CN102285913A - Synthesis method of CMP (2-chloro-5-methylpyridine) - Google Patents
Synthesis method of CMP (2-chloro-5-methylpyridine) Download PDFInfo
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Abstract
The invention relates to a synthesis method and preparation process of important pharmaceutical and pesticide intermediate-CMP (2-chloro-5-methylpyridine). The synthesis method disclosed by the invention comprises the following steps of: reacting with propionaldehyde by taking benzylamine as a raw material, reacting with an acetylating reagent, reacting with a Vilsmerier reagent generated by solid phosgene and DMF (Dimethyl Formamide) in a solvent after carrying out three-level distillation purification, distilling to obtain a crude product, regulating a pH value of the crude product, separating benzyl chloride by-product, and carrying out decompression distillation to obtain the CMP, wherein the product purity is larger than 98%, and the total yield is more than 78%. The invention has the characteristics that the synthesis method has gentle reaction conditions, the technical process is simple and environmental-friendly, and the solvent is easy to recover and use indiscriminately; and the synthesis method disclosed by the invention is suitable for industrial production.
Description
Invention field
The present invention relates to the synthetic method and the production technique of medicine and agricultural chemicals important intermediate 2-chloro-5-picoline; method of the present invention is to be raw material with the benzylamine; through reacting with propionic aldehyde; react with acetylation reagent again; the Vilsmerier reagent react that behind the three-stage distillation purifying, in solvent, generates with solid phosgene and DMF; obtain crude product through distillation then; crude product is by adjusting the pH value; tell the by product benzyl chloride; then; underpressure distillation obtains 2-chloro-5-picoline, and product purity is greater than 98%, and total recovery is more than 78%.Characteristics of the present invention are these synthesising method reacting condition gentlenesses, and technological process is simple, and is environmentally friendly, and the characteristics that solvent is easy to recovery of applied are fit to be applied to suitability for industrialized production.
Background of invention
2-chloro-5-picoline (being called for short CMP) is the important intermediate of synthetic anabasine insecticide, also is the important source material of producing medicine industry.Because Provado and acetamiprid have become the large-tonnage kind, and the importance of 2-chloro-5-picoline also becomes increasingly conspicuous, and production and consumption from now on still has stronger tendency, therefore, research and development had great importance at 2-chloro-5-picoline in recent years.
At present mainly contain five kinds of methods about 2-chloro-5-picoline synthetic:
One: with the 3-picoline is raw material, synthetic through reactions such as nitrogen oxidation, chlorinations, this class methods raw material is easy to get, reactions steps is few, cost is lower, but such method route poor selectivity, by product is many, and product separation and purification difficulty is difficult to obtain highly purified product, perhaps the purifying cost is too high, and yield is low.(EP0393453，EP0512436)
Its two: with nicotinic acid is raw material, synthetic through reaction such as superchlorination, reduction, these class methods, reactions steps is more, operate also comparatively loaded down with trivial details, more because the shortage of raw material nicotinic acid, nicotinic acid domestic production output seldom, cost is higher, therefore very difficult industrialization.(EP0569947)
Its three: with morpholine, propionic aldehyde is raw material, and synthetic through reactions such as cyclisation, dehydrogenation, chlorination, this method route is longer, operate also comparatively loaded down with trivial detailsly, and environmental pollution is serious, and totally cost is higher.(US4612377，US4645839)
Its four: with cyclopentadiene, propenal is raw material, synthetic through reactions such as Diels-Alder reaction, Michael additions, this route obtains 2-chloro-5-chloromethylpyridine by the exploitation of U.S. Rayleigh company by direct cyclization, has avoided chlorination process to generate by product; At present domestic corporation adopts this route suitability for industrialized production mostly, and still, because cyclopentadiene lower boiling, low-flash, spontaneous combustion easily, and polymerization easily, so there are a large amount of three wastes problems in this route, and problems (US 05229519) such as complicated operation, potential safety hazard.
Its five: with benzylamine, propionic aldehyde is raw material, synthetic through reactions such as cyclisation, phosphorus oxychloride chlorinations, this method exists yield low at present, total recovery 68%, wherein when Synthetic 2-chloro-5-picoline, there is the problem of product and by product benzyl chloride and separated from solvent difficulty, is difficult to obtain the product of higher degree, this method will realize industrialization, need do a large amount of improvement.(EP?0546418，US5304651)
Summary of the invention
The objective of the invention is to overcome the existing existing shortcoming of synthetic method, provide a kind of raw material be easy to get, easy and simple to handle, the three wastes are few, the 2-chloro-5-picoline synthetic method of high yield, this method adopts the domestic solid phosgene that is easy to get to do raw material, methylene dichloride is made solvent, adopt means such as hcl as extraction agent separation, the 2-chloro-5-picoline of the synthetic high level of high yield, all steps do not have severe condition, simple to operate, environmentally friendly, have remarkable social benefit and economic benefit, be fit to suitability for industrialized production.
