CN109206363A - A kind of novel environment-friendly process preparing 2- chlorine apellagrin - Google Patents
A kind of novel environment-friendly process preparing 2- chlorine apellagrin Download PDFInfo
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- CN109206363A CN109206363A CN201710572452.0A CN201710572452A CN109206363A CN 109206363 A CN109206363 A CN 109206363A CN 201710572452 A CN201710572452 A CN 201710572452A CN 109206363 A CN109206363 A CN 109206363A
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- Prior art keywords
- niacin
- chlorine apellagrin
- chlorine
- synthetic method
- oxidation
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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
- C07D213/80—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 present invention relates to a kind of novel environment-friendly process for preparing 2- chlorine apellagrin, it is with niacin (I) for raw material, it is aoxidized under aqueous systems catalyst action through hydrogen peroxide N- and N- oxidation niacin (II) is made, then under the action of organic base, 2- chloronicotinoyl chloride (III) is synthesized through phosphorus oxychloride chlorination, then hydrolyzed, be refining to obtain 2- chlorine apellagrin (IV).This method avoid the use of benzene and acetic acid, process flow is short, safety and environmental protection, good product quality and high income, is an environmental-friendly green syt route, is suitable for industrialized production.
Description
Technical field
The invention belongs to medication chemistries and pesticide field, are related to a kind of green synthesis method of 2- chlorine apellagrin.
Background technique
2- chlorine apellagrin is mainly used for new and effective herbicide nicosulfuron (Nicosulfuron) and Diflufenican
(Diflufenican), novel systemic fungicide Boscalid (Boscalid), antibacterial agent and Anti-cancer medicament intermediate 2- chlorine
The agricultures such as the synthesis of pyridine -3- phosphinylidyne-nitrogen-containing heterocycle compound and hiv reverse transcriptase inhibitor nevirapine (Nevirapine)
The synthesis of medicine and medicine intermediate.Research for 2- chlorine apellagrin, foreign countries begin to early in the 1970s.Earliest is special
Benefit is the Lonza company application of Switzerland in 1977, and patent is preferably at most Japan, such as the glorious chemistry of Japan, Japanese organic synthesis one
A little well-known companies have all applied for patent (JP5914459).And the country is the research just begun with from 2003 to 2- chlorine apellagrin
Article and patent report (CN101367760A, CN101117332A).The synthetic route of 2- chlorine apellagrin is main both at home and abroad at present
There are two major classes: first is that based on existing pyridine ring parent, chlorination or introducing relevant functional group directly on pyridine ring to synthesize
Target product；Second is that selecting suitable straight chain reactive compound, target product is synthesized by grafting and closed loop.These two types of routes
All respectively there is its advantage and disadvantage: it is first kind route simple process, low in cost, but product purity is undesirable；Second class route produces
Product purity is high, meets pharmaceutical requirements, but complex process, the cost is relatively high.By raw material point, niacin method, 3- cyano pyrrole can be divided into
The chloro- 3- picoline oxidizing process of pyridine method, 2-, cyan-acetic ester method, malonaldehyde method etc..The side of chlorine is introduced directly on pyridine ring
Method mainly includes niacin method and cigarette cyanogen method, and the method for main use industrial at present.Chlorination is mainly wrapped on pyridine ring
Niacin method and cigarette cyanogen method are included, this is also the method industrially mainly used at present.
It is industrial at present that N- oxidation cigarette is made through hydrogen peroxide oxidation in toluene and acetic acid solvent with niacin (or nicotinic acid nitrile)
Acid (or N- aoxidize nicotinic acid nitrile), then through phosphorus oxychloride and phosphorus pentachloride chlorination, hydrolyze, be refining to obtain to obtain 2- chlorine apellagrin.According to document report
Road, this method yield and product purity be not high (mainly 6- chlorine apellagrin impurity content is higher), to obtain qualified products need to be through more
Secondary purification process, high production cost, and use a large amount of benzene and acetic acid as solvent, synthesis 2- chlorine cigarette when synthesizing N- oxide
POCl is removed when sour3It also needs using a large amount of PCl outside5, generate a large amount of acid environmental protection pressure for causing the disposal of three wastes containing chlorine and phosphorus-containing wastewater
Power is significantly increased and the problems such as production process occupational health hazards increased risk.
