A preparation method and preparation device of 7-dehydrocholesterol and vitamin D3

Abstract

The present invention belongs to the field of organic synthesis, and specifically relates to a method and apparatus for preparing 7-dehydrocholesterol and vitamin D3. The method for preparing 7-dehydrocholesterol comprises subjecting a raw material, 7-toluenesulfonylhydrazone-3-cholesterol acetate, to a dehydrazone reaction in the presence of lithium amide and a co-catalyst, wherein the co-catalyst is an amine compound containing two tertiary amine groups in the same molecule. The present invention uses an amine compound containing two tertiary amine groups in the same molecule as a co-catalyst, thereby effectively improving the yield and purity of 7-dehydrocholesterol.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a preparation method and a preparation device for 7-dehydrocholesterol and vitamin D3. Background Art

[0002] Vitamin D3, a fat-soluble vitamin soluble in organic matter, is known as the "sunshine vitamin." It is essential for humans and animals. Vitamin D3 has multiple physiological functions, including improving the body's absorption of calcium and phosphorus, maintaining saturated plasma calcium and phosphorus levels; promoting growth and bone calcification, and promoting healthy teeth; increasing phosphorus absorption through the intestinal wall and reabsorption through the renal tubules; maintaining normal blood citrate levels; and preventing amino acid loss through the kidneys.

[0003] 7-dehydrocholesterol can form vitamin D3 by ultraviolet irradiation. Therefore, the preparation of 7-dehydrocholesterol is a key step in the preparation of vitamin D3. Among them, the upper debromination method is a traditional method for synthesizing 7-dehydrocholesterol. The specific process is shown in chemical formula (I). The upper debromination method requires the use of a large amount of bromine-containing raw materials, which is extremely environmentally unfriendly. In addition, the final selectivity of this reaction route is not high, and a large amount of by-product 4,6-diencholesterol is present. The total yield is only between 42% and 50%. At the same time, due to the poor separation effect of the by-product and 7-dehydrocholesterol, the purity of 7-dehydrocholesterol is not high, which affects the quality of the final product vitamin D3.

[0004]

[0005] To address these shortcomings, researchers have developed a novel oxidation process for preparing 7-dehydrocholesterol. The detailed process is shown in Chemical Formula (II). Specifically, cholesterol undergoes hydroxyl protection, allylic oxidation, hydrazolation, dehydrazolysis, and deprotection to yield 7-dehydrocholesterol. This route offers advantages such as high overall reaction yield, high selectivity for the final product, the absence of 4,6-dienylcholesterol as a byproduct, and simplified product purification.

[0006]

[0007] The dehydrazone reaction is a key step in the oxidation process. The base-catalyzed decomposition of the benzyl sulfonyl hydrazone of aldehydes and ketones to form alkenes is called the Bamford-Stevens reaction, while the reaction that occurs when using organolithium as the base is called the Shapiro reaction. The dehydrazone reaction is the Bamford-Stevens-Shapiro olefination reaction. CN101220075A discloses a dehydrazone method using sodium hydride as the base, with a yield of only 70% and a purity of only 42%. CN102030794A discloses a dehydrazone method using chlorobenzene as the solvent in the presence of various lithium-containing bases, with a yield of only 74-85% and a purity of only 57-77%. Summary of the Invention

[0008] The purpose of the present invention is to overcome the defects of low yield and purity when preparing 7-dehydrocholesterol by existing methods, and to provide a preparation method and preparation device of 7-dehydrocholesterol and vitamin D3 that can improve the yield and purity.

[0009] In the traditional dehydrazone reaction process, when non-lithium reagents are used as bases, due to their weak activity, more carbene intermediates will be produced, resulting in more by-products and reducing the yield and purity of 7-dehydrocholesterol. When other lithium reagents are used as bases, due to their strong activity, the hydrazone itself is easily destroyed by the base, resulting in more side reactions and lower yield and content.

[0010] After in-depth research, the inventors of the present invention discovered that using lithium amide as a catalyst and simultaneously adding a specific co-catalyst—an amine compound containing two tertiary amine groups in the same molecule—during the dehydrazone reaction can enhance the activity of lithium amide and complete the dehydrazone reaction at a lower temperature. This not only avoids the production of carbene intermediates and reduces carbene byproducts, but also prevents the extensive destruction of 7-toluenesulfonylhydrazone-3-cholesterol acetate, thereby improving the yield and purity of 7-dehydrocholesterol. Based on this, the present invention was completed.

[0011] Specifically, the present invention provides a method for preparing 7-dehydrocholesterol, wherein the method comprises subjecting a raw material of 7-toluenesulfonylhydrazone-3-cholesterol acetate to a dehydrazone reaction in the presence of lithium amide and a co-catalyst, wherein the co-catalyst is an amine compound containing two tertiary amine groups in the same molecule.

[0012] In a preferred embodiment, the co-catalyst is tetramethylethylenediamine and / or N,N-dimethylpropyleneurea.

[0013] In a preferred embodiment, the amount of the co-catalyst is 1% to 5% of the mole number of 7-toluenesulfonylhydrazone-3-cholesterol acetate.

[0014] In a preferred embodiment, the 7-p-toluenesulfonylhydrazone-3-cholesterol acetate raw material is prepared according to the following method: 7-ketocholesterol acetate and p-toluenesulfonylhydrazine are subjected to a hydrazolation reaction in the presence of concentrated hydrochloric acid.

[0015] In a preferred embodiment, the conditions of the hydrazolation reaction include a temperature of 50° C. to 55° C. and a time of 1 to 10 h.

[0016] In a preferred embodiment, the hydrazolation reaction is carried out using methanol as a solvent.

[0017] In a preferred embodiment, the method for preparing 7-dehydrocholesterol further comprises, before the dehydrazone reaction, purifying the 7-p-toluenesulfonylhydrazone-3-cholesterol acetate raw material with a strong alkaline resin to remove residual concentrated hydrochloric acid and p-toluenesulfonic acid.

[0018] In a preferred embodiment, the strong basic resin is a macroporous strong basic styrene anion exchange resin.

[0019] In a preferred embodiment, the purification treatment using a strong basic resin is performed by dissolving the 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material in a non-polar solvent, adding water and mixing evenly, continuously passing the resulting mixture through a strong basic resin column, and then removing methanol and water through a falling film evaporator to obtain a methanol-free and water-free 7-toluenesulfonylhydrazone-3-cholesterol acetate solution.

[0020] In a preferred embodiment, the non-polar solvent is selected from at least one of chlorobenzene, toluene and xylene.

