CN103044301A - Photochemical synthesis method of 25-hydroxy vitamin D3 - Google Patents

Photochemical synthesis method of 25-hydroxy vitamin D3 Download PDF

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CN103044301A
CN103044301A CN2011103150312A CN201110315031A CN103044301A CN 103044301 A CN103044301 A CN 103044301A CN 2011103150312 A CN2011103150312 A CN 2011103150312A CN 201110315031 A CN201110315031 A CN 201110315031A CN 103044301 A CN103044301 A CN 103044301A
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CN103044301B (en
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李嫕
陈金平
曾毅
李迎迎
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Technical Institute of Physics and Chemistry of CAS
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Abstract

The invention discloses a photochemical synthesis method of 25-hydroxy vitamin D3. The photochemical synthesis method comprises the following steps of: dissolving 25-hydroxy-7-dehydrocholesterol in a mixed solvent system containing a polar solvent and a non-polar solvent, and adding an antioxidant to react under the illumination; separating and recovering the 25-hydroxy-7-dehydrocholesterol after reacting; and heating to isomerize reactants retained after the 25-hydroxy-7-dehydrocholesterol is separated, and then freezing the isomerized reactants to recrystalize to obtain 25-hydroxy vitamin D3 crystals. The photochemical synthesis method disclosed by the invention has the main advantages that the conversion rate of 25-hydroxy-7-dehydrocholesterol open-loop under each time of illumination is below 40 percent through controlling the reactant concentration and the illumination time, and the 25-hydroxy vitamin D3 crystals with the purity of being more than 99 percent can be obtained without column chromatography isolation in the purifying process; and the photochemical synthesis method disclosed by the invention is simple in production process, improved in utilization efficiency of raw materials, saved in cost and suitable for large-scale production.

Description

Photochemistry is synthesized 25-hydroxy-vitamin D 3Method
Technical field
The present invention relates to utilize organic photochemistry method composite reactive vitamins D 3Technical field, be specifically related to the synthetic 25-hydroxy-vitamin D of photochemistry 3Method.
Background technology
Vitamins D (is called for short later on: VD) be the derivative of steroid, exist with 10 various ways at occurring in nature, wherein with vitamins D 3(be called for short later on: VD 3) the humans and animals body is had nutritional significance most.VD 3It is the humans and animals requisite liposoluble vitamin of growing, grow, breed, sustain life and keep fit, its major physiological effect is absorption and the sclerotin calcification that promotes calcium, phosphorus in the intestines, improve blood calcium and serium inorganic phosphorus concentration, regulate calcium, phosphorus metabolism and the balance of body.But studies show that vitamins D 3Not active in vivo, can not participate in the absorption of calcium phosphorus in the body directly, must in human or animal body, change into active physiological metabolism thing after, just can demonstrate its physiologically active.Vitamins D 3The effect of at first passing through the 25-hydroxylase after the absorption in liver transforms into 25-hydroxy-vitamin D 3, and then in kidney under the effect of 1 α-hydroxylase further hydroxylation become 1 α, the 25-dihydroxyvitamin D 3(such as figure below).1 α, the 25-dihydroxyvitamin D 3It is vitamins D 3Activity form, finally participate in Calcium and phosphorous absorption in the body, this be so far known to the strongest active VD 3Metabolite.
Figure BDA0000099409460000011
In recent years, along with vitamins D 3Synthetic method ripe and perfect gradually, its market requirement also tends to balance, and for activated vitamin D 3The market requirement more vigorous, 25-hydroxy-vitamin D 3It is a kind of very important activated vitamin D 3, no matter be as the pharmaceutical prod raw material, or animal feedstuff additive, all than VD 3More effective, have more using value and marketable value.25-hydroxy-vitamin D 3It is the preparation activated vitamin D 3Other series derivates, such as 1 α, the 25-dihydroxyvitamin D 3(the vitamins D of entirely living 3), the important source material of calcipotriol etc., simultaneously it also be one than usual vitamin D 3More excellent fodder additives.Studies show that 25-hydroxy-vitamin D 3Biological value be usual vitamin D 33～5 times, produce the aspect such as motility rate and all have good effect for improving edible animal meat quality and transformation efficiency and improving animal.Being widely used in the market CAS HyD 1.25% is exactly a kind of 25-hydroxy-vitamin D that contains 3Animal feedstuff additive, every annual sales amount reaches several hundred million yuans, has wide market outlook.U.S. DSM nutritional prod company limited is at 25-hydroxy-vitamin D 3Production on occupy monopoly position, and China does not also have the scale operation 25-hydroxy-vitamin D at present 3Enterprise, therefore realize the 25-hydroxy-vitamin D with high added value 3Industrialization have good economic benefit and social benefit.
