CN106243028A - A kind of oxidation step synthesizes the method for 2 chlorine apellagrins - Google Patents
A kind of oxidation step synthesizes the method for 2 chlorine apellagrins Download PDFInfo
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- CN106243028A CN106243028A CN201610609234.5A CN201610609234A CN106243028A CN 106243028 A CN106243028 A CN 106243028A CN 201610609234 A CN201610609234 A CN 201610609234A CN 106243028 A CN106243028 A CN 106243028A
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- China
- Prior art keywords
- oxidation step
- chlorine apellagrin
- synthesis
- chlorine
- acid
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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
- C07D213/78—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
- C07D213/807—Processes of preparation by oxidation of pyridines or condensed pyridines
-
- 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
Abstract
The invention discloses a kind of method that oxidation step synthesizes 2 chlorine apellagrins, with 2 chlorine 3 dichloromethyl pyridines as raw material, add alkali, with the mixture of water and polar organic solvent as solvent, Ru/C is catalyst, and dioxygen oxidation obtains 2 chlorine apellagrin solution, then through acid out, sucking filtration, wash, dry to obtain white solid powder 2 chlorine apellagrin, the method technique is simple, and yield is high, reaches more than 90%；With oxygen as oxidant, environmentally friendly；Employ can the heterogeneous Ru/C catalyst of time, product is easily isolated；Oxidation reaction system is nonacid system, overcomes problem of environmental pollution, meets the requirement of cleanly production.
Description
Technical field
The invention belongs to chemical industry organic synthesis field, the method being specifically related to a kind of oxidation step synthesis 2-chlorine apellagrin.
Background technology
2-chlorine apellagrin is important pesticide and medicine intermediate, mainly for the preparation of new and effective herbicide nicosulfuron,
Anti-inflammatory analgesic niflumic acid, pranoprofen and HIV Revertase inhibitor nevirapine.Therefore, to the preparation of 2-chlorine apellagrin and life
The research of production. art is significant.The synthesis technique of 2-chlorine apellagrin has multiple:
(1) with nicotinic acid or nicotinonitrile, as raw material, (US4144238, US40815, JP169672, Chinese Medicine industry is miscellaneous
Will, 2004.35 (5), 267), aoxidize through hydrogen peroxide nitrogen, then react with phosphorus oxychloride or phosphorus pentachloride under triethylamine is catalyzed,
Chlorination synthesis 2-chlorine apellagrin.This route is widely used at present in industrialization, but there is product yield and the relatively low (reaction of purity
During generate 6-chlorine apellagrin isomer) problem；Chlorination reagent phosphorus oxychloride or five is used additionally, the most a large amount of in course of reaction
Chlorethoxyfos, the acidic wastewater containing phosphorus of generation is difficult to process, easily causes the oxygen enrichment of environment, and environmental pollution is serious, along with country
The strict enforcement of environmental law Laws & Regulations, uses the producer of this technique to face and stops production or limit the destiny produced.
(2) utilize after cyan-acetic ester chlorination with acrylic aldehyde Michael's addition, after cyclization, hydrolysis obtains 2-chlorine apellagrin.Should
Method reaction condition is gentleer, but is easily generated dichloro-by-product in cyan-acetic ester chlorination process, and acrylic aldehyde is volatile, malicious
Property relatively big and chloro cyan-acetic ester is slow with acrylic aldehyde addition, reactions steps is longer, and process conditions are complicated.
(US5493028, Tetrahedron 51,48,1995,13177-13184)
(3) with 2-chloro-3-picoline as raw material, oxidized synthesis 2-chlorine apellagrin.The method mainly has nitration mixture oxidizing process
And potassium permanganate oxidation method (ES5011982).Nitration mixture oxidizing process requirement condition is harsh (190～210 DEG C), and equipment investment is big；High
Potassium manganate method yield relatively low (65%), used oxidant potassium permanganate is expensive, and produces substantial amounts of Mn-bearing waste water, makes
Become environmental pollution, be therefore not suitable for the production of 2-chlorine apellagrin.
Summary of the invention
It is an object of the invention to overcome prior art to easily cause environmental pollution, reaction scheme length and oxidant expensive
Not enough, it is provided that the method for a kind of oxidation step synthesis 2-chlorine apellagrin, the method technique is simple, and yield is high, overcomes environment dirty
Dye problem, meets the requirement of cleanly production.
