Process for the production of benzyl alcohol compounds

Abstract

The application belongs to the technical field of medicine, and particularly relates to a production process of a benzyl alcohol compound. Toluene organic matter is dissolved in an organic solvent, stirring is started, a halide salt solution and a sodium bisulfite solution are added, and then a reflux reaction is carried out after temperature rising, extraction is carried out, rotary evaporation is carried out, and an oily compound is obtained; the oily compound is stirred with water, a reflux reaction is carried out after temperature rising, and extraction is carried out, and then a benzyl alcohol compound is obtained. The application is environment-friendly, can react without using an inducer, and is extremely suitable for industrial production due to simple feeding mode.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a production process for benzyl alcohol compounds. Background Technology

[0002] o-Nitrobenzyl alcohol, also known as 2-nitrobenzyl alcohol, is an important fine chemical intermediate. It is a brown or pale yellow crystalline powder at room temperature. Its core application is as a key raw material in drug synthesis, such as in the production of the analgesic tramadol hydrochloride. It is also used in the synthesis of biologically active heterocyclic compounds, such as 3-amino-3,4-dihydro-1H-quinoline-2-one drugs. Because the nitro group in its molecule can undergo specific photolysis reactions under light, it is often used as a photoprotective group in high-end fields such as photoresists, photocontrolled drug release systems, and biological probes. In academic research, it is also used as a biomaterial or organic compound in life science experiments. Furthermore, it can be used as an intermediate in the synthesis of pesticides, dyes, and other fine chemicals.

[0003] m-Nitrobenzyl alcohol is mainly used in the synthesis of fine chemicals such as pharmaceuticals, pesticides and dyes, and is also used as a matrix in fast atom bombardment mass spectrometry and liquid secondary ion mass spectrometry to assist in the ionization of samples.

[0004] p-Nitrobenzyl alcohol is an organic intermediate with important applications in the pharmaceutical and chemical industries. Simply put, it is a pale yellow crystalline powder, primarily used as a "building block" in the synthesis of more complex drug and dye molecules. Industrially, p-nitrobenzyl alcohol's most important role is as a pharmaceutical and dye intermediate; it acts as a "part" in the synthesis of more complex molecules, such as the antibiotic imipenem.

[0005] Chinese patent CN105801422A discloses a method for preparing o-nitrobenzyl alcohol, using 1,2-bis(o-nitrobenzyl)ethane as a raw material and reacting it with benzoquinone; after the reaction, excess benzoquinone and the byproduct hydroquinone are distilled off; methanol is added to the residue to dissolve it, and then sodium borohydride is added for reduction; after the reduction reaction, the solvent methanol is recovered, and the target product o-nitrobenzyl alcohol is collected by distillation at 160-165℃ / 15mmHg. This patented method is simple and the byproducts can be recovered and reused, but the reaction conditions are highly dangerous. Summary of the Invention

[0006] The purpose of this invention is to provide a production process for benzyl alcohol compounds that is environmentally friendly, allows the reaction to proceed without the use of an inducing agent, has a simple feeding method, and is highly suitable for industrial production.

[0007] The production process of benzyl alcohol compounds according to the present invention includes the following steps: (1) Halogenation reaction: Dissolve toluene-based organic compounds in an organic solvent, start stirring, add halide salt solution and sodium bisulfite solution, heat and reflux reaction, extract, rotary evaporate to obtain oily compound; (2) Hydrolysis reaction: The oily compound and water are stirred, heated and refluxed to extract benzyl alcohol compounds.

[0008] In step (1), the toluene-like organic compound is one or more of o-nitrotoluene, m-nitrotoluene, or p-nitrotoluene.

[0009] In step (1), the organic solvent is one or more of ethyl acetate, 1,2-dichloroethane, dichloromethane, ethanol, acetone or petroleum ether; the ratio of toluene-based organic compound to organic solvent is 1:8.5-10, wherein the toluene-based organic compound is expressed in g and the organic solvent is expressed in ml.

[0010] In step (1), the halide solution is prepared by dissolving halide in water. The mass ratio of halide to water is 1:2-5. The halide is one or more of sodium chlorate, potassium chlorate, sodium bromate, potassium bromate, sodium iodate, or potassium iodate. The mass ratio of halide to toluene-like organic compounds is 1.1-3.5:1.

