CN112250621A - Synthetic method of clodinafop-propargyl - Google Patents
Synthetic method of clodinafop-propargyl Download PDFInfo
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- CN112250621A CN112250621A CN202011011714.4A CN202011011714A CN112250621A CN 112250621 A CN112250621 A CN 112250621A CN 202011011714 A CN202011011714 A CN 202011011714A CN 112250621 A CN112250621 A CN 112250621A
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- clodinafop
- propargyl
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- etherate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/643—2-Phenoxypyridines; Derivatives thereof
Abstract
The invention relates to the field of chemical industry, and discloses a synthetic method of clodinafop-propargyl, which comprises the following steps: dissolving DHPPA in an organic solvent, heating to 50 ℃, adding an antioxidant and potassium hydroxide, heating to 60 ℃, starting to dropwise add 2, 3-difluoro-5-chloropyridine, and heating to 70 ℃ after dropwise addition, and keeping the temperature; after the heat preservation is finished, the organic solvent is removed by pressure reduction, water is added after the organic solvent is completely removed, the pH value is adjusted to 1-2, cooling and separation are carried out, and etherate is obtained by filtering and washing; dissolving etherate in DMF, heating until the etherate is completely dissolved, adding potassium carbonate, heating to 60 ℃, dropwise adding chloropropyne, and keeping the temperature at 60-70 ℃ after dropwise adding; adding water and toluene, stirring for dissolving, standing for layering, and washing after heat preservation; and (4) decoloring the organic layer, filtering, desolventizing the filtrate by water vapor, and slicing to obtain the clodinafop-propargyl finished product. The synthesis method enables the isomer in the clodinafop-propargyl product to be controlled to be about 1% (area content) on the premise of omitting the purification step.
Description
Technical Field
The invention relates to the field of chemical industry, and particularly relates to a synthetic method of clodinafop-propargyl.
Background
The content of 2, 3-difluoro-5-chloropyridine available in the market at present is about 96%, wherein 3% (area normalization method) isomers exist, and in the synthetic process of the clodinafop-propargyl, the 3% (area normalization method) isomers can finally form about 3% (area normalization method) isomers of clodinafop-propargyl along with the reaction, so that the quality of the final clodinafop-propargyl product is influenced.
In order to improve the purity of clodinafop-propargyl products, purification steps are generally adopted in the currently disclosed synthetic route of clodinafop-propargyl, so that the synthetic steps are relatively complicated and the synthetic efficiency is low.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the problems in the prior art, the invention provides a synthetic method of clodinafop-propargyl, which can effectively reduce the generation of isomers on the premise of omitting a purification step, so that the isomers in the clodinafop-propargyl product are controlled to be about 1% (area normalization), and the prepared clodinafop-propargyl product meets the national standard.
The technical scheme is as follows: the invention provides a synthetic method of clodinafop-propargyl, which comprises the following steps: s1: dissolving DHPPA in an organic solvent, heating to 50 ℃, adding an antioxidant and potassium hydroxide, starting to dropwise add 2, 3-difluoro-5-chloropyridine when the temperature is raised to 60 ℃, heating to 70 ℃ after dropwise addition, and keeping the temperature for 4.5-5.5 hours; s2: after the heat preservation is finished, the organic solvent is removed under reduced pressure, water is added after the organic solvent is completely removed, the pH value is adjusted to be 1-2, cooling and separation are carried out, and then filtering and washing are carried out, so as to obtain etherate; s3: dissolving the etherate in DMF, heating to full dissolution of the etherate, adding potassium carbonate, heating to 60 ℃, dropwise adding chloropropyne, and keeping the temperature at 60-70 ℃ for 3.5-4.5 hours after dropwise adding; s4: adding water and toluene, stirring and dissolving after heat preservation is finished, standing and layering, and washing for one to two times by using a NaCl aqueous solution with the mass fraction of 5%; s5: and (4) decoloring the layered organic layer, filtering, desolventizing the water vapor of the filtrate, and slicing to obtain the clodinafop-propargyl finished product.
