CN102452976A - Method for synthesizing 2-chloro-5-trifluoromethylpyridine - Google Patents
Method for synthesizing 2-chloro-5-trifluoromethylpyridine Download PDFInfo
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- CN102452976A CN102452976A CN2010105219680A CN201010521968A CN102452976A CN 102452976 A CN102452976 A CN 102452976A CN 2010105219680 A CN2010105219680 A CN 2010105219680A CN 201010521968 A CN201010521968 A CN 201010521968A CN 102452976 A CN102452976 A CN 102452976A
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Abstract
The invention relates to a method for synthesizing 2-chloro-5-trifluoromethylpyridine. In the method, the 2-chloro-5-trifluoromethylpyridine is synthesized by performing three-step reaction, namely N-oxidation, benzoyl chloride chlorination and chorine gas chlorination on 3-methylpyridine serving as an initial raw material. In the reaction process of preparing 2-chloro-5-methylpyridine from N-oxy-3-methylpyridine, an isomer 2-chloro-3-methylpyridine of which the property is similar to that of the target product is not required to be separated, and the 2-chloro-5-methylpyridine can be directly used for the next-step reaction, so that the separation process is simplified, and operation efficiency is improved; and the whole synthesis route is easy to operate, reaction conditions are mild, and the requirement on an equipment material is low.
Description
Technical field
The present invention relates to the preparation method of a kind of medicine and pesticide intermediate 2-chloro-5-5-flumethiazine.
Background technology
2-chloro-5-5-flumethiazine is a kind of important 5-flumethiazine class industrial chemicals; Can be by its synthetic many compound with special purpose; Be applicable to a kind of important midbody of preparation pharmaceuticals, agrochemicals and biotechnological formulation, particularly produce the key intermediate of kind agricultural chemicals such as efficient pesticides UC 62644, highy potent herbicide fluazifop and efficient germicide PP-192.The method of Synthetic 2-chloro-5-5-flumethiazine comprises by raw material classification: pyridine, 2-amino-5-picoline, nicotinic acid, 3-picoline wherein are considered to that with the compound method that the 3-picoline is produced 2-chloro-5-5-flumethiazine development potentiality is arranged most.With the 3-picoline is that the compound method of raw material has two kinds; The one, minute one-step chlorination with fluoridize; Two is step chlorofluorinations; The former with the chlorination of 3-picoline after again under catalyst action with HF reaction, the latter then directly carries out a step chlorofluorination with the 3-picoline and obtains title product, this technology is owing to the total recovery that in technology, improves can be recycled after the by product dechlorination, can drop to trade refuse the advantage of minimally and extensively had an optimistic view of; But once through yield is low because of existing, catalyst activity is because of shortcomings such as oversize easy inactivations of time, makes to realize that there are many difficulties in industriallization.
Summary of the invention
Technical problem to be solved by this invention is the compound method that a kind of 2-chloro-5-5-flumethiazine is provided to the above-mentioned state of the art; With the 3-picoline is raw material; Obtain key intermediate 2-chloro-5-nitrapyrin through N-oxidation, ring chlorinated; Obtain 2-chloro-5-5-flumethiazine through further fluoridizing again, this synthetic route has that raw material cheaply is easy to get, reaction conditions is comparatively gentle, reaction process is easy to advantages such as control.
The present invention solves the problems of the technologies described above the technical scheme that is adopted to be: a kind of 2-chloro-5-5-flumethiazine compound method is characterized in that steps in sequence is:
(1) N-oxygen-3-picoline is synthetic: using hydrogen peroxide to be oxygenant, is solvent with the glacial acetic acid, under acidity, reacts, and the mol ratio of 3-picoline and hydrogen peroxide is 1: 1.4～1.5,70～80 ℃ of temperature of reaction, and the reaction times is 18～24 hours;
(2) 2-chloro-5-picoline is synthetic: use Benzoyl chloride 99min. to be chlorizating agent; Make solvent with methylene dichloride; Triethylamine is made acid-acceptor; The mol ratio of N-oxygen-3-picoline and Benzoyl chloride 99min. is 1: 1.4～1.6, and the add-on of acid-acceptor is 1.3-1.7 a times of N-oxygen-3-picoline mole number, and stirring and reflux state reacted 3～4 hours down;
(3) 2-chloro-5-nitrapyrin is synthetic: make chlorizating agent with chlorine; Diisopropyl azodicarboxylate is made initiator, and orthodichlorobenzene is made solvent, and the Diisopropyl azodicarboxylate add-on is 5%～8% of a 2-chloro-5-picoline quality; 120～140 ℃ of temperature stir reaction down 18～20 hours; Chlorine is for slowly feed continuously, and it is all right to reach bubbling;
(4) 2-chloro-5-5-flumethiazine is synthetic: make fluorizating agent with anhydrous potassium fluoride; Cetyl trimethylammonium bromide (CTAB) is made phase-transfer catalyst; DMSO 99.8MIN. is made solvent; The mol ratio of 2-chloro-5-nitrapyrin and anhydrous potassium fluoride is 1: 2～2.4, and the add-on of CTAB is 6～10% of a 2-chloro-5-nitrapyrin quality, and stirring and reflux state reacted 5～7 hours down.
