Preparation of vitamin D from stigmasterol3Is a new method for industrialization
阅读说明：本技术 一种以豆甾醇为原料制备维生素d3的工业化新方法 (Preparation of vitamin D from stigmasterol3Is a new method for industrialization ) 是由 付书清 张�林 徐敏 曹怀塘 于 2021-02-07 设计创作，主要内容包括：本发明提供一种以豆甾醇为原料制备维生素D-3的工业化新方法,豆甾醇依次经羟基乙酰化、侧链氧化、侧链接异戊烷还原、氢化制得胆固醇醋酸酯,然后再依次经氧化、腙化、脱腙、水解、光照等步骤即制得维生素D-3。本发明开发了一种由豆甾醇制备维生素D-3的新方法,反应条件温和、收率高,适于工业化生产。(The invention provides a method for preparing vitamin D by taking stigmasterol as a raw material 3 The new industrial process includes the steps of successively hydroxyl acetylation, side chain oxidation, reduction of side chain isopentane, hydrogenation to prepare cholesterol acetate, successively oxidation, hydrazonation, deazone, hydrolysis, illumination, etc. to prepare vitamin D 3 . The invention develops a method for preparing vitamin D from stigmasterol 3 The new method has mild reaction conditions and high yield, and is suitable for industrial production.)
1. Vitamin D3The preparation method is characterized by sequentially comprising the following 9 steps: (1) preparation of stigmasterol acetate (IX), (2) preparation of side chain oxide (VIII), (3) preparation of side chain isopentanizing reduction (VII), (4) hydrogenation preparation of cholesterol acetate (VI), (5) oxidation preparation of 7-ketoneBase-cholesterol acetate (V), (6) hydrazones are synthesized into 7-p-toluenesulfonylhydrazone-cholesterol acetate (IV), (7) dehydro-cholesterol acetate (III) is prepared by dehydro-hydrazone, (8) 7-dehydro-cholesterol (II) is prepared by hydrolysis, and (9) vitamin D is synthesized by illumination3(I); the route is as follows:
2. vitamin D according to claim 13The method for producing (1) is characterized in that the step (1) comprises: dissolving stigmasterol (X) in a reaction solvent with the weight of 10-20 times, and adding an acid-binding agent with the same molar weight as the stigmasterol and a catalyst with the weight of 1-5% of the stigmasterol; adding an esterification reagent with the molar weight of 1-2 times of stigmasterol in batches at the solvent reflux temperature, continuously refluxing until the raw materials are completely reacted, filtering to remove an acid-binding agent, recovering the solvent to dryness, and recrystallizing by using a crystallization solvent to obtain an acicular crystal compound IX;
the reaction solvent is selected from dichloromethane, n-hexane, cyclohexane, dichloroethane, petroleum ether, preferably n-hexane;
the acid-binding agent is selected from potassium carbonate, sodium bicarbonate and sodium carbonate, preferably potassium carbonate;
the catalyst is selected from pyridine, lutidine, DMAP, PPY and TMAJ, and pyridine is preferred;
the esterification reagent is selected from acetyl chloride and acetic anhydride, preferably acetic anhydride;
the crystallization solvent is selected from dichloromethane, n-hexane, cyclohexane, dichloroethane, petroleum ether, methanol, ethanol, preferably ethanol.
3. Vitamin D according to claim 13The method for producing (2) is characterized in that the step (2) comprises: dissolving a compound IX in a reaction solvent with the weight of 40-60 times, cooling the mixture to-70-30 ℃ in a cold tank, introducing mixed gas of oxygen and ozone for reaction, monitoring by TLC until the reaction of the raw materials is finished, introducing nitrogen, heating the reaction system to zero,dissolving thiourea in an amount which is 1-2 times of the molar weight of the compound IX in a mixed solvent in an amount which is 5-15 times of the weight of the compound IX, adding the mixture into a reaction system, heating to room temperature, and stirring for reaction for 10-20 hours; filtering off white precipitate, washing the precipitate with a proper amount of mixed solvent, merging the washing liquid into the filtrate, and carrying out reduced pressure concentration and crystallization on the filtrate to obtain a compound VIII; optionally, 200-300 mesh silica gel which is 0.5 time of the weight of the compound IX is added into the reaction system before the reaction, and after the reaction is finished, the compound IX and the white precipitate are filtered together to remove;
the reaction solvent is selected from ethanol or methanol, preferably ethanol;
the mixed solvent is selected from 80-95 wt% ethanol-water solution or 80-95 wt% methanol-water solution, preferably ethanol-water solution.