Preferably, in the S1, the molar ratio between the DHPPA, the potassium hydroxide and the 2, 3-difluoro-5-chloropyridine is 0.4: 0.95-1: 0.44-0.5.
Preferably, in the S3, the molar ratio between the etherate, the potassium carbonate and the chloropropyne is 0.2 mol: 0.2-0.23 mol: 0.25-0.3 mol.
Preferably, in the S1, the antioxidant is sodium sulfite.
Preferably, in the S1, the organic solvent is acetonitrile.
Preferably, in the S2, hydrochloric acid with the mass fraction of 30% is added dropwise to adjust the pH value to be 1-2.
Preferably, in the S5, activated carbon is added to decolor the organic layer at 50 ℃.
The synthesis principle is as follows:
has the advantages that: in the synthesis method, after strong base potassium hydroxide is added in the step of preparing the intermediate etherate, 2, 3-difluoro-5-chloropyridine and the isomer 2, 5-difluoro-3-chloropyridine thereof can remove one fluorine atom in the presence of a reducing agent sodium sulfite to generate the 3-fluoro-5-chloropyridine, and the principle is as follows:
Detailed Description
The present invention will be described in detail with reference to specific examples.
Embodiment 1:
72.9g (0.4 mol) of DHPPA was dissolved in 200g of acetonitrile, the mixture was stirred and heated to 50 ℃ and 0.3g of sodium sulfite and 55g (0.97 mol) of KOH were added thereto, 66g (0.44 mol) of 2, 3-difluoro-5-chloropyridine was added dropwise after the temperature was raised to 60 ℃ and the mixture was heated to 70 ℃ after the completion of the addition and then the temperature was maintained for 5 hours. And (3) after the heat preservation is finished, removing acetonitrile under reduced pressure, removing acetonitrile completely, adding 200g of water, dropwise adding 30% hydrochloric acid to adjust the pH to be =1, cooling and separating out, filtering and washing to obtain an etherate dry product: 124.6 g.
62.3g (about 0.2 mol) of etherate and 82g of DMF are added into a 500mL four-mouth bottle, the mixture is heated until the materials are completely dissolved, 30g (0.22 mol) of potassium carbonate is added, the temperature is raised to 60 ℃, 20g (0.27 mol) of chloropropyne is added dropwise, and the temperature is kept for 4 hours at 65 ℃ after the dropwise addition. And after the heat preservation is finished, 100g of water and 130g of toluene are added, the mixture is stirred, dissolved, kept stand and layered, and washed twice by 100g of NaCl aqueous solution with the mass fraction of 5%. Adding 5g of activated carbon into the layered organic layer, decoloring at 50 ℃, filtering, and removing toluene from the filtrate by using a rotary evaporator to obtain 62.9g of a finished product of clodinafop-propargyl, wherein the content is as follows: 97.8% (external standard method), total yield: 90 percent.
Embodiment 2:
72.9g (0.4 mol) of DHPPA was dissolved in 200g of acetonitrile, the mixture was stirred and heated to 50 ℃ to add 0.3g of sodium sulfite and 53.3g (0.95 mol) of KOH, 66g (0.44 mol) of 2, 3-difluoro-5-chloropyridine was added dropwise after the temperature was raised to 60 ℃ and the mixture was heated to 70 ℃ after the completion of the addition and then the temperature was maintained for 5 hours. And (3) after the heat preservation is finished, removing acetonitrile under reduced pressure, removing acetonitrile completely, adding 200g of water, dropwise adding 30% hydrochloric acid to adjust the pH to be =1, cooling and separating out, filtering and washing to obtain an etherate dry product: 124 g.
62g (about 0.2 mol) of etherified substance and 82g of DMF are added into a 500mL four-mouth bottle, the mixture is heated until the materials are completely dissolved, 30g (0.2 mol) of potassium carbonate is added, the mixture is heated to 60 ℃, 20g (0.27 mol) of chloropropyne is added dropwise, and the temperature is kept for 4 hours at 65 ℃ after the dropwise addition. And after the heat preservation is finished, 100g of water and 130g of toluene are added, the mixture is stirred, dissolved, kept stand and layered, and washed twice by 100g of NaCl aqueous solution with the mass fraction of 5%. Adding 5g of activated carbon into the layered organic layer, decoloring at 50 ℃, filtering, and removing toluene from the filtrate by using a rotary evaporator to obtain 62.3g of a finished product of clodinafop-propargyl, wherein the content is as follows: 98.1% (external standard method), total yield: 89 percent.