25-hydroxy-vitamin D 3Synthetic method complete synthesizing process and semi-synthesis method are arranged usually, complete synthesizing process since synthesis step long, overall yield is lower, the reasons such as separation difficulty are not suitable for suitability for industrialized production.Semi-synthetic rule is by the precursor structure of natural steroid structure or VD is modified to prepare 25-hydroxy-vitamin D 3Method.The people such as Y.Mazur propose a kind of to VD 3The common method that 25 hydroxylations of side chain are modified prepares 25-hydroxy-vitamin D 3And analogue, but the method need to VD 3Skeleton carry out again the modification of side chain after rupturing, reactions steps is complicated, by product is many, and with VD 3For raw material prepares 25-hydroxy-vitamin D 3Cost is high, be not suitable for industrialization (J.Org.Chem.1979,44,3077-3080).The people such as R.H.Hesse and L.Castedo is respectively with vitamins D 2Or analogue is raw material, prepares 25-hydroxy-vitamin D by a series of thermal chemical reactions 3, overall yield is less than 10%, and the product separation difficulty, and raw materials cost and preparation cost are all very high, are difficult to realize industrialization (J.Org.Chem.1986,51,4819-4828; J.Org.Chem.1986,51,1272-1276).Although prepare vitamins D by photochemical method 3Existing a large amount of documents and Patents report, but utilize the method directly to prepare activated vitamin D 3, 25-hydroxy-vitamin D especially 3But have no report.Simultaneously; because many times order reaction can occur in photochemical reaction usually; selectivity of product is poor, product is difficult to control; have a great impact at the introducing of 25 hydroxyls amphipathic also tool to raw material and product molecule; thereby affect its solvability in different solvents with and the kinetics of photochemistry ring-opening reaction, this has also increased the research difficulty of synthetic method in some aspects.The inventor gropes reaction conditions, through the great many of experiments screening, has finally successfully determined directly to use photochemical reaction composite reactive vitamins D 3Processing condition.
Summary of the invention
The technical problem to be solved in the present invention provides the synthetic 25-hydroxy-vitamin D of a kind of photochemistry 3Method; The method is take 25-hydroxyl-7-DHC as raw material, and illumination one goes on foot the singlet state scission of link, and thermal isomerization is reacted and the acquisition 25-hydroxy-vitamin D 3, production process is simple, has especially greatly simplified the sepn process of product and system, has improved the utilising efficiency of raw material, is applicable to large-scale commercial production.
For solving the problems of the technologies described above, photochemistry of the present invention is synthesized 25-hydroxy-vitamin D 3Method, comprise the steps:
25-hydroxyl-7-DHC is dissolved in the mixed solvent system that comprises polar solvent and non-polar solvent, adds oxidation inhibitor, illumination is reacted;
Separation and Recovery 25-hydroxyl-7-DHC after the reaction;
Remaining reactant after separating 25-hydroxyl-7-DHC is added thermal isomerization, and the freezing recrystallization that carries out obtains 25-hydroxy-vitamin D again 3Crystal; Maybe will separate reactant remaining behind 25-hydroxyl-7-DHC and be dissolved in and add thermal isomerization in the treated oil, be cooled to again room temperature, make 25-hydroxy-vitamin D 3Finish.
Further, the synthetic 25-hydroxy-vitamin D of photochemistry of the present invention 3Method, comprise the steps:
1) illumination reaction of 25-hydroxyl-7-DHC
25-hydroxyl-7-DHC is dissolved in the mixed solvent system of polar solvent and non-polar solvent, the concentration of described 25-hydroxyl-7-DHC in mixed solvent system is 3～5wt%, add oxidation inhibitor, mix, get photochemical reaction liquid; Photochemical reaction liquid is poured in the photochemical reactor of protection of inert gas, utilized the lamp and high pressure mercury reaction system to react, make 25-hydroxyl-7-DHC generation photo cleavage reaction;
2) reclaim 25-hydroxyl-7-DHC
With step 1) illumination after the reaction solution desolventizing, in the remaining solid thing, add polar solvent, quantity of solvent with just fully the solubilizing reaction thing be as the criterion, through freezing, obtain suspension liquid; This suspension liquid is filtered, unreacted 25-hydroxyl-7-DHC is separated with reaction product; Filter residue is unreacted 25-hydroxyl-7-DHC;
3) thermal isomerization reaction preparation 25-hydroxyvitamin D3 crystallization or finish
With step 2) filtrate, under protection of inert gas, 60～70 ℃ of heated and stirred 3～5 hours, add the non-polar solvent of filtrate volume 1/5～1/2 behind the cool to room temperature, carry out at low temperatures recrystallization, obtain 25-hydroxy-vitamin D 3Xln; Perhaps with step 2) filtrate removes; obtain solid product; this solid product is dissolved in the treated oil; the weight ratio of described solid product and treated oil is 1: 8～10; under protection of inert gas, be heated to 60～70 ℃, and kept 3～5 hours, then drop to 25～35 ℃; and with nitrogen or argon gas-sealed, obtain limpid high-quality 25-hydroxy-vitamin D 3Finish.
