技术领域technical field
本发明涉及合成抗病毒药物利巴韦林的关键中间体的制备，尤其涉及一锅法制备1,2,4- 三氮唑-3-甲酰胺的方法。The invention relates to the preparation of a key intermediate for synthesizing antiviral drug ribavirin, in particular to a method for preparing 1,2,4-triazole-3-carboxamide in one pot.
背景技术Background technique
利巴韦林是广谱强效的抗病毒药物，属合成核苷类药，对呼吸道合胞病毒、副流感病毒、甲肝病毒和艾滋病病毒等均有抑制作用，1,2,4-三氮唑-3-甲酰胺是合成利巴韦林的关键中间体，Witkowski等用酶催化三氮唑甲酰胺与核糖-1-磷酸合成利巴韦林，详见美国专利 US3976545。Ribavirin is a broad-spectrum and potent antiviral drug, which is a synthetic nucleoside drug, and has inhibitory effects on respiratory syncytial virus, parainfluenza virus, hepatitis A virus and HIV. 1,2,4-triazine Azole-3-carboxamide is a key intermediate for the synthesis of ribavirin. Witkowski et al. used enzymes to catalyze the synthesis of ribavirin from triazole carboxamide and ribose-1-phosphate. See US Patent No. 3,976,545 for details.
目前，制备1,2,4-三氮唑-3-甲酰胺的合成路线主要有三种，第一种是以1,2,4-三氮唑-3- 甲酸为原料经甲酯化或乙酯化生成1,2,4-三氮唑-3-甲酸甲酯或1,2,4-三氮唑-3-甲酸乙酯，再经氨解制备1,2,4-三氮唑-3-甲酰胺。向1,2,4-三氮唑-3-甲酸甲酯的甲醇溶液中通入氨气至饱和，室温下反应48小时氨解制备目标产物，反应式如下所示：At present, there are three main synthetic routes for the preparation of 1,2,4-triazole-3-carboxamide. The first is to use 1,2,4-triazole-3-carboxylic acid as raw material through methyl esterification or ethyl alcohol Esterification to generate 1,2,4-triazole-3-carboxylic acid methyl ester or 1,2,4-triazole-3-carboxylic acid ethyl ester, and then prepare 1,2,4-triazole-3-carboxylic acid ethyl ester by ammonia solution 3-Formamide. Ammonia gas was introduced into the methanol solution of 1,2,4-triazole-3-carboxylate to saturation, and the target product was prepared by ammonolysis at room temperature for 48 hours. The reaction formula is as follows:
上述第一种方法所用原料1,2,4-三氮唑-3-羧酸酯合成路线长，原料成本高，三废量大。The raw material 1,2,4-triazole-3-carboxylate used in the first method above has a long synthetic route, high cost of raw materials, and a large amount of three wastes.
第二种是以草胺酰肼为原料，与乙酸甲脒关环制备1,2,4-三氮唑-3-甲酰胺，以草酰胺肼为原料，乙醇为溶剂，加入乙酸甲脒后升温回流环化制备目标化合物1,2,4-三氮唑-3-甲酰胺。反应式如下所示：The second is to prepare 1,2,4-triazole-3-carboxamide by ring-closing oxalamidohydrazide with formamidine acetate, using oxalamidohydrazide as raw material, ethanol as solvent, and adding formamidine acetate The target compound 1,2,4-triazole-3-carboxamide was prepared by heating and reflux cyclization. The reaction formula is as follows:
上述第二种方法使用的原料乙酸甲脒由氢氰酸制备，原料不易得到，价格较高使产品成本较高。The raw material formamidine acetate used in the above-mentioned second method is prepared by hydrocyanic acid, and the raw material is difficult to obtain, and the higher price makes the product cost higher.