[0011] In step (1), the sodium bisulfite solution is prepared by dissolving sodium bisulfite in water. The mass ratio of sodium bisulfite to water is 1:1-3, and the mass ratio of sodium bisulfite to halide in the halide solution is 1:1-3.

[0012] In step (1), the temperature is raised to 80-120℃ and the reflux reaction time is 4-8h.

[0013] In step (1), the extraction is performed using an organic solvent, which is one or more of ethyl acetate, 1,2-dichloroethane, dichloromethane, ethanol, acetone, or petroleum ether.

[0014] In step (2), the mass ratio of the oily compound to water is 1:10-20.

[0015] In step (2), the temperature is raised to 80-120℃ and the reflux reaction time is 2-8h.

[0016] In step (2), the extraction is performed using an organic solvent, which is one or more of ethyl acetate, 1,2-dichloroethane, dichloromethane, or petroleum ether.

[0017] This invention uses halide salts to provide halogen atoms and reacts sodium bisulfite with the halide salts to generate elemental halogens. The generated elemental halogens react rapidly with toluene-like organic compounds dissolved in organic solvents under high temperature conditions to generate halogenated products. The halogenated products are then hydrolyzed under high temperature conditions to generate benzyl alcohol-like compounds.

[0018] The beneficial effects of this invention are as follows: (1) This invention does not directly use halogen elements, is environmentally friendly, has low requirements for experimental conditions, the reactants are easy to store, and the intermediates are non-irritating; (2) The present invention can react without the use of an inducing agent, the reaction conditions are simple, and it is easy to industrialize; (3) The present invention has high substrate conversion efficiency; (4) The feeding method of this invention is simple, and no other materials such as sodium carbonate and potassium carbonate are required. Only water is needed to carry out the hydrolysis reaction. Attached Figure Description

[0019] Figure 1 This is the hydrogen spectrum of o-nitrobenzyl alcohol.

[0020] Figure 2 This is the carbon spectrum of o-nitrobenzyl alcohol.

[0021] Figure 3 This is the hydrogen spectrum of m-nitrobenzyl alcohol.

[0022] Figure 4 This is the carbon spectrum of m-nitrobenzyl alcohol.

[0023] Figure 5 This is the hydrogen spectrum of p-nitrobenzyl alcohol.

[0024] Figure 6 This is the carbon spectrum of p-nitrobenzyl alcohol. Detailed Implementation

[0025] The present invention will be further described below with reference to embodiments.

[0026] Example 1 (1) Dissolve 6.86 g of o-nitrotoluene in 60 mL of 1,2-dichloroethane, start stirring, add sodium bromate solution (prepared by dissolving 7.55 g of sodium bromate in 22.5 mL of water) and sodium bisulfite solution (prepared by dissolving 5.21 g of sodium bisulfite in 10 mL of water), heat to 100 °C, reflux for 6 h, and after the substrate reaction is complete as detected by TLC, extract twice with 20 mL of 1,2-dichloroethane, and obtain an oily compound by rotary evaporation; (2) Add 264 ml of water to the flask, start stirring, add 22 g of the oily compound, heat to 100 °C and reflux for 4 h. TLC analysis showed the reaction was complete, with 100% conversion of o-nitrotoluene. Pure o-nitrobenzyl alcohol was obtained by extraction with 1,2-dichloroethane, yielding 85%. The 1H NMR spectrum of o-nitrobenzyl alcohol is shown below. Figure 1 The carbon spectrum of o-nitrobenzyl alcohol is shown below. Figure 2 .

[0027] Example 2 (1) Dissolve 6.86 g of m-nitrotoluene in 68 ml of ethyl acetate, start stirring, add sodium iodate solution (prepared by dissolving 15.09 g of sodium iodate in 31 ml of water) and sodium bisulfite solution (prepared by dissolving 10.41 g of sodium bisulfite in 11 ml of water), heat to 80 °C, reflux for 8 h, and after the substrate reaction is complete, TLC plate detection shows that the reaction is complete. Extract twice with 20 mL of ethyl acetate, and obtain an oily compound by rotary evaporation. (2) Add 220 ml of water to the flask, start stirring, add 22 g of the oily compound, heat to 80 °C and reflux for 8 h. TLC analysis showed the reaction was complete, with a 100% conversion of m-nitrotoluene. Pure m-nitrobenzyl alcohol was obtained by extraction with ethyl acetate, yielding 87%. The 1H NMR spectrum of m-nitrobenzyl alcohol is shown below. Figure 3 The carbon spectrum of m-nitrobenzyl alcohol is shown below. Figure 4 .

