CN103539729A - Industrial production method of chloromethyl pyridine derivative - Google Patents
Industrial production method of chloromethyl pyridine derivative Download PDFInfo
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- CN103539729A CN103539729A CN201310476356.8A CN201310476356A CN103539729A CN 103539729 A CN103539729 A CN 103539729A CN 201310476356 A CN201310476356 A CN 201310476356A CN 103539729 A CN103539729 A CN 103539729A
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- 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
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- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
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Abstract
The invention discloses an industrial production method of a chloromethyl pyridine derivative. The industrial production method comprises an oxidation reaction process, a nitration reaction process, a replacement reaction process, a rearrangement hydrolysis reaction process and a chloromethylation reaction process. 2,3-dimethyl pyridine as a raw material undergoes an oxidation reaction to produce a pyridine N-oxide, the pyridine N-oxide undergoes a nitration reaction to produce 2,3-dimethyl-4-nitropyridine-N-oxide, the 2,3-dimethyl-4-nitropyridine-N-oxide undergoes a replacement reaction to produce 4-alkoxypyridine-N-oxide, the 4-alkoxypyridine-N-oxide undergoes a rearrangement hydrolysis reaction to produce a 2-hydroxy-4-alkoxypyridine compound, and the 2-hydroxy-4-alkoxypyridine compound undergoes a chloromethylation reaction to produce the refined chloromethyl pyridine compound. The industrial production method realizes recycle of waste produced in production, realizes environmental protection and waste comprehensive utilization, changes waste into values and injurants into benefits, greatly reduces a production cost and improves product competitiveness.
Description
Technical field
The invention belongs to Synthetic Organic Chemistry technology field, be specifically related to draw azole drug intermediate---the technological process of production of chloromethylpyridine derivative.
Background technology
Digestive system is a class disease that threatens human health and be difficult to cure always, wherein the sickness rate of peptide ulceration accounts for the universe's 5%, and draw azole drug, be to treat at present the most effective medicine of peptide ulceration, therefore draw azole drug to rank among the row of 21 century ten large best-selling drugses always.This directly causes the market heavy demand of its prodrug chloromethylpyridine derivative.And China does not almost produce the producer of this type of intermediate, demand is mostly from India's import.According to investigations, cause the major cause of this phenomenon to be that technical process is long, production cost is high, in this product of suitability for industrialized production, produce that " three wastes " are difficult to process, environmental pollution is serious, recycling difficulty etc.
Chinese patent application CN102603620A(201210010970) disclose the synthetic method of a kind of chloromethylpyridine or its pyridine derivate hydrochloride, but this method is only applicable to the pyridine raw material that No. 2 positions and No. 6 positions are hydrogen.Patent of invention CN200910035011.2 discloses a kind of 2-chloromethyl-4-methoxyl group-3, the purification process of 5-dimethyl pyrazole thiamine hydrochloride, proposed to using acetone and sherwood oil according to the volume proportion of 2 ~ 3:1 the method as the washing composition of final product, the good product quality, the yield that obtain are high, but do not propose the concrete operation method of other steps.And other relevant reports are also considerably less.
For making up the vacancy of this type of compou nd synthesis technology, the present invention, from environment protection and the raw-material aspect such as recycle to greatest extent, has designed a set of complete chloromethylpyridine derivative synthesis technique flow process.
Summary of the invention
The present invention is directed to the problems referred to above that prior art exists, and the industrialized preparing process that a kind of production cost is relatively low, environmentally friendly, refuse is carried out to the chloromethylpyridine derivative of recycle is to greatest extent provided.