第三种方法是以1,2,4-三氮唑-3-羧酸二聚体为起始原料，比如德国专利DE1979-2940654 以1,2,4-三氮唑-3-羧酸二聚体为原料，在氨水中加热氨解，反应完成后蒸发掉多余的氨，生成1,2,4-三氮唑-3-甲酰胺，反应式如式3所示：The third method uses 1,2,4-triazole-3-carboxylic acid dimer as the starting material, such as the German patent DE1979-2940654 with 1,2,4-triazole-3-carboxylic acid dimer The polymer is used as a raw material, and ammonium is heated in ammonia water. After the reaction is completed, the excess ammonia is evaporated to generate 1,2,4-triazole-3-carboxamide. The reaction formula is shown in formula 3:
上述第三种方法中的1,2,4-三氮唑-3-羧酸二聚体仍需由1,2,4-三氮唑-3-羧酸经氯化亚砜脱水制备，产生二氧化硫气体污染严重，三废量大，生产成本较高。The 1,2,4-triazole-3-carboxylic acid dimer in the above third method still needs to be prepared by dehydration of 1,2,4-triazole-3-carboxylic acid through thionyl chloride to produce Sulfur dioxide gas pollution is serious, the amount of three wastes is large, and the production cost is high.
有鉴于此，提供一种反应原料廉价易得、降低生产成本、合成工艺简单的制备1,2,4-三氮唑 -3-甲酰胺的方法，具有重要意义。In view of this, it is of great significance to provide a method for preparing 1,2,4-triazole-3-carboxamide with cheap and easy-to-obtain reaction raw materials, reduced production cost, and simple synthesis process.
发明内容Contents of the invention
为了解决现有技术中的1,2,4-三氮唑-3-甲酰胺的制备方法原料成本高、合成路线繁琐以及三废量大的问题，本发明提供了一锅法制备1,2,4-三氮唑-3-甲酰胺的方法。In order to solve the problems of high raw material cost, cumbersome synthetic route and large amount of three wastes in the preparation method of 1,2,4-triazole-3-carboxamide in the prior art, the present invention provides a one-pot method for preparing 1,2, 4-Triazole-3-carboxamide method.
为了解决上述技术问题，本发明采用以下技术方案：In order to solve the above technical problems, the present invention adopts the following technical solutions:
一锅法制备1,2,4-三氮唑-3-甲酰胺的方法，草酰胺和N,N-二甲基缩醛发生缩合反应，缩合反应的产物在催化剂作用下与肼或肼盐环化反应合成1,2,4-三氮唑-3-甲酰胺，反应如下式所示：A one-pot method for preparing 1,2,4-triazole-3-carboxamide, oxamide and N,N-dimethyl acetal undergo condensation reaction, and the product of the condensation reaction reacts with hydrazine or hydrazine salt under the action of a catalyst The cyclization reaction synthesizes 1,2,4-triazole-3-carboxamide, and the reaction is shown in the following formula:
其中，N,N-二甲基缩醛中烷基R选自甲基，乙基，丙基，异丙基或正丁基。Wherein, the alkyl group R in N,N-dimethyl acetal is selected from methyl, ethyl, propyl, isopropyl or n-butyl.
本发明提供的反应原料与现有技术中的相比，草酰胺、N,N-二甲基缩醛以及肼或肼盐价格低廉，原料易得，反应是在一锅内完成，反应路线简短，工艺简单。Compared with the reaction raw materials in the prior art, the reaction raw materials provided by the present invention are oxamide, N,N-dimethyl acetal, hydrazine or hydrazine salt, which are cheap, and the raw materials are easy to obtain. The reaction is completed in one pot, and the reaction route is short ,Simple process.
所述原料草酰胺可以是通过市售购买，也可以由草酸二乙酯或草酸二甲酯经常规氨解制备而成。The raw material oxamide can be purchased from the market, or can be prepared from diethyl oxalate or dimethyl oxalate through conventional aminolysis.
所述肼为纯肼、水合肼或肼盐，优选地，所述肼盐为硫酸肼、盐酸肼或碳酸肼。The hydrazine is pure hydrazine, hydrazine hydrate or hydrazine salt, preferably, the hydrazine salt is hydrazine sulfate, hydrazine hydrochloride or hydrazine carbonate.