Embodiment 3:
72.9g (0.4 mol) of DHPPA was dissolved in 200g of acetonitrile, the mixture was stirred and heated to 50 ℃ and 0.3g of sodium sulfite and 56.1g (1mol) of KOH were added thereto, 74.7g (0.5mol) of 2, 3-difluoro-5-chloropyridine was added dropwise after the temperature was raised to 60 ℃ and the mixture was heated to 70 ℃ after the completion of the addition and then the temperature was maintained for 6 hours. And (3) after the heat preservation is finished, removing acetonitrile under reduced pressure, removing acetonitrile completely, adding 200g of water, dropwise adding 30% hydrochloric acid to adjust the pH to be =1, cooling and separating out, filtering and washing to obtain an etherate dry product: 130 g.
Feeding 65g (about 0.2 mol) of etherate and 82g of DMF (dimethyl formamide) into a 500mL four-neck flask, heating until the materials are completely dissolved, adding 30g (0.22 mol) of potassium carbonate, heating to 60 ℃, dropwise adding 20g (0.27 mol) of chloropropyne, and preserving the temperature for 4 hours at 65 ℃ after dropwise adding. And after the heat preservation is finished, 100g of water and 130g of toluene are added, the mixture is stirred, dissolved, kept stand and layered, and washed twice by 100g of NaCl aqueous solution with the mass fraction of 5%. Adding 5g of activated carbon into the layered organic layer, decoloring at 50 ℃, filtering, and removing toluene from the filtrate by using a rotary evaporator to obtain 63.9g of a finished product of clodinafop-propargyl, wherein the content is as follows: 97.4% (external standard method), total yield: 91.3 percent.
Comparative example:
adding 182g (1mol) of R-p-hydroxyphenoxypropionic acid and 600g of DMF (dimethyl formamide) into a 1000mL three-necked flask, heating to 70 ℃, adding 69g (0.5mol) of potassium carbonate while stirring, stirring for lh to drive off carbon dioxide, adding 193g of potassium carbonate (1.4mol), dropwise adding 165g (1.1mol) of 5-chloro-2, 3-fluoropyridine at 70-75 ℃ for 0.5h, and reacting for 4 h; and (3) slowly (for 2 hours) dripping 86g of chloropropyne (diluted by adding 60-70% of toluene) into the reaction container without post-treatment, and reacting for 2 hours at 70-75 ℃ to obtain the technical grade clodinafop-propargyl. Cooling, filtering, washing the filter cake with 300g of DMF in batches, removing the solvent DMF (120 ℃) from the filter cake to obtain a crude clodinafop-propargyl product, then recrystallizing with 300g of ethanol/water (9: 1, v/v), and drying in vacuum at 30 ℃ to obtain a product which is a white crystal, wherein the content of the product is 97 percent (external standard method) by liquid chromatography, and the yield is 85 percent. It can be seen that the purity of the clodinafop-propargyl ester finished product obtained in the embodiment 1 to 3 without the purification step is equal to or even higher than that of the clodinafop-propargyl ester finished product obtained in the comparative example with the purification step.
