A process for the preparation of retinol and intermediates thereof

Abstract

The application provides a preparation method of retinol and intermediates thereof, specifically, beta-ionone which is low in price and good in stability is used as a substrate, and selected HWE reagents (including (2-(methoxy(methyl)amino)-2-oxoethyl) diethyl phosphonate and 2,2-diethoxyethyl diethyl phosphonate) are used for HWE reaction, and retinol intermediates are obtained through DIBAL-H reduction or acid post-treatment, the retinol intermediates can be used for second HWE reaction with triethyl (2 E )-3-methyl-4-phosphonobutyrate, and retinol is obtained through reduction. The preparation method of the retinol intermediates has short steps, and when the retinol intermediates are used for preparation of retinol, the production cycle of the retinol is greatly shortened. The preparation method of the retinol intermediates involves relatively conventional reaction conditions, and the reaction conditions of reduction and oxidation which have safety hazards are avoided. Compared with the prior art, the application has more advantages in industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthetic chemistry technology, specifically relating to a method for preparing retinol and its intermediates. Background Technology

[0002] Vitamin A compounds are essential fat-soluble active substances for the human body, playing an irreplaceable role in vision, epithelial tissue, growth and development, immune function, and reproductive health. They maintain the integrity of the cornea, conjunctiva, respiratory tract, and digestive tract mucosa, reducing the risk of infection; promote normal bone development and cell differentiation; and play an important role in antioxidation and maintaining skin health. Deficiency can easily lead to night blindness, dry eye, rough skin, growth retardation, and weakened immunity. Retinol is the basic active form of vitamin A and also the main storage form in the body. It is a core substance for maintaining healthy skin and mucous membranes, promoting normal growth and repair of epithelial cells, and preventing dry skin and keratinization. It also participates in the regulation of reproductive system function, being crucial for sperm production and embryonic development. It can also be converted into retinal and retinoic acid in the body as needed, making it the "source molecule" of the entire vitamin A family. Natural extraction of retinol is limited by scarce biological resources and low conversion efficiency, making it impossible to meet global large-scale demand; while chemical synthesis is key to achieving large-scale, low-cost production and supporting the sustainable development of the feed, food fortification, and pharmaceutical industries.

[0003] Currently, the industrial production of retinol heavily relies on chemical synthesis. The mainstream production processes for vitamin A compounds globally include the Hoffmann-La Roche route and the BASF route. The former suffers from drawbacks such as lengthy reaction steps and high production costs, while the latter's key Wittig reaction has stringent requirements for process conditions and equipment, limiting its widespread application. In laboratory research, although synthetic methods such as retinoic acid reduction and β-carotene cleavage exist, they are often difficult to industrialize due to issues such as substrate cost, selectivity control, or cumbersome steps. To overcome the shortcomings of existing processes, researchers are constantly exploring and developing new synthetic methods. For example, patent WO2022166431A1 reports a route for the efficient synthesis of retinol from β-cyclocitral as a starting material through two chemical stamping reactions in five steps. The reaction formula is as follows:

[0004] Despite its high overall yield, this route still faces significant industrialization challenges. Firstly, the key raw material, β-cyclocitral, suffers from poor chemical stability, and the aldehyde group is prone to side reactions during preparation, storage, and transportation, leading to difficulties in its acquisition and processing, and high overall costs. Secondly, the route requires two chemical stamping reactions, both relying on expensive rhodium catalysts, further increasing material costs. Therefore, this route still faces substantial bottlenecks in terms of industrial scale-up and production cost control. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing retinol and its intermediates that uses inexpensive and more stable β-ionone as the key raw material, with a shorter reaction route, greater safety, and more promising industrialization prospects.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for preparing a retinol intermediate involves reacting β-ionone with an HWE reagent via an HWE reaction. The resulting product is then reduced with diisobutylaluminum hydride, or the reaction solution is post-treated with acid to obtain a retinaldehyde intermediate. The HWE reagent comprises diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate and / or diethyl 2,2-diethoxyethyl phosphate. The structural formula of the β-ionone is: The structural formula of the retinol intermediate is as follows: .