For achieving the above object, the step that comprises of the synthetic method of a kind of 2-chloro-5-picoline provided by the invention:
The structural formula of 2-chloro-5-picoline is as follows:
Its synthesis step is:
The concrete operations step is as follows:
Step 1: be under-20～50 ℃ the condition, in benzylamine, to drip propionic aldehyde in temperature, dropwise, stirred 1～2 hour, add solvent and alkali then, tell organic layer; Organic layer adds thermal distillation band water, after band water is complete, obtains the solution of compd B T01, can be directly used in the next step.
In the step 1 of the present invention, when adding solvent, consider that BT01 is stable under alkaline condition, therefore, solvent is selected the alkaline matter of non-protonization, and this alkaline matter comprises amine such as triethylamine, Trimethylamine 99, tripropyl amine, Tributylamine, N, accelerine, N, tertiary amine compounds such as N-Diethyl Aniline; And pyridine compounds and their such as pyridine, picoline, lutidine etc., wherein with triethylamine the best.
In the step 1 of the present invention, add alkali and help reacting carry out more complete, alkali can be selected solid potassium hydroxide, solid sodium hydroxide, 10～60% potassium hydroxide solution, 10～60% sodium hydroxide solution, wherein with sodium hydroxide solution the bests of solid potassium hydroxide and 20～60%.
In the step 1 of the present invention, reaction is preferably carried out in-20～50 ℃ temperature range, especially-10～30 ℃, and particularly-5～10 ℃.Distillation band water temp preferably in 50～120 ℃ of scopes, particularly 70～90 ℃.
Step 2: be under-20～50 ℃ the condition, in acetylation reagent, to drip BT01 solution in temperature, stirred 2～5 hours in-20～50 ℃ again; most of solvent is reclaimed in air distillation; water pump underpressure distillation to still temperature reaches 100～140 ℃ again, and then, rectification under vacuum obtains compd B T02.
In the step 2 of the present invention, choice of Solvent must be consistent with previous step, can simplify the Separation and Recovery operation of solvent like this, simultaneously, selected solvent also will serve as the purposes of acid binding agent in step 2, and solvent also mainly is an alkaline matter of selecting non-protonization, this alkaline matter comprises amine such as triethylamine, Trimethylamine 99, tripropyl amine, Tributylamine, N, accelerine, N, tertiary amine compounds such as N-Diethyl Aniline; And pyridine compounds and their such as pyridine, picoline, lutidine etc., wherein with triethylamine the best.
In the step 2 of the present invention, the preferred diacetyl oxide of acetylation reagent, Acetyl Chloride 98Min. are wherein with diacetyl oxide the best.
In the step 2 of the present invention, reaction is preferably carried out in-20～50 ℃ temperature range, especially-10～30 ℃, and particularly-5～20 ℃.
In the step 2 of the present invention, we adopt the mode of three-stage distillation to carry out the aftertreatment purifying of BT02, realize the high-recovery of solvent, reduce the pollution to environment.The terminal point of three-stage distillation is as the criterion with the still temperature control, as: air distillation to still temperature reaches 100～140 ℃, with 130～140 ℃ of the bests; Water pump underpressure distillation to still temperature reaches 100～140 ℃, with 130～140 ℃ of the bests, vacuum tightness-0.095MPa.Oil pump rectification under vacuum to still temperature reaches 140～180 ℃, with 150～160 ℃ of the bests, vacuum tightness 2mmHg.
Step 3: be under-20～20 ℃ the condition,, to be added dropwise to N in temperature with the solid phosgene dissolution with solvents, in the mixture of dinethylformamide and solvent, add BT02 again, rise to 20～50 ℃ of stirring reactions 1～3 hour, normal pressure steams solvent, and then, decompression steams the CMP crude product.Crude product extracts with hydrochloric acid soln, tells the recovery that organic layer is used for the by product benzyl chloride, and water layer is told organic layer with adjusting PH with base to 8～9, water layer merges organic layer with solvent extraction 3 times, and anhydrous sodium sulfate drying filters, desolventizing, then, underpressure distillation gets 2-chloro-5-picoline.
