CN116217416A - Preparation method of benzimidazole drug intermediate 3-nitro-4-ethylamino benzyl alcohol - Google Patents
Preparation method of benzimidazole drug intermediate 3-nitro-4-ethylamino benzyl alcoholDownload PDFInfo
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Abstract
Description
Translated fromChinese技术领域technical field
本发明涉及有机合成及药物技术领域，具体涉及苯并咪唑类药物中间体3-硝基-4-乙基氨基苯甲醇的制备方法。The invention relates to the technical fields of organic synthesis and medicine, in particular to a preparation method of 3-nitro-4-ethylaminobenzyl alcohol, an intermediate of benzimidazole drugs.
背景技术Background technique
苯并咪唑类是一类重要的化合物，在药物合成方面应用广泛。比如其可用于合成抗菌药多菌灵、阿苯达唑、芬苯达唑、奥苯达唑等；质子泵抑制剂药物奥美拉唑、兰索拉唑、泮托拉唑、雷贝拉唑等；还可用于溴结构域抑制剂（比特R.A.等人， WO2016146738A1，CN107635989B），以及鞘氨醇1-磷酸受体1拮抗剂药物（Hennessy E.J.等人，J. Med. Chem.2015, 58, 17, 7057-7075）的合成。Benzimidazoles are an important class of compounds that are widely used in drug synthesis. For example, it can be used to synthesize antibacterial drugs carbendazim, albendazole, fenbendazole, oxbendazole, etc.; proton pump inhibitor drugs omeprazole, lansoprazole, pantoprazole, rabela It can also be used for bromodomain inhibitors (Bit RA et al., WO2016146738A1, CN107635989B), and sphingosine 1-
苯并咪唑类衍生物的合成方法之一是2-硝基苯胺类化合物与羧酸类化合物缩合。本发明所涉及的3-硝基-4-乙基氨基苯甲醇即属于2-硝基苯胺类化合物，可用于合成以苯并咪唑为母核的磺胺类或2-吡啶酮类的药物合成。One of the synthesis methods of benzimidazole derivatives is the condensation of 2-nitroaniline compounds and carboxylic acid compounds. The 3-nitro-4-ethylaminobenzyl alcohol involved in the present invention belongs to 2-nitroaniline compounds, and can be used for the synthesis of sulfonamides or 2-pyridones with benzimidazole as the mother nucleus.
现有技术公开了一种3-硝基-4-乙基氨基苯甲醇的制备方法：利用微波反应，在四氢呋喃溶剂中，加入过量的二异丙基乙基胺，以3-硝基-4-氟苯甲醇为原料，与等当量的70%乙胺水溶液在120℃反应3小时得到3-硝基-4-乙基氨基苯甲醇。该方法反应条件苛刻，需利用微波反应，温度较高，原料成本高。因此针对上述问题有必要研究一种新的制备方法来合成3-硝基-4-乙基氨基苯甲醇。The prior art discloses a preparation method of 3-nitro-4-ethylaminobenzyl alcohol: utilizing microwave reaction, in tetrahydrofuran solvent, adding excess diisopropylethylamine, with 3-nitro-4 - Fluorobenzyl alcohol as raw material, react with an equivalent of 70% ethylamine aqueous solution at 120°C for 3 hours to obtain 3-nitro-4-ethylaminobenzyl alcohol. The reaction conditions of the method are harsh, microwave reaction is required, the temperature is high, and the cost of raw materials is high. Therefore it is necessary to study a new preparation method to synthesize 3-nitro-4-ethylaminobenzyl alcohol for the above problems.
发明内容Contents of the invention
为解决上述问题，本发明提供一种苯并咪唑类药物中间体3-硝基-4-乙基氨基苯甲醇的制备方法，该方法一步反应实现两种官能团的化学转化，反应条件比较温和，设备简单，易于控制，降低了原料成本，产物收率较高。In order to solve the above problems, the present invention provides a kind of preparation method of benzimidazole drug intermediate 3-nitro-4-ethylaminobenzyl alcohol, the method one-step reaction realizes the chemical conversion of two kinds of functional groups, and reaction condition is milder, The equipment is simple, easy to control, the raw material cost is reduced, and the product yield is high.
本发明的目的是以下述方式实现的：一种苯并咪唑类药物中间体3-硝基-4-乙基氨基苯甲醇的制备方法，以3-硝基-4-乙酰氨基苯甲酸为原料，在有机溶剂中与还原剂发生还原反应，合成出3-硝基-4-乙基氨基苯甲醇，其中还原剂为硼烷，二异丁基氢化铝或者红铝，或者是还原性含锂、含钠或含钾的化合物与三氟化硼/乙醚为还原剂。The object of the present invention is achieved in the following manner: a kind of preparation method of benzimidazole drug intermediate 3-nitro-4-ethylaminobenzyl alcohol, using 3-nitro-4-acetamidobenzoic acid as raw material , in an organic solvent and a reducing agent to undergo a reduction reaction to synthesize 3-nitro-4-ethylaminobenzyl alcohol, wherein the reducing agent is borane, diisobutylaluminum hydride or red aluminum, or a reducing lithium-containing , Sodium or potassium-containing compounds and boron trifluoride/ether are reducing agents.
1、硼烷作为还原剂的具体制备方法1. The specific preparation method of borane as reducing agent
（1）以3-硝基-4-乙酰氨基苯甲酸为原料，有机溶剂作为反应体系的溶剂，将原料溶解完全后，冷却条件下缓慢加入硼烷的有机溶液，并保持良好搅拌；(1) Use 3-nitro-4-acetamidobenzoic acid as the raw material and the organic solvent as the solvent of the reaction system. After the raw materials are completely dissolved, slowly add the organic solution of borane under cooling conditions and keep stirring well;
（2）硼烷的有机溶液加入完毕，撤去冷却装置，使反应体系缓慢升温，继续搅拌一段时间，反应结束后，在冷却条件下缓慢加入甲醇至无气体放出；(2) After adding the organic solution of borane, remove the cooling device, slowly heat up the reaction system, and continue to stir for a period of time. After the reaction is over, slowly add methanol under cooling conditions until no gas is released;
（3）有机溶剂减压蒸出，剩余物用碱性水溶液分散，其中的粗品用有机溶剂萃取后，洗涤，干燥，浓缩，结晶得到3-硝基-4-乙基氨基苯甲醇。(3) The organic solvent was distilled off under reduced pressure, and the residue was dispersed with an alkaline aqueous solution. The crude product was extracted with an organic solvent, washed, dried, concentrated, and crystallized to obtain 3-nitro-4-ethylaminobenzyl alcohol.
步骤（1）中反应体系的有机溶剂为四氢呋喃、二氯甲烷。The organic solvent of the reaction system in the step (1) is tetrahydrofuran and dichloromethane.
步骤（1）中硼烷的有机溶液为硼烷/四氢呋喃、硼烷/二甲硫醚。The organic solution of borane in step (1) is borane/tetrahydrofuran, borane/dimethyl sulfide.
步骤（1）中加入硼烷的有机溶剂时的体系温度控制在0-10℃，所述3-硝基-4-乙酰氨基苯甲酸与硼烷的摩尔比为1 : 2.0-3.0。When the organic solvent of borane is added in step (1), the temperature of the system is controlled at 0-10° C., and the molar ratio of 3-nitro-4-acetamidobenzoic acid to borane is 1: 2.0-3.0.
步骤（2）中反应温度为20-40℃，反应时间为2-5小时，冷却温度为5-10℃。In step (2), the reaction temperature is 20-40°C, the reaction time is 2-5 hours, and the cooling temperature is 5-10°C.