[0021] In a preferred embodiment, the amount of water used is 0.8 to 1.2 times the molar number of 7-toluenesulfonylhydrazone-3-cholesterol acetate.

[0022] In a preferred embodiment, the dehydrazone reaction is carried out by continuously mixing a non-polar solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material and a co-catalyst with a non-polar solution containing lithium amide in a pipeline reactor I, and then removing ammonia from the obtained mixed reaction product using a wiped film evaporator, and then introducing it into a pipeline reactor II for continuous dehydrazone reaction; the conditions of the continuous mixing reaction include a reaction temperature of 0 to 40°C and a residence time of 5 min to 10 min; the conditions of the continuous dehydrazone reaction include a reaction temperature of 80 to 100°C and a residence time of 5 min to 30 min.

[0023] In a preferred embodiment, the volume flow ratio of the non-polar solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material and the co-catalyst to the non-polar solution containing lithium amide is 1:(1.1-1.5).

[0024] In a preferred embodiment, the method for preparing 7-dehydrocholesterol further includes quenching the reaction solution obtained from the dehydrazone reaction with dilute hydrochloric acid and then standing to separate the layers, concentrating the obtained organic layer to obtain a concentrated solution, and subjecting it to a saponification reaction with a base in the presence of an organic solvent, and then subjecting the obtained saponification product to reduced pressure crystallization, filtration and drying to obtain 7-dehydrocholesterol.

[0025] The present invention also provides a method for preparing vitamin D3, which comprises first preparing 7-dehydrocholesterol by the above method, and then irradiating the obtained 7-dehydrocholesterol with ultraviolet light to obtain vitamin D3.

[0026] The present invention also provides a preparation device for 7-dehydrocholesterol, comprising a first preparation kettle, a second preparation kettle and a pipeline reactor, wherein the first preparation kettle is used to prepare a non-polar solution containing a raw material of 7-toluenesulfonylhydrazone-3-cholesterol acetate and a co-catalyst, the second preparation kettle is used to prepare a non-polar solution containing lithium amide, and the pipeline reactor is used to carry out a dehydrazone reaction between the non-polar solution containing the raw material of 7-toluenesulfonylhydrazone-3-cholesterol acetate and the co-catalyst and the non-polar solution containing lithium amide.

[0027] In a preferred embodiment, the 7-dehydrocholesterol preparation device further comprises a third preparation kettle and a resin column, wherein the outlet of the third preparation kettle is connected to the inlet of the resin column, and the outlet of the resin column is connected to the inlet of the first preparation kettle.

[0028] In a preferred embodiment, the 7-dehydrocholesterol preparation device further comprises a falling film evaporator disposed between the resin column and the first preparation kettle, wherein the inlet of the falling film evaporator is connected to the outlet of the resin column, and the outlet of the falling film evaporator is connected to the inlet of the first preparation kettle.

[0029] In a preferred embodiment, the pipeline reactor comprises a pipeline reactor I, a wiped film evaporator and a pipeline reactor II which are connected in sequence.

[0030] In a preferred embodiment, the 7-dehydrocholesterol preparation device further comprises a concentrator, a saponification reactor, a vacuum crystallizer, a filter and a dryer which are sequentially connected to the outlet of the pipeline reactor II.

[0031] In addition, the present invention also provides a device for preparing vitamin D3, wherein the device for preparing vitamin D3 includes the above-mentioned device for preparing 7-dehydrocholesterol and an ultraviolet irradiation device, and the outlet of the device for preparing 7-dehydrocholesterol is connected to the inlet of the ultraviolet irradiation device.

[0032] The key to the present invention is to use an amine compound containing two tertiary amine groups in the same molecule as a co-catalyst, thereby effectively improving the yield and purity of 7-dehydrocholesterol.

[0033] In a preferred embodiment, the method for preparing 7-dehydrocholesterol further includes, prior to the dehydrazone reaction, purifying the 7-(p-toluenesulfonyl)hydrazone-3-cholesterol acetate raw material with a strongly basic resin to remove residual hydrochloric acid and p-toluenesulfonic acid. This process further improves the yield and purity of 7-dehydrocholesterol. This is presumably due to the addition of concentrated hydrochloric acid required during the preparation of the 7-(p-toluenesulfonyl)hydrazone-3-cholesterol acetate raw material, and the tendency of p-toluenesulfonylhydrazine to decompose into p-toluenesulfonic acid during the reaction. These two acidic substances not only damage the 7-(p-toluenesulfonyl)hydrazone-3-cholesterol acetate during the dehydrazone reaction but also interfere with the function of the co-catalyst, ultimately affecting the product yield and purity. The traditional method for treating 7-p-toluenesulfonylhydrazone-3-cholesterol acetate is drying, but drying cannot completely remove the above two acidic substances. Strong alkaline resin can perfectly remove the residual hydrochloric acid in the 7-p-toluenesulfonylhydrazone-3-cholesterol acetate raw material and the by-product p-toluenesulfonic acid generated by the hydrazone reaction, thereby avoiding the destruction of 7-p-toluenesulfonylhydrazone-3-cholesterol acetate and the adverse effects of the co-catalyst, thereby improving the yield and purity.

[0034] In a preferred embodiment, the dehydrazone reaction is carried out by continuously mixing a non-polar solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material and a co-catalyst with a non-polar solution containing lithium amide in a pipeline reactor I, and then removing ammonia from the obtained mixed reaction product using a wiped film evaporator, and then introducing it into the pipeline reactor II for continuous dehydrazone reaction. On the one hand, the pipeline mixer can enhance the mixing effect and reduce the reaction residence time, thereby avoiding the generation of by-products. On the other hand, the wiped film evaporator can perfectly remove ammonia in the system, which can significantly reduce the damage of ammonia to the raw materials and products, avoid the deterioration of 7-toluenesulfonylhydrazone-3-cholesterol acetate and 7-dehydrocholesterol, thereby achieving high yield and high purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is a schematic diagram of the device for preparing 7-dehydrocholesterol provided by the present invention.

