the content of b is 10%. Recrystallization from 46.8ml of methanol gave 12.6g of crude product. The yield thereof was found to be 45%. The purity is 98.2%.
When the o-chlorobenzoic acid is used under the reaction conditions of Tetrahedron,60(2004), 9113-a 9119, the reaction liquid is black, the product quality is poor, and the impurities are more.
Example 2
In a four-neck flask with a thermometer and a stirrer, 15.6g of o-chlorobenzoic acid is added to be dissolved in 78.0g of sulfuric acid and 62.4g of DCM, 3.8g of sodium periodate and 13.0g of iodine are added to the reaction solution, stirring is started, the reaction temperature is controlled to be 25-30 ℃, the temperature is kept for reaction for 1h, purple solid is separated out from the reaction solution, and after the reaction of the raw materials is finished, the product content in the reaction solution is 88%, the content of 3-iodine-2-halogen-benzoic acid (a) is 8%, and the content of 3, 5-diiodo-2-halogen-benzoic acid (b) is 2%. The reaction solution was quenched into cold aqueous sodium thiosulfate solution, the reaction solution was spin dried, filtered, and recrystallized from 46.8ml of methanol to give 19.3g of 2-chloro-5-iodobenzoic acid. The yield is 68.6 percent, and the purity is 99.1 percent.1H NMR(CDCl3,400MHz),δ:11.26(s,1H)；8.32(d,1H)；7.77(dd,1H)；7.23(d,1H)。
Example 3
In a four-neck flask with a thermometer and a stirrer, 15.6g of o-chlorobenzoic acid is added and dissolved in 78.0g of sulfuric acid and 62.4g of DCM, 4.0g of potassium iodate and 13.0g of iodine are added into the reaction solution, stirring is started, the reaction temperature is controlled to be 25-30 ℃, the reaction is kept for 1 hour, purple solid is separated out from the reaction solution, after the reaction of the raw materials is finished, the content of the product in the reaction is 89%, the content of 3-iodo-2-halo-benzoic acid (a) is 9%, and the content of 3, 5-diiodo-2-halo-benzoic acid (b) is 0.5%. The reaction solution was quenched into cold aqueous sodium thiosulfate solution, the reaction solution was spin dried, filtered, and recrystallized from 46.8ml of methanol to give 19.6g of 2-chloro-5-iodobenzoic acid. The yield was 69.6% and the purity was 99.3%.
Examples 4 to 6
Sodium iodate, potassium periodate and iodic acid were tried as oxidizing agents, respectively, and other conditions were the same as in example 3. The input amount of the raw materials is 15.6g, and the raw materials are o-chlorobenzoic acid.
The yield of various oxidants is not greatly different, and the sodium iodate is more suitable from the economic aspect.
Example 7
Adding 13.9g of o-fluorobenzoic acid into a four-neck flask with a thermometer and a stirrer to dissolve in 69.5g of sulfuric acid and 55.6g of DCM, adding 4.5g of sodium iodate and 13.0g of iodine into the reaction liquid, starting stirring, controlling the reaction temperature to be 25-30 ℃, preserving the temperature for reaction for 1h, separating out a purple solid in the reaction liquid, pouring the reaction liquid into a cold sodium thiosulfate aqueous solution for quenching after the reaction of the raw materials is finished, spin-drying the reaction liquid, filtering, and recrystallizing with 41.7ml of methanol to obtain 20g of 2-fluoro-5-iodobenzoic acid. The yield was 75.8% and the purity was 99.0%.1H NMR(CDCl3,400MHz),δ:11.24(s,1H)；8.41(d,1H)；7.86(dd,1H)；7.13(d,1H).
Examples 8 to 10
Chloroform, carbon tetrachloride and 1, 2-dichloroethane were used as solvents, respectively, and the other conditions were the same as in example 7, except that o-fluorobenzoic acid was used as the starting material.
| Solvent(s) | Weight of product/g | Yield/% | Purity/%) |
| Chloroform | 19.4 | 73.5％ | 99.29％ |
| Carbon tetrachloride | 19.2 | 72.8％ | 99.13％ |
| 1, 2-dichloroethane | 18.7 | 70.8％ | 99.06％ |
Therefore, chloroform and carbon tetrachloride are controlled solvents, so that the yield of the 1, 2-dichloroethane is low and the toxicity is high. Methylene chloride was used as a solvent for the experiment.
