CN105272907A - Method for preparing 4-chloro-3-methoxy-2-methyl-1H-pyridine - Google Patents
Method for preparing 4-chloro-3-methoxy-2-methyl-1H-pyridine Download PDFInfo
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- CN105272907A CN105272907A CN201410246109.3A CN201410246109A CN105272907A CN 105272907 A CN105272907 A CN 105272907A CN 201410246109 A CN201410246109 A CN 201410246109A CN 105272907 A CN105272907 A CN 105272907A
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Abstract
The invention relates to a method for preparing 4-chloro-3-methoxy-2-methyl-1H-pyridine. Triphosgene is used to chloridize a raw material 4-chloro-3-methoxy-2-methyl-1H-pyridine as a chloridizing agent, so generation of phosphate solids and phosphorus-containing wastewater in the post-treatment process is avoided, and the environment protection pressure of enterprises is reduced; condition optimization makes the product yield reaches 95% or above and makes the purity reaches 97% or above, so the market competitiveness of the enterprises is improved; and triphosgene has low toxicity, so the method has the advantages of simple operation, low apparatus requirements, no strict condition of anhydrous conditions, and good safety. The above new method meets safety, environmental protection and economy requirements of industrial production.
Description
Technical field
The invention belongs to Field of Fine Chemicals category, is a kind of novel method preparing the chloro-3-methoxyl group of proton pump inhibitor pantoprazole intermediate 4--2-methyl isophthalic acid H-pyridine.
Background technology
Pantoprazole (pantoprazole, 1) be late 1990s by German BykGulden pharmaceutical factory research and production, and take the lead in Germany listing the 3rd generation proton pump inhibitor.Pantoprazole has been widely used in the hemorrhage and stressing gastric mucosa lesion for the treatment of gastric and duodenal ulcer, Gastroesophageal reflux disease companion erosive esophagitis, urgent peptic ulcer, short treating period, dosage is few, curative effect is good, safety performance is good, recurrence rate is low, is proton pump inhibitor choice drug of new generation, has wide market outlook.This patent is mainly to the research of the synthesis technique of the chloro-3-methoxyl group of pantoprazole important intermediate 4--2-picoline (2).The structural formula of compound 1 and 2 is as follows:
Consider the factors such as quality, cost and suitability for industrialized production, from 3-methoxyl group-2-methyl-4(1H) (3)s obtained the chloro-3-methoxyl group of 4--2-picoline (2) through chlorination to-pyridone.Within 1989, EP0304732A2 makes public for the first time the method for synthesis 4-chloro-3-methoxyl group-2-picoline (2), adopts phosphorus oxychloride as chlorizating agent, yield 65.2%, and without aftertreatment, directly carry out next step reaction, synthetic route is as follows:
Xuzhou Normal University's journal (natural science edition), 2003,21,42-45 has delivered the preparation method of the chloro-3-methoxyl group of 4--2-picoline.Get phosphorus oxychloride, 3-methoxyl group-2-methyl-4 (1H)-pyridone is slowly added under ice-water bath, reflux 10h, phosphorus oxychloride is boiled off under decompression, add toluene wash, removing toluene, is poured into water resistates, limit bevelling stirs, and the NaOH solution adjust ph adding 20% is 10 ~ 11.With dichloromethane extraction 3 times, extraction liquid is washed with water to neutrality, adds anhydrous sodium sulfate drying, normal pressure steaming vibrating dichloromethane, obtains brown aromatising flavour liquid, yield 83%.
Write phosphorus oxychloride 450ml (4.9mol) in the Master's thesis of Song Wei state of Shandong University in 2007 and at room temperature slowly add raw material 95g (0.68mol), the joining day controls in 2h.Be warming up to 80 ~ 90 DEG C, insulation 12 ~ 14h, TLC follow the tracks of and are reacted to the disappearance of raw material spot.Be down to room temperature, instillation fills in the reaction flask of frozen water, with sheet adjusting PH with base=10 ~ 12, and, at room temperature extract three times with ethylene dichloride, evaporate to dryness ethylene dichloride obtains the chloro-3-methoxyl group of 4--2-picoline, yield 73.62%.
Within 2010,3-methoxyl group-2-methyl-4 (1H)-pyridone solid is added in phosphorus oxychloride by CN101875629A, wherein the mass percent of 3-methoxyl group-2-methyl-4 (1H)-pyridone solid and phosphorus oxychloride is 1:18, then be heated to 80 ~ 90 DEG C and be back to dissolving, highly basic NaOH is used to regulate pH to be 5, use organic solvent extraction again 3 ~ 4 times, combining extraction liquid, pressure reducing and steaming organic solvent, obtain the chloro-3-methoxyl group of brown 4--2-picoline liquid, yield 79%.