Preferably, step 1) in, in the described mixed solvent system, polar solvent and non-polar solvent volume ratio are 9～4: 1.
Preferably, described polar solvent is selected from one or more in the following material: methyl alcohol, ethanol, propyl alcohol, Virahol.
Preferably, described non-polar solvent is selected from one or more in the following material: carbonatoms is less than or equal to eight alkane solvents or its mixture.
Preferably, described non-polar solvent is one or more in the following material: boiling point is 30～60 ℃ sherwood oil, sherwood oil, octane, normal heptane, normal hexane, hexanaphthene, pentamethylene, Skellysolve A, the iso-pentane that boiling point is 60～90 ℃.
Preferably, described step 1) in, the mol ratio of 25-hydroxyl-7-DHC and oxidation inhibitor is 500～2000: 1.
Preferably, the antioxidant described step 1) is 2,6-di-t-butyl-p-methyl phenol or 2,6-di-t-butyl-p methoxy phenol.
Preferably, described step 1) in, the temperature of control photochemical reaction liquid is carried out at ambient temperature.
Preferably, described step 1) in, described high voltage mercury lamp power is 500W, illumination reaction 15～30 minutes.
Preferably, described step 1) in, use the high performance liquid chromatography monitoring reaction course, the control feed stock conversion is 20～40%.Preferably, the control feed stock conversion is 30～39%.
Preferably, described step 2) in, described freezing referring to: freezing more than 3 hours under-15～-10 ℃ condition.
Preferably, described step 3) in, carry out at low temperatures recrystallization and refer to: under-10～-20 ℃ temperature, carry out recrystallization.
Preferably, each above step is all carried out under protection of inert gas.
Preferably, described rare gas element is nitrogen or argon gas.
Preferably, described treated oil is refining salad oil or refining peanut oil.
The present invention utilizes 25-hydroxyl-7-DHC photochemistry open loop to prepare the process of 25-hydroxyvitamin D3 referring to accompanying drawing 1.
The present invention by high-performance liquid chromatogram determination the dynamic experiment data of 25-hydroxyl-7-DHC photochemistry open loop (referring to accompanying drawing 2, liquid-phase condition: flow velocity 1ml/min, detect wavelength 254nm, moving phase: normal hexane/amylalcohol=97.5/2.5), experiment shows photochemical product 25-hydroxyl-Previtamin D 3Can further change into by product 25-hydroxyl-bright sterol and 25-hydroxyl-tachysterol under illumination, especially the ratio of two by products obviously increases in the situation of high conversion, and product increases ratio and not obvious.Therefore, the contriver finds that through great many of experiments the transformation efficiency of control 25-hydroxyl-7-DHC below 40%, can access the by product of relatively a high proportion of product and low ratio.
The present invention by 25-hydroxyl-7 dehydrocholesterol in ethanol molar extinction coefficient and differing temps under the absorption spectrum (referring to accompanying drawing 3) of saturated solution, measured its solubleness under differing temps, this dissolubility data is the prerequisite by Crystallization Separation raw material and product, 25-hydroxyl-7 dehydrocholesterol solubleness under the differing temps in ethanol is as follows: 15 ℃ (greater than 2wt%), 0 ℃ (greater than 2wt%),-5 ℃ (1.5wt%),-15 ℃ (0.84wt%) ,-20 ℃ (0.49wt%).Data show raw material in changes in solubility more than 0 ℃ and not obvious, all greater than 2wt% ,-10 ℃ of one next obvious reduction, therefore can pass through the recrystallization separate raw materials below-10 ℃.
