CN107216286B - Preparation method of 5-bromomethyl-2, 3-pyridine dimethyl dicarboxylate - Google Patents
Preparation method of 5-bromomethyl-2, 3-pyridine dimethyl dicarboxylate Download PDFInfo
- Publication number
- CN107216286B CN107216286B CN201710502061.1A CN201710502061A CN107216286B CN 107216286 B CN107216286 B CN 107216286B CN 201710502061 A CN201710502061 A CN 201710502061A CN 107216286 B CN107216286 B CN 107216286B
- Authority
- CN
- China
- Prior art keywords
- dimethyl
- bromomethyl
- pyridinedicarboxylate
- methyl
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
Abstract
The invention discloses a preparation method of 5-bromomethyl-2, 3-pyridine dimethyl dicarboxylate, which is prepared by taking 5-methyl-2, 3-pyridine dimethyl dicarboxylate as a starting material and carrying out bromination reaction in an organic solvent in the presence of azodiisobutyronitrile; the bromination reaction is carried out with hydrobromic acid in the presence of sodium bromate. According to the method, hydrobromic acid is used as a bromination reagent, and sodium bromate and azobisisobutyronitrile are used as an initiator, so that the production of byproducts can be greatly reduced, the yield of the byproduct is about 1% in a single reaction, and the yield of the byproduct in a circulating reaction is about 2%, so that the yield of the byproduct is over 90%.
Description
Technical Field
The invention belongs to the technical field of herbicide intermediate preparation, and particularly relates to a preparation method of 5-bromomethyl-2, 3-pyridine dimethyl dicarboxylate.
Background
Imazamox, an imidazolinone herbicide developed by cyanamide (now BASF) in the united states, is an inhibitor of acetolactate synthase (ALS) or Acetohydroxyacid Synthase (AHAs), which is absorbed, conducted and accumulated in meristems through leaves, inhibits the activity of AHAs, causes the cessation of biosynthesis of the branched-chain amino acids, valine, leucine and isoleucine, interferes with DNA synthesis and cell mitosis and plant growth, and finally causes plant death. The imazamox has good development prospect in China and huge market space, and the future development will keep gradually rising.
Dimethyl 5-bromomethyl-2, 3-pyridinedicarboxylate is a key intermediate for the preparation of imazamox.
U.S. Pat. No. 4, 5288866A discloses a process for preparing dimethyl 5-bromomethyl-2, 3-pyridinedicarboxylate by brominating dimethyl 5-methyl-2, 3-pyridinedicarboxylate as a starting material in the presence of azobisisobutyronitrile in a carbon tetrachloride solvent with N-bromosuccinimide; the method has the following disadvantages: only 57% of the target product, in particular up to 23% of the (dibromo) by-product, leads to a low yield, not exceeding 75% even when used cyclically.
World patent document WO2010055042a1 discloses a process for the preparation of dimethyl 5-bromomethyl-2, 3-pyridinedicarboxylate by brominating dimethyl 5-methyl-2, 3-pyridinedicarboxylate as a starting material in dichloroethane solvent in the presence of azobisisobutyronitrile; the method has the following disadvantages: more by-products, besides the dibromo by-product, there is a tribromo by-product, so its conversion is only 50%, indicating that its yield is lower.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a preparation method of 5-bromomethyl-2, 3-pyridine dimethyl dicarboxylate with fewer byproducts and higher yield of target products.
The technical scheme for realizing the above purpose of the invention is as follows: a preparation method of 5-bromomethyl-2, 3-pyridine dimethyl dicarboxylate, it is with 5-methyl-2, 3-pyridine dimethyl dicarboxylate as the starting material, in the presence of azodiisobutyronitrile, in organic solvent undergo bromination reaction to get final product; the bromination reaction is carried out with hydrobromic acid in the presence of sodium bromate.