本发明提供的缩合反应的有机溶剂为极性有机溶剂；所述极性有机溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、甲酰胺、N-甲基吡咯烷酮或醇类有机溶剂；作为优选，所述醇类有机溶剂为甲醇、乙醇、异丙醇、丁醇、正戊醇、异戊醇或乙二醇的一种或几种，更为优选地，醇类有机溶剂为异戊醇。The organic solvent of the condensation reaction provided by the present invention is a polar organic solvent; the polar organic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, formaldehyde Amide, N-methylpyrrolidone or alcohol organic solvent; As preferably, the alcohol organic solvent is one or more of methanol, ethanol, isopropanol, butanol, n-amyl alcohol, isoamyl alcohol or ethylene glycol One, more preferably, the alcoholic organic solvent is isoamyl alcohol.
整个反应体系的压力为0.1-5Mpa，反应的加热方式为直接常规加热或微波加热方式。The pressure of the whole reaction system is 0.1-5Mpa, and the heating method of the reaction is direct conventional heating or microwave heating.
本发明还提供了由上述方法制备的1,2,4-三氮唑-3-甲酰胺。The present invention also provides 1,2,4-triazole-3-carboxamide prepared by the above method.
本发明提供了一锅法制备1,2,4-三氮唑-3-甲酰胺的方法。该方法的草酰胺、N,N-二甲基缩醛以及肼或肼盐价格低廉，原料易得，反应是在一锅内完成，合成路线短；同时反应产物经冷却、过滤、水洗及干燥即可得产物，后处理方便简单；反应不会产生污染，三废量少，适合于工业化生产。The invention provides a one-pot method for preparing 1,2,4-triazole-3-carboxamide. In this method, oxamide, N,N-dimethyl acetal and hydrazine or hydrazine salt are cheap, and the raw materials are easy to obtain. The reaction is completed in one pot, and the synthesis route is short; at the same time, the reaction product is cooled, filtered, washed and dried. The product can be obtained, and the post-treatment is convenient and simple; the reaction will not produce pollution, the amount of three wastes is small, and it is suitable for industrial production.
具体实施方式Detailed ways
本发明公开了一锅法制备1,2,4-三氮唑-3-甲酰胺的方法，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明当中。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。The invention discloses a one-pot method for preparing 1,2,4-triazole-3-carboxamide. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters to realize it. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and the relevant personnel can obviously make changes or appropriate changes and combinations to the method and application described herein without departing from the content, spirit and scope of the present invention to realize and Apply the technology of the present invention.
本发明提供的制备方法中，还包括对产物进行纯化的步骤。具体地，包括对产物进行冷却、过滤、水洗及干燥等步骤。The preparation method provided by the invention also includes the step of purifying the product. Specifically, the steps of cooling, filtering, washing with water and drying are included.
下面结合实施例，进一步阐述本发明：Below in conjunction with embodiment, further set forth the present invention:
实施例1Example 1
将草酰胺(15.0g，0.17mol)加入到250mL的三口瓶中，加入100mL正丁醇，室温下滴加N,N-二甲基乙缩醛(25.0g，0.17mol)，升温至60℃反应8小时，TLC检测N,N-二甲基乙缩醛完全转化，然后向反应混合物中加入水合肼(0.17mol)和甲酸(7.82g，0.17mol)，升温至120℃回流反应10小时，经TLC检测反应完全。将温度降至室温，将析出固体抽滤并悬浮于水中，加入氢氧化钠调节水相pH值为中性，所得固体经过滤，用水洗涤，干燥得白色固体12.4g，收率65％，熔点316℃-317℃。Add oxamide (15.0g, 0.17mol) into a 250mL three-necked flask, add 100mL of n-butanol, add N,N-dimethyl acetal (25.0g, 0.17mol) dropwise at room temperature, and heat up to 60°C After reacting for 8 hours, TLC detected the complete conversion of N,N-dimethyl acetal, then added hydrazine hydrate (0.17 mol) and formic acid (7.82 g, 0.17 mol) to the reaction mixture, and raised the temperature to 120° C. for reflux reaction for 10 hours. The reaction was complete as detected by TLC. Lower the temperature to room temperature, filter the precipitated solid with suction and suspend it in water, add sodium hydroxide to adjust the pH value of the aqueous phase to be neutral, filter the obtained solid, wash with water, and dry to obtain 12.4 g of white solid, yield 65%, melting point 316°C-317°C.
