CN111039874B - Zero-wastewater preparation method of 2-amino-4-methylpyrimidine compound - Google Patents
Zero-wastewater preparation method of 2-amino-4-methylpyrimidine compound Download PDFInfo
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- 239000002351 wastewater Substances 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- -1 2-amino-4-methylpyrimidine compound Chemical class 0.000 title claims description 14
- 238000000034 method Methods 0.000 claims abstract description 16
- GHCFWKFREBNSPC-UHFFFAOYSA-N 2-Amino-4-methylpyrimidine Chemical class CC1=CC=NC(N)=N1 GHCFWKFREBNSPC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229960000789 guanidine hydrochloride Drugs 0.000 claims abstract description 8
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 claims abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 22
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 7
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 7
- 229960004198 guanidine Drugs 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- NDEMNVPZDAFUKN-UHFFFAOYSA-N guanidine;nitric acid Chemical compound NC(N)=N.O[N+]([O-])=O.O[N+]([O-])=O NDEMNVPZDAFUKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 2
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 7
- PJCCSZUMZMCWSX-UHFFFAOYSA-N 4,4-Dimethoxy-2-butanone Chemical compound COC(OC)CC(C)=O PJCCSZUMZMCWSX-UHFFFAOYSA-N 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 241000223600 Alternaria Species 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 241000221785 Erysiphales Species 0.000 description 1
- 206010027146 Melanoderma Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010039509 Scab Diseases 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- VGBNSONMEGTIDX-UHFFFAOYSA-N methyl 2-[(4-methylpyrimidin-2-yl)carbamoylsulfamoyl]benzoate Chemical group COC(=O)C1=CC=CC=C1S(=O)(=O)NC(=O)NC1=NC=CC(C)=N1 VGBNSONMEGTIDX-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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Abstract
本发明公开了一种2‑胺基‑4‑甲基嘧啶化合物的零废水制备方法，具体的，4,4‑二甲氧基‑2‑丁酮和盐酸胍在碱条件下反应，经过简单后处理即可得到产物。此方法由于没有工艺废水生成，解决了目前生产中产生了大量废水的问题。操作过程简单稳定，安全性高，能耗低，易于工业化的实施。The invention discloses a zero-wastewater preparation method of 2-amino-4-methylpyrimidine compounds. Specifically, 4,4-dimethoxy-2-butanone and guanidine hydrochloride are reacted under alkaline conditions, and the process is simple The product can be obtained after post-treatment. This method solves the problem that a large amount of waste water is produced in the current production because no process waste water is generated. The operation process is simple and stable, the safety is high, the energy consumption is low, and the industrialized implementation is easy.
Description
技术领域technical field
本发明公开了一种2-胺基-4-甲基嘧啶化合物的制备方法。The invention discloses a preparation method of 2-amino-4-methylpyrimidine compound.
背景技术Background technique
2-胺基-4-甲基嘧啶是一类具有良好生物活性的含氮杂环化合物，在生物体内有很重要的生理作用，并被广泛应用于医药及农药合成中。1968年Shephard等人报道了其杀菌活性，其作用方式是干扰细胞内分泌蛋白质的转移过程。对苹果褐腐病、黑星病、灰霉病有优异的防效，对白粉病、柑桔树脂病、黑斑病、叶斑病及交链孢菌产生的病害有很好的防效。同时2-胺基-4-甲基嘧啶也是超高效磺酰脲除草剂单嘧磺隆和单嘧磺酯的中间体。2-Amino-4-methylpyrimidine is a kind of nitrogen-containing heterocyclic compound with good biological activity. It has very important physiological functions in organisms and is widely used in the synthesis of medicine and pesticides. In 1968, Shephard et al. reported its bactericidal activity, and its mode of action was to interfere with the transfer process of endocrine proteins in cells. It has excellent control effect on apple brown rot, scab and gray mold, and has good control effect on powdery mildew, citrus resin disease, black spot, leaf spot and diseases caused by Alternaria. At the same time, 2-amino-4-methylpyrimidine is also an intermediate of super-efficient sulfonylurea herbicides monosulfuron-methyl and monosulfuronate.