The molar ratio of the dimethyl 5-methyl-2, 3-pyridinedicarboxylate to the hydrobromic acid is 1: 1-1: 3, and preferably 1: 2.
The molar ratio of the dimethyl 5-methyl-2, 3-pyridinedicarboxylate to the sodium bromate is 1: 0.1-1: 1, and preferably 1: 0.4.
The molar ratio of the dimethyl 5-methyl-2, 3-pyridinedicarboxylate to the azobisisobutyronitrile is 1: 0.05-1: 0.5, preferably 1: 0.1.
The organic solvent is dichloroethane, acetonitrile, Dimethylformamide (DMF), tetrahydrofuran or toluene, preferably dichloroethane.
The bromination reaction temperature is a reflux reaction temperature.
The bromination reaction time is 1-5 h, preferably 2 h.
The invention has the following positive effects: (1) according to the method, hydrobromic acid is used as a bromination reagent, and sodium bromate and azobisisobutyronitrile are used as an initiator, so that the production of byproducts can be greatly reduced, the yield of the byproduct is about 1% in a single reaction, and the yield of the byproduct in a circulating reaction is about 2%, so that the yield of the byproduct is over 90%. (2) The method also avoids using highly toxic liquid bromine, has the advantages of easily obtained raw materials, simple and convenient process, less side reaction and safe operation, and is suitable for industrial mass production.
Detailed Description
(example 1)
The preparation of dimethyl 5-bromomethyl-2, 3-pyridinedicarboxylate in this example was as follows:
50g of dimethyl 5-methyl-2, 3-pyridinedicarboxylate (0.24 mol), 128g of dichloroethane, 14.5g of sodium bromate (0.096 mol), 3.92g of azobisisobutyronitrile (0.024 mol) and 130g of water were added to a reaction flask, heated to reflux, 97g of 40 wt.% hydrobromic acid (0.48 mol) was added dropwise over about 2h, and the reflux reaction was continued for 2h with continued incubation.
After the reaction, the reaction solution was cooled to room temperature (15-25 ℃ C., the same applies below), the pH of the reaction solution was adjusted to 6.0. + -. 0.2 with 30wt% aqueous sodium hydroxide solution, the mixture was stirred and then allowed to stand for layering, and the organic layer was washed with water and then the solvent was removed under reduced pressure to obtain 68g of a reddish brown liquid.
HPCL shows that the reddish brown liquid after this single reaction contains 65.8% of the target product, 31.3% of dimethyl 5-methyl-2, 3-pyridinedicarboxylate and 0.9% of dimethyl 5-dibromomethyl-2, 3-pyridinedicarboxylate.
The unreacted raw materials in the separated reddish brown liquid are recycled and used for further bromination, the total yield reaches 95.2 percent after about 3 times of bromination, and the content of the 5-dibromomethyl-2, 3-pyridine dimethyl dicarboxylate is 1.8 percent.
(examples 2 to 6)
The preparation method of each example is basically the same as that of example 1 except for the differences shown in Table 1.
TABLE 1
| Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 | |
| 5-methyl-2, 3-pyridinedicarboxylic acid dimethyl ester | 50g，0.24mol | 50g，0.24mol | 50g，0.24mol | 50g，0.24mol | 50g，0.24mol | 100g，0.48mol |
| 40wt% hydrobromic acid | 97g，0.48mol | 48.5g，0.24mol | 145.5g，0.72mol | 97g，0.48mol | 97g，0.48mol | 194g，0.96mol |
| Bromoinic acid sodium salt | 14.5g，0.096mol | 14.5g，0.096mol | 14.5g，0.096mol | 3.63g，0.024mol | 36.3g，0.240mol | 29.0g，0.192mol |
| Target product of single reaction | 65.8% | 65.5% | 66.1% | 65.2% | 65.3% | 65.7% |
| Residual raw material of single reaction | 31.3% | 31.5% | 31.5% | 31.1% | 31.3% | 31.2% |
| Dibromo by-product of single reaction | 0.9% | 1.1% | 0.7% | 1.3% | 1.2% | 1.0% |
| Cyclic reaction of dibromo by-products | 1.8% | 2.1% | 1.6% | 2.3% | 2.2% | 1.8% |
| Total yield of the cyclic reaction | 95.2% | 94.8% | 95.6% | 94.3% | 94.6% | 95.3% |
(comparative examples 1 to 4)
The comparative examples were prepared substantially the same as in example 1, except that the differences are shown in Table 2.
