CN103073505B - The method of 4-chloro-6-methoxylpyrimidin synthesis 4,6-dichloro pyrimidine - Google Patents
The method of 4-chloro-6-methoxylpyrimidin synthesis 4,6-dichloro pyrimidine Download PDFInfo
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- CN103073505B CN103073505B CN201310030263.2A CN201310030263A CN103073505B CN 103073505 B CN103073505 B CN 103073505B CN 201310030263 A CN201310030263 A CN 201310030263A CN 103073505 B CN103073505 B CN 103073505B
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Abstract
The present invention relates to the method for a kind of 4-chloro-6-methoxylpyrimidin synthesis 4,6-dichloro pyrimidine.It is characterized in that: under anhydrous organic amine exists, react with phosphorus oxychloride and 4-chloro-6-methoxylpyrimidin, the product mixture obtained, then slough excessive phosphorus oxychloride by underpressure distillation; Be added drop-wise in mixture of ice and water after the mixture of underpressure distillation is cooled to 60-80 DEG C, with organic solvent extraction, then decompression steams part organic solvent, and crystallisation by cooling obtains product.The method reduces the danger of building-up reactions, improves the utilization ratio of 4,6-dichloro pyrimidines in Azoxystrobin synthesis technique, reduces production cost, reduces solid waste, alleviates the burden to environment.Adopt preparation method of the present invention, the purity of 4,6-dichloro pyrimidine is high, and yield is high.
Description
Technical field
The present invention relates to the method for a kind of 4-chloro-6-methoxylpyrimidin synthesis 4,6-dichloro pyrimidine.
Background technology
4; 6-dichloro pyrimidine is generally used as chemical intermediate; can be widely used in the synthesis of the bioactive compoundss such as agricultural chemicals, medicine and intermediate, be the compound with Important Economic value, but in Azoxystrobin building-up process; some is 4 years old; 6-dichloro pyrimidine can react with sodium methylate and change into by-product 4-chloro-6-methoxylpyrimidin, not only reduces the utilization ratio of 4,6-dichloro pyrimidine; add production cost, certain burden is also brought to environment protection.US20020042514 reports with the reaction of 4-chloro-6-methoxylpyrimidin photoreactive gas, makees catalyzer at organic amine or its salt, synthesis 4,6-dichloro pyrimidine.But phosgene used in its synthetic method has larger toxicity, well-known phosgene is colourless, and withered grass taste gas, very easily leaks, and greatly dangerous, lethal quantity is less, does not effectively give treatment to method, there is more potential safety hazard when there is life injury.The present invention takes phosphorus oxychloride to replace phosgene, although phosphorus oxychloride also has stronger toxicity, as long as carry out individual's effectively protection, the harm of phosphorus oxychloride is completely within controlled range.
Summary of the invention
The object of the invention is to overcome above-mentioned deficiency, a kind of 4-chloro-6-methoxylpyrimidin is provided to synthesize 4, the method of 6-dichloro pyrimidine, the method reduces the danger of building-up reactions, improve the utilization ratio of 4,6-dichloro pyrimidines in Azoxystrobin synthesis technique, reduce production cost, reduce solid waste, alleviate the burden to environment.
The object of the present invention is achieved like this:
The method of a kind of 4-chloro-6-methoxylpyrimidin synthesis 4,6-dichloro pyrimidine, under anhydrous organic amine exists, reacts with phosphorus oxychloride and 4-chloro-6-methoxylpyrimidin, the product mixture obtained, then sloughs excessive phosphorus oxychloride by underpressure distillation; Be added drop-wise in mixture of ice and water after the mixture of underpressure distillation is cooled to 60-80 DEG C, with organic solvent extraction, then decompression steams part organic solvent, and crystallisation by cooling obtains product.
In aforesaid method, the siccative of organic amine is sheet NaOH, and organic amine is triethylamine, DMF(dimethyl formamide), DIPEA, DMA, N, N-Diethyl Aniline, N, N-diisobutyl ethamine or N, N-di-isopropyl propylamine.