Summary of the invention
It is an object of the invention to: one kind is provided using niacin as raw material, and the ring of 2- chlorine apellagrin is synthesized through N- oxidation and chlorination
The problems such as protecting, green syt new method, solving using niacin as the environmental protection of Material synthesis 2- chlorine apellagrin, cost, product quality.
Technical scheme is as follows: with niacin (I) for raw material, under the action of catalyst through dioxygen water oxygen in aqueous systems
Change and N- oxidation niacin (II) is made, then obtain 2- chloronicotinoyl chloride (III) through phosphorus oxychloride chlorination under the action of organic base, finally
Hydrolyze to obtain 2- chlorine apellagrin (IV).Its synthetic route is as follows:
Method of the invention specifically comprises the following steps:
(1) N- aoxidizes the preparation of niacin (II): being raw material under the action of catalyst through H with niacin (I)2O2It is anti-that oxidation occurs
It answers, is made niacin nitrogen oxides (II).
(2) preparation of 2- chlorine apellagrin (IV): above walk obtained niacin nitrogen oxides under the action of organic base with trichlorine oxygen
Phosphorus is reacted to obtain 2- chloronicotinoyl chloride (III), is most hydrolyzed afterwards, purifies to obtain 2- chlorine apellagrin.
As a preferred technical solution, in step (1), the molar ratio of the niacin and hydrogen peroxide is 1.05~1.5: 1, into
One step is preferably 1.05~1.2: 1
As a preferred technical solution, in step (1), oxidant hydrogen peroxide concentration is 20~35%, further preferably
30~35%
As a preferred technical solution, in step (1), the catalyst is molybdic acid, and dosage is niacin (I) quality
0.1~1.0%, further preferably 0.5~0.8.
As a preferred technical solution, in step (1), the temperature of the dropwise addition of hydrogen peroxide is preferably 90~95 DEG C, further
Preferably 92~95 DEG C；90~100 DEG C of the reaction time of insulation reaction temperature control, it is excellent to be further selected as 95~100 DEG C.
As a preferred technical solution, in step (1), after oxidation reaction, reaction solution is cooled to 0~5 DEG C, N- oxygen
Change niacin to be largely precipitated, filter the N- oxidation niacin of precipitation, 80 DEG C or less dryings to moisture can carry out in next step lower than 0.5%
Chlorination reaction.
As a preferred technical solution, in step (1), the N- in the unreacted niacin of oxidation reaction and mother liquor aoxidizes niacin
Recycling circuits sequentially set the following steps are included: the mother liquor that oxidation reaction is obtained by filtration put into time batch oxidation reaction based on water
With.
As a preferred technical solution, in step (2), the organic base is the alkylamines such as triethylamine, tri-n-butylamine, preferably
For triethylamine, the molar ratio of triethylamine and N- oxidation niacin (II) is 1.9: 1.
As a preferred technical solution, in step (2), phosphorus oxychloride and N- oxidation niacin (II) molar ratio be 5.0~
7.7: 1, preferably 6.8: 1.
As a preferred technical solution, in step (2), triethylamine dropping temperature is controlled in 0~20 DEG C, preferably 10~20
℃；Chlorination reaction temperature is controlled at 10~100 DEG C, and preferably 15~100 DEG C of 5~10h of section at the uniform velocity gradient increased temperature reacts.
As a preferred technical solution, in step (2), water ring vacuum pump is decompressed to 5000Pa distillation after chlorination reaction
Unreacted phosphorus oxychloride is recycled, when no distillate, switching oil pump is decompressed to 400Pa and carries out rectifying, collects 97-98 DEG C of fraction
White solid 2- chloronicotinoyl chloride is obtained, 2- chlorine apellagrin is hydrolyzed to obtain.