1H NMR(DMSO-d6,500MHz),δ:7.68,7.92(bs,1H+1H,NH),8.39(s,1H,CH)；HRMScalcd for:C3H5N4O[M+H+]113.0463,found:113.0468。1H NMR (DMSO-d6, 500MHz), δ: 7.68, 7.92 (bs, 1H+1H, NH), 8.39 (s, 1H, CH); HRMScalcd for: C3H5N4O[M+H+] 113.0463, found: 113.0468.
实施例2Example 2
将草酰胺(15.0g，0.17mol)加入到250mL的三口瓶中，加入100mL异戊醇，室温下滴加N,N-二甲基甲缩醛(20.2g，0.17mol)，升温至80℃反应8小时，TLC检测N,N-二甲基甲缩醛完全转化。向反应混合物中加入盐酸肼(17.5g，0.17mol)和乙酸(20.4g，0.340mol)，升温至130℃回流反应10小时。经TLC检测反应完全。将温度降至室温，将析出固体抽滤并悬浮于水中，加入氢氧化钠调节水相pH值为中性。所得固体经过滤，用水洗涤，干燥得白色固体13.3g，收率70％，熔点316℃-317℃。Add oxamide (15.0g, 0.17mol) into a 250mL three-necked flask, add 100mL of isoamyl alcohol, add N,N-dimethylformal (20.2g, 0.17mol) dropwise at room temperature, and raise the temperature to 80°C After reacting for 8 hours, TLC detected that the N,N-dimethylformal was completely converted. Hydrazine hydrochloride (17.5 g, 0.17 mol) and acetic acid (20.4 g, 0.340 mol) were added to the reaction mixture, and the temperature was raised to 130° C. for reflux reaction for 10 hours. The reaction was complete as detected by TLC. The temperature was lowered to room temperature, the precipitated solid was suction filtered and suspended in water, and sodium hydroxide was added to adjust the pH value of the aqueous phase to be neutral. The resulting solid was filtered, washed with water, and dried to obtain 13.3 g of a white solid with a yield of 70% and a melting point of 316°C-317°C.
1H NMR(DMSO-d6,500MHz),δ:7.68,7.92(bs,1H+1H,NH),8.39(s,1H,CH)；HRMScalcd for:C3H5N4O[M+H+]113.0463,found:113.0468。1H NMR (DMSO-d6, 500MHz), δ: 7.68, 7.92 (bs, 1H+1H, NH), 8.39 (s, 1H, CH); HRMScalcd for: C3H5N4O[M+H+] 113.0463, found: 113.0468.
实施例3Example 3
将草酰胺(15.0g，0.17mol)加入到250mL的三口瓶中，加入100mL N,N-二甲基乙酰胺，室温下滴加N,N-二甲基甲缩醛(20.2g，0.17mol)，升温至50℃反应8小时，TLC检测N,N-二甲基甲缩醛完全转化。向反应混合物中加入碳酸肼(47.9g，0.51mol)丙酸(25.2g，0.34mol)，升温至80℃回流反应10小时。经TLC检测反应完全。将温度降至室温，将析出固体抽滤并悬浮于水中，加入氢氧化钠调节水相pH值为中性。所得固体经过滤，用水洗涤，干燥得白色固体11.0g，收率58％，熔点316℃-317℃。Add oxamide (15.0g, 0.17mol) into a 250mL three-necked flask, add 100mL of N,N-dimethylacetamide, and drop N,N-dimethylformaldehyde (20.2g, 0.17mol ), the temperature was raised to 50° C. for 8 hours, and TLC detected the complete conversion of N,N-dimethylformal. Hydrazine carbonate (47.9 g, 0.51 mol) and propionic acid (25.2 g, 0.34 mol) were added to the reaction mixture, and the temperature was raised to 80° C. for reflux reaction for 10 hours. The reaction was complete as detected by TLC. The temperature was lowered to room temperature, the precipitated solid was suction filtered and suspended in water, and sodium hydroxide was added to adjust the pH value of the aqueous phase to be neutral. The resulting solid was filtered, washed with water, and dried to obtain 11.0 g of a white solid with a yield of 58% and a melting point of 316°C-317°C.