[0007] In some embodiments, the HWE reaction is carried out in a first organic solvent in the presence of a non-nucleophilic base or an alkyl organometallic reagent, wherein the non-nucleophilic base includes one or more of sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, potassium tert-butoxide, and potassium hexamethyldisilamide; the alkyl organometallic reagent includes one or more of isopropyl magnesium chloride, isopropyl magnesium bromide, sec-butyl magnesium bromide, n-butyllithium, sec-butyllithium, methyllithium, methyl magnesium bromide, and alkyl copper lithium; and the first organic solvent includes one or more of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, methyl tert-butyl ether, and ethylene glycol dimethyl ether.

[0008] Furthermore, the molar amount of the non-nucleophilic base or alkyl organometallic reagent is 1 to 2.5 times the molar amount of the β-ionone, for example, the molar amount of the non-nucleophilic base or alkyl organometallic reagent is 1, 1.5, 2.0, or 2.5 times the molar amount of the β-ionone.

[0009] In some embodiments, the HWE reaction is carried out at 20-60°C, for example, at 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C or 60°C.

[0010] In some embodiments, the molar amount of the HWE reagent is 1 to 2.5 times the molar amount of the β-ionone, specifically 1, 1.5, 2.0, or 2.5 times.

[0011] According to some specific embodiments, the HWE reagent is premixed with the non-nucleophilic base or alkyl organometallic reagent at 0~5°C, the resulting premix is ​​further mixed with the β-ionone at 0~5°C, and the resulting mixture undergoes the HWE reaction at 20~60°C.

[0012] According to some specific embodiments, the preparation method further includes post-processing, which includes: diluting the reaction system after reduction treatment with diisobutylaluminum hydride or after acid post-treatment with water, separating the aqueous phase, extracting the aqueous phase with a lipid solvent to obtain an organic phase, and drying and concentrating the obtained organic phase.

[0013] In some specific embodiments, the reduction treatment of diisobutylaluminum hydride is as follows: the product obtained from the HWE reaction is mixed with diisobutylaluminum hydride in a second organic solvent, and reacted at -80~-60°C to obtain the retinol intermediate, wherein the second organic solvent includes dichloromethane and / or tetrahydrofuran.

[0014] Further, the β-ionone and the diethyl 2-(2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate were subjected to an HWE reaction in a first organic solvent in the presence of a non-nucleophilic base or an alkyl organometallic reagent. After the reaction was completed, the product was separated from the reaction system. The product is: .

[0015] Specifically, the non-nucleophilic base includes one or more of sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, potassium tert-butoxide, and potassium hexamethyldisilamide; the alkyl organometallic reagent includes one or more of isopropyl magnesium chloride, isopropyl magnesium bromide, sec-butyl magnesium bromide, n-butyllithium, sec-butyllithium, methyllithium, methyl magnesium bromide, and alkyl copper lithium; and the first organic solvent includes one or more of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, methyl tert-butyl ether, and ethylene glycol dimethyl ether.

[0016] In some other specific embodiments, the acid post-treatment is as follows: quenching the HWE reaction with water or a saturated ammonium chloride aqueous solution, mixing the quenched reaction system with acid or acid solution, and reacting at room temperature to obtain the retinol intermediate.

[0017] More preferably, the acid post-treatment uses one or more of oxalic acid, hydrochloric acid, trifluoroacetic acid, citric acid, sulfuric acid, sodium bisulfate, and potassium bisulfate.

[0018] More preferably, the acid post-treatment uses an oxalic acid solution with a mass concentration of 0.1% to 5% or a hydrochloric acid solution with a mass concentration of 36 wt% to 38 wt%.

[0019] Further, the β-ionone and the 2,2-diethoxyethyl phosphate diethyl ester are subjected to an HWE reaction in a first organic solvent in the presence of a non-nucleophilic base or an alkyl organometallic reagent until the β-ionone is completely reacted.

[0020] Specifically, the non-nucleophilic base includes one or more of sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, potassium tert-butoxide, and potassium hexamethyldisilamide; the alkyl organometallic reagent includes one or more of isopropyl magnesium chloride, isopropyl magnesium bromide, sec-butyl magnesium bromide, n-butyllithium, sec-butyllithium, methyllithium, methyl magnesium bromide, and alkyl copper lithium; and the first organic solvent includes one or more of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, methyl tert-butyl ether, and ethylene glycol dimethyl ether.