Within 2012, CN102304083A discloses the method for the chloro-3-methoxyl group of synthesis 4--2-picoline.Under ice-water bath, 3-methoxyl group-2-methyl-4 (1H)-pyridone solid is slowly added in phosphorus oxychloride, reflux 8h, phosphorus oxychloride is boiled off under decompression, add toluene wash, removing toluene, be poured into water by resistates, limit bevelling stirs, and the NaOH solution adjust ph adding 20% is 10.With dichloromethane extraction 3 times, extraction liquid is washed with water to neutrality, adds anhydrous sodium sulfate drying, normal pressure steaming vibrating dichloromethane, obtains brown aromatising flavour liquid, yield 82%.
The method of the chloro-3-methoxyl group of Chinese and foreign documents report synthesis 4--2-picoline is all adopt phosphorus oxychloride chlorination process.Phosphorus oxychloride is a kind of liquid of water white stink with irritating, acutely be fuming in damp atmosphere, be hydrolyzed into phosphoric acid and hydrogenchloride, cause production environment severe, for improving yield, production process needs strictly to control anhydrous condition, improves equipment, the erosion resistance of pipeline, stopping property, increases production cost; In addition, current industrial employing is using phosphorus oxychloride as reaction solvent, and charging capacity need exceed more than 10 times of feed molar amount; Aftertreatment needs reaction solution to pour in frozen water, and buck is washed, and produces a large amount of phosphoric acid salt solid aggravation post-processing difficulty in treating processes; A large amount of phosphorus-containing wastewater discharge increases cost for wastewater treatment; And, exist in industrial employing phosphorus oxychloride chlorination process production process and produce instability, yield about 80%.We wish to find more green, economy, environmental protection and be applicable to industrialized method and carry out alternative phosphorus oxychloride for this reason.
Summary of the invention
In order to overcome the deficiencies in the prior art, the object of the present invention is to provide that a kind of cost is low, raw material availability is high, the method for good product quality, the chloro-3-methoxyl group of eco-friendly synthesis 4--2-methyl isophthalic acid H-pyridine.
Triphosgene (Triphosgene), has another name called solid phosgene, and chemical name is two (trichloromethyl) carbonic ethers, and being called for short BTC, is a kind of stable solid chemical compound.Triphosgene as chlorizating agent, molten, boiling point is high, volatility is low, toxicity is low, simple to operate, pollute little, even if also only have a small amount of decomposition in distillation temperature (206 DEG C), therefore very safe in storage, transport and use procedure.Abroad, the synthesis that BTC is widely used in medicine, agricultural chemicals, dyestuff, pigment and seed selection macromolecular material is produced, and has the good reputation of " laboratory and industrial gold mine ".
Unique distinction of the present invention is that using triphosgene to substitute phosphorus oxychloride carries out chlorination reaction to 3-methoxyl group-2-methyl-4 (1H)-pyridone, and last handling process does not produce phosphoric acid salt solid and phosphorus-containing wastewater, reduces environmental protection of enterprise pressure; Chlorination process is simple, mild condition, and equipment requirements is low, produces safer; Yield can be made to reach more than 95% by condition optimizing, purity reaches more than 97%, directly carries out the next step, more economically.This technique meets the feature of industrial environmental protection, economy, safety.
The present invention relates to the method for the chloro-3-methoxyl group of a kind of triphosgene synthesis 4--2-methyl isophthalic acid H-pyridine.
Detailed process is as follows: be dissolved in a kind of solvent or mixed solvent by 3-methoxyl group-2-methyl-4 (1H)-pyridone and organic bases or mineral alkali, the massfraction of organic bases or mineral alkali is 1% ~ 20% of raw material.Stir, control solution temperature at 0 ~ 50 DEG C, add triphosgene solid in batches or be dissolved with the solution of triphosgene, the mol ratio of triphosgene and raw material is 1:1 ~ 6:1, and 40 ~ 60 DEG C of stirring reaction 1 ~ 18h, TLC tracking reacts completely, stopped reaction.Regulate pH to 6 ~ 9 with mineral alkali, get oil reservoir washing, drying, distillation obtains the chloro-3-methoxyl group of 4--2-methyl isophthalic acid H-pyridine.
The present invention adopts a kind of alkali to carry out induced reaction as the catalyzer of reaction.Investigate mineral alkalis such as sodium hydroxide, sodium carbonate and Anhydrous Ferric Chlorides, find that the catalytic effect of mineral alkali is very low, in experimentation, most of product is impurity, target product yield only about 20%; Organic bases DMA, triethylamine, DMAP, DMF etc. are investigated, finds the good catalytic activity of organic bases, but it is because the boiling point of DMA is higher, water-soluble poor, affect product purity, the good catalytic activity of DMF and DMAP and triethylamine.Final selection DMF and DMAP and triethylamine in one or mixing as catalyzer.