步骤（3）中碱性水溶液为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾水溶液。The alkaline aqueous solution in step (3) is an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.
步骤（3）中萃取时所用萃取剂为乙酸乙酯、二氯甲烷。The extractant used during the extraction in step (3) is ethyl acetate and dichloromethane.
2、二异丁基氢化铝为还原剂的具体制备方法2. The specific preparation method of diisobutylaluminum hydride as reducing agent
（1）以3-硝基-4-乙酰氨基苯甲酸为原料，有机溶剂作为反应体系的溶剂，将原料溶解完全后，冷却条件下缓慢加入二异丁基氢化铝的有机溶液，并保持良好搅拌；(1) Use 3-nitro-4-acetamidobenzoic acid as the raw material and organic solvent as the solvent of the reaction system. After the raw materials are completely dissolved, slowly add the organic solution of diisobutylaluminum hydride under cooling conditions and keep it well stir;
（2）滴加完毕，撤去冷却装置，使反应体系缓慢升温，继续搅拌一段时间，反应结束后，在冷却条件下缓慢加入酒石酸钾钠的饱和溶液至无气体放出；(2) After the dropwise addition is completed, the cooling device is removed, the reaction system is heated up slowly, and stirring is continued for a period of time. After the reaction is completed, slowly add a saturated solution of potassium sodium tartrate under cooling conditions until no gas is released;
（3）加入有机溶剂萃取后，合并有机相，洗涤，干燥，浓缩，结晶得到3-硝基-4-乙基氨基苯甲醇。(3) After adding an organic solvent for extraction, the organic phases were combined, washed, dried, concentrated, and crystallized to obtain 3-nitro-4-ethylaminobenzyl alcohol.
步骤（1）中有机溶剂为甲苯、四氢呋喃、二氯甲烷。The organic solvent in step (1) is toluene, tetrahydrofuran, dichloromethane.
步骤（1）中二异丁基氢化铝的有机溶液为二异丁基氢化铝/甲苯、二异丁基氢化铝/正己烷。The organic solution of diisobutyl aluminum hydride in step (1) is diisobutyl aluminum hydride/toluene, diisobutyl aluminum hydride/n-hexane.
步骤（1）中反应温度为0-10℃，所述3-硝基-4-乙酰氨基苯甲酸与二异丁基氢化铝的摩尔比为1 : 5.0-10.0。In step (1), the reaction temperature is 0-10°C, and the molar ratio of 3-nitro-4-acetamidobenzoic acid to diisobutylaluminum hydride is 1: 5.0-10.0.
步骤（2）中反应温度为20-40℃，反应时间为2-6小时，冷却温度为5-10℃。In step (2), the reaction temperature is 20-40°C, the reaction time is 2-6 hours, and the cooling temperature is 5-10°C.
步骤（3）中萃取时所用萃取剂为乙酸乙酯、二氯甲烷。The extractant used during the extraction in step (3) is ethyl acetate and dichloromethane.
3、红铝为还原剂的具体制备方法3. The specific preparation method of red aluminum as reducing agent
（1）以3-硝基-4-乙酰氨基苯甲酸为原料，有机溶剂作为反应体系的溶剂，将原料溶解完全后，冷却条件下缓慢加入红铝的有机溶液，并保持良好搅拌；(1) Use 3-nitro-4-acetamidobenzoic acid as the raw material and organic solvent as the solvent of the reaction system. After the raw materials are completely dissolved, slowly add the organic solution of red aluminum under cooling conditions and keep stirring well;
（2）滴加完毕，撤去冷却装置，使反应体系缓慢升温，继续搅拌一段时间，反应结束后，在冷却条件下缓慢加入碱性水溶液淬灭；(2) After the dropwise addition is completed, the cooling device is removed, the reaction system is heated up slowly, and the stirring is continued for a period of time. After the reaction is completed, the alkaline aqueous solution is slowly added under cooling conditions to quench;
（3）加入有机溶剂萃取后，合并有机相，洗涤，干燥，浓缩，结晶得到3-硝基-4-乙基氨基苯甲醇。(3) After adding an organic solvent for extraction, the organic phases were combined, washed, dried, concentrated, and crystallized to obtain 3-nitro-4-ethylaminobenzyl alcohol.
步骤（1）中有机溶剂为甲苯、四氢呋喃。The organic solvent in step (1) is toluene and tetrahydrofuran.
步骤（1）中红铝的有机溶液为红铝/甲苯。The organic solution of red aluminum in step (1) is red aluminum/toluene.
步骤（1）中反应温度为0-10℃，所述3-硝基-4-乙酰氨基苯甲酸与红铝的摩尔比为1 : 5.0-7.0。In step (1), the reaction temperature is 0-10°C, and the molar ratio of the 3-nitro-4-acetamidobenzoic acid to red aluminum is 1: 5.0-7.0.
步骤（2）中反应温度为60-80℃，反应时间为1-3小时，冷却温度为5-10℃。In step (2), the reaction temperature is 60-80°C, the reaction time is 1-3 hours, and the cooling temperature is 5-10°C.
步骤（2）中碱性水溶液为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾水溶液。The alkaline aqueous solution in step (2) is an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.
步骤（3）中萃取时所用萃取剂为乙酸乙酯、二氯甲烷。The extractant used during the extraction in step (3) is ethyl acetate and dichloromethane.
4、还原性含锂、含钠或含钾的化合物与三氟化硼/乙醚为还原剂的具体制备方法4. Specific preparation method of reductive lithium-, sodium- or potassium-containing compound and boron trifluoride/ether as reducing agent
（1）以3-硝基-4-乙酰氨基苯甲酸为原料，有机溶剂作为反应体系的溶剂，将原料溶解完全后，冷却条件下缓慢加入含锂、含钠或含钾的还原性化合物与三氟化硼/乙醚，并保持良好搅拌；(1) Use 3-nitro-4-acetamidobenzoic acid as the raw material and organic solvent as the solvent of the reaction system. After the raw materials are completely dissolved, slowly add lithium-containing, sodium-containing or potassium-containing reducing compounds and Boron trifluoride/ether, and keep stirring well;
（2）加料完毕，撤去冷却装置，使反应体系缓慢升温至回流，继续搅拌一段时间，反应结束后，在冷却条件下缓慢依次加入1/9-1/11溶剂体积的甲醇和浓度8%-12%的稀盐酸，直到无气体释放出为止，停止加入稀盐酸，加毕，继续搅拌回流0.5小时；加入稀盐酸的量由实验现象决定，需缓慢加入稀盐酸，直到无气体释放出为止，停止加入稀盐酸，可认为此时淬灭完全。(2) After the feeding is completed, the cooling device is removed, the reaction system is slowly heated to reflux, and the stirring is continued for a period of time. After the reaction is completed, 1/9-1/11 of the solvent volume of methanol and the concentration of 8%- 12% dilute hydrochloric acid, until no gas is released, stop adding dilute hydrochloric acid, after the addition, continue to stir and reflux for 0.5 hours; the amount of dilute hydrochloric acid to be added is determined by the experimental phenomenon, it is necessary to slowly add dilute hydrochloric acid until no gas is released, Stop adding dilute hydrochloric acid, it can be considered that the quenching is complete at this time.