Example 11
After 20.0g of o-bromobenzoic acid is dissolved in 100.0g of sulfuric acid and 80.0g of DCM in a four-neck flask provided with a thermometer and a stirrer, 4.5g of sodium iodate and 13.0g of iodine are added into the reaction liquid, stirring is started, the reaction temperature is controlled to be 25-30 ℃, the temperature is kept for reaction for 1h, purple solid is separated out from the reaction liquid, after the reaction of the raw materials is finished, the reaction liquid is poured into cold sodium thiosulfate aqueous solution for quenching, the reaction liquid is dried in a spinning mode, filtered, and recrystallized by 40ml of methanol, and 21.4g of 2-bromo-5-iodobenzoic acid can be obtained. The yield is 65.8 percent, and the purity is 98.3 percent.1H NMR(CDCl3,400MHz),δ:11.26(s,1H)；8.22(d,1H)；7.58(dd,1H)；7.37(d,1H).
Example 12
In a four-necked flask equipped with a thermometer and a stirrer, 24.8g of o-iodobenzoic acid was charged to conduct an experiment, and the other conditions were the same as in example 8, whereby 18.7g of 2, 5-diiodobenzoic acid was obtained. The yield is 50.1 percent, and the purity is 98.5 percent.1H NMR(CDCl3,400MHz),δ:11.25(s,1H)；8.02(d,1H)；7.47(dd,1H)；7.53(d,1H).
Example 13
After 20.0g of o-bromobenzoic acid is dissolved in 40g of sulfuric acid and 80g of DCM in a four-neck flask with a thermometer and a stirrer, 4.5g of sodium iodate and 13.0g of iodine are added into the reaction liquid, stirring is started, the reaction temperature is controlled to be 25-30 ℃, heat preservation reaction is carried out for 1h, purple solid is separated out from the reaction liquid, after the reaction of the raw materials is finished, the reaction liquid is poured into cold sodium thiosulfate aqueous solution for quenching, the reaction liquid is dried by spinning, filtered, and recrystallized by 60ml of methanol, and 21.7g of 2-bromo-5-iodobenzoic acid is obtained. The yield is 66.7 percent, and the purity is 99.0 percent.
Therefore, the process can use less sulfuric acid and solvent to obtain a more economical process.
Claims (2)
1. A synthetic method of 2-halogen-5-iodobenzoic acid is characterized by comprising the following steps:
under the action of sulfuric acid, carrying out iodination reaction on o-halobenzoic acid and an iodination reagent in an organic solvent, and carrying out post-treatment after complete reaction to obtain the 2-halo-5-iodobenzoic acid;
the structure of the o-halogenobenzoic acid is shown as the formula (I):
the structure of the 2-halogen-5-iodobenzoic acid is shown as the formula (II):
in the formulas (I) - (II), X is selected from-Cl;
the iodination reagent consists of an oxidant and iodine; the oxidant is selected from one or more of potassium periodate, sodium periodate, potassium iodate, sodium iodate and iodic acid;
the organic solvent is dichloromethane;
the post-treatment comprises the following steps: pouring the reaction solution into a cold reducing aqueous solution for quenching, evaporating the solvent to dryness, and recrystallizing to obtain the 2-halogen-5-iodobenzoic acid;
the reducing aqueous solution is selected from one or more of aqueous solutions of sodium hypophosphite, sodium bisulfite and sodium hydrosulfite;
the solvent used for recrystallization is methanol, ethanol, DCM, acetonitrile or MTBE;
the mass ratio of the dosage of the o-halobenzoic acid to the dosage of the sulfuric acid is 1: 5.
2. The method for synthesizing 2-halo-5-iodobenzoic acid according to claim 1, wherein the mass ratio of the o-halobenzoic acid to the organic solvent is 1: 0.5-50.