1H NMR(DMSO-d6,500MHz),δ:7.68,7.92(bs,1H+1H,NH),8.39(s,1H,CH)；HRMScalcd for:C3H5N4O[M+H+]113.0463,found:113.0468。1H NMR (DMSO-d6, 500MHz), δ: 7.68, 7.92 (bs, 1H+1H, NH), 8.39 (s, 1H, CH); HRMScalcd for: C3H5N4O[M+H+] 113.0463, found: 113.0468.
实施例4Example 4
将草酰胺(15.0g，0.17mol)加入到250mL的三口瓶中，加入100mL二甲基亚砜，室温下滴加N,N-二甲基正丁缩醛(34.5g，0.17mol)，升温至80℃反应8小时，TLC检测N,N-二甲基正丁缩醛完全转化。向反应混合物中加入硫酸肼(22.1g，0.17mol)和对甲苯磺酸(29.2g，0.17mol)，升温至140℃反应5小时。经TLC检测反应完全。将温度降至室温，将析出固体抽滤并悬浮于水中，加入氢氧化钠调节水相pH值为中性。所得固体经过滤，用水洗涤，干燥得白色固体12.2g，收率64％，熔点316℃-317℃。Add oxamide (15.0g, 0.17mol) into a 250mL three-necked flask, add 100mL dimethyl sulfoxide, add N,N-dimethyl n-butyral (34.5g, 0.17mol) dropwise at room temperature, and heat up Reaction at 80°C for 8 hours, TLC detection of complete conversion of N,N-dimethyl n-butyral. Hydrazine sulfate (22.1 g, 0.17 mol) and p-toluenesulfonic acid (29.2 g, 0.17 mol) were added to the reaction mixture, and the temperature was raised to 140° C. for 5 hours. The reaction was complete as detected by TLC. The temperature was lowered to room temperature, the precipitated solid was suction filtered and suspended in water, and sodium hydroxide was added to adjust the pH value of the aqueous phase to be neutral. The resulting solid was filtered, washed with water, and dried to obtain 12.2 g of a white solid with a yield of 64% and a melting point of 316°C-317°C.
1H NMR(DMSO-d6,500MHz),δ:7.68,7.92(bs,1H+1H,NH),8.39(s,1H,CH)；HRMScalcd for:C3H5N4O[M+H+]113.0463,found:113.0468。1H NMR (DMSO-d6, 500MHz), δ: 7.68, 7.92 (bs, 1H+1H, NH), 8.39 (s, 1H, CH); HRMScalcd for: C3H5N4O[M+H+] 113.0463, found: 113.0468.
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。The above is only a preferred embodiment of the present invention, it should be pointed out that, for those of ordinary skill in the art, without departing from the principle of the present invention, some improvements and modifications can also be made, and these improvements and modifications can also be made. It should be regarded as the protection scope of the present invention.
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| CN201810661846.8ACN108863965A (en) | 2018-06-25 | 2018-06-25 | The method that one kettle way prepares 1,2,4- triazole -3- formamide |
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| CN201810661846.8ACN108863965A (en) | 2018-06-25 | 2018-06-25 | The method that one kettle way prepares 1,2,4- triazole -3- formamide |
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