CN102603620B - Synthetic method of chloromethylpyridine or pyridine derivative hydrochloride of chloromethylpyridine - Google Patents

Synthetic method of chloromethylpyridine or pyridine derivative hydrochloride of chloromethylpyridine Download PDF

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CN102603620B
CN102603620B CN201210010970.0A CN201210010970A CN102603620B CN 102603620 B CN102603620 B CN 102603620B CN 201210010970 A CN201210010970 A CN 201210010970A CN 102603620 B CN102603620 B CN 102603620B
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pyridine
chloromethylpyridine
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chlorination
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CN102603620A (en
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秦必政
薛谊
徐强
李维思
赵华阳
周颖
钱勇
肖云
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Jiangsu Zhongbang Pharmaceutical Coltd
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Abstract

The invention discloses a synthetic method of chloromethylpyridine or pyridine derivative hydrochloride of the chloromethylpyridine. The synthetic method is characterized in that according to the method, the positioning effect of substitutional groups is used for carrying out chloromethylation reaction, raw materials of pyridine or pyridine derivatives are subjected to Friedel-Crafts acylation reaction under the catalyst effect, No.2 sites or No.6 sites of the pyridine or the pyridine derivatives take electrophilic substitution reaction, then, hydroxymethylpyridine or hydroxymethylpyridine derivatives are obtained through reduction reaction, next, the chloromethylpyridine or the pyridine derivative hydrochloride is obtained through chlorination reaction, and the structure of the obtained product is shown in the description. The method has the advantages that the reaction steps are few, the cost is low, the purity is high, the yield is high, the operation is safe, and the method is suitable for large-scale industrial production.