The 2-3 that the add-on of described glacial acetic acid solvent, dichloromethane solvent, orthodichlorobenzene solvent, dimethyl sulfoxide solvent is respectively 3-picoline raw material and respectively goes on foot the midbody consumption doubly, 4-5 doubly, 4-5 doubly, 2-3 doubly.Here add-on adopts mole.
Reflux state in said step (2), the step (4) adopts slight boiling condition,
Compared with prior art; The invention has the advantages that: with the 3-picoline is starting raw material; Synthesized 2-chloro-5-nitrapyrin through N-oxidation, Benzoyl chloride 99min. chlorination, chlorinated with chlorine 3 step reaction,, need not to tell the character isomer 2-chloro-3-picoline very close and can directly be used for next step reaction with target compound generating in the reaction process of 2-chloro-5-picoline by N-oxygen-3-picoline; Simplify separable programming, improved operation efficiency.Whole synthetic route is simple to operate, reaction conditions is gentle, equipment material is less demanding.
Embodiment
Below in conjunction with embodiment the present invention is described in further detail.
Examples of implementation 1
1, N-oxygen-3-picoline is synthetic
In the 500mL four-hole boiling flask that whisking appliance, TM, prolong, constant pressure funnel are housed, add 46.6g (0.5mol) 3-picoline and 120mL Glacial acetic acid min. 99.5; Electronic stirring; Be warming up to 75 ℃; After dropwise adding 74.0mL (0.72mol) 30% (mass percent) hydrogen peroxide, insulation reaction 24h.Reaction back product steams excessive glacial acetic acid and water through decompression, is neutralized to weakly alkaline (pH=7-8) with saturated sodium bicarbonate solution, uses chloroform extraction, drying, and decompression steams solvent, gets the orange red oily liquids of 50.2g, yield 86.7%.
2,2-chloro-5-picoline is synthetic
In the 500mL four-hole boiling flask that whisking appliance, TM, prolong, constant pressure funnel are housed, add 28.7g (0.25mol) N-oxygen-3-picoline, 52mL (0.375mol) triethylamine and 100mL methylene dichloride; Be heated with stirring under little reflux state, dropwise add Benzoyl chloride 99min. 49.2g (0.35mol) with the dilution of 50mL methylene dichloride.Dropwise, continue insulation backflow 3h.Reaction finishes, and filters washing leaching cake; Merge washings and filtrating, slough solvent after, wet distillation; Isolate the oil reservoir of distillate, obtain the light yellow oily liquid of 21.8g after revolving steaming, through gas chromatographic analysis; 2-chloro-5-picoline massfraction is 81.5%, and the massfraction of 2-chloro-3-picoline is 17.8%.2-chloro-5-picoline yield is 56.3%.Product need not further to separate to purify, and can directly descend the step reaction.
3,2-chloro-5-nitrapyrin is synthetic
Adding content is 81.5% bullion 2-chloro-5-picoline 15.6g (0.1mol), 0.1g Diisopropyl azodicarboxylate and 50mL orthodichlorobenzene in the 100mL four-hole boiling flask that TM, prolong, inlet mouth, anti-mouthful soft rubber ball are housed, and feeds nitrogen; Stir; Be warming up to 80 ℃, stop logical nitrogen and switch feeding chlorine, continue to be warming up to 140 ℃; Under the constant temperature, the chlorine blistering reaction.In the reaction process, every separated 2h adds the 0.07g Diisopropyl azodicarboxylate, behind the reaction 20h, stops heating, closes the chlorine sampling valve, feeds nitrogen, and bubbling is caught up with chlorine 1h.Behind the reaction solution underpressure distillation precipitation, carry out column chromatography for separation with silica gel, use the absolute ethyl alcohol recrystallization, vacuum-drying portion obtains white solid 19.1g, and 2-chloro-5-nitrapyrin yield is 82.7%.
