CN103804287A - Preparation method of 2-chloroisonicotinate - Google Patents
Preparation method of 2-chloroisonicotinate Download PDFInfo
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- CN103804287A CN103804287A CN201410037869.3A CN201410037869A CN103804287A CN 103804287 A CN103804287 A CN 103804287A CN 201410037869 A CN201410037869 A CN 201410037869A CN 103804287 A CN103804287 A CN 103804287A
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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
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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
Abstract
The invention discloses a preparation method of 2-chloroisonicotinate. The preparation method comprises the following steps of: getting citrazinic acid as the raw material; performing chlorination reaction to obtain 2, 6-dichloroisonicotinic acid; and then performing directional dechlorination reaction to obtain 2-chloroisonicotinate. The method is simple, easy to carry out, safe, practical, relatively high in yield, and suitable for batch production.
Description
Technical field
The invention belongs to field of fine chemical, be specifically related to a kind of preparation method of Halogenated Pyridine Compounds, particularly relate to a kind of method of the selectivity dechlorination take hydrazine hydrate as dechlorinating agent.
Background technology
In Agrochemicals in recent years, numerous heterogeneous ring compound agricultural chemicals are important developing trends, they in bioactive compounds in occupation of critical role.Pyridine is a common and very important heterocycle in organic synthesis, and its application in agricultural chemicals can be traced back to the Europe of the 17th century end to 18 beginnings of the century the earliest; And the pyridine farm chemical of real organic synthesis start from the weedicide diquat of the mid-50 in last century and Paraquat (Qin Zhaohai. modern agriculture, 2003,2,1～6.).
By the systematic study to pyridine derivatives, we find that it has the multiple biological activitys such as good weeding, sterilization, expelling parasite, plant growth regulating and the disease-resistant function of inducing plant.Wherein 2,6-dichloro-isonicotinic acid is exactly a kind of beneficial agents that can inducing plant system produces disease resistance; It can produce a large amount of PR (pathogenesis-related, the course of disease is relevant) albumen by inducing plant.Research is found, while introducing different substituents, also can be shown the induction of resistance of wide spectrum on the basic framework of γ-picolinic acid.The 2-chloroisonicotinic acid of research is exactly a kind of very useful pyridine derivatives herein, and it equally has the effect of good inducing plant generation disease-resistant performance with 2,6-dichloro-isonicotinic acid and derivative thereof.Simultaneously 2-chloroisonicotinic acid is as a kind of important pesticide intermediate, and its acid amides is present in and manyly has in bioactive material as a kind of intoxicating base, particularly in weedicide, has consequence.
At present, the preparation of 2-chloroisonicotinic acid mainly contains following three kinds of methods:
(1) take 2-AMINO-4-PICOLINE as raw material, first carry out diazotization, then make the chloro-4-picoline of 2-by sandmeyer reaction; Obtain 2-chloroisonicotinic acid (Joural de Pharmacie de Belgique, 1980,35 (1): 5～11) through oxidation again;
(2), take γ-picolinic acid as raw material, first make γ-picolinic acid-N-oxide compound through oxidation, then carry out chlorination and obtain 2-chloroisonicotinic acid (Richard M.W., et al.US6509361,2003; Sendelbach S., et al.EP0633250,1995; Qin Zhaohai, waits .CN1939128, and 2007);
(3) take 4-cyanopyridine as raw material, first make 4-cyanopyridine-N-oxide compound, then to carry out chlorination and obtain the chloro-4-cyanopyridine of 2-, finally hydrolysis obtains 2-chloroisonicotinic acid (Yamamoto Y., JP2007001882,2007).
In above three kinds of methods of preparing 2-chloroisonicotinic acid, the shortcoming of method (1) is that step is comparatively loaded down with trivial details, and diazotization reaction condition harshness is easy to operate and have certain danger; Diazotization and oxidation all need be carried out under strong acidic condition, and production unit is had relatively high expectations.The shortcoming of method (2) is to prepare oxynitride need the hydrogen peroxide of high density or use catalyzer, and these methods or reaction time are longer, or reactive component complexity, and cost is higher; And the yield that oxynitride carries out chlorination is also lower.Method (3) is except having the shortcoming of method (2), more than an one-step hydrolysis reaction, cause yield further to reduce.
Summary of the invention
The object of the invention is on the basis of existing technology, a kind of 2-chloropyridines compounds process for production thereof is provided, the method is simple, safe and practical, cost is lower.
