CN105693522A - Preparation method of p-nitro-o-cresol - Google Patents
Preparation method of p-nitro-o-cresol Download PDFInfo
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- CN105693522A CN105693522A CN201610133842.3A CN201610133842A CN105693522A CN 105693522 A CN105693522 A CN 105693522A CN 201610133842 A CN201610133842 A CN 201610133842A CN 105693522 A CN105693522 A CN 105693522A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- KDQPMQNHVQVVMR-UHFFFAOYSA-N 2-methyl-4-nitrophenol Chemical compound CC1=CC([N+]([O-])=O)=CC=C1O KDQPMQNHVQVVMR-UHFFFAOYSA-N 0.000 title abstract description 25
- XTTIQGSLJBWVIV-UHFFFAOYSA-N 2-methyl-4-nitroaniline Chemical compound CC1=CC([N+]([O-])=O)=CC=C1N XTTIQGSLJBWVIV-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 239000002244 precipitate Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
- 229910001864 baryta Inorganic materials 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- 235000011121 sodium hydroxide Nutrition 0.000 claims 1
- 239000001117 sulphuric acid Substances 0.000 claims 1
- 235000011149 sulphuric acid Nutrition 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 8
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 7
- 238000010606 normalization Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 11
- 238000010992 reflux Methods 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- GAKLFAZBKQGUBO-UHFFFAOYSA-N 2-methyl-3-nitrophenol Chemical compound CC1=C(O)C=CC=C1[N+]([O-])=O GAKLFAZBKQGUBO-UHFFFAOYSA-N 0.000 description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 239000012847 fine chemical Substances 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- JXBKZAYVMSNKHA-UHFFFAOYSA-N 1h-tetrazol-1-ium-5-olate Chemical class OC=1N=NNN=1 JXBKZAYVMSNKHA-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- TYAZDNQFLGEDEA-UHFFFAOYSA-N 6-methyl-6-nitrocyclohexa-1,3-dien-1-ol Chemical compound [O-][N+](=O)C1(C)CC=CC=C1O TYAZDNQFLGEDEA-UHFFFAOYSA-N 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- -1 p-nitro-o-cresol phenol Chemical compound 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种对硝基邻甲酚的制备方法，该方法以对硝基邻甲苯胺为原料通过碱水解方式制备得到对硝基邻甲酚。本发明得到的对硝基邻甲酚纯度高，经高效液相色谱法（HPLC）测定，面积归一化法法定量测得含量大于99%，收率大于95%，本制备方法操作简便，在该方法所述的工艺条件下，重复多个批次，重复性好。
The invention discloses a preparation method of p-nitro-o-cresol, which uses p-nitro-o-toluidine as a raw material to prepare p-nitro-o-cresol through alkali hydrolysis. The p-nitro-o-cresol obtained in the present invention has high purity, and is determined by high performance liquid chromatography (HPLC), and the quantitatively measured content by the area normalization method is greater than 99%, and the yield is greater than 95%. The preparation method is easy to operate, Under the process conditions described in the method, multiple batches are repeated, and the repeatability is good.
Description
技术领域technical field
本发明涉及精细化工产品技术领域，更具体地说，本发明涉及一种对硝基邻甲酚的制备方法。The invention relates to the technical field of fine chemical products, more specifically, the invention relates to a preparation method of p-nitro-o-cresol.
背景技术Background technique
对硝基邻甲酚是一种重要的精细化工中间体，比如国际专利WO2015016373A1公开报道了对硝基邻甲酚作为一种中间体制备了一系列作为杀虫剂的四唑啉酮类化合物；中国发明专利申请CN104557688A中报道了采用对硝基邻甲酚合成一种新型多靶向性的治疗肿瘤药物索拉菲尼（sorafenib）的中间体。另外，对硝基邻甲酚还具有一定的生物活性，比如1985年公开的捷克专利CzechCS218346B1中报道，它和氨基苯甲酸组合具有植物生长促进作用。p-nitro-o-cresol is an important fine chemical intermediate. For example, the international patent WO2015016373A1 publicly reported that p-nitro-o-cresol was used as an intermediate to prepare a series of tetrazolinone compounds as pesticides; In the Chinese invention patent application CN104557688A, it is reported that p-nitro-o-cresol is used to synthesize an intermediate of a novel multi-targeted drug for treating tumors, sorafenib. In addition, p-nitro-o-cresol also has a certain biological activity. For example, it was reported in the Czech patent CzechCS218346B1 published in 1985 that it has a plant growth-promoting effect in combination with aminobenzoic acid.