4,2-chloro-5-5-flumethiazine is synthetic
In the 100mL four-hole boiling flask that TM, reflux condensing tube and whisking appliance are housed; Add 23.3g (0.1mol) 2-chloro-5-nitrapyrin and 50mL methyl-sulphoxide; Be warming up to 100 ℃ under stirring; Adding is newly ground and through exsiccant 11.6g anhydrous potassium fluoride and phase-transfer catalyst cetyl trimethylammonium bromide 1.9g, is continued to be warming up to little reflux state and react under nitrogen protection.React after 6 hours, stop heating, cooled and filtered; And, merge washings and filtrating with an amount of ETHYLE ACETATE washing leaching cake, carry out underpressure distillation after steaming solvent; Collect the cut of boiling point at 80～81 ℃ (70mmHg), obtain 14.7g 2-chloro-5-5-flumethiazine, yield is 80.2%.
Examples of implementation 2
1, N-oxygen-3-picoline is synthetic
Synthetic as the first step among the embodiment 1, just change temperature of reaction into 80 ℃, the insulation reaction time that splashes into behind the hydrogen peroxide still is 24h, must 50.7g N-oxygen-3-picoline after same treatment, yield is 87.6%.
2,2-chloro-5-picoline is synthetic
Synthetic as the step of second among the embodiment 1; Just the consumption with the acid-acceptor triethylamine changes 0.35mol into; Other reagent dosages are all identical with operation; Obtain mixture 21.2 grams of 2-chloro-5-picoline and 2-chloro-3-picoline at last, the percentage composition of the two is respectively 81.4% and 17.5%, and the yield of 2-chloro-5-picoline is 54.9%.
3,2-chloro-5-nitrapyrin is synthetic
Synthetic as the step of the 3rd among the embodiment 1, just change temperature of reaction into 120 ℃, get 2-chloro-5-nitrapyrin 18.7g, yield is 81.0%.
4,2-chloro-5-5-flumethiazine is synthetic
Synthetic like the 4th among the embodiment 1 step, the consumption that just changes the consumption of anhydrous potassium fluoride into 13.8g, cetyl trimethylammonium bromide changes 2.1g into, obtains 14.9g 2-chloro-5-5-flumethiazine at last, and yield is 81.1%.
Examples of implementation 3
1, N-oxygen-3-picoline is synthetic
Synthetic as the first step among the embodiment 1, just change temperature of reaction into 75 ℃, the insulation reaction time that splashes into behind the hydrogen peroxide still is 24h, must 51.4gN-oxygen-3-picoline after same treatment, yield is 88.8%.
2,2-chloro-5-picoline is synthetic
Synthetic as the step of second among the embodiment 1; Just the consumption with Benzoyl chloride 99min. changes 56.2g (0.4mol) into; Other reagent dosages are all identical with operation; Obtain mixture 21.8 grams of 2-chloro-5-picoline and 2-chloro-3-picoline at last, the percentage composition of the two is respectively 81.6% and 17.6%, and the yield of 2-chloro-5-picoline is 56.5%.
3,2-chloro-5-nitrapyrin is synthetic
Synthetic as the step of the 3rd among the embodiment 1, just the bubbling speed with chlorine improves 1 times, gets 2-chloro-5-nitrapyrin 19.3g, and yield is 83.5%.
4,2-chloro-5-5-flumethiazine is synthetic
Synthetic like the step of the 4th among the embodiment 1, just the consumption with anhydrous potassium fluoride changes 12.8g into, and other reagent dosages are constant with operation, obtain 14.4g 2-chloro-5-5-flumethiazine at last, and yield is 78.6%.