Description

The synthetic method of a kind of chloromethylpyridine or its pyridine derivate hydrochloride
Technical field:
The invention belongs to chemical field, be specifically related to the synthetic method of a kind of chloromethylpyridine or its pyridine derivate hydrochloride, chloromethylpyridine and pyridine derivate hydrochloride are the important industrial chemicals of various agricultural chemicals, medicine intermediate, Insecticides (tech) & Herbicides (tech), sterilant, and present method directly generates 2-chloromethylpyridine and pyridine derivate from pyridine or its pyridine derivate.
Background technology:
Chloromethylpyridine and pyridine derivate hydrochloride are the important industrial chemicals of various agricultural chemicals, medicine intermediate, Insecticides (tech) & Herbicides (tech), sterilant.At present pyridine and pyridine derivate directly go up methyl, and with the expensive precious metal industrial chemicals such as lithium methide, methyl iodide, or just direct cyclization becomes on 2-position, to have methyl, then leads to chlorine, carries out chlorination.Some technology are on oxygen, to methylate to pyridine nitric oxide with methyl-sulfate, and then after being oxidized, make 2-4-hydroxymethylpiperidine and pyridine derivate, chlorination obtains 2-chloromethylpyridine and pyridine derivate hydrochloride again, as: US4620008, CN101337924A, SE0103553 etc.Pyridine and pyridine derivate carry out more easily connecing synthetic industrial chemicals intermediate and the bulk drug that has high added value of other groups after chloromethylation.But with lithium methide, methyl iodide etc. be raw material, cost value pressure is large, reclaim precious metal and iodine element is cumbersome; Large by methyl-sulfate toxicity, for feeding intake, operation is more dangerous.
Summary of the invention
The object of this invention is to provide the synthetic method of a kind of chloromethylpyridine and pyridine derivate hydrochloride.
The object of the invention is by following scheme implementation:
A synthetic method for chloromethylpyridine or pyridine derivate hydrochloride, the method be with pyridine or pyridine derivate through peroxidation, catalysis ethanoyl, restore with chlorination and obtain chloromethylpyridine or pyridine derivate hydrochloride.
The present invention is by following scheme implementation:
The synthetic method of a kind of chloromethylpyridine or its pyridine derivate hydrochloride; it is characterized in that the method uses substituent orientation effect to carry out chloromethylation; the method comprises carries out friedel-crafts acylation reaction by pyridine or pyridine derivate and acylting agent under catalyst action; there is electrophilic substitution reaction in No. 2 positions or No. 6 positions at pyridine or pyridine derivate; then obtain 4-hydroxymethylpiperidine or 4-hydroxymethylpiperidine derivative through reduction, then obtain chloromethylpyridine or pyridine derivate hydrochloride through chlorination.The product structure obtaining is as follows:
Described pyridine derivate is preferably nitrogen pyridine oxide derivative, wherein, and preferably R 1for H, CH 3, CH 2cH 3, Cl, OCH 3, NH 2or NO 2; Preferably R 2for H, CH 3, CH 2cH 3, Cl, OCH 3, NH 2or NO 2; Preferably R 3for H, CH 3, CH 2cH 3, Cl, OCH 3, NH 2or NO 2.On described raw material pyridine and No. 2 positions of the pyridine ring of pyridine derivate, No. 6 positions, only has H.
The temperature of reaction of described acylation reaction is 45 DEG C～95 DEG C, and the reaction times is 4～16h (preferably 4～6h), raw material pyridine or pyridine derivate: acylting agent: catalyzer=1: 1～2.5: 0.1～0.5 (mol ratio); The temperature of reaction of described reduction reaction is 45 DEG C～95 DEG C, and the reaction times is 5～16h (preferably 5～12h, most preferably 5～7h); In described chlorination, chlorination temperature is :-20 DEG C～-5 DEG C, the reaction times is 1～3h.
Described friedel-crafts acylation reaction acylting agent used is carboxylic acid halides or acid anhydrides.Preferably acylting agent is: RCOI, RCOBr, RCOCl, RCOF, (RCO) O; Described R is preferably CH 3, CH 3cH 2, CH 2=CH or CH 3(CH 2) n, wherein 3>=n>=1.
The catalyzer that friedel-crafts acylation reaction of the present invention adopts is Lewis acid; Described preferably AlCl of Lewis acid 3, ZnCl 2, MgO, ZnO, K 2cO 3or Na 2cO 3.
The preferred Fe/AcOH of reductive agent, Na/EtOH, Zn/NaOH, zinc amalgam, sodium borohydride, Lithium Aluminium Hydride, tetrahydro boron sodium, Raney nickel or palladium charcoal that reduction step of the present invention adopts; Reductive agent consumption is and the mass ratio 1 of raw material pyridine or pyridine derivate: 0.5-2; The preferred SOCl of reagent that described chlorination adopts 2, POCl 3, PCl 3, Cl 2or HCl.The consumption of chlorination reagent is to be 1 with raw material pyridine or pyridine derivate mass ratio: 0.5-4.
Taking raw material as pyridine as example reaction is as follows:
Wherein, R 1, R 2and R 3be H.
Beneficial effect of the present invention compared with the prior art: the present invention adopts the conventional industrial chemicals that contains pyridine ring to carry out acetyl glycosylation reaction, and reactions steps is few, and cost is low, and purity is high, and yield is high, operational safety, the inventive method is suitable for large-scale industrial production.
Embodiment:
Further understand the present invention by following examples, but can not limit content of the present invention.
Embodiment 1
In the flask of 500ml, add 4-methoxyl group-3 of 9.2g, 5-lutidine oxynitride, the methyl alcohol of 60ml, adds 0.8g aluminum chloride, is cooled to 0 DEG C and starts below to drip Vinyl chloroformate 7.8g, after dropwising, being warming up to temperature of reaction is 45 DEG C～95 DEG C, back flow reaction 4～6 hours, sampling analysis, until raw material 4-methoxyl group-3, till 5-lutidine oxynitride does not reduce; In system, add 6.75g tetrahydro boron sodium, temperature of reaction is 55-65 DEG C, reduces.React 5 hours, filter, filter out inorganic salt, filtrate is steamed except methyl alcohol, go out 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine, dry methylene chloride phase with dichloromethane extraction, be cooled to-10 DEG C and start to drip 14g sulfur oxychloride, and then be naturally warming up to room temperature reaction 2～3 hours, obtain 2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride, the 10.8g white solid of weighing to obtain, analyzes through HPLC: purity is 98.37%.Three-step reaction total recovery is 81.2%.
Embodiment 2