TABLE 2
| Example 1 | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | |
| 5-methyl-2, 3-pyridinedicarboxylic acid dimethyl ester | 50g，0.24mol | 50g，0.24mol | 50g，0.24mol | 50g，0.24mol | 50g，0.24mol |
| 40wt% hydrobromic acid | 97g，0.48mol | 97g，0.48mol | 97g，0.48mol | / | / |
| Bromoinic acid sodium salt | 14.5g，0.096mol | / | 18.1g，0.12mol | / | / |
| Azobisisobutyronitrile | 3.92g，0.024mol | 19.7g，0.12mol | / | 19.7g，0.12mol | 19.7g，0.12mol |
| N-bromosuccinimide | / | / | / | 85.4g，0.48mol | / |
| Liquid bromine | / | / | / | / | 38.4g，0.24mol |
| Target product of single reaction | 65.8% | 57.6% | 55.5% | 59.2% | 47.6% |
| Residual raw material of single reaction | 31.3% | 32.6% | 30.7% | 15.4% | 16.8% |
| Dibromo by-product of single reaction | 0.9% | 7.5% | 11.5% | 22.7% | 27.3% |
| Tribromo by-product in single reaction | / | / | / | / | 5.9% |
| Cyclic reaction of dibromo by-products | 1.8% | 12.3% | 18.5% | 25.4% | 29.5% |
| By-product of tribromo by-product of cyclic reaction | / | / | / | / | 7.3% |
| Overall yield of | 95.2% | 83.8% | 77.3% | 71.3% | 59.8% |
The target product in tables 1 and 2 is dimethyl 5-bromomethyl-2, 3-pyridinedicarboxylate, the raw material is dimethyl 5-methyl-2, 3-pyridinedicarboxylate, the dibromo byproduct is dimethyl 5-dibromomethyl-2, 3-pyridinedicarboxylate, and the tribromo byproduct is dimethyl 5-tribromomethyl-2, 3-pyridinedicarboxylate.
Claims (8)
1. A preparation method of 5-bromomethyl-2, 3-pyridine dimethyl dicarboxylate, it is with 5-methyl-2, 3-pyridine dimethyl dicarboxylate as the starting material, in the presence of azodiisobutyronitrile, in organic solvent undergo bromination reaction to get final product; the method is characterized in that: the bromination reaction is carried out with hydrobromic acid in the presence of sodium bromate;
the molar ratio of the dimethyl 5-methyl-2, 3-pyridinedicarboxylate to the hydrobromic acid is 1: 1-1: 3;
the molar ratio of the dimethyl 5-methyl-2, 3-pyridinedicarboxylate to the sodium bromate is 1: 0.1-1: 1.
2. The process for producing dimethyl 5-bromomethyl-2, 3-pyridinedicarboxylate according to claim 1, characterized in that: the molar ratio of the dimethyl 5-methyl-2, 3-pyridinedicarboxylate to the hydrobromic acid is 1: 2.
3. The process for producing dimethyl 5-bromomethyl-2, 3-pyridinedicarboxylate according to claim 1, characterized in that: the molar ratio of the 5-methyl-2, 3-pyridine dimethyl dicarboxylate to the sodium bromate is 1: 0.4.
4. The process for producing dimethyl 5-bromomethyl-2, 3-pyridinedicarboxylate according to claim 1, characterized in that: the molar ratio of the dimethyl 5-methyl-2, 3-pyridinedicarboxylate to the azobisisobutyronitrile is 1: 0.05-1: 0.5.