[0021] A second aspect of the present invention provides a method for preparing retinol, comprising: The retinol intermediate was prepared using the preparation method described above; The retinol intermediate is reacted with triethyl(2) E 3-methyl-4-phosphonocrotonate undergoes an HWE reaction to give the HWE product, the structural formula of which is: ; The HWE reaction product was reduced with diisobutylaluminum hydride to obtain retinol, the structural formula of which is: .

[0022] In some specific embodiments, the retinol intermediate and triethyl(2) E The reaction of 3-methyl-4-phosphonocrotonate is carried out in a third organic solvent at 20-60°C in the presence of a non-nucleophilic base or an alkyl organometallic reagent, and the HWE reaction product is reduced by diisobutylaluminum hydride in a fourth organic solvent at -80--60°C.

[0023] Specifically, the non-nucleophilic base includes one or more of sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, potassium tert-butoxide, and potassium hexamethyldisilamide; the alkyl organometallic reagent includes one or more of isopropyl magnesium chloride, isopropyl magnesium bromide, sec-butyl magnesium bromide, n-butyllithium, sec-butyllithium, methyllithium, methyl magnesium bromide, and alkyl copper lithium; the third organic solvent includes one or more of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, methyl tert-butyl ether, and ethylene glycol dimethyl ether; and the fourth organic solvent includes dichloromethane and / or tetrahydrofuran.

[0024] Due to the application of the above-mentioned technical solution, the present invention has the following advantages compared with the prior art: This invention uses inexpensive and stable β-ionone as a substrate, and performs a primary HWE reaction with selected HWE reagents (including diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate and diethyl 2,2-diethoxyethyl phosphate). The retinol intermediate is obtained by reduction with diisobutylaluminum hydride (DIBAL-H) ​​or acid post-treatment. This retinol intermediate can react with triethyl (2... E 3-Methyl-4-phosphonocrotonate undergoes a secondary HWE reaction, followed by reduction with DIBAL-H to yield retinol. The method for preparing the retinol intermediate of this invention is concise, significantly shortening the production cycle in retinol preparation. The raw materials used are stable and low-cost, the reagents are readily available, and the reaction conditions are more conventional, resulting in lower preparation costs and higher safety. The method for preparing the retinol intermediate of this invention is more suitable for the industrial production of retinol. Detailed Implementation

[0025] To address the limitations of existing retinol preparation methods, such as long reaction routes, high material costs, and stringent process and equipment requirements, which restrict the efficient industrial production of retinol, the inventors of this application propose a novel method for preparing retinol and its intermediates. This application describes a new method for preparing retinol intermediates (…). The preparation method of retinaldehyde was improved by using β-ionone as a substrate and reacting it with selected HWE reagents ((2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate diethyl ester and 2,2-diethoxyethyl phosphate diethyl ester) via an HWE reaction. The reaction product was then reduced by DIBAL-H or post-treated with acid to obtain the retinol intermediate. This method shortens the synthetic route while ensuring product yield and demonstrates excellent comprehensive process advantages: it avoids the need for the preparation of the difficult and unstable β-cyclic citral and the key steps involving chemical stamping reactions; the reaction conditions are mild, the post-treatment is simple, the required auxiliary reagents are inexpensive and readily available, and the equipment requirements are low. These characteristics together enable it to effectively shorten the cycle and reduce costs in the preparation of retinaldehyde, showing outstanding potential for industrial application.

[0026] Furthermore, the method for preparing retinol in this application is as follows: a retinol intermediate is prepared using the above preparation method; the retinol intermediate is then reacted with triethyl(2...) E 3-methyl-4-phosphonocrotonate undergoes an HWE reaction, and the structural formula of the HWE reaction product is as follows: The HWE reaction product was reduced by DIBAL-H to obtain retinol, the structural formula of which is: .

[0027] The synthetic route for retinol provided in this application is as follows: .

[0028] Compared to existing retinol synthesis routes, this synthetic route significantly shortens the path while ensuring retinol yield. It also boasts lower raw material and reagent costs, reduces reliance on harsh reaction conditions or specialized equipment, effectively lowers production complexity and costs, and demonstrates significant potential for industrial conversion.