Claims (4)
1. the compound method of a 2-chloro-5-5-flumethiazine is characterized in that steps in sequence is:
(1) N-oxygen-3-picoline is synthetic: using hydrogen peroxide to be oxygenant, is solvent with the glacial acetic acid, under acidity, reacts, and the mol ratio of 3-picoline and hydrogen peroxide is 1: 1.4～1.5,70～80 ℃ of temperature of reaction, and the reaction times is 18～24 hours;
(2) 2-chloro-5-picoline is synthetic: use Benzoyl chloride 99min. to be chlorizating agent, make solvent with methylene dichloride, triethylamine is made acid-acceptor, and the mol ratio of N-oxygen-3-picoline and Benzoyl chloride 99min. is 1: 1.4～1.6, and stirring and reflux state reacted 3～4 hours down;
(3) 2-chloro-5-nitrapyrin is synthetic: make chlorizating agent with chlorine; Diisopropyl azodicarboxylate is made initiator, and orthodichlorobenzene is made solvent, and the Diisopropyl azodicarboxylate add-on is 5%～8% of a 2-chloro-5-picoline quality; 120～140 ℃ of temperature stir reaction down 18～20 hours;
(4) 2-chloro-5-5-flumethiazine is synthetic: make fluorizating agent with anhydrous potassium fluoride; Cetyl trimethylammonium bromide is made phase-transfer catalyst; DMSO 99.8MIN. is made solvent; The mol ratio of 2-chloro-5-nitrapyrin and anhydrous potassium fluoride is 1: 2～2.4, and the add-on of cetyl trimethylammonium bromide is 6～10% of a 2-chloro-5-nitrapyrin quality, and stirring and reflux state reacted 5～7 hours down.
2. compound method according to claim 1 is characterized in that the reflux state in said step (2), the step (4) adopts slight boiling condition.
3. the 2-3 that compound method according to claim 1, the add-on that it is characterized in that described glacial acetic acid, methylene dichloride, orthodichlorobenzene, DMSO 99.8MIN. are respectively 3-picoline raw material and respectively go on foot the midbody consumption doubly, 4-5 doubly, 4-5 doubly, 2-3 doubly.
4. compound method according to claim 1 is characterized in that said chlorine for feeding continuously, and the add-on of said acid-acceptor triethylamine is 1.3-1.7 a times of N-oxygen-3-picoline mole number.
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| CN2010105219680A CN102452976A (en) | 2010-10-28 | 2010-10-28 | Method for synthesizing 2-chloro-5-trifluoromethylpyridine |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103787960A (en) * | 2014-02-27 | 2014-05-14 | 江苏省激素研究所股份有限公司 | Synthetic method of 2-chloro-5-trichloromethyl pyridine |
| CN112409245A (en) * | 2020-11-16 | 2021-02-26 | 单县欣润化工有限公司 | 2-chloro-5-trifluoromethylpyridine synthesis method and system |
| US11254642B2 (en) * | 2018-01-05 | 2022-02-22 | Zhejiang Lantian Environmental Protection Hi-Tech Co., Ltd. | Method for preparing 2-chloro-5-trifluoromethylpyridine |
Citations (2)
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| EP0557967A1 (en) * | 1992-02-26 | 1993-09-01 | Central Glass Company, Limited | Method of side-chain chlorination of 2-chloro-methylpyridine |
| CN1342648A (en) * | 2000-09-13 | 2002-04-03 | 中国科学院大连化学物理研究所 | Process for synthesizing 2-Cl-5-trifluoromethyl pyridine |
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2010
- 2010-10-28 CN CN2010105219680A patent/CN102452976A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP0557967A1 (en) * | 1992-02-26 | 1993-09-01 | Central Glass Company, Limited | Method of side-chain chlorination of 2-chloro-methylpyridine |
| CN1342648A (en) * | 2000-09-13 | 2002-04-03 | 中国科学院大连化学物理研究所 | Process for synthesizing 2-Cl-5-trifluoromethyl pyridine |
Non-Patent Citations (2)
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| 王大威等: "2-氯-5-甲基吡啶的合成研究", 《山东医药工业》 * |
| 陆一匡等: "以3-甲基吡啶为原料制备2-氯-5-甲基吡啶中氯化剂的选择", 《江苏农药》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103787960A (en) * | 2014-02-27 | 2014-05-14 | 江苏省激素研究所股份有限公司 | Synthetic method of 2-chloro-5-trichloromethyl pyridine |
| US11254642B2 (en) * | 2018-01-05 | 2022-02-22 | Zhejiang Lantian Environmental Protection Hi-Tech Co., Ltd. | Method for preparing 2-chloro-5-trifluoromethylpyridine |
| CN112409245A (en) * | 2020-11-16 | 2021-02-26 | 单县欣润化工有限公司 | 2-chloro-5-trifluoromethylpyridine synthesis method and system |
| WO2022099692A1 (en) * | 2020-11-16 | 2022-05-19 | 单县欣润化工有限公司 | Method and system for synthesizing 2-chloro-5-trifluoromethyl pyridine |
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Application publication date: 20120516 |