4. Vitamin D according to claim 13The method for producing (2), wherein the step (3) comprises: dissolving triphenylphosphine in 10-20 times of anhydrous solvent, and dissolving 1-bromoisopentane with equimolar amount in the anhydrous solvent with the same volume; under the protection of nitrogen, dropwise adding the solution into triphenylphosphine solution at low temperature while stirring; heating and stirring until reflux reaction; after the reaction is completed, cooling to room temperature, adding 1-2 times of strong base in molar weight, and continuously stirring; dissolving the compound VIII in an anhydrous solvent with the same weight, and dropwise adding the solution into the reaction system; refluxing again for reaction, and monitoring by TLC until the reaction of the raw materials is finished; cooling in ice water bath, and then dropwise adding acid water to adjust the pH value to be neutral; separating, concentrating the organic layer to dryness, and crystallizing to obtain a compound VII;
the anhydrous solvent is selected from toluene, xylene and dibutyl ether, and toluene is preferred;
the strong base is sodium tert-butoxide or potassium tert-butoxide, preferably sodium tert-butoxide;
the acid water is selected from the group consisting of aqueous hydrochloric acid, aqueous phosphoric acid, aqueous sulfuric acid, aqueous nitric acid, and preferably 10% aqueous phosphoric acid.
5. Vitamin D according to claim 13Characterized in that, the step (4) comprisesComprises the following steps: dissolving a compound VII in methanol 40-60 times of the weight of the compound VII, adding 1% palladium-carbon accounting for 5% of the weight of the compound VII into the solution, and adding ammonium formate accounting for 3-5 times of the weight of the compound VII and a catalytic amount of formic acid; after nitrogen replacement, carrying out reflux reaction until the reaction is complete; the palladium-carbon is removed by filtration, and the organic layer is concentrated and crystallized to obtain compound VI (cholesterol acetate).
6. Vitamin D according to claim 13The method for producing (5) is characterized in that the step (5) comprises: dissolving 1 part by weight of cholesterol acetate (VI) in 7-13 parts by weight of dichloroethane, acetone or acetonitrile, and adding 0.5-1% by weight of a catalyst selected from copper powder, copper chloride, cuprous chloride, chromium trioxide, NHPI or benzoyl peroxide; then adding a phase transfer reagent with the equivalent number of 2-4 times that of cholesterol acetate (VI), wherein the phase transfer reagent is selected from tetrabutylammonium bromide, tetrabutylammonium chloride and benzyltriethylammonium chloride; adding 1-2 parts by weight of tert-butyl hydroperoxide while stirring at 45-50 ℃, and reacting for 8 hours at constant temperature; after the reaction, the reaction mixture was concentrated under reduced pressure, the residue was added to ice water, extracted with n-hexane, the organic phase was further washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 7-keto-cholesterol acetate (V).
7. Vitamin D according to claim 13The method for producing (6) is characterized in that the step (6) comprises: dissolving 1 weight part of 7-keto-cholesterol acetate (V) in 7-10 weight parts of methanol, adding p-toluenesulfonyl hydrazide with the equivalent number of 1.2 times that of the 7-keto-cholesterol acetate (V) and 0.01-0.025 weight part of concentrated hydrochloric acid, refluxing for 3 hours until the reaction is complete, filtering, washing a filter cake with methanol, and drying to obtain 7-p-toluenesulfonylhydrazone-cholesterol acetate (IV).
8. Vitamin D according to claim 13The method for producing (1), characterized in that the step (7) comprises: dissolving 1 weight part of 7-p-toluenesulfonylhydrazone-cholesterol acetate (IV) in 8-10 weight parts of toluene dried by anhydrous calcium chloride, and adding 0.06-008 parts by weight of lithium hydride, refluxing and reacting for 8 hours at 120 ℃ until the reaction is complete, filtering, concentrating the filtrate, dissolving with petroleum ether, filtering the dissolved solution by a silica gel column, concentrating the filtrate to obtain a solid, and recrystallizing in methanol, ethanol or butanol to obtain the 7-dehydrocholesterol acetate (III).