[0036] Description of Reference Numerals

[0037] 1-first reactor; 2-second reactor; 3-third reactor; 4-resin column; 5-falling film evaporator; 6-pipeline reactor I; 7-wiped film evaporator; 8-pipeline reactor II. DETAILED DESCRIPTION

[0038] In the present invention, the co-catalyst is an amine compound containing two tertiary amine groups in the same molecule. Such a compound can chelate with lithium amide to enhance its activity, thereby achieving the completion of the dehydrazone reaction at a lower temperature, reducing the byproduct formed by carbene and avoiding the large-scale destruction of 7-toluenesulfonylhydrazone-3-cholesterol acetate, thereby improving the yield and purity of 7-dehydrocholesterol. The amine compound preferably has a structure shown in formula (1), wherein R1, R2, R4 and R5 are each independently a substituted or unsubstituted C1-C5 alkyl, a substituted or unsubstituted C6-C 10 cycloalkyl or substituted or unsubstituted C6-C 10 R1 and R5 may be bonded to each other to form a ring, R3 is a carbonyl group or a C1-C 10 Specific examples of C1-C5 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, or neopentyl. 10 Specific examples of the cycloalkyl group include, but are not limited to, cyclohexyl, methylcyclohexyl, ethylcyclohexyl, cyclopentyl, or methylcyclopentyl. 10 Specific examples of the aryl group include, but are not limited to, phenyl, tolyl, ethylphenyl, or naphthyl. 10 Specific examples of the alkylene group include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, tert-butylene, n-pentylene, isopentylene, tert-pentylene, neopentylene, n-hexylene, n-heptylene, n-octylene, n-nonylene, or n-decylene. The above groups may be substituted by nitrogen, oxygen, sulfur, silicon, or phosphorus to replace some of the carbon atoms. The amine compound may be specifically selected from at least one of tetramethylethylenediamine, tetramethylpropylenediamine, tetramethylhexanediamine, N,N-dimethylpropyleneurea, and N,N-diphenylurea. The inventors of the present invention have discovered that, although existing amine compounds containing two tertiary amine groups in the same molecule can enhance the activity of lithium amide and reduce the dehydrazone reaction temperature, thereby increasing the yield and purity of the product, the use of tetramethylethylenediamine and / or N,N-dimethylpropyleneurea achieves better results and is more conducive to improving the yield and purity of 7-dehydrocholesterol. In addition, the amount of the cocatalyst is preferably 1% to 5% of the mole number of 7-toluenesulfonylhydrazone-3-cholesterol acetate, such as 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% or any value therebetween.

[0039]

[0040] In the present invention, the 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material can be prepared by various existing methods, for example, it can be prepared according to the method disclosed in Organic Syntheses, Coll. Vol. 6, p. 62 (1988). Specifically, 7-ketocholesterol acetate and p-toluenesulfonylhydrazine are subjected to a hydrazolation reaction in the presence of concentrated hydrochloric acid, so that hydrochloric acid and p-toluenesulfonic acid remain in the 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material. The molar ratio of the 7-ketocholesterol acetate to p-toluenesulfonylhydrazine is preferably 1: (1.1-1.3). The amount ratio of the 7-ketocholesterol acetate to concentrated hydrochloric acid is preferably 1 kg: (5-10) mL. The conditions of the hydrazolation reaction include a temperature of preferably 50° C. to 55° C. and a time of preferably 1 to 10 hours. In addition, the hydrazolation reaction is generally carried out using methanol as a solvent. The ratio of 7-ketocholesterol acetate to methanol can be 1 kg: (10-20) L. In addition, after the hydrazoline reaction is completed, the hydrazoline reaction product is generally cooled to -15°C to -5°C to allow solid precipitation, and then solid-liquid separation is performed to obtain a raw material wet cake of 7-toluenesulfonylhydrazoline-3-cholesterol acetate.

[0041] In the present invention, as described above, since hydrochloric acid and p-toluenesulfonic acid remain in the 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material, these two acids will have an adverse effect on the dehydrazone reaction and the co-catalyst. Therefore, preferably, the preparation method of 7-dehydrocholesterol also includes, before the dehydrazone reaction, first purifying the 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material with a strong basic resin to remove the residual hydrochloric acid and p-toluenesulfonic acid therein, thereby effectively removing the acidic substances in the 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material. Specifically, the 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material can be first dissolved in a non-polar solvent and then water is added and mixed evenly, the resulting mixture is continuously passed through a strong basic resin column, and then methanol and water are removed by a falling film evaporator to obtain a methanol-free and anhydrous 7-toluenesulfonylhydrazone-3-cholesterol acetate solution. It should be noted that the term "methanol-free and water-free" herein does not mean absolutely methanol-free and water-free, but rather means that the content of methanol and water is controlled below 0.02%. The strong base resin may be a macroporous, strong base styrene-based anion exchange resin and / or a macroporous, strong base acrylic acid-based anion exchange resin, preferably a macroporous, strong base styrene-based anion exchange resin, and particularly preferably D201 macroporous, strong base styrene-based anion exchange resin. Specific examples of the non-polar solvent include, but are not limited to, at least one of chlorobenzene, toluene, and xylene. The amount of water used is trace, preferably 0.8 to 1.2 times the molar number of 7-toluenesulfonylhydrazone-3-cholesterol acetate, such as 0.8, 0.9, 1.0, 1.1, or 1.2 times.

[0042] In a preferred embodiment, the dehydrazone reaction is carried out by continuously mixing a non-polar solution containing 7-toluenesulfonylhydrazone-3-cholesteryl acetate as a raw material and a co-catalyst with a non-polar solution containing lithium amide in a pipeline reactor I, and then removing ammonia from the resulting mixed reaction product using a wiped film evaporator, and then introducing it into the pipeline reactor II for continuous dehydrazone reaction. In this case, the occurrence of side reactions can be perfectly avoided and the damage of ammonia to the raw materials and products can be significantly reduced, further improving the yield and purity of the product. Wherein, the conditions of the continuous mixing reaction preferably include a reaction temperature of 0 to 40°C, such as 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C or any value therebetween; and a residence time of 5 to 10 minutes, such as 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes or any value therebetween. The conditions for the continuous dehydrazone reaction preferably include a reaction temperature of 80 to 100°C, such as 80°C, 85°C, 90°C, 95°C, 100°C or any value therebetween; a residence time of 5 to 30 minutes, such as 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes or any value therebetween. It should be noted that the use of a wiped film evaporator to remove ammonia does not require absolute removal of ammonia, and it is sufficient to reduce the ammonia content to less than 0.05%. In addition, the volume flow ratio of the non-polar solution containing 7-toluenesulfonylhydrazone-3-cholesteryl acetate raw material and co-catalyst to the non-polar solution containing lithium amide is preferably 1:(1.1 to 1.5), such as 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5 or any value therebetween.