已有大量文献报道了2-胺基-4-甲基嘧啶的合成方法，例如：Mark C.Bagley等人在Synlett 2003,2,259–261提出用甲基炔基酮作为原料，在碱作用下和胍反应得到2-胺基-4-甲基嘧啶，但是这个方法有很大的局限性，例如原料不易得到，需要微波反应，不利于工业化。刘幸海等人在CN101851229A中采用的甲苯作溶剂，丙酮和甲酸乙酯在醇钠条件下缩合，之后和盐酸胍关环得到产品，这个方法的缺点是收率低，经过作者优化后仅仅只能达到50％的收率。同时，在蒸馏低沸物时，由于甲苯和原料共沸，需要带出大量的溶剂，而在回收溶剂的过程中，需要大量的水洗，这样就产生废水。而且倾倒的操作在生产过程中不好实现。A large number of documents have reported the synthetic method of 2-amino-4-methylpyrimidine, for example: Mark C.Bagley et al proposed using methyl alkynyl ketone as raw material in Synlett 2003,2,259-261, under the action of alkali and Guanidine reaction gives 2-amino-4-methylpyrimidine, but this method has great limitations, for example, the raw materials are not easy to obtain, and microwave reaction is required, which is not conducive to industrialization. Liu Xinghai et al. used toluene as a solvent in CN101851229A, acetone and ethyl formate were condensed under sodium alkoxide conditions, and then closed with guanidine hydrochloride to obtain the product. The disadvantage of this method is that the yield is low, and after optimization by the author, it can only reach 50% yield. At the same time, when distilling low boilers, due to the azeotropy of toluene and raw materials, a large amount of solvent needs to be taken out, and in the process of solvent recovery, a large amount of water washing is required, thus generating waste water. And the operation of dumping is difficult to realize in the production process.
发明内容Contents of the invention
基于上述问题，本发明在之前基础上，提供一种简单的2-胺基-4-甲基嘧啶的制备方法，此工艺简单，条件温和，能够解决现有的废水问题及其不好实现工业化的技术问题。Based on the above-mentioned problems, the present invention provides a simple preparation method of 2-amino-4-methylpyrimidine on the previous basis. The process is simple, the conditions are mild, and it can solve the existing wastewater problem and it is not easy to realize industrialization. technical issues.
本发明的目的是通过以下方案实现的：The purpose of the present invention is achieved by the following scheme:
一种如图所示的2-胺基-4-甲基嘧啶的制备方法，包括下述步骤：在溶剂中，4,4-二甲氧基-2-丁酮和盐酸胍在碱条件下发生关环反应得到产物。A preparation method of 2-amino-4-methylpyrimidine as shown in the figure, comprising the steps: in a solvent, 4,4-dimethoxy-2-butanone and guanidine hydrochloride under alkaline conditions A ring closure reaction occurs to obtain the product.
反应方程式如下：The reaction equation is as follows:
本发明中所述的具体的制备方法按以下步骤进行：Concrete preparation method described in the present invention carries out according to the following steps:
溶剂在搅拌下分批加入醇钠。分批加入捣碎的盐酸胍(硝酸胍)，让各物料充分接触。搅拌一段时间后，温度逐渐升高，控制一定温度下发生中和反应，释放出游离胍。The solvent was added portionwise to the sodium alkoxide with stirring. Add crushed guanidine hydrochloride (guanidine nitrate) in batches to allow the materials to fully contact. After stirring for a period of time, the temperature gradually rises, and a neutralization reaction occurs at a controlled temperature to release free guanidine.
加入原料4,4-二烷氧基-2-丁酮。升高温度继续搅拌。之后加热回流2小时。加热精馏蒸低沸物，溶液温度逐渐升高，当溶液温度达到110℃时，停止加热。开始热过滤，整个过滤体系保保持一定温度，放入上述反应液，热过滤，去掉盐，滤液冷却结晶得到产品。The starting material 4,4-dialkoxy-2-butanone was added. Increase the temperature and continue stirring. It was then heated to reflux for 2 hours. Heat and rectify to distill low boilers, the temperature of the solution rises gradually, and when the temperature of the solution reaches 110°C, stop heating. Start hot filtration, keep the entire filtration system at a certain temperature, put in the above reaction solution, heat filtration, remove salt, and cool and crystallize the filtrate to obtain the product.