Object of the present invention can reach by following measures:
The preparation method of 2-chloroisonicotinic acid: take citrazinic acid as a raw material, first carry out chlorination reaction and obtain 2,6-dichloro-isonicotinic acid, then carry out directed dechlorination reaction and obtain 2-chloroisonicotinic acid, its reaction process is as follows:
Method of the present invention comprises two steps:
1. 2, the preparation of 6-dichloro-isonicotinic acid: in chlorination reaction, citrazinic acid and (CH
3)
4nCl and chlorizating agent react.
2. the preparation of 2-chloroisonicotinic acid: in directed dechlorination reaction, 2,6-dichloro-isonicotinic acid reacts under the effect of dechlorinating agent hydrazine hydrate.
The temperature of chlorination reaction is preferably 120～145 ℃, is preferably controlled at 125～135 ℃; Reaction times is preferably 10～12 hours.
Chlorizating agent in chlorination reaction is selected from triphosgene, POCl
3or SOCl
2, preferably triphosgene.
In chlorination reaction, citrazinic acid and (CH
3)
4the mol ratio of NCl and chlorizating agent is 1:1.0～1.05:1.0～4.5.In the time that chlorizating agent is triphosgene, citrazinic acid and (CH in chlorination reaction
3)
4the mol ratio of NCl and triphosgene is 1:1.0～1.05:1.0～1.5, preferably 1:1.05:1.1.
After chlorination reaction finishes, reaction mixture is slowly added on ice, can separates out 2,6-dichloro-isonicotinic acid; Filtration separate out 2, the filtrate that 6-dichloro-isonicotinic acid obtains, leaves standstill and separates out unreacted citrazinic acid to slightly acidic with weak adjusting PH with base; Weak base used is NaHCO
3, Na
2cO
3or ammoniacal liquor.
Chlorination reaction further comprises the steps: citrazinic acid, (CH
3)
4nCl, triphosgene are put in reactor, are heated to temperature of reaction, and keep 10～12 hours; Naturally cool to subsequently room temperature, reaction solution is poured on ice, stir 2 hours, suction filtration obtains 2,6-dichloro-isonicotinic acid; Crude product after organic solvent dissolution, elimination insolubles; After filtrate drying, precipitation, can obtain 2 of purifying, 6-dichloro-isonicotinic acid.The selected organic solvent of product purification can be chloroform, ethyl acetate, methylene dichloride, wherein ethyl acetate.
Reclaiming unreacted citrazinic acid in reaction system comprises the following steps: the filtrate that chlorination reaction suction filtration is obtained adds mild alkaline treatment and is slightly acidic to pH, after leaving standstill, can separate out unreacted citrazinic acid; Reclaim in the step of citrazinic acid, weak base used can be NaHCO
3, Na
2cO
3or ammoniacal liquor, wherein preferred NaHCO
3; The slightly acidic of emphasizing in this step is slightly acidic in general sense, and it can be 6≤pH<7.
Directed dechlorination reaction temperature is preferably 45～65 ℃, and the reaction times is 2～3.5 hours; Preferably controlling is 55 ℃, and the reaction times is 3 hours.
In directed dechlorination reaction, 2,6-dichloro-isonicotinic acid first reacts at 45～65 ℃ with dechlorinating agent hydrazine hydrate, and reaction finishes and removes excess hydrazine hydrate, and the brown residue obtaining is used water dissolution again, is heated to 95～100 ℃ and also slowly adds CuSO
4the aqueous solution, adds and continues and, after reaction, to strong basicity, filter cooling rear acidifying with adjusting PH with base, can separate out 2-chloroisonicotinic acid.Wherein CuSO
4the mass content of the aqueous solution is 5%～25%.
Directed dechlorination reaction further comprises the steps: 2,6-dichloro-isonicotinic acid and the warm lower reaction of hydrazine hydrate (80wt%) water-bath; Then excessive hydrazine hydrate is removed in underpressure distillation, and the brown residue obtaining is used a small amount of water dissolution again, drips 10wt%CuSO while being heated to 100 ℃
4solution, continues to boil after dropwising 15 minutes; Subsequently by lye pH adjustment to strong basicity, then boil after 15 minutes suction filtration while hot, filtrate is cooled to after room temperature, regulates pH can separate out 2-chloroisonicotinic acid to acidity.
In directed dechlorination reaction 2, the mol ratio of 6-dichloro-isonicotinic acid, hydrazine hydrate, copper sulfate is 1:15～20:1.5～2.1, and it is preferably 1:19:2.0.
Wherein regulate pH value with alkali lye, alkali can be sodium hydroxide, potassium hydroxide, sodium carbonate or salt of wormwood, preferably sodium hydroxide, and the alkali lye in the present invention refers to the aqueous solution of alkali, wherein the mass concentration of alkali lye can be 20～80wt%, and preferred concentration of lye is 40～50wt%; In this step, regulating the strong basicity of pH value indication is 9～12, most preferably 10.5 left and right.