In the flask of 500ml, add 4-nitro-3 of 10g, 5-lutidine oxynitride, the methyl alcohol of 60ml, adds 0.5g magnesium oxide, is cooled to 0 DEG C and starts below to drip diacetyl oxide 6.2g, after dropwising, being warming up to temperature of reaction is 45 DEG C～95 DEG C, back flow reaction 4～6 hours, sampling analysis, until raw material 4-nitro-3, till 5-lutidine oxynitride does not reduce; In system, add 6.75g Lithium Aluminium Hydride, temperature of reaction is 85-95 DEG C, reduces.React 7 hours, filter, leach inorganic salt, filtrate is steamed except methyl alcohol, go out 2-methylol-4-nitro-3,5-lutidine, dry methylene chloride phase with dichloromethane extraction, be cooled to-20 DEG C and start to drip 18g phosphorus trichloride, and then be naturally warming up to room temperature reaction 2～3 hours, obtain 2-chloromethyl-4-nitro-3,5-dimethyl pyrazole thiamine hydrochloride, the 11.9g off-white color solid of weighing to obtain, analyzes through HPLC: purity is 97.73%.Three-step reaction total recovery is 84.4%.
Embodiment 3
In the flask of 500ml, add 3 of 7.3g, 5-lutidine oxynitride, the methyl alcohol of 60ml, adds 4.0g zinc chloride, is cooled to 0 DEG C and starts below to drip chloracetyl (CH 3cOCl) 9.3g, after dropwising, being warming up to temperature of reaction is 45 DEG C～95 DEG C, back flow reaction 4～6 hours, sampling analysis, until raw material 3, till 5-lutidine oxynitride does not reduce; In system, add 6.75gFe/10mlAcOH, temperature of reaction is 45-55 DEG C, reduces.React 12 hours, filter out inorganic salt, steam except methyl alcohol, go out 2-methylol-3 with dichloromethane extraction, 5-lutidine, dry methylene chloride phase, is cooled to-5 DEG C and starts to pass into 8.4g chlorine, and then be naturally warming up to room temperature reaction 1～2 hour, obtain 2-chloromethyl-3,5-dimethyl pyrazole thiamine hydrochloride, the 9.1g white solid of weighing to obtain, analyzes through HPLC: purity is 98.45%.Three-step reaction total recovery is 80.5%.
Embodiment 4
In the flask of 500ml, add the pyridine nitric oxide of 5.6g, the methyl alcohol of 60ml, add 1.6g salt of wormwood, be cooled to 0 DEG C and start below to drip propionic anhydride 19.2g, after dropwising, being warming up to temperature of reaction is 45 DEG C～95 DEG C, back flow reaction 4～6 hours, sampling analysis, until raw material 3, till 5-lutidine oxynitride does not reduce; In system, add 10gRaney nickel, reduce, temperature of reaction is 55-65 DEG C, react 5 hours, filter out inorganic salt, steam except methyl alcohol, go out 2-methylol-3 with dichloromethane extraction, 5-lutidine, dry methylene chloride phase, is cooled to-15 DEG C and passes into 4.3g hydrogenchloride, and then be naturally warming up to room temperature reaction 2～3 hours, obtain 2-chloromethyl pyridine hydrochloride, the 8.9g colorless solid of weighing to obtain, analyzes through HPLC: purity is 95.83%.Three-step reaction total recovery is 88.7%.
Embodiment 5
In the flask of 500ml, add the pyridine of 4g, the methyl alcohol of 60ml, add 2.0g aluminum chloride, be cooled to 0 DEG C and start below to drip Vinyl chloroformate 12.6g, after dropwising, being warming up to temperature of reaction is 45 DEG C～95 DEG C, back flow reaction 4～6 hours, sampling analysis, until raw material 4-methoxyl group-3, till 5-lutidine oxynitride does not reduce; In system, add 6.75g tetrahydro boron sodium, reduce.Temperature of reaction is 55-65 DEG C, react 5 hours, filter, filter out inorganic salt, filtrate is steamed except methyl alcohol, go out 2-4-hydroxymethylpiperidine with dichloromethane extraction, dry methylene chloride phase, is cooled to-10 DEG C and starts to drip 14g sulfur oxychloride, and then be naturally warming up to room temperature reaction 2～3 hours, obtain 2-chloromethyl pyridine hydrochloride, the 6.8g white solid of weighing to obtain, analyzes through HPLC: purity is 99.3%.Three-step reaction total recovery is 81.9%.
Embodiment 6
In the flask of 500ml, add 4-amino-3 of 8.2g, 5-lutidine oxynitride, the methyl alcohol of 60ml, adds 0.84g magnesium oxide, is cooled to 0 DEG C and starts below to drip diacetyl oxide 9.7g, after dropwising, being warming up to temperature of reaction is 45 DEG C～95 DEG C, back flow reaction 4～6 hours, sampling analysis, until raw material 4-amino-3, till 5-lutidine oxynitride does not reduce; In system, add 6.75g Lithium Aluminium Hydride, reduce.Temperature of reaction is 85-95 DEG C, reacts 5 hours, filters, leach inorganic salt, filtrate is steamed except methyl alcohol, goes out 2-methylol-4-amino-3 with dichloromethane extraction, 5-lutidine, dry methylene chloride phase, is cooled to-10 DEG C and starts to drip 18g phosphorus trichloride, and then be naturally warming up to room temperature reaction 2～3 hours, obtain 2-chloromethyl-4-amino-3,5-dimethyl pyrazole thiamine hydrochloride, the 10.5g off-white color solid of weighing to obtain, analyzes through HPLC: purity is 97.73%.Three-step reaction total recovery is 85.4%.
Embodiment 7
In the flask of 500ml, add the 4-of 9.3g chloro-3,5-lutidine oxynitride, the methyl alcohol of 60ml, adds 3.2g zinc chloride, is cooled to 0 DEG C and starts below to drip chloracetyl (CH 3cOCl) 10.65g, after dropwising, being warming up to temperature of reaction is 45 DEG C～95 DEG C, back flow reaction 9～10 hours, sampling analysis, until raw material 4-chlorine 3, till 5-lutidine oxynitride does not reduce; In system, add 6.75gFe/10mlAcOH, reduce.Temperature of reaction is 55-65 DEG C, reacts 5 hours, filters out inorganic salt, steam except methyl alcohol, go out 2-methylol-4-with dichloromethane extraction chloro-3,5-lutidine, dry methylene chloride phase, be cooled to subzero 10 DEG C and start to pass into 8.4g chlorine, and then be naturally warming up to room temperature reaction 2～3 hours, obtain 2-chloromethyl-4-chloro-3,5-dimethyl pyrazole thiamine hydrochloride, the 11.1g white solid of weighing to obtain, analyzes through HPLC: purity is 98.65%.Three-step reaction total recovery is 82.8%.
Embodiment 8
In the flask of 500ml, add the 3-ethylpyridine oxynitride of 7.3g, the methyl alcohol of 60ml, add 1.6g salt of wormwood, be cooled to 0 DEG C and start below to drip propionic anhydride 19.3g, after dropwising, being warming up to temperature of reaction is 45 DEG C～95 DEG C, back flow reaction 4～6 hours, sampling analysis, until raw material 3-ethylpyridine oxynitride does not reduce; In system, add 10gRaney nickel, reduce.Temperature of reaction is 75-85 DEG C, react 5 hours, filter out inorganic salt, steam except methyl alcohol, go out 2-methylol-3 with dichloromethane extraction, 5-lutidine, dry methylene chloride phase, is cooled to subzero 10 DEG C and passes into 4.3g hydrogenchloride, and then be naturally warming up to room temperature reaction 2～3 hours, obtain 2-chloromethyl 3-ethylpyridine hydrochloride, the 9.6g colorless solid of weighing to obtain, analyzes through HPLC: purity is 95.83%.Three-step reaction total recovery is 85%.