（3）有机溶剂减压蒸出，剩余物用碱性溶液氨水和有机溶剂分散，控制pH为6-8，过滤，母液分液后，水相用有机溶剂萃取，合并有机相，洗涤，干燥，浓缩，结晶得到3-硝基-4-乙基氨基苯甲醇。(3) The organic solvent is distilled off under reduced pressure, and the residue is dispersed with an alkaline solution of ammonia water and an organic solvent, and the pH is controlled to be 6-8, and filtered. After the mother liquor is separated, the aqueous phase is extracted with an organic solvent, and the organic phase is combined, washed, and dried. , concentrated and crystallized to obtain 3-nitro-4-ethylaminobenzyl alcohol.
步骤（1）中反应体系的有机溶剂为四氢呋喃、二氯甲烷。The organic solvent of the reaction system in the step (1) is tetrahydrofuran and dichloromethane.
由于步骤（2）使用了稀盐酸，这里有少量残留，使用碱性溶液方便控制pH值，但步骤（3）中碱性溶液优选氨水；氨水的浓度优选是25%-28%，其它浓度的氨水也可以，但是浓度较低的氨水，使用量会比较大。Since dilute hydrochloric acid is used in step (2), there is a small amount of residue here, and it is convenient to use an alkaline solution to control the pH value, but the alkaline solution in step (3) is preferably ammonia water; the concentration of ammonia water is preferably 25%-28%, other concentrations Ammonia water is also available, but the amount of ammonia water with a lower concentration will be larger.
步骤（3）和碱性溶液一起使用的有机溶剂是乙酸乙酯或二氯甲烷；步骤（3）中萃取时所用有机溶剂为乙酸乙酯、二氯甲烷。The organic solvent used together with the alkaline solution in the step (3) is ethyl acetate or dichloromethane; the organic solvent used in the extraction in the step (3) is ethyl acetate or dichloromethane.
步骤（1）中含锂、含钠、含钾的还原性化合物为四氢铝锂、硼氢化锂、硼氢化钠、硼氢化钾。The reducing compounds containing lithium, sodium, and potassium in step (1) are lithium aluminum hydride, lithium borohydride, sodium borohydride, and potassium borohydride.
步骤（1）中反应温度为0-10℃，所述3-硝基-4-乙酰氨基苯甲酸、含锂、含钠、含钾的还原性化合物、三氟化硼/乙醚的摩尔比为1 : 2.0-5.0 : 3.0-4.0。In step (1), the reaction temperature is 0-10°C, and the molar ratio of the 3-nitro-4-acetamidobenzoic acid, the reducing compound containing lithium, sodium, and potassium, and boron trifluoride/ether is 1 : 2.0-5.0 : 3.0-4.0.
步骤（2）中反应时间为4-8小时，冷却温度为5-10℃。反应溶剂不同，回流时温度也不一样，四氢呋喃作溶剂时反应温度一般在66℃，二氯甲烷作溶剂时反应温度一般在39℃。The reaction time in step (2) is 4-8 hours, and the cooling temperature is 5-10°C. The reaction solvent is different, and the temperature during reflux is also different. When tetrahydrofuran is used as a solvent, the reaction temperature is generally 66° C., and when dichloromethane is used as a solvent, the reaction temperature is generally 39° C.
本发明合成方法中主要的反应式：Main reaction formula in the synthetic method of the present invention:
本发明采用以上技术方案，与现有技术相比，具有以下优点：The present invention adopts the above technical scheme, and compared with the prior art, it has the following advantages:
本发明以3-硝基-4-乙酰氨基苯甲酸为原料，在有机溶剂中与还原剂发生还原反应，合成出3-硝基-4-乙基氨基苯甲醇。该制备方法只需一步合成反应，实现两种官能团的化学转化，整个反应条件温和，不需要特殊反应设备，降低了原料成本，提高了产物收率，并且在整个反应过程中无废水排放，减少了环境污染。The invention uses 3-nitro-4-acetylaminobenzoic acid as a raw material, undergoes a reduction reaction with a reducing agent in an organic solvent, and synthesizes 3-nitro-4-ethylaminobenzyl alcohol. The preparation method only needs one-step synthesis reaction to realize the chemical conversion of two functional groups. The whole reaction condition is mild, no special reaction equipment is needed, the raw material cost is reduced, the product yield is improved, and there is no waste water discharge in the whole reaction process, reducing the environmental pollution.
附图说明Description of drawings
图1为发明制备的产物3-硝基-4-乙基氨基苯甲醇的核磁共振氢谱。Fig. 1 is the proton nuclear magnetic resonance spectrum of the product 3-nitro-4-ethylaminobenzyl alcohol prepared by the invention.
图2为发明制备的产物3-硝基-4-乙基氨基苯甲醇的阳离子液相质谱图，其中，179.0为3-硝基-4-乙基氨基甲苯阳离子：
具体实施方式Detailed ways
下面结合具体实施例对本发明进行具体描述，有必要在此指出的是本实施例只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限制，该领域的技术熟练人员可以根据上述本发明的内容做出一些非本质的改进和调整。The present invention is described in detail below in conjunction with specific embodiment, it is necessary to point out that this embodiment is only used to further illustrate the present invention, can not be interpreted as the restriction to protection scope of the present invention, those skilled in the art can according to above-mentioned this invention The content of the invention makes some non-essential improvements and adjustments.
实施例1Example 1
向无水四氢呋喃（100.0 mL）中加入3-硝基-4-乙酰氨基苯甲酸（10.1 g，45.0mmol, 1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入1 M硼烷四氢呋喃溶液（90.0 mL，90.0 mmol，2.0 equiv.），即3-硝基-4-乙酰氨基苯甲酸：硼烷四氢呋喃络合物的摩尔比为1:2，保持反应温度在0-5℃。加毕，将反应体系缓慢升温至20℃，继续反应5小时后，TLC监测反应进程，反应结束。将反应体系降温至5℃，缓慢加入无水甲醇，保持体系温度在5-10℃，至无气泡产生。减压蒸出有机溶剂，剩余物用2 N 氢氧化钠水溶液（20.0 mL）分散，其中的粗品用乙酸乙酯（20.0 mL × 3）萃取，有机相用饱和食盐水洗涤（30.0 mL ×1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇7.9 g，收率89%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (10.1 g, 45.0 mmol, 1.0 equiv.) to anhydrous tetrahydrofuran (100.0 mL), stir and dissolve at room temperature, cool to 0°C, and slowly add 1 M boron under stirring Alkane tetrahydrofuran solution (90.0 mL, 90.0 mmol, 2.0 equiv.), that is, the molar ratio of 3-nitro-4-acetamidobenzoic acid: borane tetrahydrofuran complex is 1:2, keep the reaction temperature at 0-5 °C . After the addition was completed, the temperature of the reaction system was slowly raised to 20° C., and the reaction was continued for 5 hours. The reaction progress was monitored by TLC, and the reaction was completed. Cool the reaction system to 5°C, slowly add anhydrous methanol, and keep the system temperature at 5-10°C until no bubbles are generated. The organic solvent was evaporated under reduced pressure, the residue was dispersed with 2 N aqueous sodium hydroxide solution (20.0 mL), the crude product was extracted with ethyl acetate (20.0 mL × 3), and the organic phase was washed with saturated brine (30.0 mL × 1) , dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated and crystallized to obtain 7.9 g of 3-nitro-4-ethylaminobenzyl alcohol, with a yield of 89%, as a brown solid.