5. The process for producing dimethyl 5-bromomethyl-2, 3-pyridinedicarboxylate according to claim 4, characterized in that: the molar ratio of the 5-methyl-2, 3-pyridine dimethyl dicarboxylate to the azobisisobutyronitrile is 1: 0.1.
6. The process for producing dimethyl 5-bromomethyl-2, 3-pyridinedicarboxylate according to claim 1, characterized in that: the organic solvent is dichloroethane, acetonitrile, dimethylformamide, tetrahydrofuran or toluene.
7. The process for producing dimethyl 5-bromomethyl-2, 3-pyridinedicarboxylate according to claim 1, characterized in that: the bromination reaction temperature is a reflux reaction temperature.
8. The process for producing dimethyl 5-bromomethyl-2, 3-pyridinedicarboxylate according to claim 1, characterized in that: the bromination reaction time is 1-5 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710502061.1A CN107216286B (en) | 2017-06-27 | 2017-06-27 | Preparation method of 5-bromomethyl-2, 3-pyridine dimethyl dicarboxylate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710502061.1A CN107216286B (en) | 2017-06-27 | 2017-06-27 | Preparation method of 5-bromomethyl-2, 3-pyridine dimethyl dicarboxylate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107216286A CN107216286A (en) | 2017-09-29 |
| CN107216286B true CN107216286B (en) | 2020-03-31 |
Family
ID=59951373
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710502061.1A Active CN107216286B (en) | 2017-06-27 | 2017-06-27 | Preparation method of 5-bromomethyl-2, 3-pyridine dimethyl dicarboxylate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107216286B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110818627A (en) * | 2018-08-09 | 2020-02-21 | 北京颖泰嘉和生物科技股份有限公司 | Preparation method of 5-methoxymethyl-2, 3-pyridinedicarboxylic acid diester |
| CN113004197A (en) * | 2019-12-19 | 2021-06-22 | 北京颖泰嘉和生物科技股份有限公司 | Method for recovering 5-methyl-2, 3-pyridinedicarboxylic acid diester |
| CN113024455A (en) * | 2019-12-25 | 2021-06-25 | 北京颖泰嘉和生物科技股份有限公司 | Preparation method of 5-methoxymethyl-2, 3-pyridine dimethyl dicarboxylate |
| CN113968814A (en) * | 2020-07-22 | 2022-01-25 | 帕潘纳(北京)科技有限公司 | Method for preparing 5-bromomethyl-2, 3-pyridine carboxylic acid dimethyl ester |
| CN114933561A (en) * | 2022-05-09 | 2022-08-23 | 沈阳万菱生物技术有限公司 | Preparation method of 5-substituted-2, 3-pyridine dicarboxylic ester compound and quaternary ammonium salt thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0434965A2 (en) * | 1989-12-27 | 1991-07-03 | American Cyanamid Company | Alkyl esters of 5-heterocyclic-pyridine-2,3-dicarboxylic acids and 5-heterocyclic 2-(2-imidazolin-2-yl) pyridines and methods for preparation thereof |
| CN1265639A (en) * | 1997-07-30 | 2000-09-06 | 巴斯福股份公司 | Method for preparing substituted benzyl bromides |
| WO2010055042A1 (en) * | 2008-11-13 | 2010-05-20 | Basf Se | 2-[(1-cyanopropyl)carbamoyl]-5-methoxymethyl nicotinic acids and the use thereof in manufacturing herbicidal imidazolinones |
| CN102245575A (en) * | 2008-12-08 | 2011-11-16 | 巴斯夫欧洲公司 | Process for manufacturing substituted 5-methoxymethylpyridine-2,3-dicarboxylic acid derivatives |
| CN105777623A (en) * | 2016-02-29 | 2016-07-20 | 北京颖泰嘉和生物科技股份有限公司 | Method for preparing pyridine side chain methyl quaternary ammonium compound |