In aforesaid method, in 4,6-dichloro pyrimidine building-up process, reaction system is guaranteed anhydrous;
In aforesaid method, 4, after 6-dichloro pyrimidine building-up reactions terminates, the excessive phosphorus oxychloride of reaction mixture pressure reducing and steaming, the mixture after underpressure distillation is cooled to 60 ~ 80 DEG C, is added drop-wise in mixture of ice and water, to guarantee in dropping process that distilling rear mixture temperature remains on 60 ~ 80 DEG C, hydrolysis temperature remains on-5 ~ 5 DEG C, to guarantee that 4,6-dichloro pyrimidine can not be hydrolyzed.
In aforesaid method, the phosphorus oxychloride that underpressure distillation goes out can be applied mechanically to next batch.
In aforesaid method, the temperature of underpressure distillation is at 50 ~ 105 DEG C, and pressure is at-0.05 ~-0.095Mpa.
In aforesaid method, extracting organic solvent used is ethylene dichloride or methylene dichloride.
In aforesaid method, through the mixture of frozen water process, after organic solvent ethylene dichloride or dichloromethane extraction, by Calcium Chloride Powder Anhydrous or molecular sieve drying, underpressure distillation goes out part methylene chloride or ethylene dichloride, and crystallisation by cooling obtains product.
In aforesaid method, the organic solvent steamed is applied mechanically to next batch.
Specifically, synthesis preparation method of the present invention comprises the following steps:
(1) in the mixing solutions of phosphorus oxychloride and 4-chloro-6-methoxylpyrimidin, add anhydrous organic amine, its temperature of reaction controls at 70 ~ 115 DEG C, is preferably 80 ~ 105 DEG C, reaction times 3-8 hour;
(2) mixture after complete for described reaction is cooled to 55 ~ 70 DEG C, underpressure distillation goes out excessive phosphorus oxychloride, and the temperature of underpressure distillation is 65 ~ 100 DEG C; Pressure is-0.06 ~-0.095Mpa;
(3) mixture after described underpressure distillation is cooled to 60 ~ 80 DEG C, is added drop-wise in mixture of ice and water, temperature controls at-5 ~ 5 DEG C, and pH value is 3 ~ 7.
(4) mixture after underpressure distillation is added drop-wise in frozen water, filter, by methylene dichloride or the first aqueous phase extracted of ethylene dichloride, divide phase of anhydrating, then dissolving filter cake, filters, takes Calcium Chloride Powder Anhydrous or molecular sieve drying, underpressure distillation part organic solvent dichloromethane or ethylene dichloride, be cooled to-2 ~-5 DEG C of crystallizations to obtain product.
In waste water, add 30%NaOH adjust pH=12 ~ 13, underpressure distillation obtains organic amine.
The present invention is under anhydrous organic amine exists, use 4-chloro-6-methoxylpyrimidin and phosphorus oxychloride reaction obtained 4, 6-dichloro pyrimidine, because the phosphorus oxychloride facile hydrolysis in reactant produces phosphoric acid and hydrochloric acid, affect 4, 6-dichloro pyrimidine yield, in order to avoid the generation of the above results, therefore, the present invention takes underpressure distillation upon reaction completion to go out excessive phosphorus oxychloride, both the decomposition of excessive phosphorus oxychloride in water had been avoided, acidity in system is increased, thus affect 4, the yield of 6-dichloro pyrimidine, turn improve the utilization ratio of phosphorus oxychloride, cut down the consumption of raw materials, cost-saving, decrease the treatment capacity of phosphorus-containing wastewater.
Participate in the water-fast organic amine of reaction in the present invention by adding NaOH solution in waste water, pH value is 12 ~ 14, and the method for then distilling reclaims, and further so again reduces costs, and reduces the treatment capacity of ammonia nitrogen waste water.
Instrument used in the present invention, equipment and organic amine all carry out drying treatment before use, are all the hydrolysis in order to phosphorus oxychloride in inhibition system, to ensure purity and the yield of product 4,6-dichloro pyrimidine.