Beneficial effect of the present invention:
(1) to select citrazinic acid be that raw material carries out after chlorination reaction in the present invention, can reclaim unreacted raw material (rate of recovery 10% left and right); And chlorination yield higher (90% left and right).
(2) the present invention selects the triphosgene of Novel non-toxic, environmental protection as chlorizating agent, has effectively avoided corrosion and the environmental pollution of conventional chlorination reagent to equipment.
(3) the present invention selects hydrazine hydrate as dechlorinating agent, can optionally remove a chlorine atom on pyridine ring; And dechlorination condition is gentleer, and the reaction times is shorter; The cost of hydrazine hydrate is low in addition, is especially applicable to the production of short run fine chemical product in multi-usage intermittent type normal pressure reactor.
Accompanying drawing explanation
Fig. 1 is the IR spectrogram of 2,6-dichloro-isonicotinic acid.
Fig. 2 is the spectrogram of 2-chloroisonicotinic acid.
Embodiment
Embodiment 1:2, the preparation of 6-dichloro-isonicotinic acid
By citrazinic acid (77.6g, 0.5mol), (CH
3)
4nCl (57.5g, 0.525mol), triphosgene (137mL, 1.5mol) add in 1L four-hole boiling flask successively; Stir, oil bath heating, reacts 12 hours at 130 ℃; Reaction solution is cooled to after room temperature, is slowly added drop-wise to about 1Kg on ice, stir 2 hours, then filter; Gained filtrate adds NaHCO
3adjust pH to slightly acidic, leave standstill, separate out unreacted citrazinic acid, suction filtration, recovery obtain 7.8g citrazinic acid; Back filters the solid of gained, dry rear with acetic acid ethyl dissolution, refilters and removes insolubles, filtrate, after vacuum removal ethyl acetate, obtains 78.3g2,6-dichloro-isonicotinic acid, for light yellow solid, yield is 90.6% (by the citrazinic acid of actual consumption).m.p.:209.1～210.7℃。
The spectroscopic data of 2,6-dichloro-isonicotinic acid
IR (KBr, cm
-1): 3440,3104,3079,2881,2758,2606,2552,2500,1903,1844,1789,1725,1693,1664,1599,1584,1549,1422,1392,1370,1291,1259,1233,1158,1096,1004,927,896,976,817,770,682,561,445 (referring to accompanying drawings 1).
The preparation of embodiment 2:2-chloroisonicotinic acid
2,6-dichloro-isonicotinic acid (38.4g, 0.2mol), 80wt% hydrazine hydrate (240g, 3.8mol) are put in 2L four-hole boiling flask, and stirring, heating in water bath to 45 ℃, react 3 hours; The hydrazine hydrate of vacuum removal remnants, a small amount of water dissolution of the brown solid of gained; By gained solution heated and boiled, drip 640mL10wt%CuSO
4solution; Continue to boil 15 minutes, by NaOH solution furnishing strong basicity, then boil 15 minutes; Suction filtration while hot, filtrate is cooling separates out solid afterwards with hcl acidifying, and suction filtration obtains 16.3g2-chloroisonicotinic acid, is white solid, and yield is 51.8%.m.p.:231.8～233.3℃。
The spectroscopic data of 2-chloroisonicotinic acid
IR (KBr, cm
-1): 3106,2917,2904,2784,2706,2617,2662,2494,2484,1884,1800; 1716,1603,1566,1548,1459,1266,1234,1161,1160,1077,1008; 997,903,868,766,729,671,536,507,501,441 (referring to accompanying drawing 2);
1HNMR(CDCl
3,ppm):δ8.577(dd,1H),7.968(dd,1H),7.809(dd,1H).
The preparation of comparative example 1:2-chloroisonicotinic acid
Experimental technique is with embodiment 2, and temperature of reaction changes 55 ℃ into, and yield is 72.1%.
The preparation of comparative example 2:2-chloroisonicotinic acid
Experimental technique is with embodiment 2, and temperature of reaction changes 65 ℃ into, and yield is 64.2%.
Claims (10)
1. a preparation method for 2-chloroisonicotinic acid, is characterized in that take citrazinic acid as raw material, first carries out chlorination reaction and obtains 2,6-dichloro-isonicotinic acid, then carry out directed dechlorination reaction and obtain 2-chloroisonicotinic acid, and its reaction process is as follows:
2. preparation method according to claim 1, is characterized in that in chlorination reaction, citrazinic acid and (CH
3)
4nCl and chlorizating agent react preparation 2,6-dichloro-isonicotinic acid.