The present invention has following beneficial effect:
The present invention adopts mixed solvent to improve the concentration of raw material, preferably control the transformation efficiency of 25-hydroxyl-7-DHC below 40% by light application time, utilize the solubleness effect to reclaim next time photochemical reaction raw material of unreacted 25-hydroxyl-7-DHC conduct, simplified the sepn process of product and system, greatly improved reactant concn, both guaranteed photochemically reactive quantity, productive rate is improved greatly, thereby the productive rate of 25-hydroxyvitamin D3 crystallization is brought up to more than 40%, the productive rate of 25-hydroxyvitamin D3 finish is brought up to more than 60%, and production process is very simple, improved the utilising efficiency of raw material, save production cost, be applicable to large-scale commercial production.
Description of drawings
Below in conjunction with accompanying drawing the specific embodiment of the present invention is described in further detail
Fig. 1, procedure synoptic diagram of the present invention;
The dynamic experiment of Fig. 2,25-hydroxyl-7-DHC photochemistry open loop;
Fig. 3,25-hydroxyl-7-DHC in ethanol molar absorptivity and the absorption spectrum under the differing temps;
Fig. 4, the reaction solution illumination liquid phase analysis figure after 10 minutes;
Fig. 5, reclaim raw material 25-HYDROXY CHOLESTEROL liquid phase analysis figure by recrystallization;
Fig. 6, crystallization are removed filtrate behind the raw material through liquid phase analysis figure.
Embodiment
Embodiment 1
Photochemistry is synthesized 25-hydroxy-vitamin D 3Method, comprise the steps:
1) illumination reaction of 25-hydroxyl-7 dehydrocholesterol
In 500 milliliters of round-bottomed flasks, with 10 gram 25-hydroxyl-7 dehydrocholesterols at room temperature be dissolved in 280 milliliters of ethanol/Skellysolve As (6: 1, V/V) in the mixed solvent, add 20 milligram 2,6-di-t-butyl-p methoxy phenol mixes, and is configured to photochemical reaction liquid; Reaction solution is inserted in the built-in optical chemical reactor of putting 500W high voltage mercury lamp and logical nitrogen well; Regulate flow and the condensate flow of nitrogen; Start mercury lamp, and timing; Whole photochemical reaction device places in the stink cupboard of lucifuge, and promotes photothermal dispersion with a small-sized fans, is no more than 25 ℃ with the temperature that guarantees photochemical reaction liquid, avoids generating too early 25-hydroxy-vitamin D 3With high performance liquid chromatography (HPLC) monitoring reaction (seeing accompanying drawing 4), reacted transformation efficiency about 37% 10 minutes;
2) reclaim 25-hydroxyl-7 dehydrocholesterol
After above-mentioned photochemical reaction finishes, reaction solution transferred to rotation dries desolventizing in 500 milliliters of round-bottomed flasks, in remaining solid substance, add about 50 milliliters of ethanol, and after the suitable heating for dissolving, cool to room temperature and insert-15 ℃ refrigerator and cooled and froze 8 hours; Freezing rear fast filtering reclaims 25-hydroxyl-7-DHC solid 6.3 grams, Liquid Detection substantially pure (seeing accompanying drawing 5);
3) crystallization and the finish of thermal isomerization reaction 25-hydroxyvitamin D3 processed
With step 2) filtrate by Liquid Detection, raw material is removed fully, component is mainly 25-hydroxyl Previtamin D 3And 25-hydroxy-vitamin D 3And a small amount of by product (seeing accompanying drawing 6); Filtrate is divided equally into two parts (every part about 21 milliliters), a copy of it reflux under nitrogen protection is concentrated into 10 milliliters after 4 hours, and add 5 milliliters of pentanes, place-20 ℃ refrigerator and cooled to freeze and carried out recrystallization in 8 hours, freezing rear fast filtering, obtain off-white color crystal 0.80 gram, crystallization yields is about 43% (transformation efficiency calculates by 37%); The concentrated evaporate to dryness of another part obtains solids, and this solids is dissolved in the refining salad oil of 10 grams, is heated to 65 ℃ and kept 4 hours under nitrogen protection, naturally cools to 35 ℃, uses nitrogen-sealed, obtains the 25-hydroxy-vitamin D of limpid high-quality 3Finish, about 63% (transformation efficiency calculates by 37%) of productive rate.