本发明中所述的4,4-二烷氧基-2-丁酮：醇钠：胍的投料摩尔比为1:1～1.5:1～1.5，优选为1:1～1.1:1～1.2。The molar ratio of 4,4-dialkoxy-2-butanone:sodium alkoxide:guanidine in the present invention is 1:1～1.5:1～1.5, preferably 1:1～1.1:1～1.2 .
本发明中所述的溶剂为甲苯，二甲苯或者氯苯，优选为甲苯，溶剂的量为原料醇钠的5～10倍。The solvent described in the present invention is toluene, xylene or chlorobenzene, preferably toluene, and the amount of the solvent is 5 to 10 times that of the raw material sodium alkoxide.
本发明中所述的醇钠为甲醇钠，乙醇钠，异丙醇钠，叔丁醇钠，优选甲醇钠或者乙醇钠。The sodium alkoxide described in the present invention is sodium methylate, sodium ethylate, sodium isopropoxide, sodium tert-butoxide, preferably sodium methylate or sodium ethylate.
本发明中所述的胍为盐酸胍或者硝酸胍。Guanidine described in the present invention is guanidine hydrochloride or guanidine nitrate.
本发明中所述的4,4-二烷氧基-2-丁酮中烷基为甲基，乙基，异丙基。优选甲基。The alkyl group in the 4,4-dialkoxy-2-butanone described in the present invention is methyl, ethyl and isopropyl. Methyl is preferred.
本发明中所述的中和反应温度为10～50℃，优选为20～40℃，反应时间为0.5～5h。The neutralization reaction temperature in the present invention is 10-50°C, preferably 20-40°C, and the reaction time is 0.5-5h.
本发明中所述的关环反应温度为30～100℃，优选为50～70℃，反应时间为1～5h。The ring-closing reaction temperature in the present invention is 30-100° C., preferably 50-70° C., and the reaction time is 1-5 hours.
本发明中所述的热过滤温度60～150℃，优选为80～110℃。The thermal filtration temperature in the present invention is 60-150°C, preferably 80-110°C.
与现有技术相比，此发明具有以下优点：整个反应不产生废水，属于零废水工艺，并且容易工业化生产。具有良好的应用价值。Compared with the prior art, the invention has the following advantages: the whole reaction does not produce waste water, belongs to the zero waste water process, and is easy for industrialized production. It has good application value.
附图说明：Description of drawings:
图1：一种2-胺基-4-甲基嘧啶化合物的制备方法，反应方程式。Figure 1: A preparation method of 2-amino-4-methylpyrimidine compound, reaction equation.
具体实施方式Detailed ways
为了更好地叙述本发明，通过以下实施例进行具体表述，但是本发明不受这些实施例的任何限制。In order to describe the present invention better, the following examples are used for specific expression, but the present invention is not limited by these examples.
实施例1：取干净干燥的四口瓶中，加入甲苯350ml，搅拌下分批加入甲醇钠50g。通过水浴调节釜温28--32℃，分批加入研磨碎的盐酸胍85g，水浴控制温度控制在28--35℃之间，于此温度下搅拌2小时。加入原料4,4-二甲氧基-2-丁酮110g。升高温度到55-60℃搅拌。继续搅拌1小时。之后加热回流2小时。加热精馏蒸低沸物，溶液温度逐渐升高，当溶液温度达到110℃，停止加热。开始热过滤，整个过滤体系保温到100℃左右，放入上述反应液，过滤，去掉盐，滤液冷却冷却到10℃，结晶得到产品，盐用甲苯母液重新加热过滤二次。两次结晶得到的产品干燥即可得到产品2-胺基-4-甲基嘧啶：77g，纯度93.5％。Example 1: Take a clean and dry four-necked bottle, add 350 ml of toluene, and add 50 g of sodium methoxide in batches under stirring. Adjust the kettle temperature to 28--32°C with a water bath, add 85 g of ground guanidine hydrochloride in batches, control the temperature of the water-bath at 28--35°C, and stir at this temperature for 2 hours. 110 g of raw material 4,4-dimethoxy-2-butanone was added. Raise the temperature to 55-60°C and stir. Stirring was continued for 1 hour. It was then heated to reflux for 2 hours. Heat and rectify to distill low boilers, the solution temperature rises gradually, when the solution temperature reaches 110°C, stop heating. Start hot filtration, heat the entire filtration system to about 100°C, put in the above reaction solution, filter, remove the salt, cool the filtrate to 10°C, crystallize to obtain the product, reheat the salt with toluene mother liquor and filter twice. The product obtained by the two crystallizations was dried to obtain the product 2-amino-4-methylpyrimidine: 77g, with a purity of 93.5%.