9. Vitamin D according to claim 13The method for producing (2), characterized in that the step (8) comprises: dissolving 1 weight part of 7-dehydrocholesterol acetate (III) in 3-5 weight parts of methanol, adding potassium hydroxide or sodium hydroxide in an equivalent amount of 7-dehydrocholesterol acetate (III), and reacting at 50 ℃; after the reaction is finished, the pH value is adjusted to be neutral by acetic acid, solid is separated out, and the solid of the 7-dehydrocholesterol (II) is obtained by filtration.
10. Vitamin D according to claim 13The method for producing (2), characterized in that the step (9) comprises: dissolving 1 weight part of 7-dehydrocholesterol (II) in 130 weight parts of cyclohexane-methanol mixed solution with the volume ratio of 10:1 at the temperature of 30-35 ℃; pumping the reaction stock solution into 20kw high-pressure mercury lamp photochemical reaction equipment by a pump for photochemical reaction, wherein the flow rate is 15-20L/min; collecting reaction solution, concentrating under reduced pressure and low temperature at 2-8 deg.C under nitrogen protection to 1/60-1/15 with original volume, standing at 2-8 deg.C for 24 hr to separate out 7-dehydrocholesterol raw material, filtering, repeatedly performing photochemical reaction on the filtered 7-dehydrocholesterol raw material, and concentrating the filtrate under reduced pressure to obtain vitamin D3And (5) producing the product.
Technical Field
The invention relates to a method for preparing vitamin D by taking stigmasterol as a raw material3Belongs to the field of chemical medicine preparation technology.
Background
Vitamin D3(vitamin D3) The cholecalciferol is a medicine with rickets resisting activity and is widely regarded as an important substance for regulating the metabolism of calcium and phosphorus. Human body lack of vitamin D3Sometimes, the calcium and phosphorus absorption is insufficient, the normal development of bones is influenced, bones are softened, and the chondropathy is finally caused, so that a proper amount of vitamin D is formed3Supplementation is vital to human health.
Vitamin D3It is not active per se, and it needs to be metabolized into its active form by the human body to function. Now known as active vitamin D3The derivatives mainly comprise the following 3 types: 1 alpha-hydroxy vitamin D3(1α-hydroxyvitamin D3) 25-hydroxy vitamin D3(25-hydroxyvitamin D3) And 1a, 25-dihydroxyvitamin D3(1α,25-dihydroxyvitamin D3). Wherein, 1 alpha, 25-dihydroxy vitamin D3Vitamin D believed to be the most active3And (3) derivatives. Normal human body can convert common vitamin D3Conversion to active D3However, some people with impaired visceral function need to take additional active vitamin D3The normal metabolism of calcium and phosphorus in human body can be guaranteed.
In recent years, vitamin D has been implicated3Have received a great deal of attention. The researchers found vitamin D3Besides the known effects of promoting calcium and phosphorus absorption and maintaining the balance of blood calcium and blood phosphorus, the derivative also has the pharmacological activities of increasing insulin secretion, inducing cell differentiation and immunity, treating and preventing cancers, obesity, hypertension and the like. The discovery of the new research will certainly promote the researchers to the vitamin D3The pharmacological activity and the synthetic method of the derivative are further studied.
Vitamin D3Has a complicated structure, and at present, vitamin D is synthesized industrially3The method is obtained by acylation, bromine adding, bromine removing, hydrolysis and illumination heating, but because the used reagent has high toxicity, high cost and is difficult to control, a plurality of problems need to be researched and solved. Some methods have the problems of more purification steps, complex operation, high cost, being not beneficial to industrial production and the like although the yield is improved. Therefore, there is a strong need in industry for vitamin D with simple operation, high yield and low cost3A production method.
The cholesterol is vitamin D3The most key raw material for production, but the source method of cholesterol is less, the yield of cholesterol obtained in biological method reports is too low, the fermentation condition is too difficult to control, and industrial production cannot be realized; the extraction of cholesterol from animal tissues is costly, environmentally unfriendly and unsuitable for sustainable development, so that a new vitamin D production is highly necessary3The method of (1).
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a method for improving the stability of a cableProduction of vitamin D from stigmasterol3The industrial new method of (1).
