CN103044301B - Photochemical synthesis method of 25-hydroxy vitamin D3 - Google Patents

Photochemical synthesis method of 25-hydroxy vitamin D3 Download PDF

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CN103044301B
CN103044301B CN201110315031.2A CN201110315031A CN103044301B CN 103044301 B CN103044301 B CN 103044301B CN 201110315031 A CN201110315031 A CN 201110315031A CN 103044301 B CN103044301 B CN 103044301B
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CN103044301A (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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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: VD) be the derivative of steroid, at occurring in nature, with 10 various ways, exist, wherein with vitamins D later 3(be called for short: VD later 3) humans and animals body is had to 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 intestines, improve blood calcium and serium inorganic phosphorus concentration, regulate calcium, phosphorus metabolism and the balance of body.But research shows, vitamins D 3not active in vivo, can not participate in the absorption of calcium phosphorus in body directly, must in human or animal body, change into after active physiological metabolism thing, just can demonstrate its physiologically active.Vitamins D 3after absorption, first in liver, the effect through 25-hydroxylase transforms into 25-hydroxy-vitamin D 3, and then in kidney under the effect of 1 α-hydroxylase further hydroxylation become 1 α, 25-dihydroxyvitamin D 3(as figure below).1 α, 25-dihydroxyvitamin D 3it is vitamins D 3activity form, finally participate in Calcium and phosphorous absorption in body, this be so far known to the strongest active VD 3metabolite.
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 pharmaceutical prod raw material, or animal feedstuff additive, all than VD 3more effective, have more using value and marketable value.25-hydroxy-vitamin D 3to prepare activated vitamin D 3other series derivates, as 1 α, 25-dihydroxyvitamin D 3(the vitamins D of entirely living 3), the important source material of calcipotriol etc., simultaneously it be also one than usual vitamin D 3more excellent fodder additives.Research shows 25-hydroxy-vitamin D 3biological value be usual vitamin D 33~5 times, for improving the quality of edible animal meat and transformation efficiency and improving animal, be produced into the aspects such as motility rate and all there is good effect.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 scale operation 25-hydroxy-vitamin D at present 3enterprise, therefore realize the 25-hydroxy-vitamin D with high added value 3industrialization there is good economic benefit and social benefit.
25-hydroxy-vitamin D 3synthetic method conventionally have complete synthesizing process and semi-synthesis method, complete synthesizing process is because the reasons such as synthesis step is long, and overall yield is lower, 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 is prepared 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 is prepared 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, by a series of thermal chemical reactions, prepare 25-hydroxy-vitamin D 3, overall yield is less than 10%, and 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 photochemical reaction conventionally many times order reaction can occur; selectivity of product is poor, product is difficult to control; introducing at 25 hydroxyls has a great impact the amphipathic also tool of 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 great many of experiments screening, has finally successfully determined and can directly use photochemical reaction composite reactive vitamins D 3processing condition.
Summary of the invention
The technical problem to be solved in the present invention is to provide the synthetic 25-hydroxy-vitamin D of a kind of photochemistry 3method; The method be take 25-hydroxyl-7-DHC as raw material, illumination one step singlet state scission of link, and thermal isomerization is reacted and 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 reaction;
Remaining reactant after separated 25-hydroxyl-7-DHC is added to thermal isomerization, the more freezing recrystallization that carries out, 25-hydroxy-vitamin D obtained 3crystal; Or remaining reactant after separated 25-hydroxyl-7-DHC is dissolved in and in treated oil, adds thermal isomerization, then be cooled to 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, be uniformly mixed, obtain photochemical reaction liquid; Photochemical reaction liquid is poured in the photochemical reactor of protection of inert gas, utilized lamp and high pressure mercury reaction system to react, make 25-hydroxyl-7-DHC generation photo cleavage reaction;
2) reclaim 25-hydroxyl-7-DHC
By step 1) illumination after reaction solution except desolventizing, toward remaining solid thing in, add polar solvent, quantity of solvent is as the criterion with complete solubilizing reaction thing just, through freezing, obtains suspension liquid; This suspension liquid is filtered, make unreacted 25-hydroxyl-7-DHC separated with reaction product; Filter residue is unreacted 25-hydroxyl-7-DHC;
3) 25-hydroxyvitamin D3 crystallization or finish are prepared in thermal isomerization reaction
By step 2) filtrate, under protection of inert gas, 60~70 ℃ of heated and stirred 3~5 hours, after cool to room temperature, add the non-polar solvent of filtrate volume 1/5~1/2, carry out at low temperatures recrystallization, obtain 25-hydroxy-vitamin D 3xln; Or by step 2) filtrate removes; obtain solid product; this solid product is dissolved in 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 keep 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 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 following material: methyl alcohol, ethanol, propyl alcohol, Virahol.