本申请的实施例中以底物3-硝基-4-乙酰氨基苯甲酸反应完即为反应结束。TLC监测某种物质是否反应完全为现有技术中的常规方法，TLC（薄层层析色谱），如果某种物质没反应完，在254nm紫外光照射下，会在TLC硅胶板上面显示出该物质的点，如果反应完了，就不会显示该物质的点。In the examples of the present application, the completion of the reaction of the substrate 3-nitro-4-acetamidobenzoic acid is the end of the reaction. It is a conventional method in the prior art to monitor whether a certain substance reacts completely by TLC, TLC (thin layer chromatography), if a certain substance has not reacted completely, it will be displayed on the TLC silica gel plate under 254nm ultraviolet light irradiation. The point of the substance, if the reaction is over, the point of the substance will not be displayed.
实施例2Example 2
向无水四氢呋喃（100.0 mL）中加入3-硝基-4-乙酰氨基苯甲酸（10.1 g，45.0mmol, 1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入1 M硼烷四氢呋喃溶液（112.5 mL，112.5 mmol，2.5 equiv.），保持反应温度在5-10℃。加毕，将反应体系缓慢升温至20℃，继续反应4.5小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入无水甲醇，保持体系温度在5-10℃，至无气泡产生。减压蒸出有机溶剂，剩余物用2 N 氢氧化钠水溶液（20.0 mL）分散，其中的粗品用乙酸乙酯（20.0 mL × 3）萃取，有机相用饱和食盐水洗涤（30.0 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇8.2 g，收率93%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (10.1 g, 45.0 mmol, 1.0 equiv.) to anhydrous tetrahydrofuran (100.0 mL), stir and dissolve at room temperature, cool to 0°C, and slowly add 1 M boron under stirring alkane tetrahydrofuran solution (112.5 mL, 112.5 mmol, 2.5 equiv.), and keep the reaction temperature at 5-10°C. After the addition was completed, the temperature of the reaction system was slowly raised to 20° C., and the reaction was continued for 4.5 hours, and the reaction was monitored by TLC to complete. Cool the reaction system to 5°C, slowly add anhydrous methanol, and keep the system temperature at 5-10°C until no bubbles are generated. The organic solvent was evaporated under reduced pressure, the residue was dispersed with 2 N aqueous sodium hydroxide solution (20.0 mL), the crude product was extracted with ethyl acetate (20.0 mL × 3), and the organic phase was washed with saturated brine (30.0 mL × 1) , dried over anhydrous sodium sulfate, filtered, concentrated and crystallized the mother liquor to obtain 8.2 g of 3-nitro-4-ethylaminobenzyl alcohol, yield 93%, brown solid.
实施例3Example 3
向无水四氢呋喃（100.0 mL）中加入3-硝基-4-乙酰氨基苯甲酸（10.1 g，45.0mmol, 1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入1 M硼烷四氢呋喃溶液（135.0 mL，135.0 mmol，3.0 equiv.），保持反应温度在0-10℃。加毕，将反应体系缓慢升温至20℃，继续反应3.5小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入无水甲醇，保持体系温度在5-10℃，至无气泡产生。减压蒸出有机溶剂，剩余物用2 N 氢氧化钾水溶液（20.0 mL）分散，其中的粗品用二氯甲烷（50.0 mL × 3）萃取，有机相用饱和食盐水洗涤（30.0 mL × 1），无水硫酸镁干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇8.4 g，收率95%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (10.1 g, 45.0 mmol, 1.0 equiv.) to anhydrous tetrahydrofuran (100.0 mL), stir and dissolve at room temperature, cool to 0°C, and slowly add 1 M boron under stirring alkane tetrahydrofuran solution (135.0 mL, 135.0 mmol, 3.0 equiv.), and keep the reaction temperature at 0-10°C. After the addition was completed, the temperature of the reaction system was slowly raised to 20° C., and the reaction was continued for 3.5 hours, and the reaction was monitored by TLC to complete. Cool the reaction system to 5°C, slowly add anhydrous methanol, and keep the system temperature at 5-10°C until no bubbles are generated. The organic solvent was evaporated under reduced pressure, and the residue was dispersed with 2 N aqueous potassium hydroxide solution (20.0 mL), the crude product was extracted with dichloromethane (50.0 mL × 3), and the organic phase was washed with saturated brine (30.0 mL × 1) , dried over anhydrous magnesium sulfate, filtered, concentrated and crystallized the mother liquor to obtain 8.4 g of 3-nitro-4-ethylaminobenzyl alcohol, yield 95%, brown solid.
实施例4Example 4
向无水四氢呋喃（100.0 mL）中加入3-硝基-4-乙酰氨基苯甲酸（10.1 g， 45.0mmol, 1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入1 M硼烷四氢呋喃溶液（135.0 mL，135.0 mmol，3.0 equiv.），保持反应温度在0-10℃。加毕，将反应体系缓慢升温至30℃，继续反应3小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入无水甲醇，保持体系温度在5-10℃，至无气泡产生。减压蒸出有机溶剂，剩余物用饱和碳酸钠水溶液（20.0 mL）分散，其中的粗品用乙酸乙酯（20.0 mL × 3）萃取，有机相用饱和食盐水洗涤（30.0 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇8.5g，收率96%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (10.1 g, 45.0 mmol, 1.0 equiv.) to anhydrous tetrahydrofuran (100.0 mL), stir and dissolve at room temperature, cool to 0°C, and slowly add 1 M boron under stirring alkane tetrahydrofuran solution (135.0 mL, 135.0 mmol, 3.0 equiv.), and keep the reaction temperature at 0-10°C. After the addition was completed, the temperature of the reaction system was slowly raised to 30° C., and the reaction was continued for 3 hours, and the reaction was monitored by TLC to complete. Cool the reaction system to 5°C, slowly add anhydrous methanol, and keep the system temperature at 5-10°C until no bubbles are generated. The organic solvent was distilled off under reduced pressure, and the residue was dispersed with saturated aqueous sodium carbonate (20.0 mL), the crude product was extracted with ethyl acetate (20.0 mL × 3), and the organic phase was washed with saturated brine (30.0 mL × 1). Dry over sodium sulfate, filter, concentrate and crystallize the mother liquor to obtain 8.5 g of 3-nitro-4-ethylaminobenzyl alcohol, yield 96%, brown solid.
实施例5Example 5
向无水四氢呋喃（100.0 mL）中加入3-硝基-4-乙酰氨基苯甲酸（10.1 g， 45.0mmol, 1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入1 M硼烷四氢呋喃溶液（135.0 mL，135.0 mmol，3.0 equiv.），保持反应温度在0-10℃。加毕，将反应体系缓慢升温至40℃，继续反应2小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入无水甲醇，保持体系温度在5-10℃，至无气泡产生。减压蒸出有机溶剂，剩余物用饱和碳酸钾水溶液（20.0 mL）分散，其中的粗品用乙酸乙酯（20.0 mL × 3）萃取，有机相用饱和食盐水洗涤（30.0 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇8.3g，收率94%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (10.1 g, 45.0 mmol, 1.0 equiv.) to anhydrous tetrahydrofuran (100.0 mL), stir and dissolve at room temperature, cool to 0°C, and slowly add 1 M boron under stirring alkane tetrahydrofuran solution (135.0 mL, 135.0 mmol, 3.0 equiv.), and keep the reaction temperature at 0-10°C. After the addition was completed, the temperature of the reaction system was slowly raised to 40° C., and the reaction was continued for 2 hours, and the reaction was monitored by TLC to complete. Cool the reaction system to 5°C, slowly add anhydrous methanol, and keep the system temperature at 5-10°C until no bubbles are generated. The organic solvent was distilled off under reduced pressure, and the residue was dispersed with saturated potassium carbonate aqueous solution (20.0 mL), the crude product was extracted with ethyl acetate (20.0 mL × 3), and the organic phase was washed with saturated brine (30.0 mL × 1). Dry over sodium sulfate, filter, concentrate and crystallize the mother liquor to obtain 8.3 g of 3-nitro-4-ethylaminobenzyl alcohol, yield 94%, brown solid.