[0043] In the present invention, the method for preparing 7-dehydrocholesterol preferably further comprises quenching the reaction solution obtained from the dehydrazone reaction with dilute hydrochloric acid, then standing and separating the layers, concentrating the resulting organic layer, saponifying the resulting concentrated solution with a base in the presence of an organic solvent (deprotection), and then subjecting the resulting saponified product to vacuum crystallization, filtration, and drying to obtain 7-dehydrocholesterol. The main improvements of the present invention focus on the dehydrazone step, while the use of dilute hydrochloric acid quenching, standing and separating the layers, concentration, saponification reaction, vacuum crystallization, filtration, and drying are the same as those in the prior art and are not described in detail here.

[0044] The present invention provides a method for preparing vitamin D3, comprising first preparing 7-dehydrocholesterol using the above-described method, and then subjecting the resulting 7-dehydrocholesterol to ultraviolet irradiation to obtain vitamin D3. As indicated above, the main improvements of the present invention focus on the dehydrazone step, while the ultraviolet irradiation step is the same as in the prior art and is not described here.

[0045] like Figure 1As shown, the preparation device of 7-dehydrocholesterol provided by the present invention includes a first preparation kettle 1, a second preparation kettle 2 and a pipeline reactor, wherein the first preparation kettle 1 is used to prepare a non-polar solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material and a co-catalyst, the second preparation kettle 2 is used to prepare a non-polar solution containing lithium amide, and the pipeline reactor is used to carry out a dehydrazone reaction between the non-polar solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material and the co-catalyst and the non-polar solution containing lithium amide. The preparation device of 7-dehydrocholesterol preferably also includes a third preparation kettle 3 and a resin column 4, the outlet of the third preparation kettle 3 is connected to the inlet of the resin column 4, and the outlet of the resin column 4 is connected to the inlet of the first preparation kettle 1. The resin column is used to treat the 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material, which can effectively remove residual hydrochloric acid and p-toluenesulfonic acid therein, avoiding the adverse effects of these two substances on the dehydrazone reaction, and further improving the product yield and purity. The 7-dehydrocholesterol preparation apparatus preferably further comprises a falling film evaporator 5 disposed between the resin column 4 and the first preparation kettle 1, the inlet of the falling film evaporator 5 being connected to the outlet of the resin column 4, and the outlet of the falling film evaporator 5 being connected to the inlet of the first preparation kettle 1. More preferably, the apparatus further comprises a concentrator, a saponification reactor, a vacuum crystallizer, a filter, and a dryer sequentially connected to the outlet of the pipeline reactor. The pipeline reactor preferably comprises a pipeline reactor I 6, a wiped film evaporator 7, and a pipeline reactor II 8, which are sequentially connected. In this case, the pipeline mixer can not only enhance the mixing effect and reduce the reaction residence time, thereby avoiding the formation of by-products, but also remove ammonia from the system through the wiped film evaporator, reducing the damage of ammonia to the raw materials and products, and preventing the deterioration of 7-toluenesulfonylhydrazone-3-cholesterol acetate and 7-dehydrocholesterol, thereby achieving high yield and high purity. In the present invention, the terms "first," "second," and "third," as well as "I" and "II," are merely for ease of distinction and description and have no special meaning.During operation, the raw material of 7-toluenesulfonylhydrazone-3-cholesterol acetate is dissolved in a non-polar solvent in a third preparation kettle 3, a small amount of water is added, and the mixture is pumped into a resin column 4 to remove hydrochloric acid and p-toluenesulfonic acid. The mixture is then passed through a falling film evaporator 5 to remove methanol and water, and then introduced into the first preparation kettle 1 and a co-catalyst is added to obtain a non-polar solution containing the raw material of 7-toluenesulfonylhydrazone-3-cholesterol acetate and the co-catalyst; lithium amide is dissolved in a non-polar solvent in a second preparation kettle 2 to obtain a non-polar solution containing lithium amide; the non-polar solution containing the raw material of 7-toluenesulfonylhydrazone-3-cholesterol acetate and the co-catalyst in the first preparation kettle 1 and the co-catalyst are added. The non-polar solution containing lithium amide in the second preparation kettle 2 is simultaneously introduced into the pipeline reactor I6 for a mixed reaction, and then continuously introduced into the wiped film evaporator 7 to remove the ammonia therein, and then introduced into the pipeline reactor II8 for a dehydrazone reaction. After the reaction is completed, hydrochloric acid is added for quenching and the mixture is allowed to stand for stratification. The resulting organic layer is introduced into a concentrator for concentration, and the concentrated product is introduced into a saponification reactor and an alkali and an organic solvent (specifically, a mixed solution of petroleum ether and methanol) are added to carry out a saponification reaction. After the saponification reaction is completed, the obtained product is sequentially introduced into a vacuum crystallizer, a filter and a dryer to complete vacuum crystallization, filtration and drying to obtain 7-dehydrocholesterol.

[0046] The vitamin D3 production apparatus provided by the present invention comprises the aforementioned 7-dehydrocholesterol production apparatus and an ultraviolet irradiation device, wherein the outlet of the 7-dehydrocholesterol production apparatus is connected to the inlet of the ultraviolet irradiation device. The main improvements of the present invention focus on the production of 7-dehydrocholesterol, while the ultraviolet irradiation device is the same as that of the prior art and will not be described in detail here.

[0047] The present invention will be described in detail below through examples.

[0048] In the following examples and comparative examples:

[0049] The content of 7-dehydrocholesterol was detected by Agilent 1260, where the chromatographic column was Dalian Elite Hypersil ODS2 5um×4.6mm×250mm, the mobile phase was methanol:water (V / V)=95:5, the column temperature was 40°C, the detector was a UV detector, the detection wavelength was 205nm, the flow rate was 1.0mL / min, the analysis time was 60min, and the injection volume was 20uL.

[0050] 7-dehydrocholesterol yield = (A 重量 ×A 纯度 )÷A 分子量 ÷(B 流量 ×30min×w×ρ÷C 分子量), wherein A represents 7-dehydrocholesterol, B represents a chlorobenzene solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate and a co-catalyst, w represents the content of 7-toluenesulfonylhydrazone-3-cholesterol acetate in the chlorobenzene solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate and a co-catalyst, ρ represents the density of the chlorobenzene solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate and a co-catalyst, and C represents 7-toluenesulfonylhydrazone-3-cholesterol acetate.

[0051] Preparation Example: Preparation of 7-p-Toluenesulfonylhydrazone-3-cholesterol acetate

[0052] Reference: Organic Syntheses, Coll. Vol. 6, p. 62 (1988): To a 100 L reactor were added 6.0 kg of 7-ketocholesterol acetate, 3.5 kg of p-toluenesulfonyl hydrazine, 84 L of methanol, and 40 mL of concentrated hydrochloric acid. The reaction was incubated at 53-55°C for 4 h. After the reaction was completed, the temperature was lowered to -10°C to precipitate a solid, which was filtered to obtain a wet cake of 7-p-toluenesulfonylhydrazone-3-cholesterol acetate containing methanol.

