CN102584627A - Synthetic method of cyhalofop-butyl active compound - Google Patents
Synthetic method of cyhalofop-butyl active compound Download PDFInfo
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- CN102584627A CN102584627A CN2012100335966A CN201210033596A CN102584627A CN 102584627 A CN102584627 A CN 102584627A CN 2012100335966 A CN2012100335966 A CN 2012100335966A CN 201210033596 A CN201210033596 A CN 201210033596A CN 102584627 A CN102584627 A CN 102584627A
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Abstract
The invention discloses a synthetic method of a cyhalofop-butyl active compound. The method comprises the following steps of: undergoing a condensation reaction on (R)-4-hydroxyphenoxypropanoic acid and 3,4-difluorobenzonilyile serving as raw materials in an organic solvent under an alkaline catalysis condition to generate an intermediate, i.e., (R)-2-[4-(2-fluoro-4-nitrile)-phenoxyl]-propanoic acid; undergoing a photochemical reaction on the intermediate, i.e., (R)-2-[4-(2-fluoro-4-nitrile)-phenoxyl]-propanoic acid to generate an intermediate, i.e., (R)-2-[4-(2-fluoro-4-nitrile)-propionyl chloride; and undergoing a third step esterification reaction on the intermediate, i.e., (R)-2-[4-(2-fluoro-4-nitrile)-propionyl chloride and n-butyl alcohol to generate the cyhalofop-butyl active compound. The method has the advantages of simple process, low production cost, high chemical content, high optical purity and the like.
Description
Technical field
The present invention relates to the compound method of the former medicine of a kind of cyhalofopbutyl
Background technology
Cyhalofopbutyl, common name cyhalofop-butyl, other title a thousand pieces of gold, cyanogen fluorine diclofop-methyl, chemical name are (R)-2-[4-(4-cyanic acid-2-fluorophenoxy) phenoxy] butyl propionate.Being mainly used in and preventing and kill off gramineous weeds, paddy rice etc. is had good selectivity, is the only kind that paddy rice is had tight security in the fragrant phenoxy propionic acid class weedicide.Cyhalofopbutyl is not only efficient to various barnyard grass grass (comprising above the average age for marriage barnyard grass grass), also can prevent and kill off Semen Euphorbiae, lady's-grass, two ditch millet, Herba Setariae Viridis, Herba Eleusines Indicae, amur foxtail etc.
According to the domestic and foreign literature report, the synthetic route of cyhalofopbutyl mainly contains two kinds at present: (1) by 3,4-difluorobenzonilyile and Resorcinol reaction generate midbody 4-oxygen-(2 '-fluoro-4 '-cyano-benzene oxygen) dihydroxy-benzene (A); (S)-n-Butyl lactate and Tosyl chloride reaction generation midbody (S)-2-(4-Methyl benzenesulfonyl oxygen base) butyl propionate (B); Midbody (A) carries out substitution reaction with (B), and configuration reversal gets the cyhalofopbutyl of (R)-configuration.(2) Resorcinol earlier with (S)-2-(4-Methyl benzenesulfonyl oxygen base) butyl propionate (B) carries out the midbody that substitution reaction obtains configuration reversal, with 3,4-difluorobenzonilyile etherificate gets the cyhalofopbutyl of (R)-configuration again.These two kinds of methods will cause all that raw materials cost is high because adopting raw material Tosyl chloride (this reaction generates transition state midbody earlier, finally dissociates out with the form of paratoluenesulfonic acid sodium salt), the three wastes how and be difficult to defective such as improvement.While method (2) is owing to too early introducing chiral carbon atom, and the steric effect of adding in the reaction process is little, and the cyhalofopbutyl optics content that makes is low, and the ee value only is 50.1%.
Therefore, how to improve the former medicine optics of cyhalofopbutyl content, increase the ee value, reducing production costs, seek the former medicine working method of a kind of simple and direct cyhalofopbutyl is the problem that those skilled in the art study always.
Summary of the invention
The object of the present invention is to provide the compound method of the former medicine of cyhalofopbutyl that a kind of technology is simple and direct, production cost is low, chemical content is high, optical purity is high.
Technical solution of the present invention is:
The compound method of the former medicine of a kind of cyhalofopbutyl; It is characterized in that: with (R)-4-hydroxyphenoxy propionic acid, 3; The 4-difluorobenzonilyile be raw material in organic solvent, alkalescence, carry out condensation reaction under the catalytic condition and generate midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionic acid; Midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionic acid and phosgene carry out photochmeical reaction and generate midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionyl chloride, and midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionyl chloride and propyl carbinol carry out the 3rd step esterification and generate the former medicine of cyhalofopbutyl.