The above embodiments are merely illustrative of the technical concepts and features of the present invention, and the purpose of the embodiments is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (7)
1. A synthetic method of clodinafop-propargyl is characterized by comprising the following steps:
s1: dissolving DHPPA in an organic solvent, heating to 50 ℃, adding an antioxidant and potassium hydroxide, starting to dropwise add 2, 3-difluoro-5-chloropyridine when the temperature is raised to 60 ℃, heating to 70 ℃ after dropwise addition, and keeping the temperature for 4.5-5.5 hours;
s2: after the heat preservation is finished, the organic solvent is removed under reduced pressure, water is added after the organic solvent is completely removed, the pH value is adjusted to be 1-2, cooling and separation are carried out, and then filtering and washing are carried out, so as to obtain etherate;
s3: dissolving the etherate in DMF, heating to full dissolution of the etherate, adding potassium carbonate, heating to 60 ℃, dropwise adding chloropropyne, and keeping the temperature at 60-70 ℃ for 3.5-4.5 hours after dropwise adding;
s4: adding water and toluene, stirring and dissolving after heat preservation is finished, standing and layering, and washing for one to two times by using a NaCl aqueous solution with the mass fraction of 5%;
s5: and (4) decoloring the layered organic layer, filtering, desolventizing the water vapor of the filtrate, and slicing to obtain the clodinafop-propargyl finished product.
2. A method for the synthesis of clodinafop-propargyl according to claim 1, wherein in S1 the molar ratio between DHPPA, potassium hydroxide and 2, 3-difluoro-5-chloropyridine is 0.4: 0.95-1: 0.44-0.5.
3. A synthesis method of clodinafop-propargyl according to claim 1, characterized in that in S3, the molar ratio between the etherate, the potassium carbonate and the chloropropyne is 0.2 mol: 0.2-0.23 mol: 0.25-0.3 mol.
4. A synthesis process of clodinafop-propargyl according to any of claims 1 to 3, characterized in that in S1 the antioxidant is sodium sulfite.
5. A synthesis method of clodinafop-propargyl according to any of claims 1 to 3, characterized in that in S1 the organic solvent is acetonitrile.
6. A synthesis method of clodinafop-propargyl according to any of claims 1 to 3, characterized in that hydrochloric acid with a mass fraction of 30% is added dropwise in the S2 to adjust the pH to 1 to 2.
7. A synthesis method of clodinafop-propargyl according to any of claims 1 to 3, characterized in that in S5, the organic layer is decolorized by adding activated carbon at 50 ℃.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115197128A (en) * | 2022-08-17 | 2022-10-18 | 甘肃联凯生物科技有限公司 | Novel synthesis process of clodinafop-propargyl |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4640703A (en) * | 1983-12-06 | 1987-02-03 | Ciba-Geigy Corporation | 2-phenoxypropionic acid cyanamides as herbicides |
| US5274100A (en) * | 1990-10-23 | 1993-12-28 | Ciba-Geigy Corporation | Process for the preparation of (3-fluoropyridin-2-yloxy)phenoxypropionic acids |
| CN102584691A (en) * | 2012-01-12 | 2012-07-18 | 南京红太阳生物化学有限责任公司 | Novel method for synthetizing clodinafop-propargyl |
| CN105418494A (en) * | 2015-12-15 | 2016-03-23 | 南京正荣医药化学有限公司 | Preparation method of clodinafop propargyl |
| CN110894188A (en) * | 2018-09-13 | 2020-03-20 | 江苏丰山集团股份有限公司 | Preparation method of 2-substituted halogenated pyridine compound |
-
2020
- 2020-09-23 CN CN202011011714.4A patent/CN112250621A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4640703A (en) * | 1983-12-06 | 1987-02-03 | Ciba-Geigy Corporation | 2-phenoxypropionic acid cyanamides as herbicides |
| US5274100A (en) * | 1990-10-23 | 1993-12-28 | Ciba-Geigy Corporation | Process for the preparation of (3-fluoropyridin-2-yloxy)phenoxypropionic acids |
| CN102584691A (en) * | 2012-01-12 | 2012-07-18 | 南京红太阳生物化学有限责任公司 | Novel method for synthetizing clodinafop-propargyl |
| CN105418494A (en) * | 2015-12-15 | 2016-03-23 | 南京正荣医药化学有限公司 | Preparation method of clodinafop propargyl |
| CN110894188A (en) * | 2018-09-13 | 2020-03-20 | 江苏丰山集团股份有限公司 | Preparation method of 2-substituted halogenated pyridine compound |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115197128A (en) * | 2022-08-17 | 2022-10-18 | 甘肃联凯生物科技有限公司 | Novel synthesis process of clodinafop-propargyl |
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