The technical scheme of the invention is as follows:
provides a vitamin D3The preparation method sequentially comprises the following 9 steps: (1) preparation of stigmasterol acetate (IX), (2) preparation of side chain oxide (VIII), (3) preparation of side chain isopentanizing reduction product (VII), (4) hydrogenation preparation of cholesterol acetate (VI), (5) oxidation preparation of 7-keto-cholesterol acetate (V), (6) hydrazonation synthesis of 7-p-toluenesulfonylhydrazone-cholesterol acetate (IV), (7) dehydrohydrazone preparation of 7-dehydrocholesterol acetate (III), (8) hydrolysis preparation of 7-dehydrocholesterol (II), (9) illumination synthesis of vitamin D3(I); the route is as follows:
in one embodiment, the step (1) comprises: dissolving raw material stigmasterol (X) in a reaction solvent with the weight of 10-20 times, and adding an acid-binding agent with the same molar weight as the stigmasterol and a catalyst with the weight of 1-5% of the stigmasterol; adding an esterification reagent with the molar weight of 1-2 times of stigmasterol in batches at the solvent reflux temperature, continuously refluxing until the raw materials are completely reacted, filtering to remove an acid-binding agent, recovering the solvent to dryness, and recrystallizing by using a crystallization solvent to obtain an acicular crystal compound IX;
the reaction solvent is selected from dichloromethane, n-hexane, cyclohexane, dichloroethane, petroleum ether, preferably n-hexane;
the acid-binding agent is selected from potassium carbonate, sodium bicarbonate and sodium carbonate, preferably potassium carbonate;
the catalyst is selected from pyridine, lutidine, DMAP, PPY and TMAJ, and pyridine is preferred;
the esterification reagent is selected from acetyl chloride and acetic anhydride, preferably acetic anhydride;
the crystallization solvent is selected from dichloromethane, n-hexane, cyclohexane, dichloroethane, petroleum ether, methanol, ethanol, preferably ethanol.
In one embodiment, the step (2) comprises: dissolving a compound IX in a reaction solvent of 40-60 times of weight, cooling the mixture to-70-30 ℃ in a cold tank, introducing mixed gas of oxygen and ozone for reaction, monitoring by TLC until the reaction of the raw materials is finished, introducing nitrogen, heating the reaction system to zero, dissolving thiourea of 1-2 times of the compound IX in the mixed solvent of 5-15 times of weight of the compound IX in the reaction system, adding the thiourea into the reaction system, heating the mixture to room temperature, and stirring for reaction for 10-20 hours; filtering off white precipitate, washing the precipitate with a proper amount of mixed solvent, merging the washing liquid into the filtrate, and carrying out reduced pressure concentration and crystallization on the filtrate to obtain a compound VIII; optionally, 200-300 mesh silica gel which is 0.5 time of the weight of the compound IX is added into the reaction system before the reaction, and after the reaction is finished, the compound IX and the white precipitate are filtered together to remove;
the reaction solvent is selected from ethanol or methanol, preferably ethanol;
the mixed solvent is selected from 80-95 wt% ethanol-water solution or 80-95 wt% methanol-water solution, preferably ethanol-water solution.
In one embodiment, the step (3) comprises: dissolving triphenylphosphine in 10-20 times of anhydrous solvent, and dissolving 1-bromoisopentane with equimolar amount in the anhydrous solvent with the same volume; under the protection of nitrogen, dropwise adding the solution into triphenylphosphine solution at low temperature while stirring; heating and stirring until reflux reaction; after the reaction is completed, cooling to room temperature, adding 1-2 times of strong base in molar weight, and continuously stirring; dissolving the compound VIII in an anhydrous solvent with the same weight, and dropwise adding the solution into the reaction system; refluxing again for reaction, and monitoring by TLC until the reaction of the raw materials is finished; cooling in ice water bath, and then dropwise adding acid water to adjust the pH value to be neutral; separating, concentrating the organic layer to dryness, and crystallizing to obtain a compound VII;
the anhydrous solvent is selected from toluene, xylene and dibutyl ether, and toluene is preferred;
the strong base is sodium tert-butoxide or potassium tert-butoxide, preferably sodium tert-butoxide;
the acid water is selected from the group consisting of aqueous hydrochloric acid, aqueous phosphoric acid, aqueous sulfuric acid, aqueous nitric acid, and preferably 10% aqueous phosphoric acid.