文献报道的合成对硝基邻甲酚采用的反应起始原料主要是邻甲苯酚和对硝基邻甲苯胺。以邻甲苯酚作为起始原料主要通过硝化反应制得对硝基邻甲酚（Damghani,KobraKhorsietal.The reaction starting materials used in the synthesis of p-nitro-o-cresol reported in the literature are mainly o-cresol and p-nitro-o-toluidine. Using ortho-cresol as a starting material, p-nitro-o-cresol (Damghani, KobraKhorsie et al.
CurrentChemistryLetters,2014,3(4):207-214;Jereb,Marjan.CurrentOrganicChemistry,2013,17(15):1694-1700;Sana,S.etal.SyntheticCommunications,39(16),2009,2949-2953)。这类反应的缺点是由于硝化反应较难控制，经常制备得到的产物中除了主要产物对硝基邻甲酚外，还有副产物邻硝基邻甲酚和间硝基邻甲酚，甚至会产生水取代硝基邻甲酚，因此很难得到高纯度的对硝基邻甲酚。以对硝基邻甲苯胺作为起始原料主要通过重氮化水解反应(Dey,Archanetal.JournaloftheAmericanChemicalSociety,2005,127(30),10545-10559)或直接碱水解反应方式(Imoto,Mitsutakaetal.JournalofOrganicChemistry,2011,76(15):6356-6361)制备得到对硝基邻甲酚。以重氮化水解反应制备对硝基邻甲酚的缺点是收率较低，且易形成偶氮类等副产物。Imoto,Mitsutaka等（Imoto,Mitsutakaetal.JournalofOrganicChemistry,2011,76(15):6356-6361）虽然报道了采用对硝基邻甲苯胺作为原料经氢氧化钠水溶液作为反应溶剂制备得到对硝基邻甲酚，但其反应选择性为70%，收率仅为29%。Current Chemistry Letters, 2014, 3(4): 207-214; Jereb, Marjan. Current Organic Chemistry, 2013, 17(15): 1694-1700; Sana, S. et al. Synthetic Communications, 39(16), 2009, 2949-2953). The disadvantage of this type of reaction is that because the nitration reaction is difficult to control, in addition to the main product p-nitro-o-cresol, there are by-products o-nitro-o-cresol and m-nitro-o-cresol in the products that are often prepared. Water is produced to replace nitro-o-cresol, so it is difficult to obtain high-purity p-nitro-o-cresol. Using p-nitro-o-toluidine as a starting material mainly through diazotization hydrolysis (Dey, Archanetal. Journal of the American Chemical Society, 2005, 127 (30), 10545-10559) or direct alkaline hydrolysis (Imoto, Mitsutaka etal. Journal of Organic Chemistry, 2011 , 76(15):6356-6361) to obtain p-nitro-o-cresol. The disadvantage of preparing p-nitro-o-cresol by diazotization hydrolysis reaction is that the yield is low and by-products such as azos are easily formed. Imoto, Mitsutaka et al. (Imoto, Mitsutaka etal. Journal of Organic Chemistry, 2011, 76(15): 6356-6361) reported that p-nitro-o-toluidine was used as a raw material and prepared with sodium hydroxide aqueous solution as a reaction solvent to obtain p-nitro-o-cresol , but its reaction selectivity is 70%, and the yield is only 29%.
发明内容Contents of the invention
本发明的目的是为了克服现有合成对硝基邻甲酚收率不高、反应副产物多等缺陷，发现对硝基邻甲苯胺在碱液中水解反应得到高纯度固体对硝基邻甲酚，从而提供一种高收率、操作简便的高纯度对硝基邻甲酚的制备方法。The purpose of the present invention is to overcome defects such as the low yield of existing synthetic p-nitro-o-cresol and many reaction by-products, and find that p-nitro-o-toluidine is hydrolyzed in alkaline solution to obtain high-purity solid p-nitro-o-cresol phenol, thereby providing a high-yield, easy-to-operate method for the preparation of high-purity p-nitro-o-cresol.
本发明的目的是这样实现的：The purpose of the present invention is achieved like this:
一种对硝基邻甲酚的制备方法，其特征在于对硝基邻甲苯胺在碱液中，在加热下进行水解反应一定时间后，反应液用酸酸化至pH3-5后析出固体，过滤后的滤饼用水洗，抽干，真空干燥得到对硝基邻甲酚。A preparation method of p-nitro-o-cresol, which is characterized in that p-nitro-o-toluidine is hydrolyzed in lye and heated for a certain period of time, and the reaction solution is acidified to pH 3-5 with acid to precipitate solids, filtered The final filter cake was washed with water, drained, and vacuum-dried to obtain p-nitro-o-cresol.
在此反应中，所用的碱液为氢氧化钠水溶液、氢氧化钾水溶液、或氢氧化钡水溶液，碱在水中的质量浓度为5-25%。In this reaction, the lye used is sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, or barium hydroxide aqueous solution, and the mass concentration of alkali in water is 5-25%.