[0029] It should be noted that the "HWE reaction" involved in this application is a reaction used to synthesize olefins. It is an improvement on the Wittig reaction, which reduces the requirements for process conditions and equipment. The HWE reaction mainly involves the reaction of stable phosphonate derivatives with aldehydes or ketones to generate E-type olefins, forming unsaturated esters or aldehydes. Its byproduct is water-soluble phosphate, which is easily separated from the target product.

[0030] The technical solutions and effects of this application are further illustrated below with reference to specific embodiments and comparative examples. The embodiments provided below are for illustrative purposes only and are not intended to limit the invention unless otherwise stated. Therefore, the invention should not be considered limited to the following embodiments, but should be understood to include any and all obvious variations as a result of the teachings provided herein.

[0031] It should be understood that modifications that do not materially affect the activity of various embodiments of the present invention may also be covered within the definition of the invention provided herein. Therefore, the following examples are intended to illustrate the invention but not to limit it.

[0032] Unless otherwise specified, the operating methods involved in each embodiment in this application are conventional methods in the art.

[0033] Unless otherwise specified, all raw materials, reagents and equipment involved in the embodiments in this application are commercially available products.

[0034] Unless otherwise specified in this application, "acid solution" refers to an aqueous solution of an acid, such as "oxalic acid solution" which is an aqueous solution of oxalic acid, and "hydrochloric acid solution" which is an aqueous solution of hydrochloric acid.

[0035] In this application, "room temperature" means 25℃±5℃.

[0036] Example 1: This embodiment provides a method for preparing a retinol intermediate (compound 3), as detailed below:

[0037] Take a dried 500 mL three-necked reaction flask, install a thermometer and nitrogen protection device, place a magnetic stir bar, purge with nitrogen three times, add potassium tert-butoxide (14.6 g, 2.5 eq), inject 60 mL of ultra-dry tetrahydrofuran, cool the reaction system to 0℃, add 80 mL of tetrahydrofuran solution of diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate (31.1 g, 2.5 eq) after addition, keep warm and stir for 15 minutes, dissolve 10 g of substrate 6 (1.0 eq of β-ionone) in 30 mL of ultra-dry tetrahydrofuran, and add it dropwise to the above reaction system. After addition, heat to 50℃ and react for 12 h. TLC detection (PE / EA = 20 / 1 v / v) showed that substrate compound 6 disappeared. Tetrahydrofuran was removed by rotary evaporation, diluted with 100 mL of water, and stirred at room temperature for 10 min. The aqueous phase was extracted with 150 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed by vacuum evaporation to obtain crude compound 8. The crude compound 8 was transferred to a 250 mL three-necked reaction flask, equipped with a thermometer and nitrogen protection device, and a magnetic stir bar was placed in. The mixture was purged with nitrogen three times, and 100 mL of ultra-dry tetrahydrofuran was injected. The reaction system was cooled to -78 °C, and 104 mL of a 1 mol / L toluene solution of diisobutylaluminum hydride was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 1 hour. The reaction was then quenched by slowly adding 50 mL of saturated ammonium chloride solution. Dilute with 100 mL of water, separate the phases, extract the aqueous phase with 150 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate the organic solvent under reduced pressure, and chromatographically examine the residue on a silica gel column (200-300 mesh silica gel) using a gradient elution system of PE / EA (first elute with PE / EA = 20 / 1 v / v, then elute with PE / EA = 10 / 1 v / v). After concentrating the eluent to remove the organic solvent, 9.2 g of a yellow viscous oily substance, namely compound 3, was obtained, with a yield of 81%.

[0038] The results of the hydrogen nuclear magnetic resonance spectroscopy analysis are as follows: 1 H NMR (400 MHz, CDCl3) δ 10.13 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 16.2Hz, 1H), 6.21 (d, J = 16.2 Hz, 1H), 5.93 (d, J = 8.1 Hz, 1H), 2.31 (d, J =0.9 Hz, 3H), 2.04 (t, J= 6.2 Hz, 2H), 1.72 (s, 3H), 1.67 - 1.59 (m, 2H), 1.51 - 1.45 (m, 2H), 1.04 (s, 6H). Example 2: This embodiment provides another method for preparing a retinol intermediate (compound 3), as follows:

