Method for preparing benzyl alcohol raw material medicine from benzaldehyde

Abstract

The invention discloses a method for preparing a benzyl alcohol bulk drug from benzaldehyde. The method is characterized in that the benzyl alcohol bulk drug is prepared from benzaldehyde in a combined mode of Raney nickel catalytic hydrogenation and potassium borohydride assisted reduction. The method overcomes the defect of low purity of the benzyl alcohol bulk drug synthesized from benzaldehyde, and the gas phase purity of the obtained benzyl alcohol bulk drug is 99.9% or above. The benzyl alcohol raw material medicine is simple in preparation process and low in cost, the prepared benzyl alcohol raw material medicine is high in purity and free of solvent residues such as methyl alcohol or ethyl alcohol, the quality meets the medicinal requirement, and industrial production is easy.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine and chemical industry, and particularly relates to a method for preparing a benzyl alcohol raw material drug from benzaldehyde. Background Art

[0002] Benzyl alcohol, also known as benzyl alcohol, is one of the simplest aromatic alcohols. It is a colorless liquid with an aromatic smell. CAS number: 100-51-6. Benzyl alcohol is widely used in the production of raw materials, pharmaceutical excipients, spices, solvents, daily chemicals, and industrial chemicals. Benzyl alcohol has local antibacterial, antipruritic, anesthetic and analgesic effects, and is used as a disinfectant, antiseptic, and local anesthetic raw material. Benzyl alcohol, as a pharmaceutical excipient, is mainly used as a preservative for ointments or liquid medicines. Benzyl alcohol is an extremely useful fixative and is an indispensable spice for the preparation of jasmine, moonflower, ylang-ylang and other flavors. It is used to make soaps and daily cosmetic flavors. Benzyl alcohol is an important organic product and intermediate. It is the main raw material for the preparation of vitamins A, E, and K, and is also an important intermediate for pesticides. In addition, benzyl alcohol is also widely used in the production of industrial chemicals. It is used in coating solvents, photographic developers, polyvinyl chloride stabilizers, medicines, synthetic resin solvents, high boiling point solvents, paint strippers, preservatives, and is also used in the manufacture of plasticizers, fragrances, ballpoint pen oils, etc.

[0003] Because benzaldehyde has certain toxicity and genotoxicity, the Pharmacopoeia of the People's Republic of China 2020 edition clearly stipulates that the limit of benzaldehyde in benzyl alcohol APIs shall not exceed 0.1%. The Pharmacopoeia of the People's Republic of China 2020 edition stipulates the determination conditions of benzyl alcohol APIs: Related substances, determined by gas chromatography (General Rule 0521); Reference solution, take an appropriate amount of benzaldehyde reference, accurately determine, dissolve in acetone and quantitatively dilute to make a solution containing 0.5 mg of benzaldehyde per 1 ml, and shake well. Chromatographic conditions: use polyethylene glycol 20M (or similar polarity) as the stationary phase; split injection, split ratio 20:1; starting temperature is 50℃, increase the temperature to 220℃ at a rate of 5℃ per minute, and maintain for 35 minutes; injection port temperature is 200℃; detector temperature is 310℃; injection volume is 1μl; determination method: accurately measure the test solution and reference solution, inject them into gas chromatography respectively, and record the chromatogram; limit: if there is a chromatographic peak in the chromatogram of the test solution with the same retention time as benzaldehyde, the benzaldehyde content shall not exceed 0.1% according to the peak area calculated by the external standard method; if there are other impurity peaks; except for the acetone peak, calculated by the area normalization method, the single unknown impurity shall not exceed 0.02%, and the total amount of other impurities shall not exceed 0.1%; peaks in the chromatogram of the test solution that are less than 0.0001% of the main peak area are ignored.

[0004] The earliest industrial production of benzyl alcohol APIs used the Cannizzaro reaction, which was produced by the reaction of benzaldehyde with potassium hydroxide: 2C6H5CHO + KOH → C6H5CH2OH + C6H5COOK. In this method, half of the raw materials produce benzoic acid, the yield is too low, and there is a lot of residual benzaldehyde. The current industrial preparation method of benzyl alcohol is the benzyl chloride hydrolysis method, which obtains benzyl alcohol by azeotropic hydrolysis of benzyl chloride and an aqueous solution of alkali. At the same time, up to 10% of the byproduct benzyl ether is generated and there is a lot of residual benzaldehyde. The cost of benzyl alcohol APIs reduced by the borohydride system is too high.

[0005] In order to improve the product quality of benzyl alcohol API in my country, we have selected the conditions for the preparation process of benzyl alcohol API, creatively using the reaction system itself as the solvent without adding methanol, ethanol and other solvents, so that the obtained benzyl alcohol API has no residual solvents such as methanol and ethanol; for the trace amount of benzaldehyde remaining after the Raney nickel reaction, the stable potassium borohydride is used to strengthen the reduction and purification to reduce the toxic impurity benzaldehyde residue in the benzyl alcohol API, thereby improving the purity of the benzyl alcohol API. In summary, it is very necessary to develop a process for synthesizing benzyl alcohol API products with high purity, high conversion rate and low cost from benzaldehyde. Summary of the invention