实施例6Example 6
向无水二氯甲烷（200.0 mL）中加入3-硝基-4-乙酰氨基苯甲酸（10.1 g， 45.0mmol, 1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入1 M硼烷四氢呋喃溶液（135.0 mL，135.0 mmol，3.0 equiv.），保持反应温度在0-10℃。加毕，将反应体系缓慢升温至40℃，继续反应2.5小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入无水甲醇，保持体系温度在5-10℃，至无气泡产生。减压蒸出有机溶剂，剩余物用饱和碳酸钠水溶液（20.0 mL）分散，其中的粗品用乙酸乙酯（20.0 mL × 3）萃取，有机相用饱和食盐水洗涤（30.0 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇8.0g，收率91%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (10.1 g, 45.0 mmol, 1.0 equiv.) to anhydrous dichloromethane (200.0 mL), stir and dissolve at room temperature, cool to 0°C, and slowly add 1 M borane tetrahydrofuran solution (135.0 mL, 135.0 mmol, 3.0 equiv.), keep the reaction temperature at 0-10 °C. After the addition was completed, the temperature of the reaction system was slowly raised to 40° C., and the reaction was continued for 2.5 hours, and the reaction was monitored by TLC. Cool the reaction system to 5°C, slowly add anhydrous methanol, and keep the system temperature at 5-10°C until no bubbles are generated. The organic solvent was distilled off under reduced pressure, and the residue was dispersed with saturated aqueous sodium carbonate (20.0 mL), the crude product was extracted with ethyl acetate (20.0 mL × 3), and the organic phase was washed with saturated brine (30.0 mL × 1). Dry over sodium sulfate, filter, concentrate and crystallize the mother liquor to obtain 8.0 g of 3-nitro-4-ethylaminobenzyl alcohol, yield 91%, brown solid.
实施例7Example 7
向无水四氢呋喃（100.0 mL）中加入3-硝基-4-乙酰氨基苯甲酸（10.1 g，45.0mmol, 1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入2 M硼烷二甲硫醚溶液（67.5 mL，135.0 mmol，3.0 equiv.），保持反应温度在0-10℃。加毕，将反应体系缓慢升温至20℃，继续反应4.5小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入无水甲醇，保持体系温度在5-10℃，至无气泡产生。减压蒸出有机溶剂，剩余物用2 N 氢氧化钠水溶液（20.0 mL）分散，其中的粗品用二氯甲烷（50.0 mL × 3）萃取，有机相用饱和食盐水洗涤（30.0 mL × 1），无水硫酸镁干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇8.0 g，收率90%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (10.1 g, 45.0 mmol, 1.0 equiv.) to anhydrous tetrahydrofuran (100.0 mL), stir and dissolve at room temperature, cool to 0°C, and slowly add 2 M boron under stirring Alkane dimethyl sulfide solution (67.5 mL, 135.0 mmol, 3.0 equiv.), keep the reaction temperature at 0-10 °C. After the addition was completed, the temperature of the reaction system was slowly raised to 20° C., and the reaction was continued for 4.5 hours, and the reaction was monitored by TLC to complete. Cool the reaction system to 5°C, slowly add anhydrous methanol, and keep the system temperature at 5-10°C until no bubbles are generated. The organic solvent was evaporated under reduced pressure, the residue was dispersed with 2 N aqueous sodium hydroxide solution (20.0 mL), the crude product was extracted with dichloromethane (50.0 mL × 3), and the organic phase was washed with saturated brine (30.0 mL × 1) , dried over anhydrous magnesium sulfate, filtered, concentrated and crystallized the mother liquor to obtain 8.0 g of 3-nitro-4-ethylaminobenzyl alcohol, yield 90%, brown solid.
实施例8Example 8
向无水四氢呋喃（100.0 mL）中加入3-硝基-4-乙酰氨基苯甲酸（6.7 g， 29.9mmol, 1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入硼氢化钠（5.7 g，150.0mmol，5.0 equiv.）,48%三氟化硼/乙醚（17.0 g，120.0 mmol，4.0 equiv.），保持反应温度在0-5℃。加毕，将反应体系缓慢升温至回流，继续反应5小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入无水甲醇和2 N 盐酸，保持体系温度在5-10℃，至无气泡产生，加热回流0.5小时。减压蒸出有机溶剂，剩余物用质量浓度为25%的浓氨水（100.0 mL），乙酸乙酯（80.0 mL）分散，过滤，母液分液，水相用乙酸乙酯（20.0 mL × 3）萃取，合并有机相，用饱和食盐水洗涤（30.0 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇5.1 g，收率86%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (6.7 g, 29.9 mmol, 1.0 equiv.) to anhydrous tetrahydrofuran (100.0 mL), stir and dissolve at room temperature, cool to 0°C, and slowly add sodium borohydride under stirring (5.7 g, 150.0 mmol, 5.0 equiv.), 48% boron trifluoride/diethyl ether (17.0 g, 120.0 mmol, 4.0 equiv.), keep the reaction temperature at 0-5°C. After the addition, the temperature of the reaction system was slowly raised to reflux, and the reaction was continued for 5 hours, and the reaction was monitored by TLC to complete. Cool the reaction system to 5°C, slowly add anhydrous methanol and 2 N hydrochloric acid, keep the system temperature at 5-10°C until no bubbles are generated, and heat to reflux for 0.5 hours. Evaporate the organic solvent under reduced pressure, disperse the residue with 25% concentrated ammonia (100.0 mL), ethyl acetate (80.0 mL), filter, separate the mother liquor, and use ethyl acetate (20.0 mL × 3) for the aqueous phase Extract, combine the organic phases, wash with saturated brine (30.0 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate and crystallize the mother liquor to obtain 5.1 g of 3-nitro-4-ethylaminobenzyl alcohol, the yield is 86%, brown solid.
实施例9Example 9
向无水四氢呋喃（100.0 mL）中加入3-硝基-4-乙酰氨基苯甲酸（6.7 g， 29.9mmol, 1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入硼氢化钠（2.3 g，59.8mmol，2.0 equiv.）,48%三氟化硼/乙醚（12.7 g，89.7mmol，3.0 equiv.），保持反应温度在5-10℃。加毕，将反应体系缓慢升温至回流，继续反应8小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入无水甲醇和2 N 盐酸，保持体系温度在5-10℃，至无气泡产生，加热回流0.5小时。减压蒸出有机溶剂，剩余物用浓氨水（100.0 mL），乙酸乙酯（80.0 mL）分散，过滤，母液分液，水相用乙酸乙酯（20.0 mL × 3）萃取，合并有机相，用饱和食盐水洗涤（30.0 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇4.2g，收率71%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (6.7 g, 29.9 mmol, 1.0 equiv.) to anhydrous tetrahydrofuran (100.0 mL), stir and dissolve at room temperature, cool to 0°C, and slowly add sodium borohydride under stirring (2.3 g, 59.8 mmol, 2.0 equiv.), 48% boron trifluoride/diethyl ether (12.7 g, 89.7 mmol, 3.0 equiv.), keeping the reaction temperature at 5-10°C. After the addition, the temperature of the reaction system was slowly raised to reflux, and the reaction was continued for 8 hours, and the reaction was monitored by TLC to complete. Cool the reaction system to 5°C, slowly add anhydrous methanol and 2 N hydrochloric acid, keep the system temperature at 5-10°C until no bubbles are generated, and heat to reflux for 0.5 hours. The organic solvent was distilled off under reduced pressure, and the residue was dispersed with concentrated ammonia water (100.0 mL) and ethyl acetate (80.0 mL), filtered, the mother liquor was separated, the aqueous phase was extracted with ethyl acetate (20.0 mL × 3), and the organic phases were combined. Wash with saturated brine (30.0 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate and crystallize the mother liquor to obtain 4.2 g of 3-nitro-4-ethylaminobenzyl alcohol, yield 71%, brown solid.