For realizing above-mentioned purpose of the present invention, the industrialized preparing process of a kind of chloromethylpyridine derivative of the present invention by the following technical solutions:
The present invention has designed a set of complete chloromethylpyridine derivative synthesis technique flow process from environment protection and the raw-material aspect such as recycle to greatest extent.The industrialized preparing process of a kind of chloromethylpyridine derivative of the present invention adopts following raw materials for production, technical process:
1) oxidizing reaction: by 2,3-lutidine dilutes by 3 times of volumes of acetic acid, drip the vitriol oil of catalytic amount, be warmed up to 80 ~ 100 ℃, the hydrogen peroxide that dropping mass concentration is 28 ~ 32%, dropwises insulation reaction 4 ~ 5 h, react complete, use reductive agent cancellation, vacuum distillation recovered solvent, debris---pyridine nitric oxide is directly carried out the next step; The acetic acid distilling is separated with azeotropic distillation with water, the acetic acid recycling obtaining.The mass concentration of hydrogen peroxide generally take 30% as good;
2) nitration reaction: the pyridine nitric oxide of oxidizing reaction gained is added to the vitriol oil at temperature <10 ℃, be warming up to subsequently 80 ~ 90 ℃, slowly drip the nitration mixture of the vitriol oil and concentrated nitric acid volume ratio 2.5 ~ 3.5:1, in this reactions steps, note adding NO
2tail gas absorption equipment is beneficial to environment protection, dropwises insulation reaction 4 ~ 8h, take 6h as good, middle control terminal; Reaction finishes after reaction solution is cooling to pour in frozen water, under stirring, with alkali, be neutralized to pH=8 ~ 10, add ethyl acetate or other be beneficial to industrialized organic solvent extraction and isolate organic phase, dry also evaporated under reduced pressure organic phase, obtain yellow solid crude product, with ethyl alcohol recrystallization, obtain sterling 2,3-Dimethyl-4-nitropyridine-N-oxide; Extraction agent can reuse through underpressure distillation, and water is further processed and obtained Na
2sO
4, NaNO
3and other inorganic salt.In the nitration mixture dripping, take the mass concentration of the vitriol oil as 98%, the mass concentration of concentrated nitric acid is advisable as 65%, in nitration mixture, the vitriol oil and concentrated nitric acid volume ratio be take 3:1 as good;
3) substitution reaction: by nitration reaction, obtain 2,3-Dimethyl-4-nitropyridine-N-oxide joins K
2cO
3, alcohol, acetonitrile and TBAB mixing solutions in, 60 ~ 80 ℃ of reaction 5 ~ 6 h, middle control terminal; After reacting completely, cooling and underpressure distillation, gained cut can reuse after determining alcohol content; The dope obtaining after underpressure distillation extracts and filters with toluene, and filtrate decompression distillation, obtains 4-alkoxy pyridines oxynitride, the toluene recycling of recovery, and filter cake is inorganic salt, merges processing with the waste water in nitration reaction;
4) reset hydrolysis reaction: in the 4-alkoxy pyridines oxynitride obtaining to substitution reaction, add diacetyl oxide and dense H
2sO
490 ~ 105 ℃ of reaction 8 ~ 12h, TLC detection reaction terminal, underpressure distillation obtains the mixing solutions of rearrangement product and a small amount of residual acetic acid and diacetyl oxide, add wherein NaOH solution to regulate PH to neutral, add again the reaction that is hydrolyzed of 10 ~ 15%NaOH solution of 3eq, 55 ~ 65 ℃ of reaction 7 ~ 15h, TLC detection reaction terminal, after reacting completely, cooling and be extracted with ethyl acetate, extraction liquid is dry, filtration, filtrate decompression distillation, obtains 2-methylol-4-alkoxy pyridines compound.The acetic acid of underpressure distillation gained and the mixed solution of diacetyl oxide reclaim by fractionation separates, recycling; Extraction agent ethyl acetate also reuses; The sodium-acetate waste water obtaining, discharges after doing further environmental protection treatment;
5) chloromethylation: 2-methylol-4-alkoxy pyridines compound that rearrangement hydrolysis reaction is obtained is dissolved in methylene dichloride, and add the DMF of catalytic amount, add alkali liquor absorption device, under-10 ~ 10 ℃ of conditions, add sulfur oxychloride, insulation reaction 3 ~ 6 h, after reacting completely, the volume of distillation and concentration to five/mono-to 1/7th, drip wherein ethyl acetate, slowly separate out white crystalline solid, filter, acetone-ethyl alcohol recrystallization for filter cake, obtain refining chloromethylpyridine derivative product of the present invention, filtrate adds cold NaOH solution-treated discharge, ethyl acetate also can reclaim by underpressure distillation, the sulfur oxychloride of Distillation recovery and the mixture of methylene dichloride, then reuse after adding appropriate sulfur oxychloride to determine ratio.
The present invention adopts after above technical scheme, and the refuse producing in process obtains recycle, has both protected environment, and the waste resource of comprehensive utilization, turns waste into wealth again, and turn harm into good, and significantly reduced production cost, be to achieve many things at one stroke.Research shows, adopts the industrialized preparing process of a kind of chloromethylpyridine derivative provided by the invention, and the chloromethylpyridine derivative of producing reduces by 40 ~ 60% than the price of imported product, and the competitive power of product is strong.