Embodiment 2
Photochemistry is synthesized 25-hydroxy-vitamin D 3Method, comprise the steps:
1) illumination reaction of 25-hydroxyl-7 dehydrocholesterol
In 500 milliliters of round-bottomed flasks, with 10 gram 25-hydroxyl-7 dehydrocholesterols at room temperature be dissolved in 280 milliliters of Virahol/octanes (9: 1, V/V) in the mixed solvent, add 20 milligram 2,6-di-t-butyl-p methoxy phenol mixes, and is configured to photochemical reaction liquid; Reaction solution inserted put the 500W high voltage mercury lamp well and in the built-in optical chemical reactor of logical nitrogen; Regulate flow and the condensate flow of nitrogen; Start mercury lamp, and timing; Whole photochemical reaction device places in the stink cupboard of lucifuge, and promotes photothermal dispersion with a small-sized fans, is no more than 25 ℃ with the temperature that guarantees photochemical reaction liquid, avoids generating too early 25-hydroxy-vitamin D 3With high performance liquid chromatography (HPLC) monitoring reaction, reacted transformation efficiency about 32% 10 minutes;
2) reclaim 25-hydroxyl-7 dehydrocholesterol
After above-mentioned photochemical reaction finishes, reaction solution is transferred to rotation drying desolventizing in 500 milliliters of round-bottomed flasks, in remaining solid substance, add about 50 milliliters of Virahols, and suitably after the heating for dissolving, cool to room temperature and insert-15 ℃ refrigerator and cooled and froze 10 hours; Freezing rear fast filtering, the 25-that is recycled hydroxyl-7-DHC solid 6.8 grams, Liquid Detection substantially pure;
3) crystallization and the finish of thermal isomerization reaction 25-hydroxyvitamin D3 processed
With step 2) filtrate by Liquid Detection, raw material is removed fully, component is mainly 25-hydroxyl Previtamin D 3And 25-hydroxy-vitamin D 3And a small amount of by product; Filtrate is divided equally into two parts (every part about 22 milliliters), a copy of it reflux under nitrogen protection is concentrated into 10 milliliters after 3 hours, and add 5 milliliters of octanes, place-20 ℃ refrigerator and cooled to freeze and carried out recrystallization in 8 hours, freezing rear fast filtering, obtain off-white color crystal 0.66 gram, crystallization yields is about 41% (transformation efficiency calculates by 32%); The concentrated evaporate to dryness of another part obtains solids, and this solids is dissolved in the refining peanut oil of 10 grams, is heated to 65 ℃ and kept 4 hours under nitrogen protection, cools to 35 ℃, uses nitrogen-sealed, obtains the 25-hydroxy-vitamin D of limpid high-quality 3Finish, about 62% (transformation efficiency calculates by 32%) of productive rate.
Embodiment 3
Photochemistry is synthesized 25-hydroxy-vitamin D 3Method, comprise the steps:
1) illumination reaction of 25-hydroxyl-7 dehydrocholesterol
In 500 milliliters of round-bottomed flasks, with 10 gram 25-hydroxyl-7 dehydrocholesterols at room temperature be dissolved in 280 ml methanol/normal hexane (4: 1, V/V) in the mixed solvent, add 20 milligram 2,6-di-t-butyl-p methoxy phenol mixes, and is configured to photochemical reaction liquid; Reaction solution inserted put the 500W high voltage mercury lamp well and in the built-in optical chemical reactor of logical nitrogen.Regulate flow and the condensate flow of nitrogen; Start mercury lamp, and timing; Whole photochemical reaction device places in the stink cupboard of lucifuge, and promotes photothermal dispersion with a small-sized fans, is no more than 25 ℃ with the temperature that guarantees photochemical reaction liquid, avoids generating too early 25-hydroxy-vitamin D 3With high performance liquid chromatography (HPLC) monitoring reaction, reacted feed stock conversion about 39% 10 minutes;
2) reclaim 25-hydroxyl-7 dehydrocholesterol
Above-mentioned photochemical reaction is transferred to desolventizing in 500 milliliters of round-bottomed flasks with reaction solution after finishing, and then adds about 50 ml methanol in remaining solid substance, and after the suitable heating for dissolving, cools to room temperature and insert-15 ℃ refrigerator and cooled to freeze 10 hours; Freezing rear fast filtering, the 25-that is recycled hydroxyl-7-DHC solid 6.1 grams, Liquid Detection substantially pure;
3) crystallization and the finish of thermal isomerization reaction 25-hydroxyvitamin D3 processed
With step 2) filtrate by Liquid Detection, raw material is removed fully, component is mainly 25-hydroxyl Previtamin D 3And 25-hydroxy-vitamin D 3And a small amount of by product; Filtrate is divided equally into two parts (every part about 22 milliliters), reflux is concentrated into 10 milliliters under a copy of it nitrogen protection after 3 hours, and add 5 ml n-hexanes, place-20 ℃ refrigerator and cooled to freeze and carried out recrystallization in 10 hours, freezing rear fast filtering, obtain off-white color crystal 0.84 gram, crystallization yields is about 43% (transformation efficiency calculates by 39%); The concentrated evaporate to dryness of another part obtains solids, and this solids is dissolved in the refining salad oil of 10 grams, is heated to 65 ℃ and kept 3 hours under the nitrogen protection, naturally cools to 35 ℃, uses nitrogen-sealed, obtains the 25-hydroxy-vitamin D of limpid high-quality 3Finish, about 65% (transformation efficiency calculates by 39%) of productive rate.