[0028] Example 3 (1) Dissolve 6.86 g of p-nitrotoluene in 65 ml of dichloromethane, start stirring, add potassium bromate solution (prepared by dissolving 22.65 g of potassium bromate in 113 ml of water) and sodium bisulfite solution (prepared by dissolving 15.63 g of sodium bisulfite in 46 ml of water), heat to 120 °C, reflux for 4 h, and after the substrate reaction is complete, TLC plate detection shows that the reaction is complete. Extract twice with 20 mL of dichloromethane, and obtain an oily compound by rotary evaporation. (2) Add 440 ml of water to the flask, start stirring, add 22 g of the oily compound, heat to 120 °C and reflux for 2 h. TLC analysis showed the reaction was complete, with a 100% conversion of p-nitrotoluene. Pure p-nitrobenzyl alcohol was obtained by extraction with dichloromethane, yielding 90%. The 1H NMR spectrum of p-nitrobenzyl alcohol is shown below. Figure 5 The carbon spectrum of p-nitrobenzyl alcohol is shown below. Figure 6 .

Claims

1. A process for producing a benzyl alcohol compound, characterized by Includes the following steps: (1) Dissolve toluene-based organic compounds in an organic solvent, turn on the stirrer, add halide solution and sodium bisulfite solution, heat and reflux, extract, and rotary evaporate to obtain an oily compound; (2) The oily compound and water were stirred, heated and then refluxed to extract benzyl alcohol compounds.

2. The production process of benzyl alcohol compounds according to claim 1, characterized in that... In step (1), the toluene-like organic compound is one or more of o-nitrotoluene, m-nitrotoluene, or p-nitrotoluene.

3. The production process of benzyl alcohol compounds according to claim 1, characterized in that... In step (1), the organic solvent is one or more of ethyl acetate, 1,2-dichloroethane, dichloromethane, ethanol, acetone or petroleum ether; the ratio of toluene-based organic compound to organic solvent is 1:8.5-10, wherein the toluene-based organic compound is expressed in g and the organic solvent is expressed in ml.

4. The production process of benzyl alcohol compounds according to claim 1, characterized in that... In step (1), the halide solution is prepared by dissolving halide in water. The mass ratio of halide to water is 1:2-5. The halide is one or more of sodium chlorate, potassium chlorate, sodium bromate, potassium bromate, sodium iodate, or potassium iodate. The mass ratio of halide to toluene-like organic compounds is 1.1-3.5:

1.

5. The production process of benzyl alcohol compounds according to claim 1, characterized in that... In step (1), the sodium bisulfite solution is prepared by dissolving sodium bisulfite in water. The mass ratio of sodium bisulfite to water is 1:1-3, and the mass ratio of sodium bisulfite to halide in the halide solution is 1:1-3.

6. The production process of benzyl alcohol compounds according to claim 1, characterized in that... In step (1), the temperature is raised to 80-120℃ and the reflux reaction time is 4-8h.

7. The production process of benzyl alcohol compounds according to claim 1, characterized in that... In step (1), the extraction is performed using an organic solvent, which is one or more of ethyl acetate, 1,2-dichloroethane, dichloromethane, ethanol, acetone, or petroleum ether.

8. The production process of benzyl alcohol compounds according to claim 1, characterized in that... In step (2), the mass ratio of the oily compound to water is 1:10-20.

9. The production process of benzyl alcohol compounds according to claim 1, characterized in that... In step (2), the temperature is raised to 80-120℃ and the reflux reaction time is 2-8h.

10. The production process of benzyl alcohol compounds according to claim 1, characterized in that... In step (2), the extraction is performed using an organic solvent, which is one or more of ethyl acetate, 1,2-dichloroethane, dichloromethane, or petroleum ether.

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