Claims (4)

1. the synthetic method of a chloromethylpyridine or its pyridine derivate hydrochloride; it is characterized in that the method uses substituent orientation effect to carry out chloromethylation; raw material pyridine or pyridine derivate under catalyst action, are carried out friedel-crafts acylation reaction by the method; there is electrophilic substitution reaction in No. 2 positions or No. 6 positions at pyridine or pyridine derivate; then obtain 4-hydroxymethylpiperidine or 4-hydroxymethylpiperidine derivative through reduction reaction; obtain chloromethylpyridine or pyridine derivate hydrochloride through chlorination again, the product structure obtaining is as follows:
Wherein, R 1for H, CH 3, CH 2cH 3, Cl, OCH 3, NH 2or NO 2; R 2for H, CH 3, CH 2cH 3, Cl, OCH 3, NH 2or NO 2; R 3for H, CH 3, CH 2cH 3, Cl, OCH 3, NH 2or NO 2; The temperature of reaction of described acylation reaction is 45 DEG C ~ 95 DEG C, and the reaction times is 4 ~ 16h, raw material pyridine or pyridine derivate: acylting agent: catalyzer=1: 1 ~ 2.5: 0.1 ~ 0.5, and described ratio is mol ratio; The temperature of reaction of described reduction reaction is 45 DEG C ~ 95 DEG C, and the reaction times is 5 ~ 16h; In described chlorination, chlorination temperature is :-20 DEG C ~-5 DEG C, the reaction times is 1 ~ 3h; Described acylting agent is: RCOI, RCOBr, RCOCl, RCOF, (RCO) O; Catalyzer is Lewis acid; The reductive agent that reduction reaction adopts is: Fe/AcOH, Na/EtOH, Zn/NaOH, zinc amalgam, Lithium Aluminium Hydride, tetrahydro boron sodium, Raney nickel or palladium charcoal; Described pyridine derivate is nitrogen pyridine oxide derivative; Described R is CH 3, CH 3cH 2, CH 2=CH or CH 3(CH 2) n, wherein 3>=n>=1.
2. synthetic method according to claim 1, is characterized in that described Lewis acid is AlCl 3, ZnCl 2, MgO, ZnO, K 2cO 3or Na 2cO 3.
3. synthetic method according to claim 1, is characterized in that reductive agent consumption is is 1:0.5-2 with the mass ratio of raw material.
4. synthetic method according to claim 1, is characterized in that the reagent that described chlorination adopts is SOCl 2, POCl 3, Cl 2or HCl; The consumption of chlorination reagent is than being 1:0.5-4 with raw materials quality.
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CN104974078A (en) * 2015-06-25 2015-10-14 黄荣辉 Preparation method of 2-methyl-6-chloromethylpyridinehydrochloride
CN105198799A (en) * 2015-11-03 2015-12-30 江苏梦得电镀化学品有限公司 Preparation method of 2-methyl-6-(chloromethyl) pyridine hydrochloride
CN111638303B (en) * 2020-06-08 2022-06-24 安徽大学 Distinguish metal ion Al3+And Zn2+Method (2)

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