Accompanying drawing explanation
Fig. 1 is oxidizing reaction process flow sheet;
Fig. 2 is nitration reaction technical process;
Fig. 3 is substitution reaction process flow sheet;
Fig. 4 resets hydrolysis reaction process flow sheet;
Fig. 5 is chloromethylation process flow sheet;
The production method process flow sheet of a kind of chloromethylpyridine derivative of Fig. 6 the present invention.
Embodiment
For describing the present invention, below in conjunction with embodiment, the industrialized preparing process of a kind of chloromethylpyridine derivative of the present invention is described in further details:
By Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, found out, the industrialized preparing process of a kind of chloromethylpyridine derivative of the present invention comprises oxidizing reaction, nitration reaction, substitution reaction, rearrangement hydrolysis reaction, chloromethylation totally 5 reactions steps.
1. oxidizing reaction
Oxidizing reaction process flow sheet is as shown in Figure 1 found out, by 2,3-lutidine dilutes by 3 times of volumes of acetic acid, drips the vitriol oil of catalytic amount, is warmed up to 80 ~ 100 ℃, drip 30% hydrogen peroxide, dropwise insulation reaction 4 ~ 5 h, react complete, use reductive agent cancellation, vacuum distillation recovered solvent, debris is directly carried out the next step.The acetic acid distilling is separated with azeotropic distillation with water, the acetic acid recycling obtaining.
2. nitration reaction
Nitration reaction process flow sheet as shown in Figure 2 finds out, the pyridine nitric oxide of step 1 gained adds the vitriol oil at temperature <10 ℃, is warming up to subsequently 80 ~ 90 ℃, and the nitration mixture that slowly drips the vitriol oil and concentrated nitric acid volume ratio 3:1 (adds NO
2tail gas absorption equipment), dropwise insulation reaction 6h, middle control terminal; Reaction finishes after reaction solution is cooling to pour in frozen water, under stirring, with alkali, be neutralized to pH=8 ~ 10, add ethyl acetate to extract and isolate organic phase, dry also evaporated under reduced pressure organic phase, obtain yellow solid crude product, with ethyl alcohol recrystallization, obtain sterling 2,3-Dimethyl-4-nitropyridine-N-oxide; Extraction agent can reuse through underpressure distillation, and water is further processed and obtained Na
2sO
4, NaNO
3and other inorganic salt.
3. substitution reaction
Substitution reaction process flow sheet as shown in Figure 3 finds out, in step 2, obtain 2,3-Dimethyl-4-nitropyridine-N-oxide joins K
2cO
3, alcohol, acetonitrile and TBAB mixing solutions in, 60 ~ 80 ℃ of reaction 5 ~ 6 h, middle control terminal; After reacting completely, cooling and underpressure distillation, gained cut can reuse after determining alcohol content; The dope obtaining after underpressure distillation extracts and filters with toluene, and filtrate decompression distillation, obtains 4-alkoxy pyridines oxynitride, the toluene recycling of recovery, and filter cake is inorganic salt, merges processing with the waste water in nitration reaction;
4. reset hydrolysis reaction
Rearrangement hydrolysis reaction process flow sheet is as shown in Figure 4 found out, adds diacetyl oxide and the dense H of catalytic amount to step 3 in the 4-alkoxy pyridines oxynitride obtaining
2sO
490 ~ 105 ℃ of reaction 8 ~ 12h, TLC detection reaction terminal, underpressure distillation obtains the mixing solutions of rearrangement product and a small amount of residual acetic acid and diacetyl oxide, add wherein NaOH solution to regulate PH to neutral, add again the reaction that is hydrolyzed of 10 ~ 15%NaOH solution of 3eq, 55 ~ 65 ℃ of reaction 7 ~ 15h, TLC detection reaction terminal, after reacting completely, cooling and be extracted with ethyl acetate, extraction liquid is dry, filtration, filtrate decompression distillation, obtains 2-methylol-4-alkoxy pyridines compound.The acetic acid of underpressure distillation gained and the mixed solution of diacetyl oxide reclaim by fractionation separates, recycling; Extraction agent ethyl acetate also reuses; The sodium-acetate waste water obtaining, discharges after doing further environmental protection treatment;