在此反应中，加热温度为95℃-115℃,水解反应一定时间在24-72小时。In this reaction, the heating temperature is 95°C-115°C, and the hydrolysis reaction takes 24-72 hours.
在反应后处理中，采用酸为盐酸、硫酸或磷酸。In post-reaction treatment, the acid used is hydrochloric acid, sulfuric acid or phosphoric acid.
本发明制备的对硝基邻甲酚纯度高，经高效液相色谱法（HPLC）测定，面积归一化法法定量测得含量大于99%，收率大于95%，本制备方法操作简便，在该方法所述的工艺条件下，重复多个批次，重复性好。The p-nitro-o-cresol prepared by the present invention has high purity, and is measured by high-performance liquid chromatography (HPLC), and the quantitatively measured content by the area normalization method is greater than 99%, and the yield is greater than 95%. The preparation method is easy to operate, Under the process conditions described in the method, multiple batches are repeated, and the repeatability is good.
HPLC条件：流动相：0.2%磷酸水溶液/乙腈:35：65（V/V），流速:1ml/min；柱温:30℃，紫外检测器检测波长为251nm。HPLC conditions: mobile phase: 0.2% phosphoric acid aqueous solution/acetonitrile: 35:65 (V/V), flow rate: 1ml/min; column temperature: 30°C, and the detection wavelength of the ultraviolet detector is 251nm.
附图说明Description of drawings
图1为本发明实施例1制备的产物质谱图；Fig. 1 is the mass spectrogram of the product prepared by the embodiment of the present invention 1;
图2为本发明实施例1制备的产物色谱图；Fig. 2 is the product chromatogram prepared by the embodiment of the present invention 1;
图3为本发明实施例2制备的产物质谱图；Fig. 3 is the mass spectrogram of the product that the embodiment of the present invention 2 prepares;
图4为本发明实施例2制备的产物色谱图；Fig. 4 is the product chromatogram that the embodiment of the present invention 2 prepares;
图5为本发明实施例3制备的产物质谱图；Fig. 5 is the mass spectrogram of the product prepared by the embodiment of the present invention 3;
图6为本发明实施例3制备的产物色谱图；Fig. 6 is the product chromatogram prepared by the embodiment of the present invention 3;
图7为本发明实施例4制备的产物质谱图；Fig. 7 is the mass spectrogram of the product prepared by the embodiment of the present invention 4;
图8为本发明实施例4制备的产物色谱图。Figure 8 is a chromatogram of the product prepared in Example 4 of the present invention.
具体实施方式detailed description
以下实施例是为了举例说明本发明，但不足以限制本发明以其他通常的方式得以实现。The following examples are intended to illustrate the present invention, but not to limit the present invention to be carried out in other common ways.
实施例1Example 1
在装有温度计、搅拌器、回流冷凝器的2000毫升的四口瓶中加入60.8g对硝基邻甲苯胺（0.4mol）和200g氢氧化钠和600ml水，加热至115℃并保持反应24小时后停止加热，加500ml水，过滤,滤液慢慢加入盐酸调节反应液的pH至4左右，析出黄色固体，待冷却至室温后过滤，过滤分别用1000ml水洗涤滤饼三次，抽干，50℃真空干燥箱中干燥4小时，得到黄色对硝基苯酚固体，收率98.1%，质谱定性，ESI-MS(m/z):152.0[M-H]-（图1）；采用HPLC法测定其含量，从表1及图2可知本实施例对硝基邻甲酚含量99.12%。Add 60.8g of p-nitro-o-toluidine (0.4mol), 200g of sodium hydroxide and 600ml of water into a 2000ml four-necked flask equipped with a thermometer, a stirrer, and a reflux condenser, heat to 115°C and keep the reaction for 24 hours Then stop heating, add 500ml of water, filter, slowly add hydrochloric acid to the filtrate to adjust the pH of the reaction solution to about 4, and precipitate a yellow solid, wait to cool to room temperature and filter, filter and wash the filter cake three times with 1000ml of water, drain, and store at 50°C Dry in a vacuum oven for 4 hours to obtain a yellow p-nitrophenol solid with a yield of 98.1%, qualitative by mass spectrometry, ESI-MS (m/z): 152.0 [MH] - (Figure 1); its content was determined by HPLC method, As can be seen from Table 1 and Fig. 2, the p-nitro-o-cresol content of the present embodiment is 99.12%.
表1峰结果Table 1 Peak results
。 .