[0053] Example 1

[0054] (1) Chlorobenzene was added to the wet cake of 7-toluenesulfonylhydrazone-3-cholesterol acetate obtained in the preparation example to dissolve the mixture, and 0.23 L of water was added to mix the mixture evenly. The resulting material was then pumped through a column containing D201 strong basic resin at a flow rate of 1.0 L / min. Methanol and water were then removed by a falling film evaporator. The hot water temperature of the falling film evaporator was set at 40° C. and the vacuum degree was set at −0.085 MPa. 35.0 L of chlorobenzene solution of 7-toluenesulfonylhydrazone-3-cholesterol acetate was obtained, wherein the methanol content was 0.01%, the water content was 0.01%, the acid value was 0.01 mgKOH / g, and the 7-toluenesulfonylhydrazone-3-cholesterol acetate content was 19.80%. To 3.5 L of 7-toluenesulfonylhydrazone-3-cholesterol acetate chlorobenzene solution, add 7.1 g of tetramethylethylenediamine and mix well to obtain a chlorobenzene solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material and co-catalyst, which is set aside.

[0055] (2) Stir and disperse 0.75 kg of lithium amide and 52.5 L of chlorobenzene evenly to obtain a chlorobenzene solution containing lithium amide, which is set aside.

[0056] (3) The temperature of pipeline reactor I is set to 30°C, the flow rate of chlorobenzene solution containing lithium amide is set to 5.25 L / h, and the flow rate of chlorobenzene solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate and co-catalyst is set to 3.5 L / h. The two streams of materials enter pipeline reactor I at the same time to start the reaction. The residence time is 5 minutes. The material flowing out of pipeline reactor I is continuously introduced into the wiped film evaporator for ammonia removal. The vacuum of the wiped film evaporator is set to -0.085 MPa and the temperature is set to 30°C. The outlet of the wiped film evaporator is connected to the pipe. The reaction temperature of pipeline reactor II was set to 100° C. and the residence time was 5 min. After the reaction was completed, 5% hydrochloric acid was introduced into pipeline reactor II at a flow rate of 2.2 L / h for quenching. The quenched material was allowed to stand for stratification, and the organic layer was separated. The organic layer was collected 30 minutes after the system stabilized. The organic layer was concentrated and added with petroleum ether:methanol (V / V) = 2 L:6 L and 0.08 kg of potassium hydroxide. Saponification reaction was carried out at 55° C. After the reaction was completed, reduced pressure crystallization, filtration, and drying were carried out to obtain 0.455 kg of 7-dehydrocholesterol with a yield of 94.8% and a purity of 98.1%.

[0057] Example 2

[0058] (1) Prepare a chlorobenzene solution of 7-toluenesulfonylhydrazone-3-cholesterol acetate according to the method of Example 1. Add 1.4 g of tetramethylethylenediamine to 3.5 L of the chlorobenzene solution of 7-toluenesulfonylhydrazone-3-cholesterol acetate and mix well to obtain a chlorobenzene solution containing the 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material and the co-catalyst, which is then used for standby use.

[0059] (2) A chlorobenzene solution containing lithium amide was prepared according to the method of Example 1.

[0060] (3) The temperature of pipeline reactor I is set to 40 ° C, the flow rate of chlorobenzene solution containing lithium amide is set to 3.85 L / h, the flow rate of chlorobenzene solution containing 7-toluenesulfonylhydrazone-3-cholesteryl acetate chlorobenzene and co-catalyst is set to 3.5 L / h, and the two streams of materials enter pipeline reactor I at the same time to start the reaction. The residence time is 10 min. The material flowing out of pipeline reactor I is continuously introduced into the wiped film evaporator for ammonia removal. The vacuum of the wiped film evaporator is set to -0.085 MPa and the temperature is set to 30 ° C; the outlet of the wiped film evaporator is connected to Connect pipeline reactor II, set the reaction temperature of pipeline reactor II to 100°C, and the residence time to 30 min. After the reaction is completed, 5% hydrochloric acid at a flow rate of 2.2 L / h is introduced into pipeline reactor II for quenching. The quenched material is allowed to stand and stratify, and the organic layer is separated. The organic layer is collected 30 minutes after the system stabilizes, and the organic layer is concentrated. After that, petroleum ether:methanol (V / V) = 2L:6L and 0.08 kg of potassium hydroxide are added, and saponification reaction is carried out at 55°C. After the reaction is completed, vacuum crystallization, filtration, and drying are carried out to obtain 0.45 kg of 7-dehydrocholesterol with a yield of 91.8% and a purity of 95.1%.

[0061] Example 3

[0062] (1) A chlorobenzene solution of 7-toluenesulfonylhydrazone-3-cholesterol acetate was prepared according to the method of Example 1. 4.7 g of N,N-dimethylpropylene urea was added to 3.5 L of the chlorobenzene solution of 7-toluenesulfonylhydrazone-3-cholesterol acetate and the mixture was mixed uniformly to obtain a chlorobenzene solution containing the 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material and the co-catalyst, which was then set aside.

[0063] (2) A chlorobenzene solution containing lithium amide was prepared according to the method of Example 1.

[0064] (3) The temperature of pipeline reactor I is set to 0°C, the flow rate of chlorobenzene solution containing lithium amide is set to 4.9 L / h, and the flow rate of chlorobenzene solution containing 7-toluenesulfonylhydrazone-3-cholesteryl acetate chlorobenzene and co-catalyst is set to 3.5 L / h. The two streams of materials enter pipeline reactor I at the same time to start the reaction. The residence time is 10 min. The material flowing out of pipeline reactor I is continuously introduced into the wiped film evaporator for ammonia removal. The vacuum of the wiped film evaporator is set to -0.085 MPa and the temperature is set to 30°C. The outlet of the wiped film evaporator is connected to Pipeline reactor II, the reaction temperature of pipeline reactor II was set to 80°C, the residence time was 20 min, and after the reaction was completed, 5% hydrochloric acid was introduced into pipeline reactor II at a flow rate of 2.2 L / h for quenching. The quenched material was allowed to stand and stratify, and the organic layer was separated. The organic layer was collected 30 minutes after the system stabilized, and the organic layer was concentrated and added with petroleum ether:methanol (V / V) = 2L:6L and 0.08 kg of potassium hydroxide. Saponification reaction was carried out at 55°C. After the reaction was completed, reduced pressure crystallization, filtration, and drying were carried out to obtain 0.46 kg of 7-dehydrocholesterol with a yield of 94.5% and a purity of 97.5%.