实施例10Example 10
向无水四氢呋喃（100.0 mL）中加入3-硝基-4-乙酰氨基苯甲酸（6.7 g， 29.9mmol, 1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入硼氢化锂（2.6 g，119.6mmol，4.0 equiv.）,48%三氟化硼/乙醚（12.7 g，89.7 mmol，3.0 equiv.），保持反应温度在0-10℃。加毕，将反应体系缓慢升温至回流，继续反应6小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入无水甲醇和2 N 盐酸，保持体系温度在5-10℃，至无气泡产生，加热回流0.5小时。减压蒸出有机溶剂，剩余物用浓氨水（100.0 mL），乙酸乙酯（80.0 mL）分散，过滤，母液分液，水相用乙酸乙酯（20.0 mL × 3）萃取，合并有机相，用饱和食盐水洗涤（30.0 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇4.9g，收率83%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (6.7 g, 29.9 mmol, 1.0 equiv.) to anhydrous tetrahydrofuran (100.0 mL), stir and dissolve at room temperature, cool to 0°C, and slowly add lithium borohydride under stirring (2.6 g, 119.6 mmol, 4.0 equiv.), 48% boron trifluoride/diethyl ether (12.7 g, 89.7 mmol, 3.0 equiv.), keeping the reaction temperature at 0-10°C. After the addition, the temperature of the reaction system was slowly raised to reflux, and the reaction was continued for 6 hours. After the reaction was monitored by TLC, the reaction was completed. Cool the reaction system to 5°C, slowly add anhydrous methanol and 2 N hydrochloric acid, keep the system temperature at 5-10°C until no bubbles are generated, and heat to reflux for 0.5 hours. The organic solvent was distilled off under reduced pressure, and the residue was dispersed with concentrated ammonia water (100.0 mL) and ethyl acetate (80.0 mL), filtered, the mother liquor was separated, the aqueous phase was extracted with ethyl acetate (20.0 mL × 3), and the organic phases were combined. Wash with saturated brine (30.0 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate and crystallize the mother liquor to obtain 4.9 g of 3-nitro-4-ethylaminobenzyl alcohol, yield 83%, brown solid.
实施例11Example 11
向二氯甲烷（150.0 mL）中加入3-硝基-4-乙酰氨基苯甲酸（6.7 g， 29.9 mmol,1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入硼氢化钾（5.6 g，104.6 mmol，3.5 equiv.）,48%三氟化硼/乙醚（14.8 g，104.6 mmol，3.5 equiv.），保持反应温度在0-10℃。加毕，将反应体系缓慢升温至回流，继续反应7小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入无水甲醇和2 N 盐酸，保持体系温度在5-10℃，至无气泡产生，加热回流0.5小时。减压蒸出有机溶剂，剩余物用浓氨水（100.0 mL），二氯甲烷（80.0 mL）分散，过滤，母液分液，水相用二氯甲烷（20.0 mL × 3）萃取，合并有机相，用饱和食盐水洗涤（30.0 mL× 1），无水硫酸镁干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇3.9 g，收率67%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (6.7 g, 29.9 mmol, 1.0 equiv.) into dichloromethane (150.0 mL), stir and dissolve at room temperature, cool to 0°C, slowly add potassium borohydride under stirring (5.6 g, 104.6 mmol, 3.5 equiv.), 48% boron trifluoride/diethyl ether (14.8 g, 104.6 mmol, 3.5 equiv.), keeping the reaction temperature at 0-10°C. After the addition, the temperature of the reaction system was slowly raised to reflux, and the reaction was continued for 7 hours, and the reaction was monitored by TLC to complete. Cool the reaction system to 5°C, slowly add anhydrous methanol and 2 N hydrochloric acid, keep the system temperature at 5-10°C until no bubbles are generated, and heat to reflux for 0.5 hours. The organic solvent was evaporated under reduced pressure, the residue was dispersed with concentrated ammonia water (100.0 mL) and dichloromethane (80.0 mL), filtered, the mother liquor was separated, the aqueous phase was extracted with dichloromethane (20.0 mL × 3), the organic phases were combined, Wash with saturated brine (30.0 mL×1), dry over anhydrous magnesium sulfate, filter, concentrate and crystallize the mother liquor to obtain 3.9 g of 3-nitro-4-ethylaminobenzyl alcohol, yield 67%, brown solid.
实施例12Example 12
向无水四氢呋喃（100.0 mL）中加入3-硝基-4-乙酰氨基苯甲酸（6.7 g， 29.9mmol, 1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入四氢铝锂（4.5 g，119.6mmol，4.0 equiv.）,48%三氟化硼/乙醚（12.7 g，89.7 mmol，3.0 equiv.），保持反应温度在0-10℃。加毕，将反应体系缓慢升温至回流，继续反应4小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入无水甲醇和2 N 盐酸，保持体系温度在5-10℃，至无气泡产生，加热回流0.5小时。减压蒸出有机溶剂，剩余物用浓氨水（100.0 mL），乙酸乙酯（80.0 mL）分散，过滤，母液分液，水相用乙酸乙酯（20.0 mL × 3）萃取，合并有机相，用饱和食盐水洗涤（30.0 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇4.6g，收率79%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (6.7 g, 29.9 mmol, 1.0 equiv.) to anhydrous tetrahydrofuran (100.0 mL), stir and dissolve at room temperature, cool to 0°C, and slowly add aluminum tetrahydrogen under stirring Lithium (4.5 g, 119.6 mmol, 4.0 equiv.), 48% boron trifluoride/diethyl ether (12.7 g, 89.7 mmol, 3.0 equiv.), keeping the reaction temperature at 0-10°C. After the addition, the temperature of the reaction system was slowly raised to reflux, and the reaction was continued for 4 hours, and the reaction was monitored by TLC to complete. Cool the reaction system to 5°C, slowly add anhydrous methanol and 2 N hydrochloric acid, keep the system temperature at 5-10°C until no bubbles are generated, and heat to reflux for 0.5 hours. The organic solvent was distilled off under reduced pressure, and the residue was dispersed with concentrated ammonia water (100.0 mL) and ethyl acetate (80.0 mL), filtered, the mother liquor was separated, the aqueous phase was extracted with ethyl acetate (20.0 mL × 3), and the organic phases were combined. Wash with saturated brine (30.0 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate and crystallize the mother liquor to obtain 4.6 g of 3-nitro-4-ethylaminobenzyl alcohol, yield 79%, brown solid.