Reaction formula is following:
The described organic solvent of condensation reaction is N, N,N-DIMETHYLACETAMIDE, DMSO 99.8MIN., acetonitrile, acetone or glycol dimethyl ether, and consumption of organic solvent is 2～10 times of (R)-4-hydroxyphenoxy propionic acid quality.
The described alkali of condensation reaction is sodium hydride, sodium methylate, sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, pyridine or triethylamine, and consumption is 2～5 times of (R)-4-hydroxyphenoxy propionic acid quality, and setting-up point is 20～200 ℃; After condensation reaction is accomplished, cross and filter to remove filter residue, filtrating is used hcl acidifying after solvent is removed in underpressure distillation.
The described catalyzer of condensation reaction is phase-transfer catalyst chlorinating benzyl triethylamine, Tetrabutyl amonium bromide, 4-butyl ammonium hydrogen sulfate, bromination hexadecyl tributyl phosphorus, methyl trioctylphosphine ammonium chloride, polyoxyethylene glycol or 18 hats 6, and consumption is 1%～5% of (R)-4-hydroxyphenoxy propionic acid quality.
The solvent of photochmeical reaction is any one in toluene, YLENE, chlorobenzene, ethylene dichloride, the tetracol phenixin,, the consumption of solvent is 3～10 times of midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionic acid quality.
The phosgene consumption is 1～5 times of midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionic acid molar mass in the photochmeical reaction, and temperature of reaction is 40 ℃～150 ℃, 2～10 hours reaction times.
The used catalyzer of photochmeical reaction is organic bases, as: the 4-dimethylamino pyridine; N, accelerine, triethylamine, pyridine, N, dinethylformamide, DMAC N,N, quaternary amine or quaternary amine alkali.
Feed exsiccant nitrogen after photochmeical reaction finishes, remove remaining phosgene and hydrogen chloride gas.
Esterification propyl carbinol consumption is 1～5 times of midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionyl chloride molar mass, and temperature of reaction is 0 ℃～100 ℃, 2～7 hours reaction times.
Decompression steamed organic solvent after esterification was accomplished, and residue is with ethanol, methyl alcohol, ETHYLE ACETATE or acetone recrystallization.
The present invention and prior art relatively have following characteristics:
1, adopt (R)-4-hydroxyphenoxy propionic acid (I) and 3,4-difluorobenzonilyile (II) carries out etherification reaction, has avoided 3, bis ether by product 1 in 4-difluorobenzonilyile and the Resorcinol etherification technology, the generation of 4-two (4-cyanic acid-3 fluorophenyl) phenyl ether.Reaction preference is high, yield is high, and total recovery is (with 3,4-difluorobenzonilyile meter) more than 92%.
2, phosgenation synthetic intermediate (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionyl chloride (IV); Through adding DMF and quaternary amine composite catalyst; Reduce temperature of reaction; Racemization, impurity such as sulfur-bearing, phosphorus not in the product simultaneously be difficult for to take place in optical isomer, cyhalofopbutyl chemical content 98.0%, and optics content is more than 99%.
Below in conjunction with embodiment the present invention is described further.
Embodiment
Embodiment 1
(1) in the 1000ml four-hole boiling flask, drops into glycol dimethyl ether 500ml; (R)-and 4-hydroxyphenoxy propionic acid (I) 91g (0.5mol) [R/S=99/1], Anhydrous potassium carbonate 173.5g (2.5mol), polyoxyethylene glycol-4002g; 3,4-difluorobenzonilyile (II) 69.5g (0.5mol).Be warming up to 85～90 ℃, insulation reaction 6 hours, reaction finishes.Be cooled to room temperature, filter, filter cake washs with the 100ml glycol dimethyl ether; Merging filtrate and washings; The solvent ethylene glycol dme is sloughed in decompression, adds entry 300ml, regulates pH value to 1～2 with 10% hydrochloric acid; Add the 500ml extracted in toluene and separate, get midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionic acid (III) toluene liquid through reflux dewatering.
(2) (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionic acid (III) the toluene liquid with above-mentioned preparation is cooled to 50 ℃; Add catalyzer N 1g, quaternary amine 1g; With the speed of 1200ml/min～1400ml/min, in 40～50 ℃ of feeding phosgene, logical light is after 2 hours; Feed nitrogen rush residual phosgene and hydrogen chloride gas, midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionyl chloride (IV) toluene liquid.
(3) in (the R)-2-of above-mentioned preparation [4-(2-fluoro-4-itrile group)-phenoxy]-propionyl chloride (IV) toluene liquid, drip propyl carbinol 44.4g (0.6mol); Drip off the back 40～50 ℃ of insulation reaction 2 hours; Toluene and excessive propyl carbinol are sloughed in decompression, add ethanol (or mother liquor) 300ml recrystallization and get the former medicine 165g of cyhalofopbutyl, chemical content 98.6% [R/S=99/1]; Yield 92.4% (with 3,4-difluorobenzonilyile meter, end folding hundred).Outward appearance: white solid.