-
2017
- 2017-06-27 CN CN201710502061.1A patent/CN107216286B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0434965A2 (en) * | 1989-12-27 | 1991-07-03 | American Cyanamid Company | Alkyl esters of 5-heterocyclic-pyridine-2,3-dicarboxylic acids and 5-heterocyclic 2-(2-imidazolin-2-yl) pyridines and methods for preparation thereof |
| CN1265639A (en) * | 1997-07-30 | 2000-09-06 | 巴斯福股份公司 | Method for preparing substituted benzyl bromides |
| WO2010055042A1 (en) * | 2008-11-13 | 2010-05-20 | Basf Se | 2-[(1-cyanopropyl)carbamoyl]-5-methoxymethyl nicotinic acids and the use thereof in manufacturing herbicidal imidazolinones |
| CN102245575A (en) * | 2008-12-08 | 2011-11-16 | 巴斯夫欧洲公司 | Process for manufacturing substituted 5-methoxymethylpyridine-2,3-dicarboxylic acid derivatives |
| CN105777623A (en) * | 2016-02-29 | 2016-07-20 | 北京颖泰嘉和生物科技股份有限公司 | Method for preparing pyridine side chain methyl quaternary ammonium compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107216286A (en) | 2017-09-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107216286B (en) | Preparation method of 5-bromomethyl-2, 3-pyridine dimethyl dicarboxylate | |
| CN104478797A (en) | Preparation method of nicotinamide fungicide namely boscalid | |
| JP6201595B2 (en) | Process for producing 2-hydroxymethyl-2,3-dihydro-thieno [3,4-b] [1,4] dioxin | |
| CN109293565B (en) | Preparation method of fluopyram | |
| CN104725303A (en) | Synthetic method of 2-chloro-N-(4'-chlorodiphenyl-2-yl) nicotinamide | |
| CN106117143B (en) | A kind of preparation method of pyraclostrobin | |
| CN103896855B (en) | The synthetic method of the fluoro-6-chlorine of a kind of 4-(1-bromoethyl)-5-pyrimidine | |
| CN103509027B (en) | The preparation method of florasulam | |
| CN108203384B (en) | Method for preparing o-nitrobenzyl bromide | |
| CN103254058B (en) | Process for synthesizing 2, 3, 3, 3-tetrafluoropropionic acid | |
| CN107827735B (en) | Synthetic method of 2-hydroxy-3, 6-dichlorobenzoic acid | |
| CN112500311B (en) | Preparation process of O-3-chloro-2-propenyl hydroxylamine free alkali | |
| CN108558686B (en) | Preparation method of bupropion hydrochloride | |
| CN109232569B (en) | Green preparation method of diquat anion salt | |
| CN109053559B (en) | Preparation method of 5-methoxymethyl-2, 3-pyridine dimethyl diformate | |
| CN108358835B (en) | Preparation method of 2,3, 5-trichloropyridine | |
| CN104140356B (en) | A kind of preparation method of novel green trifluorochloroethylene | |
| CN111170846A (en) | Method for preparing 3, 3-dimethyl-2-oxo-butyric acid | |
| CN106146294B (en) | Production method of perfluoromethyl vinyl ether and intermediate thereof | |
| CN109438356B (en) | Method for purifying prochloraz technical | |
| CN100522932C (en) | Method for preparing 2-bromomethyl-2-phenyl-4-(4-chlorophenyl)-butyronitrile | |
| CN102267939A (en) | Preparation method of N-methyl-pyridine chloride | |
| CN111574439A (en) | Method for preparing 2-amino-3 chloro-5-trifluoromethylpyridine | |
| CN105348139B (en) | The synthesis technique of the acrylic azanol of 3 chlorine of O 2 | |
| CN104529846A (en) | Method for increasing yield of produced methomyl |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |