CN110734398A - process for preparing 2-chloronicotinic acid - Google Patents
process for preparing 2-chloronicotinic acid Download PDFInfo
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- CN110734398A CN110734398A CN201810804247.7A CN201810804247A CN110734398A CN 110734398 A CN110734398 A CN 110734398A CN 201810804247 A CN201810804247 A CN 201810804247A CN 110734398 A CN110734398 A CN 110734398A
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- cyanopyridine
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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
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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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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Abstract
The invention provides a preparation method of 2-chloronicotinic acids, which comprises the following steps of 1) reacting malonaldehyde with cyanoacetamide in the presence of acid to obtain a product containing 2-hydroxy-3-cyanopyridine, 2) reacting the product obtained in the step 1) with phosphorus oxychloride in the presence of alkali to generate 2-chloro-3-cyanopyridine, and 3) hydrolyzing the 2-chloro-3-cyanopyridine obtained in the step 2) to obtain the 2-chloronicotinic acid.
Description
Technical Field
The invention relates to the technical field of preparation of 2-chloronicotinic acid, in particular to a preparation method of novel 2-chloronicotinic acid.
Background
The 2-chloronicotinic acid is important pesticides and medical intermediates, is a key intermediate for synthesizing important medicaments such as efficient herbicides of nicosulfuron, diflufenican, nevirapine, mirtazapine and the like, and has important production value.
1. Chlorination of nicotinic acid
Although the process is simple, the method has the defects of high raw material price and poor product quality, and is difficult to meet the requirement of 2-chloronicotinic acid of medical grade (Said A, Brig W. pure white 2-chloronicotinic acid [ P ]. DE 2713316,1977-10-06).
2. Ethyl cyanoacetate-michael addition process
CNCH2COOC2H5+Cl2→CNCCl2COOC2H5+CNCH2COOC2H5
The process has the advantages of longer route, more types of used solvents, higher recovery difficulty and hidden danger in the aspect of environmental protection, and in addition, the used acrolein has higher toxicity and is easy to volatilize, which brings fixed difficulty to the production operation, so the process is not suitable for industrial production (Mayer Joseph. process for preparation 2-halogenic acidic acids [ P ]. USP 4081451,1978-03-28.).
3. 3-cyanopyridine chlorination process
However, the route has obvious defects of large three-waste emission amount, difficult treatment of a large amount of acid water and low yield (YukiGosei Kogyo Co. Ltd. Japan.2-chloronicotic acid [ P ]. JP 59144759,1984-08-18, Koei Kagaku Kogyo K, Japan.2-choro-3-cyanoxidine and 2-chloronicotic [ P ]. JP 56169672,1981-12-26.).
4. 2-chloro-3-methylpyridine oxidation process
The route has the advantages of simplicity, high yield and the like. However, the raw material 2-Chloro-3-methylpyridine is not produced in large quantities at present in China, so that the application of the route to large-scale production is not practical (Nie wenna, research on synthesis process of 2-chloronicotinic acid [ J ]. Hebei chemical industry, 2006,29(10):14-15, Ferre Gerardo, Cano Mondejar Juan C (Lisac S A, Spain).2-Chloro-3-pyridinecarboxylic acid [ P ]. ES 501988,1982-04-01).
In conclusion, the production of the 2-chloronicotinic acid has few routes which can be produced on a large scale at present and has problems, so that the development of new 2-chloronicotinic acid processes with industrial production value has very important social and economic values.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides novel preparation methods of 2-chloronicotinic acid, which have the advantages of short process route, high yield, less discharge of waste water and other three wastes and the like, and are suitable for large-scale production.
In order to achieve the purpose, the invention adopts the following technical scheme:
A preparation method of 2-chloronicotinic acid, which comprises the following steps:
1) reacting malondialdehyde with cyanoacetamide in the presence of acid to obtain a product containing 2-hydroxy-3-cyanopyridine;
2) reacting the product obtained in the step 1) with phosphorus oxychloride in the presence of alkali to generate 2-chloro-3-cyanopyridine;
3) hydrolyzing the 2-chloro-3-cyanopyridine obtained in the step 2) to obtain the 2-chloronicotinic acid.
The process route of the invention is as follows:
the raw material malondialdehyde used in the present invention may be malondialdehyde with or without crystal water.
Preferred embodiments are those wherein the molar ratio of malondialdehyde, cyanoacetamide, and acid in step 1) is from 1:1 to 1.2:0.1 to 0.5.
According to the preparation method, or more acids in organic acids or inorganic acids are adopted as the acid in the step 1), preferably, the acid can be but is not limited to organic acids such as acetic acid and propionic acid, also can be but is not limited to inorganic acids such as hydrochloric acid and sulfuric acid, and more preferably, the base in the step 2) can be but is not limited to triethylamine, pyridine, cyclohexylamine and the like.
In the preparation method of the invention, the reaction in the step 1) is carried out in the presence of a solvent, wherein the solvent is preferably or more of dichloromethane, ethyl acetate and chloroform, and more preferably dichloromethane.
In preferable embodiments of the preparation method, step 1) further comprises the steps of separating an organic phase from the product containing the 2-hydroxy-3-cyanopyridine obtained by the reaction in step 1), adding a saturated aqueous solution of sodium carbonate into the product containing the 2-hydroxy-3-cyanopyridine in specific embodiments, stirring, layering to separate an aqueous phase and an organic phase, separating the organic phase, drying the organic phase with anhydrous sodium sulfate, filtering to obtain a filtrate, and directly feeding the filtrate into step 2) as a raw material for the reaction with the phosphorus oxychloride, wherein in step 2), the molar ratio of the 2-hydroxy-3-cyanopyridine to the phosphorus oxychloride to the alkali is preferably 0.8:0.9-3.0: 0.7-1.5.
According to another preferred embodiments of the preparation method of the invention, step 1) further comprises the steps of separating an organic phase from the product containing 2-hydroxy-3-cyanopyridine obtained by the reaction in step 1), drying the organic phase with anhydrous sodium sulfate, filtering to obtain a filtrate, distilling off a solvent in the filtrate, and putting the filtrate into step 2) to react with phosphorus oxychloride, wherein in the scheme, phosphorus oxychloride serves as both the solvent and the reactant, and excess phosphorus oxychloride is preferably added during the reaction, and preferably, in step 2), the molar ratio of phosphorus oxychloride to alkali is 1: 0.8-1.2.
According to the preparation method of the invention, in specific embodiments, in step 3), the product obtained in step 2) is hydrolyzed under reflux in an aqueous solution of sodium hydroxide.
According to the preparation method provided by the invention, preferably, in the step 1), after dissolving malonaldehyde and cyanoacetamide in a solvent, the acid is dripped into a reaction system, the temperature of the reaction system is controlled to be not more than 15 ℃ in the acid dripping process, after the acid dripping is finished, the temperature is raised to the reflux of the system for reaction, and in specific embodiments of , the reaction time can be 5-6 hours.
Preferably, in the step 2), the alkali is dropwise added into a reaction system containing the product obtained in the step 1) and phosphorus oxychloride, the temperature of the reaction system is controlled to be 0-5 ℃, and after the alkali is dropwise added, the temperature is raised until the system is refluxed for reaction.
The technical scheme provided by the invention has the following beneficial effects:
the preparation method of the invention can overcome the defects of low yield, large discharge of three wastes, high treatment difficulty, large operation difficulty and the like in the prior art for producing the 2-chloronicotinic acid. The method takes malonaldehyde and cyanoacetamide as raw materials, and prepares the 2-chloronicotinic acid by cyclization and hydrolysis, has short route and higher yield, can avoid the generation of pyridine nitrogen oxide with potential safety hazard, greatly reduces waste water and other three wastes, has high product quality, and is particularly suitable for large-scale production.
Detailed Description
In order to better understand the technical solution of the present invention, the following example is further used to illustrate the content of the present invention, but the content of the present invention is not limited to the following example.
The starting materials used in the following examples are all commercially available in chemically pure form. The following description refers to instruments that may be involved, where the nuclear magnetism is: varian 400 MR; the mass spectrum is as follows: agilent 5975E; a micro melting point apparatus RT 3-03C; GC: agilent 7890A; liquid phase HPLC: agilent 1260.
Example 1
108g (1.0mol) of malondialdehyde (containing two water of crystallization) and 92.5g (1.1mol) of cyanoacetamide were charged into a 1000ml reaction flask, and 300ml of CH was added2Cl2Stirring and dissolving; after the system was cleared, 12g (0.2mol) of acetic acid was added dropwise thereto, and the addition was appropriately cooled so that the system temperature did not exceed 15 ℃. After the dropwise addition, slowly heating to the system for reflux, reacting for 5.5 hours, cooling the system to room temperature after the reaction is finished, adding 400ml of saturated sodium carbonate aqueous solution, stirring for half an hour, separating out a water layer, and discarding. The organic phase was dried over anhydrous sodium sulfate and filtered.
The filtrate obtained by filtration was subjected to atmospheric pressure and then to vacuum distillation to remove the solvent, thereby obtaining 106g of a pale yellow solid (a product containing 2-hydroxy-3-cyanopyridine), the HPLC purity was 96% and the yield was 88%.
Example 2
The product obtained in example 1 (containing 2-hydroxy-3-cyanopyridine, 0.88mol) was added to 250ml of POCl3(about 2.7mol) and stirring to dissolve the triethylamine, cooling the system to 0 ℃, slowly dropwise adding 101g (1.0mol) of triethylamine, controlling the temperature of the system to be between 0 and 5 ℃, and continuously stirring for half an hour at the temperature after dropwise adding; then, the temperature is slowly increased until the system is refluxed, and the reflux is maintained for 8 hours to finish the reaction. Recovering excess phosphorus oxychloride (POCl) under reduced pressure3) The system was added to 200ml of ice water, and the pH was adjusted to 11 with a small amount of NaOH to precipitate 117g of a brown precipitate (product containing 2-chloro-3-cyanopyridine), with a yield of 96.6%. The triethylamine in the mother liquor can be distilled and recovered.
Example 3
The product containing 2-hydroxy-3-cyanopyridine was prepared according to the method of example 1 except that the organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate (containing 0.88mol of 2-hydroxy-3-cyanopyridine) was directly charged into the reaction, 153g (1.0mol) of phosphorus oxychloride was added to the solution, the temperature was reduced to 0-5 ℃ and 101g (1.0mol) of triethylamine was slowly added dropwise while maintaining the temperature, after the addition was completed, the temperature was raised to reflux the system, the reaction was carried out for 18 hours, 200ml of ice water was added to the system after the reaction was completed, the pH was adjusted to 11 with NaOH, the organic layer was separated, the aqueous layer was extracted times with 150ml of dichloromethane, the organic layer was combined, dried over anhydrous sodium sulfate, filtered, and the mother liquor was distilled under atmospheric pressure to recover the solvent, yielding 112g of a light brown solid (product containing 2-chloro-3-cyanopyridine), with a yield of 92..
Example 4
69g of the product obtained in example 2 (or example 3) (2-chloro-3-cyanopyridine, 0.5mol) was added to 300ml of water, 25g of sodium hydroxide was added, the mixture was heated under reflux for hydrolysis for 3 hours, then 3.0g of activated carbon was added and stirring was continued for 0.5 hour, hot filtration was carried out, the filtrate was cooled to room temperature, pH was adjusted to 5 with concentrated hydrochloric acid, and the cake was filtered and washed with water to obtain 71g of 2-chloronicotinic acid with an HPLC purity of 99.1% and a yield of 90%. Melting point of the product: 181 ℃ and 182 ℃, MS (m/z): 157(M +), 140, 112, 76, 50.
It will be appreciated by those skilled in the art that modifications and adaptations of the invention may be made in light of the teachings of the present specification.
Claims (10)
- The preparation method of 2-chloronicotinic acid is characterized by comprising the following steps:1) reacting malondialdehyde with cyanoacetamide in the presence of acid to obtain a product containing 2-hydroxy-3-cyanopyridine;2) reacting the product obtained in the step 1) with phosphorus oxychloride in the presence of alkali to generate 2-chloro-3-cyanopyridine;3) hydrolyzing the 2-chloro-3-cyanopyridine obtained in the step 2) to obtain the 2-chloronicotinic acid.