In one embodiment, the step (4) comprises: dissolving a compound VII in methanol 40-60 times of the weight of the compound VII, adding 1% palladium-carbon accounting for 5% of the weight of the compound VII into the solution, and adding ammonium formate accounting for 3-5 times of the weight of the compound VII and a catalytic amount of formic acid; after nitrogen replacement, carrying out reflux reaction until the reaction is complete; filtering to remove palladium carbon, and concentrating and crystallizing the organic layer to obtain a compound VI (cholesterol acetate).
In one embodiment, the step (5) comprises: dissolving 1 part by weight of cholesterol acetate (VI) in 7-13 parts by weight of dichloroethane, acetone or acetonitrile, and adding 0.5-1% by weight of a catalyst selected from copper powder, copper chloride, cuprous chloride, chromium trioxide, NHPI or benzoyl peroxide; then adding a phase transfer reagent with the equivalent number of 2-4 times that of cholesterol acetate (VI), wherein the phase transfer reagent is selected from tetrabutylammonium bromide, tetrabutylammonium chloride and benzyltriethylammonium chloride; adding 1-2 parts by weight of tert-butyl hydroperoxide while stirring at 45-50 ℃, and reacting for 8 hours at constant temperature; after the reaction, the reaction mixture was concentrated under reduced pressure, the residue was taken up in ice water and extracted with n-hexane, the organic phase was further washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 7-keto-cholesterol acetate (V).
In one embodiment, the step (6) comprises: dissolving 1 part by weight of 7-keto-cholesterol acetate (V) in 7-10 parts by weight of methanol, adding p-toluenesulfonyl hydrazide with the equivalent number of 1.2 times that of the 7-keto-cholesterol acetate (V) and 0.01-0.025 part by weight of concentrated hydrochloric acid, refluxing for 3 hours until the reaction is complete, filtering, washing a filter cake with methanol, and drying to obtain 7-p-toluenesulfonylhydrazone-cholesterol acetate (IV).
In one embodiment, the step (7) comprises: dissolving 1 part by weight of 7-p-toluenesulfonylhydrazone-cholesterol acetate (IV) in 8-10 parts by weight of toluene dried by anhydrous calcium chloride, adding 0.06-0.08 part by weight of lithium hydride, carrying out reflux reaction at 120 ℃ for 8 hours until the reaction is complete, filtering, concentrating the filtrate, dissolving the filtrate by using petroleum ether, filtering the dissolved solution by using a silica gel column, concentrating the filtrate to obtain a solid, and recrystallizing the solid in methanol, ethanol or butanol to obtain 7-dehydrocholesterol acetate (III).
In one embodiment, the step (8) comprises: dissolving 1 weight part of 7-dehydrocholesterol acetate (III) in 3-5 weight parts of methanol, adding potassium hydroxide or sodium hydroxide in an equivalent amount of 7-dehydrocholesterol acetate (III), and reacting at 50 ℃; after the reaction is finished, the pH value is adjusted to be neutral by acetic acid, solid is separated out, and the solid of the 7-dehydrocholesterol (II) is obtained by filtration.
In one embodiment, the step (9) comprises: dissolving 1 weight part of 7-dehydrocholesterol (II) in 130 weight parts of cyclohexane-methanol (volume ratio 10:1) mixed solution, and maintaining the dissolving temperature at 30-35 ℃; pumping the reaction stock solution into 20KW high-pressure mercury lamp photochemical reaction equipment by using a pump to carry out photochemical reaction, wherein the flow rate is 15-20L/min; collecting reaction solution, concentrating under reduced pressure and low temperature at 2-8 deg.C under nitrogen protection to 1/60-1/15 with original volume, standing at 2-8 deg.C for 24 hr to separate out 7-dehydrocholesterol raw material, filtering, repeatedly performing photochemical reaction on the filtered 7-dehydrocholesterol raw material, and concentrating the filtrate under reduced pressure to obtain vitamin D3And (5) producing the product.
The DMAP is the abbreviation of p-dimethylaminopyridine, the PPY is the abbreviation of 2-phenylpyridine, and the TMAJ is the abbreviation of 1,1,7, 7-tetramethyl-9-azaoxazolidine.