[0065] Example 4

[0066] (1) Prepare a chlorobenzene solution of 7-toluenesulfonylhydrazone-3-cholesterol acetate according to the method of Example 1. Add 7.8 g of N,N-dimethylpropylene urea to 3.5 L of the chlorobenzene solution of 7-toluenesulfonylhydrazone-3-cholesterol acetate and mix well to obtain a chlorobenzene solution containing the 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material and the co-catalyst, which is set aside.

[0067] (2) A chlorobenzene solution containing lithium amide was prepared according to the method of Example 1.

[0068] (3) The temperature of pipeline reactor I is set to 30°C, the flow rate of chlorobenzene solution containing lithium amide is set to 5.25 L / h, and the flow rate of chlorobenzene solution containing 7-toluenesulfonylhydrazone-3-cholesteryl acetate chlorobenzene and co-catalyst is set to 3.5 L / h. The two streams of materials enter pipeline reactor I at the same time to start the reaction. The residence time is 5 minutes. The material flowing out of pipeline reactor I is continuously introduced into the wiped film evaporator for ammonia removal. The vacuum of the wiped film evaporator is set to -0.085 MPa and the temperature is set to 30°C. The outlet of the wiped film evaporator is connected to Pipeline reactor II was set at a reaction temperature of 100°C and a residence time of 10 min. After the reaction was completed, 5% hydrochloric acid was introduced into the pipeline reactor II at a flow rate of 2.2 L / h for quenching. The quenched material was allowed to stand for stratification, and the organic layer was separated. The organic layer was collected 30 minutes after the system stabilized. The organic layer was concentrated and added with petroleum ether:methanol (V / V) = 2L:6L and 0.08 kg of potassium hydroxide. Saponification reaction was carried out at 55°C. After the reaction was completed, vacuum crystallization, filtration, and drying were carried out to obtain 0.46 kg of 7-dehydrocholesterol with a yield of 95.5% and a purity of 98.2%.

[0069] Example 5 7-p-Toluenesulfonylhydrazone-3-cholesteryl acetate chlorobenzene solution does not pass through the basic resin

[0070] 7-dehydrocholesterol was prepared according to the method of Example 1, except that the chlorobenzene solution of 7-p-toluenesulfonylhydrazone-3-cholesterol acetate was not purified using a basic resin column. The remaining conditions were the same as those of Example 1, and the specific steps were as follows:

[0071] (1) Chlorobenzene was added to the wet cake of 7-toluenesulfonylhydrazone-3-cholesterol acetate obtained in the preparation example to dissolve the mixture, and 0.23 L of water was added and mixed uniformly. The resulting material was passed through a falling film evaporator to remove methanol and water. The temperature of the falling film evaporator was set at 40°C and the vacuum was set at -0.085 MPa. 35.0 L of chlorobenzene solution of 7-toluenesulfonylhydrazone-3-cholesterol acetate was obtained, wherein the methanol content was 0.02%, the water content was 0.02%, the acid value was 0.95 mgKOH / g, and the 7-toluenesulfonylhydrazone-3-cholesterol acetate content was 18.0%. 7.1 g of tetramethylethylenediamine was added to 3.5 L of the chlorobenzene solution of 7-toluenesulfonylhydrazone-3-cholesterol acetate and mixed uniformly to obtain a chlorobenzene solution containing the raw material 7-toluenesulfonylhydrazone-3-cholesterol acetate and the co-catalyst, which was set aside.

[0072] (2) Stir and disperse 0.75 kg of lithium amide and 52.5 L of chlorobenzene evenly to obtain a chlorobenzene solution containing lithium amide, which is set aside.

[0073] (3) The temperature of pipeline reactor I is set to 30°C, the flow rate of chlorobenzene solution containing lithium amide is set to 5.25 L / h, and the flow rate of chlorobenzene solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate and co-catalyst is set to 3.5 L / h. The two streams of materials enter pipeline reactor I at the same time to start the reaction. The residence time is 5 minutes. The material flowing out of pipeline reactor I is continuously introduced into the wiped film evaporator for ammonia removal. The vacuum of the wiped film evaporator is set to -0.085 MPa and the temperature is set to 30°C. The outlet of the wiped film evaporator is connected to Pipeline reactor II was set to a reaction temperature of 100°C and a residence time of 5 min. After the reaction was completed, 5% hydrochloric acid was introduced into the pipeline reactor II at a flow rate of 2.2 L / h for quenching. The quenched material was allowed to stand and separate, and the organic layer was separated. The organic layer was collected 30 minutes after the system stabilized. The organic layer was concentrated and added with petroleum ether:methanol (V / V) = 2L:6L and 0.08 kg of potassium hydroxide. Saponification reaction was carried out at 55°C. After the reaction was completed, reduced pressure crystallization, filtration, and drying were carried out to obtain 0.40 kg of 7-dehydrocholesterol with a yield of 83.4% and a purity of 89.9%.

[0074] Example 6: Removal of methanol from 7-toluenesulfonylhydrazone-3-cholesterol acetate by conventional drying method

[0075] 7-dehydrocholesterol was prepared according to the method of Example 1, except that the 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material was treated by a conventional drying method to remove methanol. The other conditions were the same as those of Example 1. The specific steps were as follows:

[0076] (1) The 7-toluenesulfonylhydrazone-3-cholesterol acetate wet cake obtained in the preparation example was dried at 40° C. to obtain 7.92 kg of 7-toluenesulfonylhydrazone-3-cholesterol acetate with a content of 94.5%. 27 L of chlorobenzene was added to dissolve the mixture to obtain a chlorobenzene solution of 7-toluenesulfonylhydrazone-3-cholesterol acetate. 7.1 g of tetramethylethylenediamine was added to 3.5 L of the chlorobenzene solution of 7-toluenesulfonylhydrazone-3-cholesterol acetate and mixed uniformly to obtain a chlorobenzene solution containing the 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material and the cocatalyst, which was then set aside.

[0077] (2) Stir and disperse 0.75 kg of lithium amide and 52.5 L of chlorobenzene evenly to obtain a chlorobenzene solution containing lithium amide, which is set aside.