The present invention investigates catalyst levels, and catalyst levels is 1% ~ 20% of raw materials quality.Experimental result shows that catalyzer charging capacity hour product purity is high, reason may be the impurity that excess catalyst and raw material, triphosgene define similar urea in reaction process, consider selectivity and yield, final optimization pass catalyzer charging capacity is 1% ~ 5% of raw materials quality.
Organic solvent of the present invention can be one or both mixture of the organic solvents such as ether, tetrahydrofuran (THF), benzene, hexanaphthene, chloroform, tetracol phenixin, 1,2-ethylene dichloride, methylene dichloride, ethanol.But consider recycled solvent problem in industrial applications, the one in proper employing ether wherein, hexanaphthene, methylene dichloride.
The triphosgene that the present invention adds and material molar ratio are 1:1 ~ 6:1.Add triphosgene amount large time, exothermic heat of reaction is comparatively strong, and the phosgene of decomposed has neither part nor lot in reaction and directly steams with methylene dichloride, causes phosgene to lose; Triphosgene amount hour, feedstock conversion is insufficient, and final optimization pass mol ratio is 1:1 ~ 3:1.
The present invention has investigated the impact of three kinds of feeding sequences on yield and purity: 1) 3-methoxyl group-2-methyl-4 (1H)-pyridone, triphosgene, catalysts and solvents add reactor together; 2) 3-methoxyl group-2-methyl-4 (1H)-pyridone, catalysts and solvents are added in reactor, and then drip triphosgene solution and react; 3) triphosgene, catalysts and solvents are added in reactor, and then drip 3-methoxyl group-2-methyl-4 (1H)-pyridone and react; 4) 3-methoxyl group-2-methyl-4 (1H)-pyridone, catalysts and solvents are added in reactor, then add triphosgene solid in batches.When vigorous reaction after catalyzer and triphosgene contact reacts in reaction process, release large calorimetric, solvent vigorous reflux, can not effective control temperature, cause producing a series of impurity, by contrast, preferred feeding mode is the mixed solution that triphosgene solution is added dropwise to raw material and catalyzer in 0.5 ~ 3h.
Triphosgene of the present invention adds fashionable, and controlling solution temperature is 0 ~ 50 DEG C, and add the insulation of rear mixed solution and continue stirring reaction to 20 ~ 60 DEG C, consider transformation efficiency, yield and time cost, can be optimized for 10 ~ 20 DEG C and add triphosgene, 20 ~ 40 DEG C of insulations continue to stir.
The NaOH that the present invention can add 6mol/L at the end of reaction regulates pH6 ~ 9, and the precipitation at least that alkali adds is insufficient, affect quality product, and the sodium salt waste water then produced too much added is more, therefore can optimize the add-on of NaOH, and optimal ph scope is for being 7 ~ 8.
The invention provides the novel process of synthesis 4-chloro-3-methoxyl group-2-methyl isophthalic acid H-pyridine, its unique distinction is to use triphosgene first as chlorizating agent to raw material 3-methoxyl group-2-methyl-4(1H)-pyridone carries out chlorination reaction.Make yield reach more than 95% by condition optimizing, purity reaches more than 97%, directly carries out next step reaction without the need to purifying.
Relative to prior art: the chlorizating agent volatility that (1) the present invention selects is low, toxicity is low, without the need to strictly controlling anhydrous condition, security is good; (2) reaction conditions of the present invention is gentle, and simple to operate, equipment requirements is low; (3) raw material availability of the present invention is high, side reaction is few, product purity is high, improves quality product on the one hand, decreases cost simultaneously, reduce the difficulty of wastewater treatment.(4) products obtained therefrom content of the present invention is high, directly carries out next step reaction without the need to refining; (5) present invention, avoiding the generation of phosphoric acid salt solid and phosphorus-containing wastewater, environmental friendliness, be applicable to suitability for industrialized production.
Embodiment
embodiment 1
3-methoxyl group-2-methyl-4(1H is added in there-necked flask)-pyridone (139g, 1mol) is with 100ml methylene dichloride, and stirring at normal temperature is dissolved, then adds 30g triethylamine.15 DEG C of dichloromethane solutions adding 888g (3mol) triphosgene, add in 1h, are warming up to 45 DEG C and stir 8h, TLC and follow the tracks of and react completely, stopped reaction.PH to 8 is adjusted with 6mol/LNaOH solution, stratification, water layer dichloromethane solvent extracts, merge oil reservoir, saturated common salt is washed, anhydrous sodium sulfate drying, and underpressure distillation obtains brownly having aromaticity liquid 4-chloro-3-methoxyl group-2-methyl isophthalic acid H-pyridine (134.5g), yield 85.4%, purity 94.0%.