实施例2：取干净干燥的四口瓶中，加入二甲苯200ml，搅拌下分批加入乙醇钠31.5g。通过水浴调节釜温28--32℃，分批加入研磨碎的盐酸胍42.5g，水浴控制温度控制在28--35℃之间，于此温度下搅拌2小时。加入原料4,4-二甲氧基-2-丁酮。升高温度到55-60℃搅拌。继续搅拌1小时。之后加热回流2小时。加热精馏蒸低沸物，溶液温度逐渐升高，当溶液温度达到110℃，停止加热。开始热过滤，整个过滤体系保温到100℃左右，放入上述反应液，过滤，去掉盐，滤液冷却到10℃左右，结晶得到产品，盐用二甲苯母液重新加热过滤二次，就可以得到比较纯的氯化钠。两次结晶得到的产品干燥即可得到产品2-胺基-4-甲基嘧啶：37.4g，纯度94.1％。Example 2: Take a clean and dry four-necked bottle, add 200ml of xylene, and add 31.5g of sodium ethylate in batches under stirring. Adjust the temperature of the kettle to 28-32°C with a water bath, add 42.5 g of ground guanidine hydrochloride in batches, control the temperature of the water bath at 28-35°C, and stir at this temperature for 2 hours. The starting material 4,4-dimethoxy-2-butanone was added. Raise the temperature to 55-60°C and stir. Stirring was continued for 1 hour. It was then heated to reflux for 2 hours. Heat and rectify to distill low boilers, the solution temperature rises gradually, when the solution temperature reaches 110°C, stop heating. Start hot filtration, heat the entire filtration system to about 100°C, put in the above reaction solution, filter, remove the salt, cool the filtrate to about 10°C, crystallize to obtain the product, reheat and filter the salt with xylene mother liquor twice, and you can get a comparison pure sodium chloride. The product obtained by the two crystallizations was dried to obtain the product 2-amino-4-methylpyrimidine: 37.4 g, with a purity of 94.1%.
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| CN101851229A (en) * | 2010-06-11 | 2010-10-06 | 浙江工业大学 | N-substituted pyridinoyl-N-substituted pyrimidinylthiourea derivatives and their preparation and application |
| CN107108644A (en) * | 2014-11-11 | 2017-08-29 | 皮奎尔治疗公司 | Difluoromethyl aminopyridine and difluoromethyl aminopyrimidine |
| CN107619388A (en) * | 2016-07-13 | 2018-01-23 | 南京天印健华医药科技有限公司 | Heterocyclic compound as FGFR inhibitor |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101851229A (en) * | 2010-06-11 | 2010-10-06 | 浙江工业大学 | N-substituted pyridinoyl-N-substituted pyrimidinylthiourea derivatives and their preparation and application |
| CN107108644A (en) * | 2014-11-11 | 2017-08-29 | 皮奎尔治疗公司 | Difluoromethyl aminopyridine and difluoromethyl aminopyrimidine |
| CN107619388A (en) * | 2016-07-13 | 2018-01-23 | 南京天印健华医药科技有限公司 | Heterocyclic compound as FGFR inhibitor |
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| Flexible Synthesis of Pyrimidines with Chiral Monofluorinated and Difluoromethyl Side Chains;Pierre Bannwarth et al.;《J. Org. Chem.》;20090519;4646-4649 * |
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