Embodiment 2
(1) in the 1000ml four-hole boiling flask, drop into methyl-sulphoxide 500ml, (R)-4-hydroxyphenoxy propionic acid (I) 91g (0.5mol) [R/S=99/1], Anhydrous potassium carbonate 173.5g (2.5mol); Tetrabutyl amonium bromide 2g; 3,4-difluorobenzonilyile (II) 69.5g (0.5mol) is warming up to 85 ℃～90 ℃; Insulation reaction 10 hours, reaction finishes.Be cooled to room temperature, filter, filter cake washs with the 100ml methyl-sulphoxide; Merging filtrate and washings; The solvent methyl-sulphoxide is sloughed in decompression, adds entry 300ml, regulates pH value to 1～2 with 10% hydrochloric acid; Add the 500ml extracted in toluene and separate, get midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionic acid (III) toluene liquid through reflux dewatering.
Photochemical, esterification with among the embodiment 1 step (2), (3).The former medicine 150g of gained cyhalofopbutyl, chemical content 94.8% [R/S=97/3], yield 84% (with 3,4-difluorobenzonilyile meter, end folding hundred).Outward appearance: brown solid.
Embodiment 3
(1) midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionic acid (III) is synthetic with the step among the embodiment 1 (1).
(2) in (the R)-2-of above-mentioned preparation [4-(2-fluoro-4-itrile group)-phenoxy]-propionic acid (III) toluene liquid, add catalyzer DMF1g.Be warming up to 80 ℃～90 ℃; With the speed of 1200ml/min～1400ml/min, feed phosgene, logical light is after 2 hours; Feed nitrogen rush residual phosgene and hydrogen chloride gas, midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionyl chloride (IV) toluene liquid.
(3) esterification with among the embodiment 1 step (3).The former medicine 151g of gained cyhalofopbutyl, chemical content 96.8% [R/S=75/25], yield 84.6% (with 3,4-difluorobenzonilyile meter, end folding hundred).Outward appearance: white solid.
Embodiment 4
(1) midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionic acid (III) is synthetic with the step among the embodiment 1 (1).
(2) (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionic acid (III) the toluene liquid with above-mentioned preparation is cooled to 50 ℃; Dripping thionyl chloride 71.4g (0.6mol); Be warming up to (80～90) ℃ insulation reaction after dripping off 2 hours; The excessive sulfur oxychloride of pressure reducing and steaming gets midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionyl chloride (IV) again.
(3) esterification with in the instance 1 step (3).The former medicine 145g of gained cyhalofopbutyl, chemical content 90.5% [R/S=73/27], yield 81.2% (with 3,4-difluorobenzonilyile meter, do not roll over hundred).Outward appearance: yellow solid.
Claims (10)
1. the compound method of the former medicine of cyhalofopbutyl; It is characterized in that: with (R)-4-hydroxyphenoxy propionic acid, 3; The 4-difluorobenzonilyile be raw material in organic solvent, alkalescence, carry out condensation reaction under the catalytic condition and generate midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionic acid; Midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionic acid and phosgene carry out photochmeical reaction and generate midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionyl chloride, and midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionyl chloride and propyl carbinol carry out the 3rd step esterification and generate the former medicine of cyhalofopbutyl.
2. the compound method of the former medicine of cyhalofopbutyl according to claim 1; It is characterized in that: the described organic solvent of condensation reaction is N, N,N-DIMETHYLACETAMIDE, DMSO 99.8MIN., acetonitrile, acetone or glycol dimethyl ether, and consumption of organic solvent is 2～10 times of (R)-4-hydroxyphenoxy propionic acid quality.
3. the compound method of the former medicine of cyhalofopbutyl according to claim 1 and 2; It is characterized in that: the described alkali of condensation reaction is sodium hydride, sodium methylate, sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, pyridine or triethylamine; Consumption is 2～5 times of (R)-4-hydroxyphenoxy propionic acid quality, and setting-up point is 20～200 ℃; After condensation reaction is accomplished, cross and filter to remove filter residue, filtrating is used hcl acidifying after solvent is removed in underpressure distillation.
4. the compound method of the former medicine of cyhalofopbutyl according to claim 1 and 2; It is characterized in that: the described catalyzer of condensation reaction is phase-transfer catalyst chlorinating benzyl triethylamine, Tetrabutyl amonium bromide, 4-butyl ammonium hydrogen sulfate, bromination hexadecyl tributyl phosphorus, methyl trioctylphosphine ammonium chloride, polyoxyethylene glycol or 18 hats 6, and consumption is 1%～5% of (R)-4-hydroxyphenoxy propionic acid quality.