embodiment 2
Operational condition, with embodiment 1, does not add catalyzer, the charging capacity of triphosgene is reduced to 296g (3mol), add all the other conditions constant, reaction 18h, finally obtaining the chloro-3-methoxyl group of 4--2-methyl isophthalic acid H-pyridine finished weight is 103.1g, yield 65.4%, purity 56.7%.
embodiment 3
Operational condition adds 888g (3mol) triphosgene solid with embodiment Isosorbide-5-Nitrae 5 DEG C in batches, and insulated and stirred 4h, TLC follow the tracks of and react completely, stopped reaction.Finally obtaining the chloro-3-methoxyl group of 4--2-methyl isophthalic acid H-pyridine finished weight is 120.0g, yield 76.2%, purity 96.3%.
embodiment 4
200ml ether being added 3-methoxyl group-2-methyl-4(1H) in-pyridone (139g, 1mol) and 888g (3mol) triphosgene solid, stirring at normal temperature is dissolved.30g triethylamine 1h drips.45 DEG C are stirred 15h, TLC tracking and react completely, stopped reaction.PH to 8 is adjusted with 6mol/LNaOH solution, stratification, water layer extracted with diethyl ether, merge oil reservoir, saturated common salt is washed, anhydrous sodium sulfate drying, and underpressure distillation obtains brownly having aromaticity liquid 4-chloro-3-methoxyl group-2-methyl isophthalic acid H-pyridine (125.7g), yield 79.8%, purity 86.7%.
Protection scope of the present invention is not limited only to above embodiment, and every claims are mentioned, and the distortion that those skilled in the art can be extrapolated to is all in protection domain.
Claims (9)
1. prepare the method for the chloro-3-methoxyl group of 4--2-methyl isophthalic acid H-pyridine for one kind, with 3-methoxyl group-2-methyl-4 (1H)-pyridone for raw material, it is characterized in that using triphosgene as chlorizating agent, last handling process does not produce phosphoric acid salt solid and phosphorus-containing wastewater.
2. method according to claim 1, it is characterized in that said method comprising the steps of: at 0 ~ 50 DEG C, 3-methoxyl group-2-methyl-4 (1H)-pyridone, triphosgene, catalyzer and organic solvent are added in reactor, at 20 ~ 60 DEG C, stirring reaction 1 ~ 15h, after reacting completely, regulate pH to 6 ~ 9 with alkali, get oil reservoir washing, drying, distillation obtains the chloro-3-methoxyl group of 4--2-methyl isophthalic acid H-pyridine.
3. method according to claim 2, is characterized in that described reaction dosing form adopts mixed solution triphosgene solution being added raw material and catalyzer in 0.5 ~ 3h.
4. method according to claim 2, is characterized in that described raw material mixing temperature is 10 ~ 20 DEG C.
5. method according to claim 2, is characterized in that described temperature of reaction is 20 ~ 40 DEG C.
6. method according to claim 2, is characterized in that organic solvent is one in ether, hexanaphthene, methylene dichloride or mixing.
7. method according to claim 2, is characterized in that described catalyzer is one in DMF, DMAP and triethylamine or mixing.
8. method according to claim 2, is characterized in that the feeding quantity of catalyzer is 1% ~ 5% of 3-methoxyl group-2-methyl-4 (1H)-pyridone massfraction.
9. method according to claim 2, is characterized in that the mol ratio of triphosgene and 3-methoxyl group-2-methyl-4 (1H)-pyridone is 1:1 ~ 3:1.
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| CN105646368A (en) * | 2016-03-03 | 2016-06-08 | 深圳诺普信农化股份有限公司 | Preparation method of 2, 4-dichloro-5-methoxy pyrimidine |
| CN109608391A (en) * | 2018-12-11 | 2019-04-12 | 安徽金禾实业股份有限公司 | The chlorination synthesis technology of chlorination workshop section in pyridiniujm production |
| 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 |
| CN114560873A (en) * | 2021-12-27 | 2022-05-31 | 浙江日出药业有限公司 | Preparation method of 3-chloromethyl-6-chloro-oxazole [4,5-b ] pyridine-2 (3H) ketone |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105646368A (en) * | 2016-03-03 | 2016-06-08 | 深圳诺普信农化股份有限公司 | Preparation method of 2, 4-dichloro-5-methoxy pyrimidine |
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| CN114560873A (en) * | 2021-12-27 | 2022-05-31 | 浙江日出药业有限公司 | Preparation method of 3-chloromethyl-6-chloro-oxazole [4,5-b ] pyridine-2 (3H) ketone |
| CN114560873B (en) * | 2021-12-27 | 2023-02-28 | 浙江日出药业有限公司 | Preparation method of 3-chloromethyl-6-chloro-oxazole [4,5-b ] pyridine-2 (3H) ketone |
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