[0039] Take a dried 500 mL three-necked reaction flask, install a thermometer and nitrogen protection device, place a magnetic stir bar, purge with nitrogen three times, and inject 60 mL of ultra-dry tetrahydrofuran and 47 mL of tetrahydrofuran solution of 2 mol / L isopropyl magnesium bromide. Cool the reaction system to 0 °C, and add 80 mL of tetrahydrofuran solution of diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate (31.1 g, 2.5 eq). After the addition is complete, keep warm and stir for 15 minutes. Dissolve 10 g of substrate 6 (1.0 eq of β-ionone) in 30 mL of ultra-dry tetrahydrofuran and add it dropwise to the above reaction system. After the addition is complete, raise the temperature to 50 °C and react for 12 h. TLC detection (PE / EA = 20 / 1 v / v) showed that substrate compound 6 disappeared. Tetrahydrofuran was removed by rotary evaporation, diluted with 100 mL of water, and stirred at room temperature for 10 min. The aqueous phase was extracted with 150 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed by vacuum evaporation to obtain crude compound 8. The crude compound 8 was transferred to a 250 mL three-necked reaction flask, equipped with a thermometer and nitrogen protection device, and a magnetic stir bar was placed in. The mixture was purged with nitrogen three times, and 100 mL of ultra-dry tetrahydrofuran was injected. The reaction system was cooled to -78 °C, and 104 mL of a 1 mol / L diisobutylaluminum hydride toluene solution was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 1 hour. The reaction was then quenched by slowly adding 50 mL of saturated ammonium chloride solution. Dilute with 100 mL of water, separate the phases, extract the aqueous phase with 150 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate the organic solvent under reduced pressure, and chromatographically examine the residue on a silica gel column (200-300 mesh silica gel) using a gradient elution system of PE / EA (first elute with PE / EA = 20 / 1 v / v, then elute with PE / EA = 10 / 1 v / v). After concentrating the eluent to remove the organic solvent, 8.4 g of a yellow viscous oily substance, namely compound 3, was obtained, with a yield of 74%.

[0040] Example 3: This embodiment provides another method for preparing a retinol intermediate (compound 3), as follows:

[0041] Take a dried 500 mL three-necked reaction flask, install a thermometer and nitrogen protection device, place a magnetic stir bar, purge with nitrogen three times, add sodium hydride (60% mineral oil dispersion, 2.3 g, 1.1 eq), inject 60 mL of ultra-dry tetrahydrofuran, cool the reaction system to 0℃, add 80 mL of tetrahydrofuran solution of diethyl 2,2-diethoxyethylphosphonate (14.5 g, 1.1 eq) dropwise, keep warm and stir for 15 minutes, dissolve 10 g of substrate 6 (β-ionone 1.0 eq) in 30 mL of ultra-dry tetrahydrofuran, and add it dropwise to the above reaction system. After the addition is complete, heat to 50℃ and react for 12 h. TLC detection (PE / EA = 20 / 1 v / v) showed that substrate compound 6 disappeared, and 2 mL of water was slowly added dropwise to quench the reaction. Add 5 mL of concentrated hydrochloric acid (36-38 wt%), stir at room temperature for 5 h, dilute with 100 mL of water, separate the phases, extract the aqueous phase with 100 mL of ethyl acetate, combine the organic phases, dry to anhydrous sodium sulfate, filter, evaporate the organic solvent under reduced pressure, and chromatographically examine the residue on a silica gel column (200-300 mesh silica gel) using a gradient elution system of PE / EA (first elute with PE / EA = 20 / 1 v / v, then elute with PE / EA = 10 / 1 v / v). After concentrating the eluent to remove the organic solvent, 9.3 g of a yellow viscous oily substance, namely compound 3, was obtained, with a yield of 82%.

[0042] Example 4: This embodiment provides another method for preparing a retinol intermediate (compound 3), as follows: .