Compared with prior art, the invention has the beneficial effects as follows:
The method reduces the danger of building-up reactions, improves the utilization ratio of 4,6-dichloro pyrimidines in Azoxystrobin synthesis technique, reduces production cost, reduces solid waste, alleviates the burden to environment.Adopt preparation method of the present invention, the purity of 4,6-dichloro pyrimidine is high, and yield is high.
Embodiment
Below by embodiment, the present invention is described, but the present invention is not limited to following examples.
Embodiment 1: by 4-chloro-6-methoxylpyrimidin (100g, 0.985mol, content 98.5%) add phosphorus oxychloride (400g, 2.61moL), then add with the dried DMF(dimethyl formamide of sheet NaOH) 30g, heat up, temperature of reaction controls at 80 ~ 85 DEG C, react 7 hours, be cooled to 60 DEG C, underpressure distillation goes out excessive phosphorus oxychloride, the temperature of underpressure distillation is 85 DEG C, obtain 185g phosphorus oxychloride, the reaction mixture (temperature controls at 60 ~ 80 DEG C) of remainder is added drop-wise in frozen water, temperature is 0 DEG C, separate out yellow crystal, control pH=6, filter out 4, 6-dichloro pyrimidine, by the first aqueous phase extracted of ethylene dichloride, divide phase of anhydrating, and then dissolution filter go out 4, 6-dichloro pyrimidine, suction filtration, with the dry ethylene dichloride organic solvent of Calcium Chloride Powder Anhydrous, decompression steams part ethylene dichloride, decrease temperature crystalline obtains faint yellow needle-like solid 4, 6-dichloro pyrimidine 139.37g, purity 99.6%, yield 95.6%.
Embodiment 2: by 4-chloro-6-methoxylpyrimidin (100g, 0.985mol, content 98.5%) add phosphorus oxychloride (400g, 2.61moL), then add with the dried N of sheet NaOH, N-diisopropylethylamine 38g, heat up, temperature of reaction controls at 100 DEG C, react 7 hours, be cooled to 60 DEG C, underpressure distillation goes out excessive phosphorus oxychloride, the temperature of underpressure distillation is 85 DEG C, obtain 191.6g phosphorus oxychloride, the reaction mixture (temperature controls at 60 ~ 80 DEG C) of remainder is added drop-wise in frozen water, temperature is 0 DEG C, separate out yellow crystal, control pH=6, filter out 4, 6-dichloro pyrimidine, by the first aqueous phase extracted of methylene dichloride, divide phase of anhydrating, and then dissolution filter go out 4, 6-dichloro pyrimidine, suction filtration, with the dry ethylene dichloride organic solvent of Calcium Chloride Powder Anhydrous, decompression steams part ethylene dichloride, decrease temperature crystalline obtains faint yellow needle-like solid 4, 6-dichloro pyrimidine 138.37g, purity 99.3%, yield 97.55%.
The recovery of DIPEA, in waste water, add 30%NaOH adjust pH=12 ~ 13, underpressure distillation obtains DIPEA 35.3g.
Embodiment 3: by 4-chloro-6-methoxylpyrimidin (100g, 0.985mol, content 98.5%) add phosphorus oxychloride (400g, 2.61moL), then add with the dried N of sheet NaOH, accelerine 30g, heat up, temperature of reaction controls at 110 DEG C, react 8 hours, be cooled to 55 DEG C, underpressure distillation goes out excessive phosphorus oxychloride, the temperature of underpressure distillation is 85 DEG C, obtain 185g phosphorus oxychloride, the reaction mixture (temperature controls at 60 ~ 80 DEG C) of remainder is added drop-wise in frozen water, temperature is 0 DEG C, separate out yellow crystal, control pH=6, filter out 4, 6-dichloro pyrimidine, by the first aqueous phase extracted of ethylene dichloride, divide phase of anhydrating, and then dissolution filter go out 4, 6-dichloro pyrimidine, suction filtration, with the dry ethylene dichloride organic solvent of Calcium Chloride Powder Anhydrous, decompression steams part ethylene dichloride, decrease temperature crystalline obtains faint yellow needle-like solid 4, 6-dichloro pyrimidine 133.5g, purity 99.3%, yield 94.12%.