The vitamin D provided by the invention3The novel industrial production method has the following advantages:
(1) stigmasterol is used as a raw material, and the stigmasterol is widely existed in various plants, so that the stigmasterol is easier to obtain than the traditional cholesterol raw material, and a new route is provided for the industrial production of vitamin D3;
(2) the method has the advantages of mild reaction conditions, simple and convenient operation, high yield and strong industrial operability in each step, and is suitable for industrial production.
Detailed Description
The present invention is described in further detail with reference to the following examples, but the present invention is not limited thereto, and any equivalent replacement in the field made in accordance with the present disclosure is included in the scope of the present invention.
EXAMPLE 1 preparation of stigmasterol acetate (IX)
10Kg of stigmasterol was added to a 1000L enamel reactor, to which 200g of pyridine and 3.2Kg of powdered potassium carbonate were added. The enamel kettle was closed and 200L of n-hexane was vacuum sucked in. The stirring was started and the jacket was heated to an internal temperature of 60 ℃. 2.96Kg of acetic anhydride was added dropwise while maintaining the temperature. The reaction was continued for 3 hours while maintaining the temperature after the completion of the dropwise addition. After the reaction was complete as judged by thin layer chromatography. Filtering with stainless steel plate frame while hot, leaching the filter cake with 40L fresh n-hexane, mixing n-hexane solutions, and vacuum concentrating to dry to obtain white solid. Adding 100L ethanol into the white solid, refluxing and dissolving at 80 ℃ to be clear, cooling and crystallizing, and separating out 10.8Kg of white needle-shaped product compound IX, wherein the yield is 98%.
Example 2 preparation of side chain oxide (VIII)
Adding 10Kg of compound IX into 500L of ethanol, cooling to-50 ℃ by using a cold tank, introducing oxygen (containing 1% of ozone which is freshly prepared by an ozone machine) under the stirring condition, and oxidizing; tracking the thin layer until the oxidation is finished; replacing oxygen with nitrogen after the oxidation is finished; slowly heating the system to 0 ℃;
adding 2000g of thiourea into 20L of 90% ethanol water, dissolving and clearing, and slowly adding into an oxidation reaction system; slowly raising the temperature to room temperature and stirring for 16 hours; after the reaction is completed, filtering to remove the precipitate; the precipitate was washed with 2000ml of 90% ethanol water; mixing the filtrates, concentrating at 60 deg.C until the volume reaches 50L, and cooling for crystallization; the mixture was filtered to obtain 6.4Kg of a white solid compound VIII in a yield of 78%.
If 5Kg of silica gel (200-300 mesh) is additionally added into the reaction system before the reaction, 7.6Kg of the compound VIII can be prepared with the yield of 93% under the same conditions.
EXAMPLE 3 preparation of side chain Isovalerylated reductants (VII)
Adding 5.85Kg of triphenylphosphine into 120L of toluene to dissolve and clear; dissolving 3.39Kg of 1-bromoisopentane in 4.5L of toluene; under the protection of nitrogen, dropwise adding 1-bromoisopentane into a triphenylphosphine solution at room temperature while stirring; heating and stirring until reflux reaction; cooling to room temperature after the reaction is completed; adding 2.85Kg of sodium tert-butoxide, and continuously stirring;
5.58Kg of compound VIII is dissolved in 6L of toluene and is dripped into the reaction system; refluxing again for reaction, and monitoring by TLC until the reaction of the raw materials is finished; cooling in ice water bath, dripping 10% phosphoric acid water after cooling, and adjusting the pH value to be neutral; separating, concentrating the toluene layer to dryness, refluxing and dissolving with 75L methanol, naturally cooling and crystallizing to obtain 5.61Kg of compound VII with 88% yield.
EXAMPLE 4 hydrogenation to prepare Cholesterol acetate (VI)
Adding 5.0Kg of compound VII and 150L of methanol into a 100L reaction kettle, directly adding 250g of palladium carbon (the content of the palladium carbon is 1%), stirring uniformly, and adding 2.83Kg of ammonium formate and 25ml of formic acid; the system is protected by nitrogen, and reflux reaction is carried out until the reaction is complete; filtering to remove palladium carbon, leaching the palladium carbon with 2.5L of methanol, merging methanol liquid, concentrating to 25L, and cooling for crystallization; 5.0Kg of white needle-like compound VI was precipitated with a yield of 99.6%.