- 2. The method according to claim 1, wherein the molar ratio of malondialdehyde, cyanoacetamide and acid in step 1) is 1:1-1.2: 0.1-0.5.
- 3. The method according to claim 1 or 2, wherein the acid in step 1) is or inorganic acid, preferably or two of acetic acid or propionic acid, and the inorganic acid is hydrochloric acid or sulfuric acid, and the base in step 2) is or more of triethylamine, pyridine or cyclohexylamine.
- 4. The method of any of claims 1-3, wherein the step 1) reaction is performed in the presence of a solvent, preferably or more of dichloromethane, ethyl acetate, chloroform.
- 5. The method according to claim 4, wherein the step 1) further comprises the steps of: separating an organic phase from a product containing 2-hydroxy-3-cyanopyridine obtained by the reaction in the step 1); drying the organic phase by using anhydrous sodium sulfate, and filtering to obtain filtrate;directly feeding the filtrate into the step 2) to be used as a raw material for reacting with the phosphorus oxychloride.
- 6. The process according to claim 5, wherein in the step 2), the molar ratio of the 2-hydroxy-3-cyanopyridine to the phosphorus oxychloride to the base is from 0.8:0.9 to 3.0:0.7 to 1.5.
- 7. The method according to claim 4, wherein the step 1) further comprises the steps of: separating an organic phase from a product containing 2-hydroxy-3-cyanopyridine obtained by the reaction in the step 1); drying the organic phase by using anhydrous sodium sulfate, and filtering to obtain filtrate;evaporating the solvent in the filtrate, and then putting the filtrate into the step 2) to react with the phosphorus oxychloride.
- 8. The method according to claim 7, wherein in the step 2), the molar ratio of phosphorus oxychloride to alkali is 1 to 3: 0.8-1.2.
- 9. The method according to any one of claims 1 to 8 to , wherein in step 3), the product obtained in step 2) is hydrolyzed under reflux in an aqueous solution of sodium hydroxide.
- 10. The preparation method of , according to any one of claims 4-9, wherein in step 1), after dissolving malondialdehyde and cyanoacetamide in a solvent, the acid is added dropwise into the reaction system, the temperature of the reaction system is controlled to be not more than 15 ℃ during the acid addition, and after the acid addition is completed, the temperature is raised to reflux the system for reaction;in the step 2), the alkali is dropwise added into a reaction system containing 2-hydroxy-3-cyanopyridine and phosphorus oxychloride, the temperature of the reaction system is controlled to be 0-5 ℃, and after the alkali is dropwise added, the temperature is raised until the system is refluxed for reaction.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114181139A (en) * | 2021-12-27 | 2022-03-15 | 四川仁安药业有限责任公司 | Synthetic method of 5-halogenated nicotinic acid |
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| US4081451A (en) * | 1975-03-20 | 1978-03-28 | Schering Corporation | Process for preparing 2-halogeno nicotinic acids |
| JPH08301847A (en) * | 1995-04-28 | 1996-11-19 | Koei Chem Co Ltd | Production of 2-chloro-3-substituted pyridine |
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2018
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| US4081451A (en) * | 1975-03-20 | 1978-03-28 | Schering Corporation | Process for preparing 2-halogeno nicotinic acids |
| JPH08301847A (en) * | 1995-04-28 | 1996-11-19 | Koei Chem Co Ltd | Production of 2-chloro-3-substituted pyridine |
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| 朱卓越，等: "3-溴-1，６-萘啶-５（６Ｈ）-酮的合成", 《华中师范大学学报（自然科学版）》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114181139A (en) * | 2021-12-27 | 2022-03-15 | 四川仁安药业有限责任公司 | Synthetic method of 5-halogenated nicotinic acid |
| CN114181139B (en) * | 2021-12-27 | 2023-12-08 | 四川仁安药业有限责任公司 | Synthesis method of 5-halogenated nicotinic acid |
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