In the step 3 of the present invention, solvent can be non-protonization material, such as normal hexane, toluene, benzene,
Dimethylbenzene etc., chlorinated solvent such as methylene dichloride, trichloromethane, chlorobenzene, ethylene dichloride etc. are wherein with methylene dichloride the best.
In the step 3 of the present invention, the post processing mode of employing is: distill out crude product, extract with hydrochloric acid soln then, tell the by product benzyl chloride, water layer is transferred pH to 8～9, tells organic layer, water layer merges organic layer, anhydrous sodium sulfate drying with solvent extraction 3 times, filter, desolventizing, then, underpressure distillation, get 2-chloro-5-picoline, product purity can reach 99%.
In the step 3 of the present invention, carry out in the temperature range that reaction is preferred-20～20 ℃, especially-10～10 ℃, particularly-5～5 ℃.
2-chloro-5-picoline synthetic method of the present invention, technical essential are to add solvent in BT01 synthetic, adopt distillation to be with the drying mode of water, have both improved yield, have reduced the use of siccative again, have reduced cost, have reduced pollution; When the aftertreatment purifying of BT02, adopted the mode of three-stage distillation, realized the high-recovery of solvent, reduced pollution environment.In the reaction process of BT03, adopt lower boiling compounds as solvents, help the separation and purification of product; In the last handling process of BT03, adopt and distill out crude product earlier, crude product extracts with hydrochloric acid soln then, tell the recovery that organic layer is used for the by product benzyl chloride, water layer is with adjusting PH with base to 8～9, tell organic layer, water layer merges organic layer, anhydrous sodium sulfate drying with solvent extraction 3 times, filter, desolventizing, then, underpressure distillation obtains 2-chloro-5-picoline, the present invention can provide the total recovery more than 78%, product purity is greater than 98%, institute do not have in steps severe condition, simple to operate, environmentally friendly, solvent is easy to recovery of applied, is fit to be applied to industrial production.
Embodiment
In order to be illustrated more clearly in the present invention, hereinafter adopt indefiniteness embodiment to be described further.
Embodiment one
(1) BT01's is synthetic
In the 500ml there-necked flask, add 107g (1.0mol) benzylamine, cryosel is bathed and is cooled to below 5 ℃.Slowly drip 61.9g (1.05mol) propionic aldehyde, dropwise, stirring reaction 10 minutes adds the 75g triethylamine then, stirs 10 minutes.Add 20g sodium hydroxide solution (30%), stir minutes about 20 minutes, process temperature is controlled at below 5 ℃.Static layering is divided water-yielding stratum then, and the triethylamine extraction with 50g merges organic layer.Heating air distillation triethylamine band water after band water finishes, is cooled to room temperature, is directly used in the next step.
(2) BT02's is synthetic
Be equipped with in 1000mL and add diacetyl oxide 105g (1.0mol) in the four-hole boiling flask of constant pressure funnel, stir, cryosel is bathed cooling; BT01 solution and 122g triethylamine that the reaction of last step is obtained mix, and add in the constant pressure funnel; When reacting liquid temperature in the flask is reduced to below 5 ℃, begin to drip the mixture of BT01 and triethylamine; After dropwising, temperature control-5～20 ℃ reaction 3 hours; Most of triethylamine is reclaimed in air distillation, and the still temperature is no more than 140 ℃; The water pump underpressure distillation, the azeotrope of collection acetate and triethylamine, the still temperature is no more than 140 ℃; 130～150 ℃ cut 176g is collected in oil pump decompression (2mmHg) rectifying, and GC normalizing content is that 94.1%, two step yield is 88%.
(3) BT03's is synthetic
Add DMF89.7g (1.15mol) and methylene dichloride 200ml in the four-hole boiling flask of 1000ml, stir, cryosel is bathed and is cooled to below 0 ℃, drips the solution of 211g (0.71mol) solid phosgene and 250ml methylene dichloride.After dropwising,, stirred 10 minutes, have a large amount of white solids to generate with 250ml dichloromethane rinse dropping funnel.The 176gBT02 that the step reaction obtains in the dropping is after dropwising, with 250ml dichloromethane rinse dropping funnel, naturally rose to stirring at room reaction 1 hour, and added the thermal distillation desolventizing, when still temperature rise to 80 ℃, change receiving bottle, collect front-end volatiles, be used for the extraction of following concentrated hydrochloric acid benzyl chloride.When still temperature rise to 130 ℃, the water pump underpressure distillation after most of product steams, promotes still temperature rise to 150 ℃, up to there not being fraction to steam.Steam the concentrated hydrochloric acid extraction of thing with 300ml * 3, combining water layer is used 300ml dichloromethane extraction one time, merges organic layer, uses anhydrous sodium sulfate drying.Filter, 179～181 ℃ cut is collected in the organic layer distillation, is benzyl chloride.The water layer adjust pH is 8～9, with 300ml * 3 dichloromethane extractions, merges organic layer, uses anhydrous sodium sulfate drying.Filter, the organic layer distillation, 118～120 ℃ cut 102g is collected in the water pump decompression, is product 2-chloro-5-picoline, GC normalizing content 99.0%, 91.1%, three step of single step yield total recovery 78.9%.