Preferably, described non-polar solvent is selected from one or more in 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 following material: boiling point is the sherwood oil of 30~60 ℃, 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, control the temperature of photochemical reaction liquid and carry 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 high performance liquid chromatography monitoring reaction course, controlling feed stock conversion is 20~40%.Preferably, controlling feed stock conversion is 30~39%.
Preferably, described step 2) in, described freezing referring to: freezing more than 3 hours under the condition of-15~-10 ℃.
Preferably, described step 3) in, carry out at low temperatures recrystallization and refer to: at the temperature of-10~-20 ℃, 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 process that the open loop of 25-hydroxyl-7-DHC photochemistry prepares 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 3under illumination, can further change into by product 25-hydroxyl-bright sterol and 25-hydroxyl-tachysterol, especially the in the situation that of high conversion, the ratio of two by products obviously increases, and product increases ratio not obvious.Therefore, contriver, through great many of experiments, finds that the transformation efficiency of controlling 25-hydroxyl-7-DHC, below 40%, can access the by product of relatively a high proportion of product and lower ratio.
The present invention is by the absorption spectrum (referring to accompanying drawing 3) of saturated solution under the molar extinction coefficient of 25-hydroxyl-7 dehydrocholesterol in ethanol and differing temps, measured its solubleness under differing temps, this dissolubility data is by the prerequisite of Crystallization Separation raw material and product, dehydrocholesterol solubleness under differing temps in ethanol in 25-hydroxyl-7 is as follows: 15 ℃ (being greater than 2wt%), 0 ℃ (being greater than 2wt%),-5 ℃ (1.5wt%),-15 ℃ (0.84wt%) ,-20 ℃ (0.49wt%).Data show that raw material, in more than 0 ℃ changes in solubility not obvious, is all greater than 2wt% ,-10 ℃ of one next obvious reduction, and therefore can be following by recrystallization separate raw materials at-10 ℃.
The present invention has following beneficial effect:
The present invention adopts mixed solvent to improve the concentration of raw material, the transformation efficiency of preferably controlling 25-hydroxyl-7-DHC by light application time is below 40%, utilize solubleness effect to reclaim unreacted 25-hydroxyl-7-DHC as photochemical reaction raw material next time, simplified the sepn process of product and system, greatly improved reactant concn, both guaranteed photochemically reactive quantity, can make again productive rate greatly improve, 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, saved production cost, be applicable to large-scale commercial production.
Accompanying drawing explanation
Below in conjunction with accompanying drawing, the specific embodiment of the present invention is described in further detail
Fig. 1, procedure schematic diagram of the present invention;
The dynamic experiment of Fig. 2,25-hydroxyl-7-DHC photochemistry open loop;
Molar absorptivity in ethanol of Fig. 3,25-hydroxyl-7-DHC and the absorption spectrum under differing temps;
Fig. 4, the reaction solution illumination liquid phase analysis figure after 10 minutes;
Fig. 5, by recrystallization, reclaim raw material 25-HYDROXY CHOLESTEROL liquid phase analysis figure;
Fig. 6, crystallization are removed filtrate after 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, by 10 grams of 25-hydroxyl-7 dehydrocholesterols be at room temperature dissolved in 280 milliliters of ethanol/Skellysolve As (6: 1, V/V) in 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 logical nitrogen well; Regulate flow and the condensate flow of nitrogen; Start mercury lamp, and timing; Whole photochemical reaction device is placed in the stink cupboard of lucifuge, and promotes photothermal dispersion with a small-sized fans, to guarantee that the temperature of photochemical reaction liquid is no more than 25 ℃, avoids generating too early 25-hydroxy-vitamin D 3; With high performance liquid chromatography (HPLC) monitoring reaction (seeing accompanying drawing 4), react transformation efficiency approximately 37% 10 minutes;
2) reclaim 25-hydroxyl-7 dehydrocholesterol
After above-mentioned photochemical reaction finishes, reaction solution is transferred in 500 milliliters of round-bottomed flasks to rotation and dry except desolventizing, toward remaining solid substance in, add approximately 50 milliliters of ethanol, and after suitable heating for dissolving, cool to room temperature and insert the refrigerator and cooled of-15 ℃ and freeze 8 hours; Freezing rear fast filtering, reclaims 6.3 grams of 25-hydroxyl-7-DHC solids, Liquid Detection substantially pure (seeing accompanying drawing 5);
3) crystallization and the finish of thermal isomerization reaction 25-hydroxyvitamin D3 processed
By step 2) filtrate by Liquid Detection, raw material is removed completely, 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 (approximately 21 milliliters every part), a copy of it reflux under nitrogen protection is concentrated into 10 milliliters after 4 hours, and add 5 milliliters of pentanes, being placed in the refrigerator and cooled of-20 ℃ freezes and within 8 hours, carries out recrystallization, freezing rear fast filtering, obtain 0.80 gram, off-white color crystal, crystallization yields is about 43% (transformation efficiency calculates by 37%); Another part of concentrated evaporate to dryness, obtains solids, and this solids is dissolved in 10 grams of refining salad oils, is heated to 65 ℃ and keep 4 hours under nitrogen protection, naturally cools to 35 ℃, with nitrogen-sealed, obtains the 25-hydroxy-vitamin D of limpid high-quality 3finish, productive rate approximately 63% (transformation efficiency calculates by 37%).