In order to solve the problems referred to above, the technical solution used in the present invention is such that a kind of oxidation step synthesis 2-chlorine cigarette
The method of acid, with 2-chloro-3-dichloromethyl pyridine as raw material, adds alkali, with the mixture of water and polar organic solvent as solvent,
Ru/C is catalyst, and dioxygen oxidation obtains 2-chlorine apellagrin solution, then through acid out, sucking filtration, wash, dry to obtain white solid powder 2-
Chlorine apellagrin.
The chemical reaction that the present invention relates to is shown below:
It is raw material that the present invention have chosen 2-chloro-3-dichloromethyl pyridine, and with 2-chloro-3-chloromethylpyridine for raw material phase
Ratio, in the basic conditions, pyridine ring side chain substituents dichloromethyl direct hydrolysis can generate aldehyde, and substituent group chloromethyl can only
Hydrolysis generates alcohol, so that follow-up oxidation reaction is more easy to occur, and then yield is higher.
Experiments verify that, have chosen the mixture of water and polar organic solvent as solvent, simple only with water with relative
For solvent so that reactant more mixes, accelerate reaction rate, shorten the response time, improve yield.
Described alkali one in sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, alkali and 2-chloro-3-dichloromethane
The mol ratio of yl pyridines is 0.5～3.
The consumption of described catalyst Ru/C is the 1%～5% of 2-chloro-3-dichloromethyl pyridine quality.
In described solvent, the consumption of water is 1～10 times of the quality of 2-chloro-3-dichloromethyl pyridine, polar organic solvent
3～8 times of the quality that consumption is 2-chloro-3-dichloromethyl pyridine, wherein, described polar organic solvent be preferably acetonitrile,
One in oxolane, ethanol, methanol.
In oxidation step course of reaction, reaction temperature is 50～150 DEG C, preferably 90～110 DEG C；Reaction pressure is
3MPa～6MPa, preferably 4～5MPa.Response time is 4～40h, preferably 8～12h.
The detailed process of described acid out be acid adding regulation solution pH value be 1-2, wherein, acid used is hydrochloric acid, sulphuric acid
Or the one in nitric acid, preferably hydrochloric acid.
Beneficial effect:
The invention provides the new method of a kind of oxidation step synthesis 2-chlorine apellagrin, the method technique is simple, and yield height (reaches
More than 90%)；With oxygen as oxidant, environmentally friendly；Employ can the heterogeneous Ru/C catalyst of time, product is easy
In separation；Oxidation reaction system is nonacid system, overcomes problem of environmental pollution, meets the requirement of cleanly production.
Detailed description of the invention
In order to deepen the understanding of the present invention, below in conjunction with embodiment, the invention will be further described, this embodiment
It is only used for explaining the present invention, is not intended that limiting the scope of the present invention.
Embodiment 1
2-chloro-3-dichloromethyl pyridine 80g (0.4mol), water 40g, acetonitrile 240g, sodium carbonate 48g, Ru/C (10%Ru,
In terms of butt) 1.6g, join in the autoclave reactor of 500ml, feed intake end, and kettle replacement of oxygen is then charged with O2Extremely
Reactor pressure is 3MPa, is warming up to 100 DEG C, starts reaction, and reactor pressure declines, and persistently fills into O2, maintain reaction pressure
Between 3.5-4MPa, when kettle pressure remains unchanged, reaction terminates (response time 12h).Cooling, sucking filtration reclaims Ru/C and urges
Agent was applied mechanically for next time, and filtrate precipitation reclaims acetonitrile, and raffinate adds hydrochloric acid acid out (regulation solution pH value is 1), has a large amount of
White precipitate occurs, sucking filtration, washing, dries, obtains white solid 2-chlorine apellagrin 59.8g, 2-chlorine apellagrin purity 98.2%, yield
93.6%.
Embodiment 2
Such as method and the condition synthesis of embodiment 1, only reaction temperature being adjusted to 140 DEG C, polar organic solvent is tetrahydrochysene furan
Mutter 300g.Response time foreshortens to 4h, and post processing obtains white solid 2-chlorine apellagrin 62.4g, 2-chlorine apellagrin purity 96.2%, yield
95.4%.