实施例2Example 2
在装有温度计、搅拌器、回流冷凝器的2000毫升的四口瓶中加入30.4g对硝基邻甲苯胺（0.2mol）和100g氢氧化钠和900ml水，加热至回流，回流50小时后停止加热，加500ml水，过滤,滤液慢慢加入硫酸调节反应液的pH至3左右，析出黄色固体，待冷却至室温后过滤，过滤分别用1000ml水洗涤滤饼三次，抽干，50℃真空干燥箱中干燥4小时，得到黄色对硝基苯酚固体，收率98.5%,质谱定性，ESI-MS(m/z):152.0[M-H]-（图3），采用HPLC法测定其含量，从表2及图4可知本实施例对硝基邻甲酚含量99.39%。Add 30.4g of p-nitro-o-toluidine (0.2mol), 100g of sodium hydroxide and 900ml of water into a 2000ml four-necked flask equipped with a thermometer, agitator, and reflux condenser, heat to reflux, and stop after reflux for 50 hours Heat, add 500ml of water, filter, slowly add sulfuric acid to the filtrate to adjust the pH of the reaction solution to about 3, precipitate a yellow solid, wait to cool to room temperature, filter, filter, wash the filter cake with 1000ml of water three times, drain, and vacuum dry at 50°C Dry in the oven for 4 hours to obtain a yellow p-nitrophenol solid with a yield of 98.5%, qualitative by mass spectrometry, ESI-MS (m/z): 152.0 [MH] - (Figure 3), and determine its content by HPLC method, from the table 2 and Fig. 4 as can be known the present embodiment p-nitro-o-cresol content 99.39%.
表2峰结果Table 2 Peak results
。 .
实施例3Example 3
在装有温度计、搅拌器、回流冷凝器的1000毫升的四口瓶中加入6.08g对硝基邻甲苯胺（0.04mol）和20g氢氧化钾和380ml水，加热至95℃并保持反应72小时后停止加热，过滤,滤液慢慢加入磷酸调节反应液的pH至5左右，析出黄色固体，待冷却至室温后过滤，过滤分别用100ml水洗涤滤饼三次，抽干，50℃真空干燥箱中干燥4小时，得到对硝基苯酚，收率96.5%,ESI-MS(m/z):152.0[M-H]-（图5），采用HPLC法测定其含量，从表3及图6可知本实施例对硝基邻甲酚含量99.03%。Add 6.08g of p-nitro-o-toluidine (0.04mol) and 20g of potassium hydroxide and 380ml of water into a 1000ml four-necked flask equipped with a thermometer, a stirrer and a reflux condenser, heat to 95°C and keep the reaction for 72 hours Then stop heating, filter, slowly add phosphoric acid to the filtrate to adjust the pH of the reaction solution to about 5, and precipitate a yellow solid. After cooling to room temperature, filter, wash the filter cake with 100ml water for three times, drain, and place in a vacuum oven at 50°C. Dry for 4 hours to obtain p-nitrophenol with a yield of 96.5%, ESI-MS (m/z): 152.0 [MH] - (Fig. 5), and measure its content by HPLC. From Table 3 and Fig. 6, we can see that this practice For example, the content of p-nitro-o-cresol is 99.03%.
表3峰结果Table 3 Peak results
。 .
实施例4Example 4
在装有温度计、搅拌器、回流冷凝器的500毫升的四口瓶中加入12.16g对硝基邻甲苯胺（0.08mol）和40g氢氧化钡和160ml水，加热至回流，回流35小时后停止加热，加200ml水，过滤,滤液慢慢加入盐酸调节反应液的pH至3左右，析出黄色固体，待冷却至室温后过滤，过滤分别用200ml水洗涤滤饼三次，抽干，50℃真空干燥箱中干燥4小时，得到对硝基苯酚，收率95.8%，ESI-MS(m/z):152.0[M-H]-（图7），采用HPLC法测定其含量，从表4及图8可知本实施例对硝基邻甲酚含量99.34%。Add 12.16g of p-nitro-o-toluidine (0.08mol), 40g of barium hydroxide and 160ml of water into a 500ml four-necked flask equipped with a thermometer, a stirrer, and a reflux condenser, heat to reflux, and stop after reflux for 35 hours Heat, add 200ml of water, filter, slowly add hydrochloric acid to the filtrate to adjust the pH of the reaction solution to about 3, precipitate a yellow solid, wait to cool to room temperature, filter, filter, wash the filter cake with 200ml of water three times, drain, and vacuum dry at 50°C Dry in the oven for 4 hours to obtain p-nitrophenol with a yield of 95.8%, ESI-MS (m/z): 152.0[MH] - (Figure 7), and determine its content by HPLC, as can be seen from Table 4 and Figure 8 The content of p-nitro-o-cresol in this embodiment is 99.34%.
表4峰结果Table 4 Peak results
。 .
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