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, by 10 grams of 25-hydroxyl-7 dehydrocholesterols be at room temperature dissolved in 280 milliliters of Virahol/octanes (9: 1, V/V) in 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 and put 500W high voltage mercury lamp well and lead in the built-in optical chemical reactor of nitrogen; Regulate flow and the condensate flow of nitrogen; Start mercury lamp, and timing; Whole photochemical reaction device is placed in the stink cupboard of lucifuge, and promotes photothermal dispersion with a small-sized fans, to guarantee that the temperature of photochemical reaction liquid is no more than 25 ℃, avoids generating too early 25-hydroxy-vitamin D 3; With high performance liquid chromatography (HPLC) monitoring reaction, react transformation efficiency approximately 32% 10 minutes;
2) reclaim 25-hydroxyl-7 dehydrocholesterol
After above-mentioned photochemical reaction finishes, reaction solution is transferred to rotation in 500 milliliters of round-bottomed flasks to be dried except desolventizing, in remaining solid substance, add approximately 50 milliliters of Virahols, and suitably after heating for dissolving, cool to room temperature and insert the refrigerator and cooled of-15 ℃ and freeze 10 hours; Freezing rear fast filtering, 6.8 grams of the 25-being recycled hydroxyl-7-DHC solids, Liquid Detection substantially pure;
3) crystallization and the finish of thermal isomerization reaction 25-hydroxyvitamin D3 processed
By step 2) filtrate by Liquid Detection, raw material is removed completely, 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 (approximately 22 milliliters every part), a copy of it reflux under nitrogen protection is concentrated into 10 milliliters after 3 hours, and add 5 milliliters of octanes, being placed in the refrigerator and cooled of-20 ℃ freezes and within 8 hours, carries out recrystallization, freezing rear fast filtering, obtain 0.66 gram, off-white color crystal, crystallization yields is about 41% (transformation efficiency calculates by 32%); Another part of concentrated evaporate to dryness, obtains solids, and this solids is dissolved in 10 grams of refining peanut oil, is heated to 65 ℃ and keep 4 hours under nitrogen protection, cools to 35 ℃, with nitrogen-sealed, obtains the 25-hydroxy-vitamin D of limpid high-quality 3finish, productive rate approximately 62% (transformation efficiency calculates by 32%).