Embodiment 4
Photochemistry is synthesized 25-hydroxy-vitamin D 3Method, comprise the steps:
1) illumination reaction of 25-hydroxyl-7 dehydrocholesterol
In 500 milliliters of round-bottomed flasks, with 10 gram 25-hydroxyl-7 dehydrocholesterols at room temperature be dissolved in 280 milliliters of propyl alcohol/hexanaphthenes (7: 1, V/V) in the mixed solvent, add 20 milligram 2,6-di-t-butyl-p methoxy phenol mixes, and is configured to photochemical reaction liquid; Reaction solution inserted put the 500W high voltage mercury lamp well and in the built-in optical chemical reactor of logical nitrogen; Regulate flow and the condensate flow of nitrogen.Start mercury lamp, and timing; Whole photochemical reaction device places in the stink cupboard of lucifuge, and promotes photothermal dispersion with a small-sized fans, is no more than 25 ℃ with the temperature that guarantees photochemical reaction liquid, avoids generating too early 25-hydroxy-vitamin D 3With high performance liquid chromatography (HPLC) monitoring reaction, reacted feed stock conversion 24% 10 minutes;
2) reclaim 25-hydroxyl-7 dehydrocholesterol
Above-mentioned photochemical reaction is transferred to desolventizing in 500 milliliters of round-bottomed flasks with reaction solution after finishing, and then adds about 50 milliliters of propyl alcohol in the residue solid substance, and after the suitable heating for dissolving, cools to room temperature and insert-15 ℃ refrigerator and cooled to freeze 6 hours; Freezing rear fast filtering, the 25-that is recycled hydroxyl-7-DHC solid 7.6 grams, Liquid Detection substantially pure.
3) crystallization and the finish of thermal isomerization reaction 25-hydroxyvitamin D3 processed
With step 2) filtrate by Liquid Detection, raw material is removed fully, component is mainly 25-hydroxyl Previtamin D 3And 25-hydroxy-vitamin D 3And a small amount of by product; Filtrate is divided equally into two parts (every part about 22 milliliters), a copy of it reflux under nitrogen protection is concentrated into 10 milliliters after 3 hours, and add 5 milliliters of hexanaphthenes, place-20 ℃ refrigerator and cooled to freeze and carried out recrystallization in 10 hours, freezing rear fast filtering, obtain off-white color crystal 0.53 gram, crystallization yields is about 44% (transformation efficiency calculates by 24%); The concentrated evaporate to dryness of another part obtains solids, and this solids is dissolved in the refining peanut oil of 10 grams, is heated to 65 ℃ and kept 5 hours under nitrogen protection, naturally cools to 35 ℃, uses nitrogen-sealed, obtains the 25-hydroxy-vitamin D of limpid high-quality 3Finish, about 66% (transformation efficiency calculates by 24%) of productive rate.
Embodiment 5
Repeat embodiment 1, its difference only is that described polar solvent is the mixture of equal portions methyl alcohol and propyl alcohol; Described non-polar solvent is that boiling point is 30-60 ℃ sherwood oil.
Embodiment 6
Repeat embodiment 2, its difference only is that described polar solvent is the mixture of equal portions ethanol and Virahol; Described non-polar solvent is that boiling point is 60-90 ℃ sherwood oil.
Embodiment 7
Repeat embodiment 3, its difference only is that described polar solvent is the mixture of equal portions ethanol and Virahol; Described non-polar solvent is the pentamethylene of equal portions and the mixture of iso-pentane.