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| CN110590541A (en) * | 2019-10-16 | 2019-12-20 | 吕东 | Preparation method of 5-bromo-2-chlorobenzoic acid |
| CN112194661B (en) * | 2020-10-22 | 2021-06-08 | 威海同丰海洋生物科技有限公司 | Preparation method of 4-amino-7-iodopyrrolo [2, l-f ] [ l,2,4] triazine |
| CN113582847B (en) * | 2021-07-16 | 2023-09-12 | 湖北工业大学 | Improved method for preparing iodo-benzoic acid (ester) by sandmeyer reaction |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101525322A (en) * | 2009-01-20 | 2009-09-09 | 中国药科大学 | New technology for synthesizing Corey lactonic acid by pan boiling method |
| CN103539662A (en) * | 2013-10-18 | 2014-01-29 | 雅本化学股份有限公司 | Preparation and recovery method of 2-methyl-5-iodobenzoic acid |
| CN104086361A (en) * | 2014-07-25 | 2014-10-08 | 南通市华峰化工有限责任公司 | Preparation method of 2-chloro-5-iodobenzoic acid |
| CN106748721A (en) * | 2016-11-17 | 2017-05-31 | 山东铂源药业有限公司 | A kind of preparation method of the iodo-benzoic acid of 2 chlorine 5 |
| WO2018089904A1 (en) * | 2016-11-11 | 2018-05-17 | 3-V Biosciences, Inc. | Heterocyclic modulators of lipid synthesis |
| WO2018112094A1 (en) * | 2016-12-15 | 2018-06-21 | Amgen Inc. | 1,4-thiazine dioxide and 1,2,4-thiadiazine dioxide derivatives as beta-secretase inhibitors and methods of use |
-
2019
- 2019-05-31 CN CN201910469871.0A patent/CN110078613B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101525322A (en) * | 2009-01-20 | 2009-09-09 | 中国药科大学 | New technology for synthesizing Corey lactonic acid by pan boiling method |
| CN103539662A (en) * | 2013-10-18 | 2014-01-29 | 雅本化学股份有限公司 | Preparation and recovery method of 2-methyl-5-iodobenzoic acid |
| CN104086361A (en) * | 2014-07-25 | 2014-10-08 | 南通市华峰化工有限责任公司 | Preparation method of 2-chloro-5-iodobenzoic acid |
| WO2018089904A1 (en) * | 2016-11-11 | 2018-05-17 | 3-V Biosciences, Inc. | Heterocyclic modulators of lipid synthesis |
| CN106748721A (en) * | 2016-11-17 | 2017-05-31 | 山东铂源药业有限公司 | A kind of preparation method of the iodo-benzoic acid of 2 chlorine 5 |
| WO2018112094A1 (en) * | 2016-12-15 | 2018-06-21 | Amgen Inc. | 1,4-thiazine dioxide and 1,2,4-thiadiazine dioxide derivatives as beta-secretase inhibitors and methods of use |
Non-Patent Citations (5)
| Title |
|---|
| Heterogeneous Electron Transfer Processes in Self-Assembled Monolayers of Amine Terminated Conjugated Molecular Wires;Christoph Lambert et al.;《Langmuir》;20061010;第22卷(第21期);第8807-8812页 * |
| Selective cross-coupling of 1-ethynyl-4-iodobenzenes with activated arylacetylenes;A. I. Kovalev et al.;《Russian Chemical Bulletin, International Edition》;20040831;第53卷(第8期);第1749-1754页 * |
| Synthesis of fluazolate via the application of regioselective [3+2] cyclocondensation and nucleophilic substitution-cyclization strategies;Min-Tsang Hsieh et al.;《Tetrahedron》;20160929;第72卷(第39期);第5880-5885页 * |
| Synthesis of Fluorescent oligo(p-phenyleneethynylene) (OPE3) via Sonogashira Reactions;Mariana Flores-Jarillo et al.;《Journal of the Mexican Chemical Society》;20150630;第59卷(第2期);第151-160页 * |
| SYNTHESIS OF IODOHIPPURIC ACIDS.I.2,5-,3,5-AND 3,4-DIIODOHIPPURIC ACIDS;CARL J. KLEMME et al.;《J. Org. Chem》;19401231;第5卷(第3期);第227-234页 * |
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