Claims (5)
1. the synthetic method of a 2-chloro-5-picoline, described method comprises following three steps:
Step 1: be under-20～50 ℃ the condition, in benzylamine, to drip propionic aldehyde in temperature, dropwise, stirred 1～2 hour, add solvent and alkali then, tell organic layer; Organic layer adds thermal distillation band water, after band water is complete, obtains the solution of compd B T01, can be directly used in the next step.
Step 2: be under-20～50 ℃ the condition, in acetylation reagent, to drip BT01 solution in temperature, stirred 2-5 hour in-20～50 ℃ again; most of solvent is reclaimed in air distillation; water pump underpressure distillation to still temperature reaches 100～140 ℃ again, and then, the oil pump rectification under vacuum obtains compd B T02.
Step 3: be under-20～20 ℃ the condition,, to be added dropwise to N in temperature with the solid phosgene dissolution with solvents, in the mixture of dinethylformamide and solvent, add BT02 again, rise to 20～50 ℃ of stirring reactions 1～3 hour, normal pressure steams solvent, and then, decompression steams the CMP crude product.Crude product extracts with hydrochloric acid soln, tells the recovery that organic layer is used for the by product benzyl chloride, and water layer is told organic layer with adjusting PH with base to 8～9, water layer merges organic layer with solvent extraction 3 times, and anhydrous sodium sulfate drying filters, desolventizing, then, underpressure distillation gets 2-chloro-5-picoline.
2. according to the method for claim 1, it is characterized in that in the described step 2, choice of Solvent must be consistent with previous step, can simplify the Separation and Recovery operation of solvent like this, simultaneously, selected solvent also will serve as the purposes of acid binding agent in step 2, solvent also mainly is the alkaline matter of selecting non-protonization, and this alkaline matter comprises amine such as triethylamine, Trimethylamine 99, tripropyl amine, Tributylamine, N, accelerine, N, tertiary amine compounds such as N-Diethyl Aniline; And pyridine compounds and their such as pyridine, picoline, lutidine etc., wherein with triethylamine the best.
3. according to the method for claim 1, it is characterized in that in the described step 2 that the preferred diacetyl oxide of acetylation reagent, Acetyl Chloride 98Min. are wherein with diacetyl oxide the best.
4. according to the method for claim 1, it is characterized in that in the described step 2 that reaction is preferably carried out in-20～50 ℃ temperature range, especially-10～30 ℃, particularly-5～20 ℃.The solid phosgene dissolution with solvents is added dropwise to N, in the mixture of dinethylformamide and solvent, adds BT02 again.
5. according to the method for claim 1, it is characterized in that in the described step 3 that solvent can be non-protonization material, such as normal hexane, toluene, benzene, dimethylbenzene etc., chlorinated solvent such as methylene dichloride, trichloromethane, chlorobenzene, ethylene dichloride etc. are wherein with methylene dichloride the best
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532007A (en) * | 2010-12-13 | 2012-07-04 | 中国中化股份有限公司 | Method for preparing 2-chloro-5-substituted pyridine |
| CN105330592A (en) * | 2015-11-23 | 2016-02-17 | 上海晋景化学有限公司 | Preparation method of 2-chloro-5-picoline |
| CN106518912A (en) * | 2015-09-15 | 2017-03-22 | 江苏海阔生物医药有限公司 | Preparation method for manufacturing dialkyl chlorophosphate reagent from benzylamine-propanal |
| CN106518911A (en) * | 2015-09-15 | 2017-03-22 | 江苏海阔生物医药有限公司 | Method of preparing dialkyl chlorophosphate reagent from polyvinyl alcohol |