Embodiment 3
Such as method and the condition synthesis of embodiment 1, only oxygen pressure is changed to 4.5～5MPa reactions.Response time contracts
Being as short as 8h, post processing obtains white solid 2-chlorine apellagrin 61.9g, 2-chlorine apellagrin purity 97.9%, yield 96.8%.
Embodiment 4
Such as the method for embodiment 1 and condition synthesis, only reaction temperature is changed to 50 DEG C, oxygen pressure change to 3～
3.5MPa, polar organic solvent is methanol 240g.Response time 40h, post processing obtains white solid 2-chlorine apellagrin 56.8g, 2-chlorine
Nicotinic acid purity 98.8%, yield 90.2%.
Embodiment 5
Such as the method for embodiment 1 and condition synthesis, it is only to apply mechanically the Ru/C of ten times to urge by fresh Ru/C catalyst change
Agent.Response time becomes 13h, and post processing obtains white solid 2-chlorine apellagrin 59.0g, 2-chlorine apellagrin purity 98.0%, yield
92%.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all essences in the present invention
Within god and principle, any modification, equivalent substitution and improvement etc. made, should be included within the scope of the present invention.
Claims (10)
1. the method for an oxidation step synthesis 2-chlorine apellagrin, it is characterised in that with 2-chloro-3-dichloromethyl pyridine as raw material,
Adding alkali, with the mixture of water and polar organic solvent as solvent, Ru/C is catalyst, and dioxygen oxidation obtains 2-chlorine apellagrin solution,
Then through acid out, sucking filtration, wash, dry to obtain white solid powder 2-chlorine apellagrin.
The method of oxidation step the most according to claim 1 synthesis 2-chlorine apellagrin, it is characterised in that described alkali is selected from carbon
One in acid sodium, sodium bicarbonate, potassium carbonate, potassium bicarbonate.
Oxidation step the most according to claim 1 and 2 synthesis 2-chlorine apellagrin method, it is characterised in that described alkali with
The mol ratio of 2-chloro-3-dichloromethyl pyridine is 0.5 ~ 3.
The method of oxidation step the most according to claim 1 synthesis 2-chlorine apellagrin, it is characterised in that described catalyst
The consumption of Ru/C is the 1% ~ 5% of 2-chloro-3-dichloromethyl pyridine quality.
5. the method synthesizing 2-chlorine apellagrin according to the oxidation step described in claim 1 or 4, it is characterised in that described solvent
The consumption of middle water is 1 ~ 10 times of the quality of 2-chloro-3-dichloromethyl pyridine, and the consumption of polar organic solvent is 2-chloro-3-dichloro
3 ~ 8 times of the quality of picoline.
The method of oxidation step the most according to claim 1 synthesis 2-chlorine apellagrin, it is characterised in that react at oxidation step
During, reaction temperature is 50 ~ 140 DEG C.
The method of oxidation step the most according to claim 1 synthesis 2-chlorine apellagrin, it is characterised in that react at oxidation step
During reaction pressure be 3MPa ~ 6MPa.
The method of oxidation step the most according to claim 1 synthesis 2-chlorine apellagrin, it is characterised in that react at oxidation step
During, the response time is 4 ~ 40h.
The method of oxidation step the most according to claim 1 synthesis 2-chlorine apellagrin, it is characterised in that the tool of described acid out
Body process is that acid adding regulates solution PH=1-2.
The method of oxidation step the most according to claim 9 synthesis 2-chlorine apellagrin, it is characterised in that described acid out
Used in the process of acid one in hydrochloric acid, sulphuric acid or nitric acid.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109836376A (en) * | 2019-04-10 | 2019-06-04 | 江苏汉阔生物有限公司 | One kind is in the method that 2,3- pyridinedicarboxylic acid is that raw material prepares 2- chloro-nicotinic acid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109836376A (en) * | 2019-04-10 | 2019-06-04 | 江苏汉阔生物有限公司 | One kind is in the method that 2,3- pyridinedicarboxylic acid is that raw material prepares 2- chloro-nicotinic acid |
| CN109836376B (en) * | 2019-04-10 | 2022-03-22 | 江苏汉阔生物有限公司 | Method for preparing 2-chloronicotinic acid by using 2, 3-dipicolinic acid as raw material |
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Application publication date: 20161221 |