[0006] Through a large number of experiments on the synthesis of benzyl alcohol raw materials from benzaldehyde, it was found that expensive platinum carbon and palladium carbon do not have a good catalytic reduction effect on the reaction, while the reduction effect of borohydride alone is good, the post-processing is troublesome, and the cost is too high. The cheap Raney nickel is reversible as a catalyst, that is, it can reduce the aldehyde group to the hydroxyl group and dehydrogenate the hydroxyl group to the aldehyde group during the distillation process. The purpose of the present invention is to provide a preparation method for synthesizing benzyl alcohol raw materials from benzaldehyde, which is achieved by combining Raney nickel and potassium borohydride-assisted reduction to obtain a benzyl alcohol raw material with a GC purity of more than 99.9%. The invention has the following advantages: firstly, more than 99% of the benzaldehyde raw material is reduced by catalytic hydrogenation using cheap Raney nickel, and the remaining benzaldehyde raw material within 1% is reduced by potassium borohydride, so that the amount of potassium borohydride used is very small, the cost is not increased, and the reversible dehydrogenation reaction of Raney nickel is inhibited; since the reaction is thorough, the GC purity of benzyl alcohol is high; then, the residual nickel element impurities and trace impurities are removed by reduced pressure distillation; the reaction system itself is creatively used as a solvent without adding methanol, ethanol and other solvents, so that the obtained benzyl alcohol raw material does not have residual solvents such as methanol and ethanol; the purity of the obtained benzyl alcohol raw material is high, and finally the obtained benzyl alcohol raw material has a GC purity of more than 99.9%.

[0007] In order to solve the above technical problems, the technical solution of the present invention is: a method for preparing a benzyl alcohol raw material drug with a GC purity of more than 99.9% by synthesizing benzaldehyde, comprising the following steps: 1) Add benzaldehyde and Raney nickel catalyst into the autoclave, introduce nitrogen to replace, then introduce hydrogen and control the hydrogen pressure at 7-10 kg, maintain the temperature at 50-80°C for reaction, and use Raney nickel to catalyze hydrogenation to reduce ≥99% of benzaldehyde; 2) After the hydrogen pressure stops decreasing, the reaction is maintained for 30 minutes, the temperature is lowered to 10°C to 30°C, the material is discharged, and the Raney nickel catalyst is filtered out; 3) Add a certain amount of potassium borohydride to the filtrate, keep it at 60℃~90℃ for a period of time to completely reduce the remaining small amount of benzaldehyde with potassium borohydride; 4) The reaction liquid is distilled under reduced pressure to obtain benzyl alcohol API with a GC purity of more than 99.9%.

[0008] The benzaldehyde used in the present invention is an industrial bulk raw material that can be purchased from the market; Raney nickel is a solid heterogeneous catalyst composed of fine grains of nickel-aluminum alloy with a porous structure, which is usually used as a hydrogenation catalyst for organic compounds and can be used for hydrogenation reduction reactions of compounds containing unsaturated bonds such as aldehydes and ketones. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 It is the reference solution of the benzaldehyde raw material used in the present invention.

[0010] Figure 2 It is the GC spectrum of the benzyl alcohol bulk drug prepared by the present invention.

[0011] Figure 3 It is the GC spectrum of the present invention. Implementation

[0012] In order to make the purpose, technical scheme and advantages of the present invention clearer, the preferred embodiments of the present invention are described in detail below. It should be understood that the embodiments are only for illustrating the present invention, not for limiting the scope of protection of the present invention. GC is the abbreviation of gas chromatography. GC is the abbreviation of gas chromatography; FID is the full name of flameionization detector, which is a flame ionization detector. It is a highly sensitive universal detector that responds to almost all organic substances, but has no response or very small response to inorganic substances, inert gases or substances that do not dissociate in flames. Example

[0013] 40.0 g of benzaldehyde and 3.3 g of Raney nickel were added to a 1L autoclave, and nitrogen was introduced to replace the air 3 times, and then hydrogen was introduced, and the hydrogen pressure was controlled to 7-10 kg. The reaction temperature was controlled at 50°C-80°C until the hydrogen pressure no longer decreased, and the temperature was lowered to 10°C-30°C to discharge the material, and the Raney nickel catalyst was filtered out; 1 g of potassium borohydride was added to the filtrate, and the temperature was kept at 60°C-90°C for 2 hours, and the reaction solution was vacuum distilled and vacuum distilled, and the normal boiling products were collected to obtain 38.0 g of benzyl alcohol raw material, with a yield of 93.2% and a GC purity of 99.96%.

[0014] As can be seen from the above examples, the preparation method of benzyl alcohol API disclosed in the present invention can produce benzyl alcohol API with a gas phase purity of more than 99.9%. The above preferred embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail through the above preferred embodiments, it should be understood by those skilled in the art that any various changes made to it in form and detail are within the scope defined by the claims of the present invention.

Claims

1. A method for preparing benzyl alcohol bulk drug from benzaldehyde, characterized in that The aldehyde reduction reaction is carried out by combining Raney nickel catalytic hydrogenation and potassium borohydride assisted reduction, and then vacuum distillation is performed to obtain the benzyl alcohol raw material with a GC purity of more than 99.9%.

2. The method according to claim 1, characterized in that The following steps are used to synthesize benzyl alcohol API with GC purity above 99.9% from benzaldehyde: 1) Add benzaldehyde and Raney nickel catalyst into the autoclave, introduce nitrogen to replace, then introduce hydrogen and control the hydrogen pressure at 7-10 kg, maintain the temperature at 50-80°C for reaction, and use Raney nickel to catalyze hydrogenation to reduce ≥99% of benzaldehyde; 2) After the hydrogen pressure stops decreasing, the reaction is maintained for 30 minutes, the temperature is lowered to 10°C to 30°C, the material is discharged, and the Raney nickel catalyst is filtered out; 3) Add a certain amount of potassium borohydride to the filtrate, keep it at 60℃~90℃ for a period of time to completely reduce the remaining small amount of benzaldehyde with potassium borohydride; 4) The reaction liquid is subjected to vacuum distillation, and the normal boiling products are collected to obtain benzyl alcohol API with a GC purity of more than 99.9%.

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