实施例13Example 13
向无水甲苯（100 mL）中加入3-硝基-4-乙酰氨基苯甲酸（6.7 g， 29.9 mmol, 1.0equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入1.5 M 二异丁基氢化铝/甲苯（99.7mL，149.5 mmol，5.0 equiv.）,保持反应温度在0-5℃。加毕，将反应体系缓慢升温至20℃，继续反应6小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入酒石酸钾钠的饱和溶液，保持体系温度在5-10℃，至无气泡产生。分液，水相用乙酸乙酯（20.0 mL × 3）萃取，合并有机相，用饱和食盐水洗涤（30.0 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇3.8 g，收率65%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (6.7 g, 29.9 mmol, 1.0 equiv.) into anhydrous toluene (100 mL), stir and dissolve at room temperature, cool to 0°C, slowly add 1.5 M di Isobutylaluminum hydride/toluene (99.7 mL, 149.5 mmol, 5.0 equiv.), keep the reaction temperature at 0-5°C. After the addition was completed, the temperature of the reaction system was slowly raised to 20° C., and the reaction was continued for 6 hours, and the reaction was monitored by TLC to complete. Cool the reaction system to 5°C, slowly add a saturated solution of potassium sodium tartrate, and keep the system temperature at 5-10°C until no bubbles are generated. Separate the layers, extract the aqueous phase with ethyl acetate (20.0 mL × 3), combine the organic phases, wash with saturated brine (30.0 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate and crystallize the mother liquor to obtain 3-nitro- 4-Ethylaminobenzyl alcohol 3.8 g, yield 65%, brown solid.
实施例14Example 14
向无水甲苯（100 mL）中加入3-硝基-4-乙酰氨基苯甲酸（6.7 g， 29.9 mmol, 1.0equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入1.5 M 二异丁基氢化铝/甲苯（149.5 mL，224.3 mmol，7.5 equiv.）,保持反应温度在5-10℃。加毕，将反应体系缓慢升温至30℃，继续反应4小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入酒石酸钾钠的饱和溶液，保持体系温度在5-10℃，至无气泡产生。分液，水相用乙酸乙酯（20.0 mL ×3）萃取，合并有机相，用饱和食盐水洗涤（30.0 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇4.7 g，收率80%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (6.7 g, 29.9 mmol, 1.0 equiv.) into anhydrous toluene (100 mL), stir and dissolve at room temperature, cool to 0°C, slowly add 1.5 M di Isobutylaluminum hydride/toluene (149.5 mL, 224.3 mmol, 7.5 equiv.), keep the reaction temperature at 5-10°C. After the addition was completed, the temperature of the reaction system was slowly raised to 30° C., and the reaction was continued for 4 hours, and the reaction was monitored by TLC to complete. Cool the reaction system to 5°C, slowly add a saturated solution of potassium sodium tartrate, and keep the system temperature at 5-10°C until no bubbles are generated. Separate the layers, extract the aqueous phase with ethyl acetate (20.0 mL × 3), combine the organic phases, wash with saturated brine (30.0 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the mother liquor to obtain 3-nitro- 4-Ethylaminobenzyl alcohol 4.7 g, yield 80%, brown solid.
实施例15Example 15
向无水甲苯（100.0 mL）中加入3-硝基-4-乙酰氨基苯甲酸（6.7 g， 29.9 mmol,1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入1.5 M 二异丁基氢化铝/甲苯（199.3 mL，299.0 mmol，10.0 equiv.）,保持反应温度在5-10℃。加毕，将反应体系缓慢升温至40℃，继续反应2小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入酒石酸钾钠的饱和溶液，保持体系温度在5-10℃，至无气泡产生。分液，水相用乙酸乙酯（20.0 mL ×3）萃取，合并有机相，用饱和食盐水洗涤（30.0 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇4.9 g，收率83%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (6.7 g, 29.9 mmol, 1.0 equiv.) into anhydrous toluene (100.0 mL), stir and dissolve at room temperature, cool to 0°C, slowly add 1.5 M di Isobutylaluminum hydride/toluene (199.3 mL, 299.0 mmol, 10.0 equiv.), keep the reaction temperature at 5-10°C. After the addition was completed, the temperature of the reaction system was slowly raised to 40° C., and the reaction was continued for 2 hours, and the reaction was monitored by TLC to complete. Cool the reaction system to 5°C, slowly add a saturated solution of potassium sodium tartrate, and keep the system temperature at 5-10°C until no bubbles are generated. Separate the layers, extract the aqueous phase with ethyl acetate (20.0 mL × 3), combine the organic phases, wash with saturated brine (30.0 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the mother liquor to obtain 3-nitro- 4-Ethylaminobenzyl alcohol 4.9 g, yield 83%, brown solid.
实施例16Example 16
向无水四氢呋喃（100.0 mL）中加入3-硝基-4-乙酰氨基苯甲酸（6.7 g， 29.9mmol, 1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入1 M 二异丁基氢化铝/正己烷（224.3 mL，224.3 mmol，7.5 equiv.）,保持反应温度在0-10℃。加毕，将反应体系缓慢升温至40℃，继续反应4小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入酒石酸钾钠的饱和溶液至无气体放出，保持体系温度在5-10℃，至无气泡产生。分液，水相用乙酸乙酯（20.0 mL × 3）萃取，合并有机相，用饱和食盐水洗涤（30.0 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇4.5 g，收率77%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (6.7 g, 29.9 mmol, 1.0 equiv.) to anhydrous tetrahydrofuran (100.0 mL), stir and dissolve at room temperature, cool to 0°C, and slowly add 1 M di Isobutylaluminum hydride/n-hexane (224.3 mL, 224.3 mmol, 7.5 equiv.), keep the reaction temperature at 0-10°C. After the addition was completed, the temperature of the reaction system was slowly raised to 40° C., and the reaction was continued for 4 hours, and the reaction was monitored by TLC to complete. Cool the reaction system to 5°C, slowly add a saturated solution of potassium sodium tartrate until no gas is released, and keep the system temperature at 5-10°C until no bubbles are generated. Separate the layers, extract the aqueous phase with ethyl acetate (20.0 mL × 3), combine the organic phases, wash with saturated brine (30.0 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate and crystallize the mother liquor to obtain 3-nitro- 4-Ethylaminobenzyl alcohol 4.5 g, yield 77%, brown solid.
实施例17Example 17
向二氯甲烷（150.0 mL）中加入3-硝基-4-乙酰氨基苯甲酸（6.7 g， 29.9 mmol,1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入1 M 二异丁基氢化铝/正己烷（224.3 mL，224.3 mmol，7.5 equiv.）,保持反应温度在0-10℃。加毕，将反应体系缓慢升温至40℃，继续反应5小时后，TLC监测反应结束。将反应体系降温至5℃，缓慢加入酒石酸钾钠的饱和溶液至无气体放出，保持体系温度在5-10℃，至无气泡产生。分液，水相用二氯甲烷（20.0 mL × 3）萃取，合并有机相，用饱和食盐水洗涤（30.0 mL × 1），无水硫酸镁干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇4.0 g，收率68%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (6.7 g, 29.9 mmol, 1.0 equiv.) into dichloromethane (150.0 mL), stir and dissolve at room temperature, cool to 0°C, and slowly add 1 M di Isobutylaluminum hydride/n-hexane (224.3 mL, 224.3 mmol, 7.5 equiv.), keep the reaction temperature at 0-10°C. After the addition was complete, the temperature of the reaction system was slowly raised to 40° C., and the reaction was continued for 5 hours, and the reaction was monitored by TLC to complete. Cool the reaction system to 5°C, slowly add a saturated solution of potassium sodium tartrate until no gas is released, and keep the system temperature at 5-10°C until no bubbles are generated. The liquid was separated, the aqueous phase was extracted with dichloromethane (20.0 mL × 3), the organic phases were combined, washed with saturated brine (30.0 mL × 1), dried over anhydrous magnesium sulfate, filtered, and the mother liquor was concentrated and crystallized to obtain 3-nitro- 4-Ethylaminobenzyl alcohol 4.0 g, yield 68%, brown solid.