Remarkable result of the invention:
1, it after catalyst is added in the present invention, using water as oxidation solvent, effectively prevents conventional acetic acid and toluene is made
Solvent is to the burn into occupational health of equipment and the harm of environment.
2, the present invention selects chlorination reagent and solvent of the phosphorus oxychloride as chlorination reaction, and unreacted phosphorus oxychloride is complete
Recycled is recycled, instead of traditional phosphorus pentachloride and methanol as solvent bring occupational health hazards.
3, the present invention synthesizes 2- chlorine apellagrin through oxidation, chlorination and hydrolysis three-step reaction, product contains using niacin as starting material
Amount up to 99.8%, yield is up to 91.6%.
4, reaction condition of the present invention is mild, process flow is short, production cost is low, oxidation and chlorination reaction process using water and
The recyclable recycled of phosphorus oxychloride, it is an environmental-friendly green syt route that no waste water, which generates, is suitable for commercial scale
Metaplasia produces.
Specific embodiment
Embodiment 1:
It is added into three-necked flask and sequentially adds water 100ml, niacin 100g, molybdic acid 0.66g, 92 DEG C are warming up to, to temperature
Start that hydrogen peroxide 104ml is added dropwise after stabilization, at the uniform velocity dropwise addition 3h, 95 DEG C of heat preservations 3h, TLC detect Nicotinic Acid Content < after being added dropwise
0.5%, heat preservation terminates to be down to 0-5 DEG C, stirs 0.5h, filtering, and mother liquor waits for that lower batch oxidation reaction is recycled, and 60 DEG C of filter cake true
It is empty dry that white crystalline powder N- aoxidizes niacin 108.7g, yield 97.4% [HPLC content 99.8%, moisture 0.22%, mp
DEG C 261.4-261.6 (260-262 DEG C of document)].
Phosphorus oxychloride 146ml is added into three-necked flask, ice bath stirring is cooled to 10 DEG C and starts to be slowly added to N- oxidation cigarette
Then 36ml triethylamine (0.26mol) is added dropwise at 15 DEG C in sour 32g (0.23mol), drop finish at the uniform velocity gradient increased temperature to 100 DEG C it is anti-
Answer 6h.
Above-mentioned reaction solution is cooled to 50 DEG C, and water ring vacuum pump is decompressed to 5000Pa and is distilled to recover phosphorus oxychloride, when nothing distillates
When object, switching oil pump is decompressed to 400Pa and carries out rectifying, will be collected into 97-98 DEG C of fraction colourless transparent liquid (60 DEG C) and slowly adds
Enter in 0-5 DEG C of water of stirring, hydrolysis 0.5h, with 30% liquid alkaline adjusting pH value to 1.5 ± 0.1, stir 0.5h, filter,
Mother liquor waits for that lower batch hydrolysis uses, and 60 DEG C of filter cake are dried in vacuo to obtain white crystalline powder 2- chlorine apellagrin 32.0g, yield
87.7% [HPLC content 99.8%, moisture 0.22%, mp178.6-178.9 DEG C (178-180 DEG C of document)].
Embodiment 2:
It is added into three-necked flask and sequentially adds N- oxidation niacin mother liquor 100ml, niacin 100g, molybdic acid 0.66g, be warming up to
92 DEG C, temperature starts that hydrogen peroxide 104ml is added dropwise after stablizing, at the uniform velocity dropwise addition 3h, and 95 DEG C of heat preservations 3h, TLC detect cigarette after being added dropwise
Acid content < 0.5%, heat preservation terminate to be down to 0-5 DEG C, stir 0.5h, filtering, and mother liquor waits for that lower batch oxidation reaction is recycled, filter
60 DEG C of cake are dried in vacuo to obtain white crystalline powder N- oxidation niacin 111.7g, yield 99.6% [HPLC content 99.8%, moisture
0.21%, mp261.4-261.6 DEG C (260-262 DEG C of document)].