EXAMPLE 5 Oxidation preparation of 7-keto-cholesterol acetate (V)
Dissolving 5Kg of cholesterol acetate (VI) prepared in example 4 in 50L of dichloroethane, acetone or acetonitrile (weight 39-62 Kg), adding 38g of catalyst copper powder, copper chloride or chromium trioxide; adding 11Kg of phase transfer reagent tetrabutylammonium bromide, adding 6.75L (about 6.1Kg) of tert-butyl hydroperoxide while stirring at 45-50 ℃, and reacting at constant temperature for 8 hours; concentrating under reduced pressure after reaction, adding residue into 25L ice water, adding 25L n-hexane, filtering, separating several layers of filtrate, back extracting water layer with n-hexane 12.5L × 2, mixing organic phases, washing with saturated sodium chloride water solution 8L × 2, and drying with anhydrous sodium sulfate; filtering, decompressing and concentrating the filtrate to obtain 4.58 kg of 7-keto-cholesterol acetate (V) with the yield of 88.7 percent.
EXAMPLE 6 Hydrazone Synthesis of 7-p-toluenesulfonylhydrazone-cholesterol acetate (IV)
Dissolving 2.5Kg of 7-keto-cholesterol acetate (V) in 25L (about 19.8Kg) of methanol, adding p-toluenesulfonyl hydrazide in an amount 1.2 times the equivalent amount of 7-keto-cholesterol acetate (V), adding 50mL (about 59g) of concentrated hydrochloric acid, and refluxing at 65 deg.C for 3 hours until the reaction is complete, wherein the solution is changed from transparent to pasty; filtering, washing the filter cake with methanol, drying to no moisture and solvent to obtain 2.8Kg of 7-p-toluenesulfonylhydrazone-cholesterol acetate (IV) with 81% yield.
EXAMPLE 7 Dehydrazone preparation of 7-dehydrocholesterol acetate (III)
Dissolving 2.8Kg of 7-p-toluenesulfonylhydrazone-cholesterol acetate (IV) prepared in example 6 in 28L (24.25Kg) of toluene dried with anhydrous calcium chloride, dispersing 200g of lithium hydride in the dried toluene, adding to the reaction system, and refluxing at 120 ℃ for 8 hours until the reaction is complete; filtering to remove salts such as calcium chloride and the like, washing a filter cake with toluene, combining toluene liquid, concentrating under reduced pressure to obtain oily matter, dissolving the oily matter with petroleum ether, pumping into a silica gel column for filtering, concentrating the filtrate to obtain light yellow solid 2.0Kg, refluxing and dissolving the light yellow solid in 15L of methanol or ethanol or butanol, concentrating under reduced pressure to 10L, cooling, and separating out white-yellowish crystals 7-dehydrocholesterol acetate (III) 1.7Kg with the yield of 87%.
EXAMPLE 8 preparation of 7-dehydrocholesterol (II) by hydrolysis
1.7Kg (3.991eq) of 7-dehydrocholesterol acetate (III) obtained in example 7 was dissolved in 8L (about 6.3Kg) of methanol, and 3.991eq of potassium hydroxide or sodium hydroxide was added thereto to carry out a reaction at 50 ℃; after the reaction is finished, the pH value is adjusted to be neutral by acetic acid, solid is separated out, and 1.4Kg of 7-dehydrocholesterol (II) solid is obtained by filtration, with the yield of 91%.
EXAMPLE 9 Synthesis of vitamin D by light irradiation3(Ⅰ)
Dissolving 1.0Kg of 7-dehydrocholesterol (II) in 150L (about 117Kg) of cyclohexane-methanol (volume ratio of 10:1) mixed solution, and ensuring the dissolving temperature to be 30-35 ℃; pumping the reaction stock solution into 20KW high-pressure mercury lamp photochemical reaction equipment by using a pump, wherein the flow rate is 15-20L/min; collecting reaction liquid, concentrating at 2-8 deg.C under nitrogen protection under reduced pressure at low temperature to 50-200L, standing at 2-8 deg.C for 24 hr to separate out 7-dehydrocholesterol raw material, filtering at 2-8 deg.C, repeatedly performing photochemical reaction on the filtered 7-dehydrocholesterol raw material, and concentrating the filtrate under reduced pressure to obtain vitamin D30.3Kg of oil.