5. chloromethylation
Chloromethylation process flow sheet is as shown in Figure 5 found out, 2-methylol-4-alkoxy pyridines compound that reaction in step 4 is obtained is dissolved in methylene dichloride, and add the DMF of catalytic amount, add alkali liquor absorption device, under-10 ~ 10 ℃ of conditions, add sulfur oxychloride, insulation reaction 3 ~ 6 h, after reacting completely, the volume of distillation and concentration to five/mono-to 1/7th, drip wherein ethyl acetate, slowly separate out white crystalline solid, filter, acetone-ethyl alcohol recrystallization for filter cake, obtain refining chloromethylpyridine derivative product of the present invention, filtrate adds cold NaOH solution-treated discharge, ethyl acetate also can reclaim by underpressure distillation, the sulfur oxychloride of Distillation recovery and the mixture of methylene dichloride, then reuse after adding appropriate sulfur oxychloride to determine ratio
The production method process flow sheet of a kind of chloromethylpyridine derivative of the present invention as shown in Figure 6 in conjunction with Fig. 1, 2, 3, 4, 5 find out, the present invention includes oxidizing reaction, nitration reaction, substitution reaction, reset hydrolysis reaction, chloromethylation is totally 5 reactions steps, raw material 2, 3-lutidine generates pyridine nitric oxide through peroxidation, pyridine nitric oxide prepares 2 through digestion reaction, 3-Dimethyl-4-nitropyridine-N-oxide, through substitution reaction, obtain 4-alkoxy pyridines oxynitride again, then through resetting hydrolysis reaction, obtain 2-hydroxyl-4-alkoxy pyridines compound, finally by crossing chloromethylation, obtain refining chloromethylpyridine compound.
Claims (4)
1. an industrialized preparing process for chloromethylpyridine derivative, is characterized in that it adopts following raw materials for production, technical process:
1) oxidizing reaction: by 2,3-lutidine dilutes with acetic acid, drip a certain amount of vitriol oil, be warmed up to 80 ~ 100 ℃, the hydrogen peroxide that dropping mass concentration is 28 ~ 32%, dropwises insulation reaction 4 ~ 5 h, react complete, use reductive agent cancellation, vacuum distillation recovered solvent, debris---pyridine nitric oxide is directly carried out the next step; The acetic acid distilling is separated with azeotropic distillation with water, the acetic acid recycling obtaining;
2) nitration reaction: the pyridine nitric oxide of oxidizing reaction gained is added to the vitriol oil at temperature <10 ℃, be warming up to subsequently 80 ~ 90 ℃, slowly drip the nitration mixture of the vitriol oil and concentrated nitric acid volume ratio 2.5 ~ 3.5:1, in this reactions steps, note adding NO
2tail gas absorption equipment is beneficial to environment protection, dropwises insulation reaction 4 ~ 8h, take 6h as good, middle control terminal; Reaction finishes after reaction solution is cooling to pour in frozen water, under stirring, with alkali, be neutralized to pH=8 ~ 10, add ethyl acetate or other be beneficial to industrialized organic solvent extraction and isolate organic phase, dry also evaporated under reduced pressure organic phase, obtain yellow solid crude product, with ethyl alcohol recrystallization, obtain sterling 2,3-Dimethyl-4-nitropyridine-N-oxide; Extraction agent can reuse through underpressure distillation, and water is further processed and obtained Na
2sO
4, NaNO
3and other inorganic salt.