[0078] (3) The temperature of pipeline reactor I is set to 30°C, the flow rate of chlorobenzene solution containing lithium amide is set to 5.25 L / h, and the flow rate of chlorobenzene solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate and co-catalyst is set to 3.5 L / h. The two streams of materials enter pipeline reactor I at the same time to start the reaction. The residence time is 5 minutes. The material flowing out of pipeline reactor I is continuously introduced into the wiped film evaporator for ammonia removal. The vacuum of the wiped film evaporator is set to -0.085 MPa and the temperature is set to 30°C. The outlet of the wiped film evaporator is connected to Pipeline reactor II was set at a reaction temperature of 100°C and a residence time of 5 min. After the reaction was completed, 5% hydrochloric acid was introduced into the pipeline reactor II at a flow rate of 2.2 L / h for quenching. The quenched material was allowed to stand for stratification, and the organic layer was separated. The organic layer was collected 30 minutes after the system stabilized. The organic layer was concentrated and added with petroleum ether:methanol (V / V) = 2L:6L and 0.08 kg of potassium hydroxide. Saponification reaction was carried out at 55°C. After the reaction was completed, vacuum crystallization, filtration, and drying were carried out to obtain 0.42 kg of 7-dehydrocholesterol with a yield of 84.5% and a purity of 94.4%.

[0079] Example 7 Dehydrazone Reaction Using Only One Inline Mixer and No Wiped Film Evaporator

[0080] 7-Dehydrocholesterol was prepared according to the method of Example 1, except that the dehydrazone reaction in step (3) was carried out only in a pipeline mixer and no wiped film evaporator was included. The remaining conditions were the same as those of Example 1. The specific steps were as follows:

[0081] (1) Chlorobenzene was added to the wet cake of 7-toluenesulfonylhydrazone-3-cholesterol acetate obtained in the preparation example to dissolve the mixture, and 0.23 L of water was added to mix the mixture evenly. The resulting material was then pumped through a column containing D201 strong basic resin at a flow rate of 1.0 L / min. Methanol and water were then removed by a falling film evaporator. The hot water temperature of the falling film evaporator was set at 40° C. and the vacuum degree was set at −0.085 MPa. 35.0 L of chlorobenzene solution of 7-toluenesulfonylhydrazone-3-cholesterol acetate was obtained, wherein the methanol content was 0.01%, the water content was 0.01%, the acid value was 0.01 mgKOH / g, and the 7-toluenesulfonylhydrazone-3-cholesterol acetate content was 19.80%. To 3.5 L of 7-toluenesulfonylhydrazone-3-cholesterol acetate chlorobenzene solution, add 7.1 g of tetramethylethylenediamine and mix well to obtain a chlorobenzene solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material and co-catalyst, which is set aside.

[0082] (2) Stir and disperse 0.75 kg of lithium amide and 52.5 L of chlorobenzene evenly to obtain a chlorobenzene solution containing lithium amide, which is set aside.

[0083] (3) The flow rate of the chlorobenzene solution containing lithium amide was set to 5.25 L / h, and the flow rate of the chlorobenzene solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate and the co-catalyst was set to 3.5 L / h. The two streams of materials entered the pipeline reactor at the same time to start the reaction. The reaction temperature of the pipeline reaction was 100°C, and the residence time was 10 min. After the reaction was completed, 5% hydrochloric acid at a flow rate of 2.2 L / h was introduced into the pipeline reactor for quenching. The quenched materials entered the layer separation, and the organic layer was separated. The organic layer was collected 30 minutes after the system stabilized. After the organic layer was concentrated, petroleum ether: methanol (V / V) = 2L:6L and 0.08 kg of potassium hydroxide were added, and saponification reaction was carried out at 55°C. After the reaction was completed, reduced pressure crystallization, filtration, and drying were carried out to obtain 0.42 kg of 7-dehydrocholesterol with a yield of 80.1% and a purity of 89.9%.

[0084] Example 8 Using non-preferred amine compounds as co-catalysts

[0085] 7-Dehydrocholesterol was prepared according to the method of Example 1, except that tetramethylethylenediamine was replaced with tetramethylhexanediamine in the same molar amount. Other conditions were the same as in Example 1, and 0.43 kg of 7-dehydrocholesterol was obtained with a yield of 85.8% and a purity of 93.1%.

[0086] Example 9 Using non-preferred amine compounds as co-catalysts

[0087] 7-Dehydrocholesterol was prepared according to the method of Example 3, except that N,N-dimethylpropylene urea was replaced with the same molar amount of N,N-diphenyl urea. The other conditions were the same as those of Example 1, and 0.42 kg of 7-dehydrocholesterol was obtained with a yield of 80.5% and a purity of 90.5%.

[0088] Comparative Example 1: No co-catalyst

[0089] 7-dehydrocholesterol was prepared according to the method of Example 1, except that no co-catalyst was added. The other conditions were the same as those of Example 1. The specific steps were as follows:

[0090] (1) Chlorobenzene was added to the wet cake of 7-toluenesulfonylhydrazone-3-cholesterol acetate obtained in the preparation example to dissolve the mixture, and 0.23 L of water was added to mix the mixture evenly. The resulting material was then pumped through a column containing D201 strong basic resin at a flow rate of 1.0 L / min. Methanol and water were then removed by a falling film evaporator. The hot water temperature of the falling film evaporator was set at 40° C. and the vacuum degree was set at −0.085 MPa. 35.0 L of chlorobenzene solution of 7-toluenesulfonylhydrazone-3-cholesterol acetate was obtained, wherein the methanol content was 0.01%, the water content was 0.01%, the acid value was 0.01 mgKOH / g, and the 7-toluenesulfonylhydrazone-3-cholesterol acetate content was 19.80%.

[0091] (2) Stir and disperse 0.75 kg of lithium amide and 52.5 L of chlorobenzene evenly to obtain a chlorobenzene solution containing lithium amide, which is set aside.

[0092] (3) The temperature of pipeline reactor I was set to 30°C, the flow rate of chlorobenzene solution containing lithium amide was set to 5.25 L / h, and the flow rate of 7-toluenesulfonylhydrazone-3-cholesteryl acetate chlorobenzene solution was set to 3.5 L / h. The two streams of materials entered pipeline reactor I at the same time to start the reaction. The residence time was 5 min. The materials flowing out of pipeline reactor I were continuously introduced into the wiped film evaporator for ammonia removal. The vacuum of the wiped film evaporator was set to -0.085 MPa and the temperature was set to 30°C. The outlet of the wiped film evaporator was connected to the pipeline reactor I. The reaction temperature of pipeline reactor II was set to 100° C., and the residence time was 5 min. After the reaction was completed, 5% hydrochloric acid was introduced into pipeline reactor II at a flow rate of 2.2 L / h for quenching. The quenched material was allowed to stand for stratification, and the organic layer was separated. The organic layer was collected 30 minutes after the system stabilized. The organic layer was concentrated and then added with petroleum ether:methanol (V / V) = 2 L:6 L and 0.08 kg of potassium hydroxide. Saponification reaction was carried out at 55° C. After the reaction was completed, reduced pressure crystallization, filtration, and drying were carried out to obtain 0.42 kg of 7-dehydrocholesterol with a yield of 78.5% and a purity of 88.5%.