Embodiment 8
Repeat embodiment 4, its difference only is that described shielding gas is selected argon gas.
Embodiment 9
Repeat embodiment 1～4, its difference only is that described oxygenant is 2,6-di-t-butyl-p-methyl phenol.
Embodiment 10
Repeat embodiment 1～4, its difference only is, described step 3) in freeze-10 ℃ refrigerator and cooled and to carry out recrystallization in 10 hours.
Embodiment 11
Repeat embodiment 1～4, its difference only is, described step 3) in freeze-15 ℃ refrigerator and cooled and to carry out recrystallization in 8 hours.
Obviously, the above embodiment of the present invention only is for example of the present invention clearly is described, and is not to be restriction to embodiments of the present invention.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.Here can't give all embodiments exhaustive.Everyly belong to the row that apparent variation that technical scheme of the present invention extends out or change still are in protection scope of the present invention.

Claims (15)

1. photochemistry is synthesized 25-hydroxy-vitamin D 3Method, it is characterized in that, comprise the steps:
25-hydroxyl-7-DHC is dissolved in the mixed solvent system that comprises polar solvent and non-polar solvent, adds oxidation inhibitor, illumination is reacted;
Separation and Recovery 25-hydroxyl-7-DHC after the reaction;
Remaining reactant after separating 25-hydroxyl-7-DHC is added thermal isomerization, and the freezing recrystallization that carries out obtains 25-hydroxy-vitamin D again 3Crystal; Maybe will separate reactant remaining behind 25-hydroxyl-7-DHC and be dissolved in and add thermal isomerization in the treated oil, be cooled to again room temperature, make 25-hydroxy-vitamin D 3Finish.
2. synthesize as claimed in claim 1 25-hydroxy-vitamin D 3Method, it is characterized in that, comprise the steps:
1) illumination reaction of 25-hydroxyl-7-DHC
25-hydroxyl-7-DHC is dissolved in the mixed solvent system of polar solvent and non-polar solvent, the concentration of described 25-hydroxyl-7-DHC in mixed solvent system is 3～5wt%, add oxidation inhibitor, mix, get photochemical reaction liquid; Photochemical reaction liquid is poured in the photochemical reactor of protection of inert gas, utilized the lamp and high pressure mercury reaction system to react, make 25-hydroxyl-7-DHC generation photo cleavage reaction;
2) reclaim 25-hydroxyl-7-DHC
With step 1) reaction solution desolventizing after the illumination, in the residue solid substance, add polar solvent, quantity of solvent with just fully the solubilizing reaction thing be as the criterion, through freezing, obtain suspension liquid; This suspension liquid is filtered, unreacted 25-hydroxyl-7-DHC is separated with reaction product; Filter residue is unreacted 25-hydroxyl-7-DHC;
3) thermal isomerization reaction preparation 25-hydroxyvitamin D3 crystallization or finish
With step 2) filtrate, under protection of inert gas, 60～70 ℃ of heated and stirred 3～5 hours, add the non-polar solvent of filtrate volume 1/5～1/2 behind the cool to room temperature, carry out at low temperatures recrystallization, obtain 25-hydroxy-vitamin D 3Xln; Perhaps with step 2) filtrate is concentrated, obtains solid product, this solid product is dissolved in the treated oil; under protection of inert gas, be heated to 60～70 ℃, and kept 3～5 hours, then drop to 25～35 ℃; and with nitrogen or argon gas-sealed, obtain limpid high-quality 25-hydroxy-vitamin D 3Finish.
3. synthesize as claimed in claim 1 or 2 25-hydroxy-vitamin D 3Method, it is characterized in that: in the described mixed solvent system, the volume ratio of polar solvent and non-polar solvent is 9～4: 1.
4. synthesize as claimed in claim 1 or 2 25-hydroxy-vitamin D 3Method, it is characterized in that: described polar solvent is selected from one or more in the following material: methyl alcohol, ethanol, propyl alcohol, Virahol.
5. synthesize as claimed in claim 1 or 2 25-hydroxy-vitamin D 3Method, it is characterized in that: described non-polar solvent is selected from carbonatoms and is less than or equal to eight alkane solvents or its mixture; Preferably, described non-polar solvent is one or more in the following material: boiling point is 30-60 ℃ sherwood oil, sherwood oil, octane, normal heptane, normal hexane, hexanaphthene, pentamethylene, Skellysolve A, the iso-pentane that boiling point is 60-90 ℃.