In waste water, add 30%NaOH adjust pH=12 ~ 13, underpressure distillation obtains DIPEA 25.4g.
Embodiment 4: by 4-chloro-6-methoxylpyrimidin (100g, 0.985mol, content 98.5%) add phosphorus oxychloride (400g, 2.61moL), then add with the dried N of sheet NaoDH, N-Diethyl Aniline 35g, heat up, temperature of reaction controls at 100 DEG C, react 6 hours, be cooled to 65 DEG C, underpressure distillation goes out excessive phosphorus oxychloride, the temperature of underpressure distillation is 85 DEG C, obtain 201.1g phosphorus oxychloride, the reaction mixture (temperature controls at 60 ~ 80 DEG C) of remainder is added drop-wise in frozen water, temperature is 0 DEG C, separate out yellow crystal, control pH=6, filter out 4, 6-dichloro pyrimidine, by the first aqueous phase extracted of ethylene dichloride, divide phase of anhydrating, and then dissolution filter go out 4, 6-dichloro pyrimidine, suction filtration, with the dry ethylene dichloride organic solvent of Calcium Chloride Powder Anhydrous, decompression steams part ethylene dichloride, decrease temperature crystalline obtains faint yellow needle-like solid 4, 6-dichloro pyrimidine 135.5g, purity 99.8%, yield 95.53%,
The recovery of N, N-Diethyl Aniline, in waste water, add 30%NaOH adjust pH=12 ~ 13, underpressure distillation obtains DIPEA 30.9g.
Claims (4)
1. a 4-chloro-6-methoxylpyrimidin synthesis 4, the method of 6-dichloro pyrimidine, it is characterized in that: by the 4-chloro-6-methoxylpyrimidin 100g of content 98.5%, i.e. 0.985mol, add phosphorus oxychloride 400g, i.e. 2.61mol, then add with the dried DMF dimethyl formamide 30g of sheet NaOH, heat up, temperature of reaction controls at 80 ~ 85 DEG C, react 7 hours, be cooled to 60 DEG C, underpressure distillation goes out excessive phosphorus oxychloride, the temperature of underpressure distillation is 85 DEG C, obtain 185g phosphorus oxychloride, the temperature of remainder is controlled to be added drop-wise in frozen water at the reaction mixture of 60 ~ 80 DEG C, temperature is 0 DEG C, separate out yellow crystal, control pH=6, filter out 4, 6-dichloro pyrimidine, by the first aqueous phase extracted of ethylene dichloride, divide phase of anhydrating, and then dissolution filter go out 4, 6-dichloro pyrimidine, suction filtration, with the dry ethylene dichloride organic solvent of Calcium Chloride Powder Anhydrous, decompression steams part ethylene dichloride, decrease temperature crystalline obtains faint yellow needle-like solid.
2. a 4-chloro-6-methoxylpyrimidin synthesis 4, the method of 6-dichloro pyrimidine, it is characterized in that: by the 4-chloro-6-methoxylpyrimidin 100g of content 98.5%, i.e. 0.985mol, add phosphorus oxychloride 400g, i.e. 2.61mol, then add with the dried N of sheet NaOH, N-diisopropylethylamine 38g, heat up, temperature of reaction controls at 100 DEG C, react 7 hours, be cooled to 60 DEG C, underpressure distillation goes out excessive phosphorus oxychloride, the temperature of underpressure distillation is 85 DEG C, obtain 191.6g phosphorus oxychloride, the temperature of remainder is controlled to be added drop-wise in frozen water at the reaction mixture of 60 ~ 80 DEG C, temperature is 0 DEG C, separate out yellow crystal, control pH=6, filter out 4, 6-dichloro pyrimidine, by the first aqueous phase extracted of methylene dichloride, divide phase of anhydrating, and then dissolution filter go out 4, 6-dichloro pyrimidine, suction filtration, with the dry ethylene dichloride organic solvent of Calcium Chloride Powder Anhydrous, decompression steams part ethylene dichloride, decrease temperature crystalline obtains faint yellow needle-like solid 4, 6-dichloro pyrimidine.