3. preparation method according to claim 1 and 2, the temperature that it is characterized in that chlorination reaction is 120～145 ℃; Chlorizating agent in chlorination reaction is selected from triphosgene, POCl
3or SOCl
2.
4. preparation method according to claim 2, is characterized in that in chlorination reaction, citrazinic acid and (CH
3)
4the mol ratio of NCl and chlorizating agent is 1:1.0～1.05:1.0～4.5.
5. preparation method according to claim 3, is characterized in that described chlorizating agent is triphosgene, citrazinic acid and (CH in chlorination reaction
3)
4the mol ratio of NCl and triphosgene is 1:1.0～1.05:1.0～1.5.
6. preparation method according to claim 2, after it is characterized in that chlorination reaction finishes, is slowly added to reaction mixture on ice, can separate out 2,6-dichloro-isonicotinic acid; Filtration separate out 2, the filtrate obtaining after 6-dichloro-isonicotinic acid, leaves standstill and separates out unreacted citrazinic acid to slightly acidic with weak adjusting PH with base; Weak base used is NaHCO
3, Na
2cO
3or ammoniacal liquor.
7. preparation method according to claim 1, is characterized in that in directed dechlorination reaction, and 2,6-dichloro-isonicotinic acid reacts preparation 2-chloroisonicotinic acid under the effect of dechlorinating agent hydrazine hydrate.
8. according to the preparation method described in claim 1 or 7, the temperature that it is characterized in that directed dechlorination reaction is 45～65 ℃.
9. preparation method according to claim 7, it is characterized in that in directed dechlorination reaction, 2,6-dichloro-isonicotinic acid first reacts at 45～65 ℃ with dechlorinating agent hydrazine hydrate, reaction finishes and removes excess hydrazine hydrate, the brown residue obtaining is used water dissolution again, is heated to 95～100 ℃ and also slowly adds CuSO
4the aqueous solution, adds and continues and, after reaction, to strong basicity, filter cooling rear acidifying with adjusting PH with base, can separate out 2-chloroisonicotinic acid.
10. preparation method according to claim 9, is characterized in that in directed dechlorination reaction 2, and the mol ratio of 6-dichloro-isonicotinic acid, hydrazine hydrate, copper sulfate is 1:15～20:1.5～2.1.
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Cited By (1)
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|---|---|---|---|---|
| CN114158559A (en) * | 2021-11-18 | 2022-03-11 | 山东元泰生物工程有限公司 | Method for inducing plant defense |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004063156A1 (en) * | 2003-01-08 | 2004-07-29 | Biovitrum Ab | Novel indole derivates as fabp-4 inhibitors |
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2014
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004063156A1 (en) * | 2003-01-08 | 2004-07-29 | Biovitrum Ab | Novel indole derivates as fabp-4 inhibitors |
Non-Patent Citations (3)
| Title |
|---|
| CEDRIC KLEIN,ET AL.: "Convenient synthesis of tridentate 2,6-di(pyrazol-1-yl)-4-carboxypyridine and tetradentate 6,6-di(pyrazol-1-yl)-4,4-dicarboxy-2,2-bipyridine ligands", 《TETRAHEDRON LETTERS》, no. 52, 4 December 2010 (2010-12-04), pages 584 - 587 * |
| KEVIN E. HENEGAR, ET AL.: "Practical Asymmetric Synthesis of (S)-4-Ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione，a Key Intermediate for the Synthesis of Irinotecan and Other Camptothecin Analogs", 《JOURNAL OF ORGANIC CHEMISTRY》, no. 62, 31 December 1997 (1997-12-31), pages 6588 - 6597, XP002322583, DOI: 10.1021/jo970173f * |
| TERENCE P. KELLY, ET AL.: "A convenient synthesis of [2,6-14C]-2-chloroisonicotinic acid", 《JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS》, no. 44, 31 December 2001 (2001-12-31), pages 451 - 457 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114158559A (en) * | 2021-11-18 | 2022-03-11 | 山东元泰生物工程有限公司 | Method for inducing plant defense |
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Address after: 210047 Jiangsu Province, Nanjing city of Nanjing Chemical Industrial Park Chongfu Road No. 51 Patentee after: Jiangsu new Han Xin materials Limited by Share Ltd Address before: 210047 Jiangsu Province, Nanjing city of Nanjing Chemical Industrial Park Chongfu Road No. 51 Patentee before: Jiangsu Xinhan Co.,Ltd. |