6. synthesize as claimed in claim 1 or 2 25-hydroxy-vitamin D 3Method, it is characterized in that: in step 1) in, the mol ratio of described 25-hydroxyl-7-DHC and oxidation inhibitor is 500～2000: 1.
7. synthesize as claimed in claim 1 or 2 25-hydroxy-vitamin D 3Method, it is characterized in that: in step 1) in, described antioxidant is 2,6-di-t-butyl-p-methyl phenol or 2,6-di-t-butyl-p methoxy phenol.
8. synthesize as claimed in claim 1 or 2 25-hydroxy-vitamin D 3Method, it is characterized in that: in step 1) in, the temperature of control photochemical reaction liquid is carried out at ambient temperature.
9. synthesize as claimed in claim 1 or 2 25-hydroxy-vitamin D 3Method, it is characterized in that: in step 1) in, described high voltage mercury lamp power is 500W, illumination reaction 15～30 minutes.
10. synthesize as claimed in claim 1 or 2 25-hydroxy-vitamin D 3Method, it is characterized in that: in step 1) in, use the high performance liquid chromatography monitoring reaction course, control feed stock conversion be 20～40%; Preferably, the control feed stock conversion is 30～39%.
11. synthesize as claimed in claim 1 or 2 25-hydroxy-vitamin D 3Method, it is characterized in that: in step 2) in, described freezing referring to: freezing more than 3 hours under-15～-10 ℃ condition.
12. synthesize as claimed in claim 1 or 2 25-hydroxy-vitamin D 3Method, it is characterized in that: in step 3) in, the described recrystallization that carries out at low temperatures refers to: carry out recrystallization under-10～-20 ℃ temperature.
13. synthesize as claimed in claim 1 or 2 25-hydroxy-vitamin D 3Method, it is characterized in that: synthetic method the institute all under protection of inert gas, carry out in steps; Preferably, described rare gas element is nitrogen or argon gas.
14. synthesize as claimed in claim 1 or 2 25-hydroxy-vitamin D 3Method, it is characterized in that: in step 3) in, the weight ratio of described solid product and treated oil is 1: 8～10.
15. synthesize as claimed in claim 14 25-hydroxy-vitamin D 3Method, it is characterized in that: described treated oil is refining salad oil or refining peanut oil.
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CN106478479A (en) * 2016-08-31 2017-03-08 四川省玉鑫药业有限公司 A kind of vitamin D3Production technology
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CN115746075A (en) * 2022-10-14 2023-03-07 浙江新和成股份有限公司 Method for recovering and purifying 7-dehydrocholesterol in high-impurity-content photochemical reaction liquid in vitamin D3 production process

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CN105527364A (en) * 2015-08-26 2016-04-27 袁洪 Method for detecting 25-hydroxy-vitamin D through ultra-performance liquid chromatography-tandem mass spectrometry
CN108290921A (en) * 2015-11-30 2018-07-17 帝斯曼知识产权资产管理有限公司 The crystallization of 25- hydroxyls -7-DHC
CN108290921B (en) * 2015-11-30 2021-04-23 帝斯曼知识产权资产管理有限公司 Crystallization of 25-hydroxy-7-dehydrocholesterol
CN106478479A (en) * 2016-08-31 2017-03-08 四川省玉鑫药业有限公司 A kind of vitamin D3Production technology
CN106478479B (en) * 2016-08-31 2018-08-07 四川省玉鑫药业有限公司 A kind of vitamin D3Production technology
CN109081796A (en) * 2018-09-06 2018-12-25 山东清创化工有限公司 Photochemical syntheses vitamin D in a kind of tubular reactor2、D3Method
CN110885354A (en) * 2019-11-14 2020-03-17 浙江新和成股份有限公司 Preparation method of 7-ketone-cholesterol acetate
CN110885354B (en) * 2019-11-14 2021-04-02 浙江新和成股份有限公司 Preparation method of 7-ketone-cholesterol acetate
CN112979738A (en) * 2021-03-02 2021-06-18 浙江新和成股份有限公司 Crystallization purification method of 7-dehydrocholesterol and application thereof in VD3 production
CN112979738B (en) * 2021-03-02 2022-04-05 浙江新和成股份有限公司 Crystallization purification method of 7-dehydrocholesterol and application thereof in VD3 production
CN115746075A (en) * 2022-10-14 2023-03-07 浙江新和成股份有限公司 Method for recovering and purifying 7-dehydrocholesterol in high-impurity-content photochemical reaction liquid in vitamin D3 production process

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