3. a 4-chloro-6-methoxylpyrimidin synthesis 4, the method of 6-dichloro pyrimidine, it is characterized in that: by the 4-chloro-6-methoxylpyrimidin 100g of content 98.5%, i.e. 0.985mol, add phosphorus oxychloride 400g, i.e. 2.61mol, then add with the dried N of sheet NaOH, accelerine 30g, heat up, temperature of reaction controls at 110 DEG C, react 8 hours, be cooled to 55 DEG C, underpressure distillation goes out excessive phosphorus oxychloride, the temperature of underpressure distillation is 85 DEG C, obtain 185g phosphorus oxychloride, the temperature of remainder is controlled to be added drop-wise in frozen water at the reaction mixture of 60 ~ 80 DEG C, temperature is 0 DEG C, separate out yellow crystal, control pH=6, filter out 4, 6-dichloro pyrimidine, by the first aqueous phase extracted of ethylene dichloride, divide phase of anhydrating, and then dissolution filter go out 4, 6-dichloro pyrimidine, suction filtration, with the dry ethylene dichloride organic solvent of Calcium Chloride Powder Anhydrous, decompression steams part ethylene dichloride, decrease temperature crystalline obtains faint yellow needle-like solid 4, 6-dichloro pyrimidine.
4. a 4-chloro-6-methoxylpyrimidin synthesis 4, the method of 6-dichloro pyrimidine, it is characterized in that: by the 4-chloro-6-methoxylpyrimidin 100g of content 98.5%, i.e. 0.985mol, add phosphorus oxychloride 400g, i.e. 2.61mol, then add with the dried N of sheet NaOH, N-Diethyl Aniline 35g, heat up, temperature of reaction controls at 100 DEG C, react 6 hours, be cooled to 65 DEG C, underpressure distillation goes out excessive phosphorus oxychloride, the temperature of underpressure distillation is 85 DEG C, obtain 201.1g phosphorus oxychloride, the temperature of remainder is controlled be added drop-wise in frozen water at 60 ~ 80 DEG C of reaction mixtures, temperature is 0 DEG C, separate out yellow crystal, control pH=6, filter out 4, 6-dichloro pyrimidine, by the first aqueous phase extracted of ethylene dichloride, divide phase of anhydrating, and then dissolution filter go out 4, 6-dichloro pyrimidine, suction filtration, with the dry ethylene dichloride organic solvent of Calcium Chloride Powder Anhydrous, decompression steams part ethylene dichloride, decrease temperature crystalline obtains faint yellow needle-like solid 4, 6-dichloro pyrimidine.
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| US6441170B1 (en) * | 1999-06-26 | 2002-08-27 | Bayer Akitnegesellschaft | Method of producing 4,6-dichloropyrimidine with acid chlorides |
| US6525198B1 (en) * | 1999-08-13 | 2003-02-25 | Bayer Aktiengesellschaft | Method for producing 4,6-dichloropyrimidine with sulfur compounds and phosphorus compounds |
| CN1697829A (en) * | 2000-06-26 | 2005-11-16 | 辛甄塔有限公司 | Synthesis of chlorinated pyrimidines |
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Patent Citations (3)
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|---|---|---|---|---|
| US6441170B1 (en) * | 1999-06-26 | 2002-08-27 | Bayer Akitnegesellschaft | Method of producing 4,6-dichloropyrimidine with acid chlorides |
| US6525198B1 (en) * | 1999-08-13 | 2003-02-25 | Bayer Aktiengesellschaft | Method for producing 4,6-dichloropyrimidine with sulfur compounds and phosphorus compounds |
| CN1697829A (en) * | 2000-06-26 | 2005-11-16 | 辛甄塔有限公司 | Synthesis of chlorinated pyrimidines |
Non-Patent Citations (2)
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| 4,6-二氯嘧啶的合成研究;彭军等;《精细化工中间体》;20091231;第39卷(第6期);第15页左栏2.3.2部分 * |
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