[0093] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention without departing from the principles and purpose of the present invention.

Claims

1. A method for preparing 7-dehydrocholesterol, characterized in that: The method comprises the steps of subjecting a raw material of 7-toluenesulfonylhydrazone-3-cholesterol acetate to a dehydrazone reaction in the presence of lithium amide and a cocatalyst; the cocatalyst is tetramethylethylenediamine and / or N,N-dimethylpropyleneurea; The dehydrazone reaction comprises the following steps: continuously mixing a non-polar solution containing 7-p-toluenesulfonylhydrazone-3-cholesterol acetate as a raw material and a co-catalyst with a non-polar solution containing lithium amide in a pipeline reactor I, removing ammonia from the obtained mixed reaction product using a wiped film evaporator, and then introducing the mixed reaction product into a pipeline reactor II for continuous dehydrazone reaction; the conditions for the continuous mixing reaction include a reaction temperature of 0 to 40° C. and a residence time of 5 to 10 minutes; and the conditions for the continuous dehydrazone reaction include a reaction temperature of 80 to 100° C. and a residence time of 5 to 30 minutes.

2. The method for preparing 7-dehydrocholesterol according to claim 1, wherein The amount of the cocatalyst is 1% to 5% of the mole number of 7-toluenesulfonylhydrazone-3-cholesterol acetate.

3. The method for preparing 7-dehydrocholesterol according to claim 1, wherein The 7-p-toluenesulfonylhydrazone-3-cholesterol acetate raw material is prepared according to the following method: 7-ketocholesterol acetate and p-toluenesulfonylhydrazine are subjected to hydrazolation reaction in the presence of concentrated hydrochloric acid.

4. The method for preparing 7-dehydrocholesterol according to claim 3, wherein The conditions of the hydrazolation reaction include a temperature of 50° C. to 55° C. and a time of 1 to 10 hours.

5. The method for preparing 7-dehydrocholesterol according to claim 3, wherein The hydrazolation reaction is carried out under the condition of using methanol as solvent.

6. The method for preparing 7-dehydrocholesterol according to claim 3, wherein The method further comprises the following steps: before the hydrazone desorption reaction, purifying the 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material by using a strong alkaline resin.

7. The method for preparing 7-dehydrocholesterol according to claim 6, wherein The strong basic resin is a macroporous strong basic styrene anion exchange resin.

8. The method for preparing 7-dehydrocholesterol according to claim 6, wherein The method of using a strong basic resin for purification treatment is to dissolve the 7-p-toluenesulfonylhydrazone-3-cholesterol acetate raw material in a non-polar solvent, then add water and mix evenly, continuously pass the resulting mixture through a strong basic resin column, and then remove methanol and water through a falling film evaporator to obtain a methanol-free and water-free 7-p-toluenesulfonylhydrazone-3-cholesterol acetate solution.

9. The method for preparing 7-dehydrocholesterol according to claim 8, wherein The non-polar solvent is selected from at least one of chlorobenzene, toluene and xylene.

10. The method for preparing 7-dehydrocholesterol according to claim 8, characterized in that: The amount of water used is 0.8 to 1.2 times the molar number of 7-toluenesulfonylhydrazone-3-cholesterol acetate.

11. The method for preparing 7-dehydrocholesterol according to claim 1, wherein The volume flow ratio of the non-polar solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material and the co-catalyst to the non-polar solution containing lithium amide is 1:(1.1-1.5).

12. The method for preparing 7-dehydrocholesterol according to any one of claims 1 to 11, characterized in that: The method further comprises quenching the reaction solution obtained by the dehydrazone reaction with dilute hydrochloric acid and then standing to separate layers, concentrating the obtained organic layer, performing a saponification reaction on the obtained concentrated solution with a base in the presence of an organic solvent, and then performing reduced pressure crystallization, filtering and drying the obtained saponification product to obtain 7-dehydrocholesterol.

13. A method for preparing vitamin D3, characterized in that: The method comprises firstly preparing 7-dehydrocholesterol by the method described in any one of claims 1 to 12, and then subjecting the obtained 7-dehydrocholesterol to ultraviolet irradiation to obtain vitamin D3.

14. A device for preparing 7-dehydrocholesterol, characterized in that: The 7-dehydrocholesterol preparation device includes a first preparation kettle, a second preparation kettle and a pipeline reactor. The first preparation kettle is used to prepare a non-polar solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material and a co-catalyst, the second preparation kettle is used to prepare a non-polar solution containing lithium amide, and the pipeline reactor is used to carry out a dehydrazone reaction between the non-polar solution containing 7-toluenesulfonylhydrazone-3-cholesterol acetate raw material and a co-catalyst and the non-polar solution containing lithium amide.

15. The device for preparing 7-dehydrocholesterol according to claim 14, characterized in that: The 7-dehydrocholesterol preparation device further includes a third preparation kettle and a resin column, wherein the outlet of the third preparation kettle is communicated with the inlet of the resin column, and the outlet of the resin column is communicated with the inlet of the first preparation kettle.

16. The device for preparing 7-dehydrocholesterol according to claim 14, characterized in that: The 7-dehydrocholesterol preparation device further includes a falling film evaporator disposed between the resin column and the first preparation kettle, wherein the inlet of the falling film evaporator is connected to the outlet of the resin column, and the outlet of the falling film evaporator is connected to the inlet of the first preparation kettle.

17. The device for producing 7-dehydrocholesterol according to claim 14, characterized in that: The pipeline reactor comprises a pipeline reactor I, a wiped film evaporator and a pipeline reactor II which are connected in sequence.

18. The device for producing 7-dehydrocholesterol according to claim 17, characterized in that: The 7-dehydrocholesterol preparation device further comprises a concentrator, a saponification reactor, a vacuum crystallizer, a filter and a dryer which are sequentially connected to the outlet of the pipeline reactor II.

19. A device for preparing vitamin D3, characterized in that: The vitamin D3 preparation device comprises the 7-dehydrocholesterol preparation device according to any one of claims 14 to 18 and an ultraviolet irradiation device, and the outlet of the 7-dehydrocholesterol preparation device is connected to the inlet of the ultraviolet irradiation device.

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