实施例18Example 18
向无水甲苯（100 mL）中加入3-硝基-4-乙酰氨基苯甲酸（6.7 g， 29.9 mmol, 1.0equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入3.6 M 红铝/甲苯（49.8 mL，179.4mmol，6.0 equiv.）,保持反应温度在0-5℃。加毕，将反应体系缓慢升温至70℃，继续反应2小时后，TLC监测反应结束。将反应体系降温至5℃，搅拌下缓慢加入2 N 氢氧化钠溶液（200mL），保持体系温度在5-10℃。分液，水相用乙酸乙酯（20 mL × 3）萃取，合并有机相，用饱和食盐水洗涤（30 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇5.0 g，收率85%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (6.7 g, 29.9 mmol, 1.0 equiv.) to anhydrous toluene (100 mL), stir and dissolve at room temperature, cool to 0°C, slowly add 3.6 M red Aluminum/toluene (49.8 mL, 179.4 mmol, 6.0 equiv.), keep the reaction temperature at 0-5°C. After the addition was completed, the temperature of the reaction system was slowly raised to 70° C., and the reaction was continued for 2 hours, and the reaction was monitored by TLC to complete. The temperature of the reaction system was lowered to 5°C, and 2 N sodium hydroxide solution (200 mL) was slowly added with stirring, keeping the temperature of the system at 5-10°C. Separate the layers, extract the aqueous phase with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (30 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate and crystallize the mother liquor to obtain 3-nitro- 4-Ethylaminobenzyl alcohol 5.0 g, yield 85%, brown solid.
实施例19Example 19
向无水甲苯（100 mL）中加入3-硝基-4-乙酰氨基苯甲酸（6.7 g， 29.9 mmol, 1.0equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入3.6 M 红铝/甲苯（41.5 mL，149.5mmol，5.0 equiv.）,保持反应温度在5-10℃。加毕，将反应体系缓慢升温至70℃，继续反应3小时后，TLC监测反应结束。将反应体系降温至5℃，搅拌下缓慢加入2 N 氢氧化钾溶液（200mL），保持体系温度在5-10℃。分液，水相用乙酸乙酯（20 mL × 3）萃取，合并有机相，用饱和食盐水洗涤（30 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇4.6 g，收率78%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (6.7 g, 29.9 mmol, 1.0 equiv.) to anhydrous toluene (100 mL), stir and dissolve at room temperature, cool to 0°C, slowly add 3.6 M red Aluminum/toluene (41.5 mL, 149.5 mmol, 5.0 equiv.), keep the reaction temperature at 5-10 °C. After the addition was completed, the temperature of the reaction system was slowly raised to 70° C., and the reaction was continued for 3 hours, and the reaction was monitored by TLC to complete. The temperature of the reaction system was lowered to 5°C, and 2 N potassium hydroxide solution (200 mL) was slowly added with stirring, keeping the temperature of the system at 5-10°C. Separate the layers, extract the aqueous phase with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (30 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate and crystallize the mother liquor to obtain 3-nitro- 4-Ethylaminobenzyl alcohol 4.6 g, yield 78%, brown solid.
实施例20Example 20
向无水甲苯（100 mL）中加入3-硝基-4-乙酰氨基苯甲酸（6.7 g， 29.9 mmol, 1.0equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入3.6 M 红铝/甲苯（41.5 mL，149.5mmol，5.0 equiv.）,保持反应温度在5-10℃。加毕，将反应体系缓慢升温至80℃，继续反应3小时后，TLC监测反应结束。将反应体系降温至5℃，搅拌下缓慢加入饱和碳酸钾溶液（200mL），保持体系温度在5-10℃。分液，水相用乙酸乙酯（20 mL × 3）萃取，合并有机相，用饱和食盐水洗涤（30 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇4.7 g，收率80%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (6.7 g, 29.9 mmol, 1.0 equiv.) to anhydrous toluene (100 mL), stir and dissolve at room temperature, cool to 0°C, slowly add 3.6 M red Aluminum/toluene (41.5 mL, 149.5 mmol, 5.0 equiv.), keep the reaction temperature at 5-10 °C. After the addition was completed, the temperature of the reaction system was slowly raised to 80° C., and the reaction was continued for 3 hours, and the reaction was monitored by TLC to complete. The temperature of the reaction system was lowered to 5°C, and a saturated potassium carbonate solution (200 mL) was slowly added with stirring, keeping the temperature of the system at 5-10°C. Separate the layers, extract the aqueous phase with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (30 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate and crystallize the mother liquor to obtain 3-nitro- 4-Ethylaminobenzyl alcohol 4.7 g, yield 80%, brown solid.
实施例21Example 21
向无水四氢呋喃（100 mL）中加入3-硝基-4-乙酰氨基苯甲酸（6.7 g， 29.9 mmol,1.0 equiv.），常温搅拌溶解后，冷却至0℃，搅拌下缓慢加入3.6 M 红铝/甲苯（58.1 mL，209.3 mmol，7.0 equiv.）,保持反应温度在0-10℃。加毕，将反应体系缓慢升温至60℃，继续反应1小时后，TLC监测反应结束。将反应体系降温至5℃，搅拌下缓慢加入饱和碳酸钠溶液（200 mL），保持体系温度在5-10℃。分液，水相用二氯甲烷（20 mL × 3）萃取，合并有机相，用饱和食盐水洗涤（30 mL × 1），无水硫酸钠干燥，过滤，母液浓缩结晶得到3-硝基-4-乙基氨基苯甲醇5.0 g，收率86%，棕色固体。Add 3-nitro-4-acetamidobenzoic acid (6.7 g, 29.9 mmol, 1.0 equiv.) to anhydrous tetrahydrofuran (100 mL), stir and dissolve at room temperature, cool to 0°C, and slowly add 3.6 M red Al/toluene (58.1 mL, 209.3 mmol, 7.0 equiv.), keep the reaction temperature at 0-10°C. After the addition was completed, the temperature of the reaction system was slowly raised to 60° C., and the reaction was continued for 1 hour, and the reaction was monitored by TLC to complete. The temperature of the reaction system was lowered to 5°C, and a saturated sodium carbonate solution (200 mL) was slowly added with stirring, keeping the temperature of the system at 5-10°C. Separate the layers, extract the aqueous phase with dichloromethane (20 mL × 3), combine the organic phases, wash with saturated brine (30 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate the mother liquor to obtain 3-nitro- 4-Ethylaminobenzyl alcohol 5.0 g, yield 86%, brown solid.
另外本发明制备的产物3-硝基-4-乙基氨基苯甲醇的核磁共振氢谱和阳离子液相质谱图分别如图1和图2所示。In addition, the proton nuclear magnetic resonance spectrum and cationic liquid phase mass spectrum of the product 3-nitro-4-ethylaminobenzyl alcohol prepared by the present invention are shown in Figure 1 and Figure 2 respectively.
以上所述的仅是本发明的优选实施方式，但本发明的保护范围并不局限于此，应当指出，对于本领域的及任何熟悉本技术领域的技术人员来说，在不脱离本发明整体构思前提下，根据本发明的技术方案及其发明构思加以等同替换或改变，及作出的若干改变和改进，这些也应该视为本发明的保护范围。What has been described above is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Under the premise of the concept, equivalent replacements or changes, as well as some changes and improvements made according to the technical solution of the present invention and its inventive concept, should also be regarded as the protection scope of the present invention.
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