5. the compound method of the former medicine of cyhalofopbutyl according to claim 1 and 2; It is characterized in that: the solvent of photochmeical reaction is any one in toluene, YLENE, chlorobenzene, ethylene dichloride, the tetracol phenixin;, the consumption of solvent is 3～10 times of midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionic acid quality.
6. the compound method of the former medicine of cyhalofopbutyl according to claim 1 and 2; It is characterized in that: the phosgene consumption is 1～5 times of midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionic acid molar mass in the photochmeical reaction; Temperature of reaction is 40 ℃～150 ℃, 2～10 hours reaction times.
7. the compound method of the former medicine of cyhalofopbutyl according to claim 1 and 2 is characterized in that: the used catalyzer of photochmeical reaction is organic bases, as: the 4-dimethylamino pyridine; N, accelerine, triethylamine, pyridine, N, dinethylformamide, DMAC N,N, quaternary amine or quaternary amine alkali.
8. the compound method of the former medicine of cyhalofopbutyl according to claim 1 and 2 is characterized in that: feed exsiccant nitrogen after photochmeical reaction finishes, remove remaining phosgene and hydrogen chloride gas.
9. the compound method of the former medicine of cyhalofopbutyl according to claim 1 and 2; It is characterized in that: esterification propyl carbinol consumption is 1～5 times of midbody (R)-2-[4-(2-fluoro-4-itrile group)-phenoxy]-propionyl chloride molar mass; Temperature of reaction is 0 ℃～100 ℃, 2～7 hours reaction times.
10. the compound method of the former medicine of cyhalofopbutyl according to claim 1 and 2 is characterized in that: decompression steamed organic solvent after esterification was accomplished, and residue is with ethanol, methyl alcohol, ETHYLE ACETATE or acetone recrystallization.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105566158A (en) * | 2016-02-02 | 2016-05-11 | 江苏丰山集团股份有限公司 | Method for preparing cyhalofop-butyl |
| CN105601538A (en) * | 2016-02-02 | 2016-05-25 | 江苏丰山集团股份有限公司 | Preparation method of cyhalofop-butyl |
| CN107183028A (en) * | 2017-07-08 | 2017-09-22 | 北京燕化永乐生物科技股份有限公司 | A kind of ethyl（2R）‑2‑[4‑（The fluorophenoxy of 4 cyano group 2）Phenoxy group] propionic ester and preparation and application |
| CN109942460A (en) * | 2019-04-24 | 2019-06-28 | 湖南速博生物技术有限公司 | A method of synthesis cyhalofop-butyl |
| CN110003051A (en) * | 2019-05-06 | 2019-07-12 | 湖南速博生物技术有限公司 | A kind of preparation method of cyhalofop-butyl standard items |
| CN110208422A (en) * | 2019-06-28 | 2019-09-06 | 江苏恒生检测有限公司 | Analysis method containing impurity in a kind of pesticide cyhalofop-butyl |
| CN113767911A (en) * | 2021-09-17 | 2021-12-10 | 维讯化工（南京）有限公司 | Herbicide composition containing cyhalofop-butyl and preparation method thereof |
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| CN109651140A (en) * | 2018-12-12 | 2019-04-19 | 江苏中旗科技股份有限公司 | A kind of synthetic method of cyhalofop-butyl active compound |
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2012
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Non-Patent Citations (1)
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| 罗亮明 等: "氰氟草酯的合成", 《农药研究与应用》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105566158A (en) * | 2016-02-02 | 2016-05-11 | 江苏丰山集团股份有限公司 | Method for preparing cyhalofop-butyl |
| CN105601538A (en) * | 2016-02-02 | 2016-05-25 | 江苏丰山集团股份有限公司 | Preparation method of cyhalofop-butyl |
| CN105601538B (en) * | 2016-02-02 | 2018-01-23 | 江苏丰山集团股份有限公司 | A kind of preparation method of cyhalofop-butyl |
| CN107183028A (en) * | 2017-07-08 | 2017-09-22 | 北京燕化永乐生物科技股份有限公司 | A kind of ethyl（2R）‑2‑[4‑（The fluorophenoxy of 4 cyano group 2）Phenoxy group] propionic ester and preparation and application |
| CN109942460A (en) * | 2019-04-24 | 2019-06-28 | 湖南速博生物技术有限公司 | A method of synthesis cyhalofop-butyl |
| CN110003051A (en) * | 2019-05-06 | 2019-07-12 | 湖南速博生物技术有限公司 | A kind of preparation method of cyhalofop-butyl standard items |
| CN110208422A (en) * | 2019-06-28 | 2019-09-06 | 江苏恒生检测有限公司 | Analysis method containing impurity in a kind of pesticide cyhalofop-butyl |
| CN113767911A (en) * | 2021-09-17 | 2021-12-10 | 维讯化工（南京）有限公司 | Herbicide composition containing cyhalofop-butyl and preparation method thereof |
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