[0043] Take a dried 500 mL three-necked reaction flask, install a thermometer and nitrogen protection device, place a magnetic stir bar, and purge with nitrogen three times. Add 150 mL of ultra-dry tetrahydrofuran and diethyl 2,2-diethoxyethylphosphonate (19.8 g, 1.5 eq) sequentially. Lower the reaction system to 0°C, inject 39 mL (1.5 eq) of a 2 mol / L tetrahydrofuran solution of isopropyl magnesium chloride using a syringe, and maintain the temperature for 30 minutes. Add 80 mL of tetrahydrofuran solution containing substrate 6 (10 g, 1.0 eq of β-ionone), maintain the temperature for 15 minutes, then raise the temperature to 50°C and react for 12 h. TLC detection (PE / EA = 20 / 1v / v) showed that substrate compound 6 had disappeared. Slowly add 2 mL of saturated ammonium chloride aqueous solution to quench the reaction, then add 5 mL of concentrated hydrochloric acid (36~38 wt%), stir at room temperature for 6 h, and add 100... Dilute with mL of water, separate phases, extract the aqueous phase with 100 mL of ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, evaporate the organic solvent under reduced pressure, and chromatographically examine the residue on a silica gel column (200-300 mesh) using a gradient elution system of PE / EA (first elute with PE / EA = 20 / 1 v / v, then elute with PE / EA = 10 / 1 v / v). After concentrating the eluent to remove the organic solvent, 8.8 g of a yellow viscous oily substance, namely compound 3, was obtained, with a yield of 78%.

[0044] Example 5: This embodiment provides a method for preparing retinol from compound 3, as follows:

[0045] Take a dried 500 mL three-necked reaction flask, install a thermometer and nitrogen protection device, place a magnetic stir bar, purge with nitrogen three times, add potassium tert-butoxide (5.14 g, 2.0 eq), inject 200 mL of ultra-dry tetrahydrofuran, cool the reaction system to 0℃, and add triethyl (2... EA solution of 12.1 g (2.0 eq) of 3-methyl-4-phosphonocrotonate in tetrahydrofuran (30 mL) was added dropwise. After the addition was complete, the mixture was stirred at the controlled temperature for 15 minutes. Then, 5 g of compound 3 (1.0 eq) was dissolved in 30 mL of ultra-dry tetrahydrofuran and added dropwise to the above reaction system. After the addition was complete, the temperature was raised to 50 °C and the reaction was carried out for 12 h. TLC analysis (PE / EA = 20 / 1 v / v) showed that the starting compound 3 had disappeared. The tetrahydrofuran was removed by rotary evaporation, and the mixture was diluted with 80 mL of water. The mixture was stirred at room temperature for 10 min, and the aqueous phase was extracted with 200 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed by vacuum evaporation to obtain crude compound 11. The crude compound 11 was transferred to a 250 mL three-necked reaction flask, equipped with a thermometer and nitrogen protection device, and a magnetic stir bar was placed in place. Nitrogen was purged three times. 100 mL of ultra-dry tetrahydrofuran was injected, and the reaction system was cooled to -78 °C. 46 mL of a 1 mol / L diisobutylaluminum hydride toluene solution was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 1 hour. The reaction was then quenched by slowly adding 50 mL of saturated ammonium chloride solution. The mixture was diluted with 100 mL of water, and the phases were separated. The aqueous phase was extracted with 150 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed by vacuum distillation. The residue was subjected to silica gel column chromatography (200-300 mesh silica gel) using a gradient elution system of PE / EA (first PE / EA = 15 / 1 v / v, then PE / EA = 5 / 1 v / v). After concentrating the eluent to remove the organic solvent, 5.9 g of a yellow, viscous oily substance, namely compound 5 (retinol), was obtained, with a yield of 90%.

[0046] The results of the hydrogen nuclear magnetic resonance spectroscopy analysis are as follows: 1 H NMR (400 MHz, CDCl3) δ 10.10 (d, J = 8.1 Hz, 1H), 7.14 (dd, J =15.1, 11.5 Hz, 1H), 6.37 (d, J = 15.1, 1H), 6.34 (d, J = 16.0, 1H), 6.18 (d, J = 11.4, 1H), 6.16 (d, J = 16.1, 1H), 5.97 (d, J= 8.1 Hz, 1H), 2.33 (s,3H), 2.07 - 2.00 (m, 5H), 1.72 (s, 3H), 1.66 - 1.58 (m, 2H), 1.51 - 1.45 (m,2H), 1.03 (s, 6H). The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing a retinol intermediate, characterized in that, β-Ionone was subjected to an HWE reaction with an HWE reagent. The product was reduced with diisobutylaluminum hydride or the reaction solution was post-treated with acid to obtain a retinol intermediate. The HWE reagent included diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate and / or diethyl 2,2-diethoxyethyl phosphate. The structural formula of β-ionone is: The structural formula of the retinol intermediate is as follows: .