3) substitution reaction: by nitration reaction, obtain 2,3-Dimethyl-4-nitropyridine-N-oxide joins K
2cO
3, alcohol, acetonitrile and TBAB mixing solutions in, 60 ~ 80 ℃ of reaction 5 ~ 6 h, middle control terminal; After reacting completely, cooling and underpressure distillation, gained cut can reuse after determining alcohol content; The dope obtaining after underpressure distillation extracts and filters with toluene, and filtrate decompression distillation, obtains 4-alkoxy pyridines oxynitride, the toluene recycling of recovery, and filter cake is inorganic salt, merges processing with the waste water in nitration reaction;
4) reset hydrolysis reaction: in the 4-alkoxy pyridines oxynitride obtaining to substitution reaction, add diacetyl oxide and dense H
2sO
490 ~ 105 ℃ of reaction 8 ~ 12h, TLC detection reaction terminal, underpressure distillation obtains the mixing solutions of rearrangement product and a small amount of residual acetic acid and diacetyl oxide, add wherein NaOH solution to regulate PH to neutral, add again the reaction that is hydrolyzed of 10 ~ 15%NaOH solution of 3eq, 55 ~ 65 ℃ of reaction 7 ~ 15h, TLC detection reaction terminal, after reacting completely, cooling and be extracted with ethyl acetate, extraction liquid is dry, filtration, filtrate decompression distillation, obtains 2-methylol-4-alkoxy pyridines compound.The acetic acid of underpressure distillation gained and the mixed solution of diacetyl oxide reclaim by fractionation separates, recycling; Extraction agent ethyl acetate also reuses; The sodium-acetate waste water obtaining, discharges after doing further environmental protection treatment;
5) chloromethylation: 2-methylol-4-alkoxy pyridines compound that rearrangement hydrolysis reaction is obtained is dissolved in methylene dichloride, and add the DMF of catalytic amount, add alkali liquor absorption device, under-10 ~ 10 ℃ of conditions, add sulfur oxychloride, insulation reaction 3 ~ 6 h, after reacting completely, the volume of distillation and concentration to five/mono-to 1/7th, drip wherein ethyl acetate, slowly separate out white crystalline solid, filter, acetone-ethyl alcohol recrystallization for filter cake, obtain refining chloromethylpyridine derivative product of the present invention, filtrate adds cold NaOH solution-treated discharge, ethyl acetate also can reclaim by underpressure distillation, the sulfur oxychloride of Distillation recovery and the mixture of methylene dichloride, then reuse after adding appropriate sulfur oxychloride to determine ratio.
2. the industrialized preparing process of a kind of chloromethylpyridine derivative as claimed in claim 1, is characterized in that: at denitrification step, drip in the technical process of nitration mixture, be provided with NO
2tail gas absorption equipment.
3. the industrialized preparing process of a kind of chloromethylpyridine derivative as claimed in claim 2, is characterized in that: the mass concentration of the hydrogen peroxide dripping in oxidation step is 30%; In the nitration mixture that nitration reaction step drips, the mass concentration of the vitriol oil is 98%, the mass concentration of concentrated nitric acid is 65%, and in nitration mixture, the vitriol oil and concentrated nitric acid volume ratio are 2.5 ~ 3.5:1.
4. the industrialized preparing process of a kind of chloromethylpyridine derivative as described in claim 1,2 or 3, it is characterized in that: in chloromethylation step, temperature of reaction is-10 ~ 10 ℃, and after reacting completely, distillation and concentration to five/mono-drips ethyl acetate crystallization after 1/7th volume again.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592107A (en) * | 2015-01-16 | 2015-05-06 | 江苏中邦制药有限公司 | Synthesis method of 2,3-dimethyl-4-nitropyridine-N-oxide |
| CN104974078A (en) * | 2015-06-25 | 2015-10-14 | 黄荣辉 | Preparation method of 2-methyl-6-chloromethylpyridinehydrochloride |
| CN104974077A (en) * | 2015-06-25 | 2015-10-14 | 黄荣辉 | Synthetic method of 2-chloromethylpyridinehydrochloride |
| CN111943883A (en) * | 2020-08-21 | 2020-11-17 | 抚州三和医药化工有限公司 | Production process of Orimei chloride |
| CN112645873A (en) * | 2021-02-23 | 2021-04-13 | 荆楚理工学院 | Synthetic method of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592107A (en) * | 2015-01-16 | 2015-05-06 | 江苏中邦制药有限公司 | Synthesis method of 2,3-dimethyl-4-nitropyridine-N-oxide |
| CN104974078A (en) * | 2015-06-25 | 2015-10-14 | 黄荣辉 | Preparation method of 2-methyl-6-chloromethylpyridinehydrochloride |
| CN104974077A (en) * | 2015-06-25 | 2015-10-14 | 黄荣辉 | Synthetic method of 2-chloromethylpyridinehydrochloride |
| CN111943883A (en) * | 2020-08-21 | 2020-11-17 | 抚州三和医药化工有限公司 | Production process of Orimei chloride |
| CN112645873A (en) * | 2021-02-23 | 2021-04-13 | 荆楚理工学院 | Synthetic method of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide |
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