| CN106518908A (en) * | 2015-09-15 | 2017-03-22 | 江苏海阔生物医药有限公司 | Method of preparing dialkyl chlorophosphate reagent from morpholine-normal propionaldehyde |
| CN106699645A (en) * | 2015-07-28 | 2017-05-24 | 江苏吉华化工有限公司 | Production method for preparing 2-chloro-5-chloromethylpyridine from benzylamine-n-propionaldehyde |
| CN106810492A (en) * | 2017-01-24 | 2017-06-09 | 江苏扬农化工集团有限公司 | A kind of continous way prepares the industrialized preparing process of the picoline of 2 chlorine 5 |
| CN109232398A (en) * | 2018-09-28 | 2019-01-18 | 上海晋景化学有限公司 | A kind of preparation method of pesticide intermediate chloro--methylpyridine |
| CN109553571A (en) * | 2018-11-29 | 2019-04-02 | 内蒙古元正精细化工有限责任公司 | The method of chloro--methylpyridine is continuously prepared in a kind of microchannel |
| CN110483382A (en) * | 2019-09-18 | 2019-11-22 | 甘肃青宇新材料有限公司 | A kind of green synthesis method of 2-vhloro-5-chloromethylpyridine |
| CN110903160A (en) * | 2019-12-26 | 2020-03-24 | 山东埃森化学有限公司 | Separation and purification method of pyridine chloride and solvent |
| CN112028821A (en) * | 2020-09-26 | 2020-12-04 | 安徽金禾实业股份有限公司 | Synthetic method of 2-methyl-3-methoxy-4-chloropyridine |
| WO2022099691A1 (en) * | 2020-11-16 | 2022-05-19 | 单县欣润化工有限公司 | Device and production method for continuously generating 2-chloro-5-trifluoromethylpyridine |
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Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532007A (en) * | 2010-12-13 | 2012-07-04 | 中国中化股份有限公司 | Method for preparing 2-chloro-5-substituted pyridine |
| CN102532007B (en) * | 2010-12-13 | 2013-10-09 | 中国中化股份有限公司 | Method for preparing 2-chloro-5-substituted pyridine |
| CN106699645A (en) * | 2015-07-28 | 2017-05-24 | 江苏吉华化工有限公司 | Production method for preparing 2-chloro-5-chloromethylpyridine from benzylamine-n-propionaldehyde |
| CN106518912A (en) * | 2015-09-15 | 2017-03-22 | 江苏海阔生物医药有限公司 | Preparation method for manufacturing dialkyl chlorophosphate reagent from benzylamine-propanal |
| CN106518911A (en) * | 2015-09-15 | 2017-03-22 | 江苏海阔生物医药有限公司 | Method of preparing dialkyl chlorophosphate reagent from polyvinyl alcohol |
| CN106518908A (en) * | 2015-09-15 | 2017-03-22 | 江苏海阔生物医药有限公司 | Method of preparing dialkyl chlorophosphate reagent from morpholine-normal propionaldehyde |
| CN105330592A (en) * | 2015-11-23 | 2016-02-17 | 上海晋景化学有限公司 | Preparation method of 2-chloro-5-picoline |
| CN106810492B (en) * | 2017-01-24 | 2020-04-17 | 江苏扬农化工集团有限公司 | Industrial production method for continuously preparing 2-chloro-5-methylpyridine |
| CN106810492A (en) * | 2017-01-24 | 2017-06-09 | 江苏扬农化工集团有限公司 | A kind of continous way prepares the industrialized preparing process of the picoline of 2 chlorine 5 |
| CN109232398A (en) * | 2018-09-28 | 2019-01-18 | 上海晋景化学有限公司 | A kind of preparation method of pesticide intermediate chloro--methylpyridine |
| CN109553571A (en) * | 2018-11-29 | 2019-04-02 | 内蒙古元正精细化工有限责任公司 | The method of chloro--methylpyridine is continuously prepared in a kind of microchannel |
| CN110483382A (en) * | 2019-09-18 | 2019-11-22 | 甘肃青宇新材料有限公司 | A kind of green synthesis method of 2-vhloro-5-chloromethylpyridine |
| CN110903160A (en) * | 2019-12-26 | 2020-03-24 | 山东埃森化学有限公司 | Separation and purification method of pyridine chloride and solvent |
| CN110903160B (en) * | 2019-12-26 | 2022-06-03 | 山东埃森化学有限公司 | Separation and purification method of pyridine chloride and solvent |
| CN112028821A (en) * | 2020-09-26 | 2020-12-04 | 安徽金禾实业股份有限公司 | Synthetic method of 2-methyl-3-methoxy-4-chloropyridine |
| WO2022099691A1 (en) * | 2020-11-16 | 2022-05-19 | 单县欣润化工有限公司 | Device and production method for continuously generating 2-chloro-5-trifluoromethylpyridine |
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Application publication date: 20111221 |