2. The method for preparing the retinol intermediate according to claim 1, characterized in that, The HWE reaction is carried out in a first organic solvent in the presence of a non-nucleophilic base or an alkyl organometallic reagent. The non-nucleophilic base includes one or more of sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, potassium tert-butoxide, and potassium hexamethyldisilamide. The alkyl organometallic reagent includes one or more of the following: isopropyl magnesium chloride, isopropyl magnesium bromide, sec-butyl magnesium bromide, n-butyllithium, sec-butyllithium, methyllithium, methyl magnesium bromide, and alkyl copper lithium. The first organic solvent includes one or more of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, methyl tert-butyl ether, and ethylene glycol dimethyl ether; And / or, the molar amount of the non-nucleophilic base or alkyl organometallic reagent is 1 to 2.5 times the molar amount of the β-ionone; And / or, the HWE reagent is premixed with the nonnucleophilic base or alkyl organometallic reagent at 0-5°C, and the resulting premix is ​​further mixed with the β-ionone at 0-5°C, and the resulting mixture is subjected to the HWE reaction at 20-60°C.

3. The method for preparing the retinol intermediate according to claim 1, characterized in that, The HWE reaction was carried out at 20~60℃; And / or, the molar amount of the HWE reagent is 1 to 2.5 times the molar amount of the β-ionone; And / or, the preparation method further includes post-processing, which includes: diluting the reaction system after reduction treatment with diisobutylaluminum hydride or after acid post-treatment with water, separating the aqueous phase, extracting the aqueous phase with a lipid solvent to obtain an organic phase, and drying and concentrating the obtained organic phase.

4. The method for preparing the retinol intermediate according to any one of claims 1 to 3, characterized in that, The reduction treatment of diisobutylaluminum hydride is as follows: the product obtained from the HWE reaction is mixed with diisobutylaluminum hydride in a second organic solvent, and reacted at -80~-60℃ to obtain the retinol intermediate. The second organic solvent includes dichloromethane and / or tetrahydrofuran.

5. The method for preparing the retinol intermediate according to claim 4, characterized in that, The β-ionone and the diethyl 2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate were subjected to an HWE reaction in a first organic solvent in the presence of a non-nucleophilic base or an alkyl organometallic reagent. After the reaction was completed, the product was separated from the reaction system. The product is as follows: .

6. The method for preparing the retinol intermediate according to any one of claims 1 to 3, characterized in that, The acid post-treatment is as follows: the HWE reaction is quenched with water or a saturated ammonium chloride aqueous solution, the quenched reaction system is mixed with acid or acid solution, and the reaction is carried out at room temperature to obtain the retinol intermediate.

7. The method for preparing the retinol intermediate according to claim 6, characterized in that, The acid post-treatment uses one or more of oxalic acid, hydrochloric acid, trifluoroacetic acid, citric acid, sulfuric acid, sodium bisulfate, and potassium bisulfate; and / or, the acid post-treatment uses an oxalic acid solution with a mass concentration of 0.1% to 5% or a hydrochloric acid solution with a mass concentration of 36 wt% to 38 wt%.

8. The method for preparing the retinol intermediate according to claim 6, characterized in that, The β-ionone and the 2,2-diethoxyethyl phosphate diethyl ester were subjected to an HWE reaction in a first organic solvent in the presence of a non-nucleophilic base or an alkyl organometallic reagent until the β-ionone was completely reacted.

9. A method for preparing retinol, characterized in that, It includes: The retinol intermediate was prepared by the preparation method according to any one of claims 1 to 8; The retinol intermediate is reacted with triethyl(2) E 3-methyl-4-phosphonocrotonate undergoes an HWE reaction to give the HWE product, the structural formula of which is: ; The HWE reaction product was reduced with diisobutylaluminum hydride to obtain retinaldehyde, and the structural formula of retinaldehyde is: .

10. The method for preparing retinol according to claim 9, characterized in that, The retinol intermediate and triethyl(2) E The reaction of 3-methyl-4-phosphonocrotonate is carried out in a third organic solvent at 20-60°C in the presence of a non-nucleophilic base or an alkyl organometallic reagent, and the HWE reaction product is reduced by diisobutylaluminum hydride in a fourth organic solvent at -80--60°C.

Images