Recycling phosphorus oxychloride is added into three-necked flask and fresh phosphorus oxychloride amounts to 146ml, ice bath stirring is cooled to 10
DEG C start to be slowly added to N- oxidation niacin 32g, 36ml triethylamine is then added dropwise at 15 DEG C, drips and finish gradient and be at the uniform velocity warming up to 100
DEG C reaction 6h.
Above-mentioned reaction solution is cooled to 50 DEG C, and water ring vacuum pump is decompressed to 5000Pa and is distilled to recover phosphorus oxychloride, when nothing distillates
When object, switching oil pump is decompressed to 400Pa and carries out rectifying, will be collected into 97-98 DEG C of fraction colourless transparent liquid (60 DEG C) and slowly adds
Enter in 0-5 DEG C of water of stirring, hydrolysis 0.5h, with 30% liquid alkaline adjusting pH value to 1.5 ± 0.1, stir 0.5h, filter,
Mother liquor waits for that lower batch hydrolysis uses, and 60 DEG C of filter cake are dried in vacuo to obtain white crystalline powder 2- chlorine apellagrin 33.6g, yield
92.0% [HPLC content 99.8%, moisture 0.19%, mp178.6-178.9 DEG C (178-180 DEG C of document)].
Claims (10)
1. a kind of green synthesis method for preparing 2- chlorine apellagrin, it is characterised in that: with niacin (I) for raw material, in catalyst action
N- oxidation niacin (II) is made through hydrogen peroxide oxidation in lower aqueous systems, then is obtained under the action of organic base through phosphorus oxychloride chlorination
2- chloronicotinoyl chloride (III) by hydrolyzing to obtain 2- chlorine apellagrin (IV),
Method of the invention specifically comprises the following steps:
It (1) is raw material under the action of catalyst through H with niacin (I)2O2Oxidation reaction occurs, is made niacin nitrogen oxides (II).
(2) the niacin nitrogen oxides (II) walked on, is reacted to obtain 2- chlorine with phosphorus oxychloride under the action of organic base
Nicotinoyl chlorine (III) is most hydrolyzed afterwards, purifies to obtain 2- chlorine apellagrin (IV).
2. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (1), it is characterised in that the catalyst is
Molybdic acid.
3. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (1), it is characterised in that the catalyst is used
Amount is the 0.1~1.0% of niacin quality.
4. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (1), it is characterised in that the hydrogen peroxide is dense
Degree is 20~35%.
5. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (1), it is characterised in that the hydrogen peroxide with
Niacin molar ratio is 1.05~1.5: 1.
6. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (1), it is characterised in that the dioxygen water droplet
Heating degree is 90~98 DEG C, and hydrogen peroxide rate of addition is 15~20ml/s.
7. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (1), it is characterised in that the reaction temperature
It is 95~100 DEG C.
8. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (2), it is characterised in that the guarantor of the chlorination
The warm reaction time is 2~4h.
9. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (2), it is characterised in that the phosphorus oxychloride
It is 4.0~6.0: 1 with N- oxidation niacin (II) molar ratio.
10. the synthetic method of 2- chlorine apellagrin according to claim 1, in step (2), it is characterised in that the organic base is
Triethylamine, tri-n-butylamine etc., preferably triethylamine, the molar ratio of triethylamine and nitrogen oxides (II) are 1.9: 1.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710572452.0A CN109206363A (en) | 2017-07-06 | 2017-07-06 | A kind of novel environment-friendly process preparing 2- chlorine apellagrin |
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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 |
| CN111454203A (en) * | 2020-05-25 | 2020-07-28 | 山东京博生物科技有限公司 | Synthetic method of 2-chloro-N, N-dimethylnicotinamide |
-
2017
- 2017-07-06 CN CN201710572452.0A patent/CN109206363A/en active Pending
Cited By (3)
| 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 |
| CN111454203A (en) * | 2020-05-25 | 2020-07-28 | 山东京博生物科技有限公司 | Synthetic method of 2-chloro-N, N-dimethylnicotinamide |
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