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, by 10 grams of 25-hydroxyl-7 dehydrocholesterols be at room temperature dissolved in 280 ml methanol/normal hexane (4: 1, V/V) in 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 and put 500W high voltage mercury lamp well and lead in the built-in optical chemical reactor of nitrogen.Regulate flow and the condensate flow of nitrogen; Start mercury lamp, and timing; Whole photochemical reaction device is placed in the stink cupboard of lucifuge, and promotes photothermal dispersion with a small-sized fans, to guarantee that the temperature of photochemical reaction liquid is no more than 25 ℃, avoids generating too early 25-hydroxy-vitamin D 3; With high performance liquid chromatography (HPLC) monitoring reaction, react feed stock conversion approximately 39% 10 minutes;
2) reclaim 25-hydroxyl-7 dehydrocholesterol
After above-mentioned photochemical reaction finishes, reaction solution is transferred in 500 milliliters of round-bottomed flasks except desolventizing, then toward remaining solid substance in, added approximately 50 ml methanol, and after suitable heating for dissolving, cool to room temperature and insert the refrigerator and cooled of-15 ℃ and freeze 10 hours; Freezing rear fast filtering, 6.1 grams of the 25-being recycled hydroxyl-7-DHC solids, Liquid Detection substantially pure;
3) crystallization and the finish of thermal isomerization reaction 25-hydroxyvitamin D3 processed
By step 2) filtrate by Liquid Detection, raw material is removed completely, 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 (approximately 22 milliliters every part), under a copy of it nitrogen protection, reflux is concentrated into 10 milliliters after 3 hours, and add 5 ml n-hexanes, being placed in the refrigerator and cooled of-20 ℃ freezes and within 10 hours, carries out recrystallization, freezing rear fast filtering, obtain 0.84 gram, off-white color crystal, crystallization yields is about 43% (transformation efficiency calculates by 39%); Another part of concentrated evaporate to dryness, obtains solids, and this solids is dissolved in to 10 grams of refining salad oils, is heated to 65 ℃ and keep 3 hours under nitrogen protection, naturally cools to 35 ℃, with nitrogen-sealed, obtains the 25-hydroxy-vitamin D of limpid high-quality 3finish, productive rate approximately 65% (transformation efficiency calculates by 39%).
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, by 10 grams of 25-hydroxyl-7 dehydrocholesterols be at room temperature dissolved in 280 milliliters of propyl alcohol/hexanaphthenes (7: 1, V/V) in 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 and put 500W high voltage mercury lamp well and lead in the built-in optical chemical reactor of nitrogen; Regulate flow and the condensate flow of nitrogen.Start mercury lamp, and timing; Whole photochemical reaction device is placed in the stink cupboard of lucifuge, and promotes photothermal dispersion with a small-sized fans, to guarantee that the temperature of photochemical reaction liquid is no more than 25 ℃, avoids generating too early 25-hydroxy-vitamin D 3; With high performance liquid chromatography (HPLC) monitoring reaction, react feed stock conversion 24% 10 minutes;
2) reclaim 25-hydroxyl-7 dehydrocholesterol
After above-mentioned photochemical reaction finishes, reaction solution is transferred in 500 milliliters of round-bottomed flasks except desolventizing, then in residue solid substance, added approximately 50 milliliters of propyl alcohol, and after suitable heating for dissolving, cool to room temperature and insert the refrigerator and cooled of-15 ℃ and freeze 6 hours; Freezing rear fast filtering, 7.6 grams of the 25-being recycled hydroxyl-7-DHC solids, Liquid Detection substantially pure.
3) crystallization and the finish of thermal isomerization reaction 25-hydroxyvitamin D3 processed
By step 2) filtrate by Liquid Detection, raw material is removed completely, 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 (approximately 22 milliliters every part), a copy of it reflux under nitrogen protection is concentrated into 10 milliliters after 3 hours, and add 5 milliliters of hexanaphthenes, being placed in the refrigerator and cooled of-20 ℃ freezes and within 10 hours, carries out recrystallization, freezing rear fast filtering, obtain 0.53 gram, off-white color crystal, crystallization yields is about 44% (transformation efficiency calculates by 24%); Another part of concentrated evaporate to dryness, obtains solids, and this solids is dissolved in to 10 grams of refining peanut oil, is heated to 65 ℃ and keep 5 hours under nitrogen protection, naturally cools to 35 ℃, with nitrogen-sealed, obtains the 25-hydroxy-vitamin D of limpid high-quality 3finish, productive rate approximately 66% (transformation efficiency calculates by 24%).
Embodiment 5
Repeat embodiment 1, its difference is only, described polar solvent is the mixture of equal portions methyl alcohol and propyl alcohol; Described non-polar solvent is that boiling point is the sherwood oil of 30-60 ℃.
Embodiment 6
Repeat embodiment 2, its difference is only, described polar solvent is the mixture of equal portions ethanol and Virahol; Described non-polar solvent is that boiling point is the sherwood oil of 60-90 ℃.
Embodiment 7
Repeat embodiment 3, its difference is only, 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 is only, described shielding gas is selected argon gas.
Embodiment 9
Repeat embodiment 1~4, its difference is only, described oxygenant is 2,6-di-t-butyl-p-methyl phenol.
Embodiment 10
Repeat embodiment 1~4, its difference is only, described step 3) in the refrigerator and cooled of-10 ℃, freeze and within 10 hours, carry out recrystallization.
Embodiment 11
Repeat embodiment 1~4, its difference is only, described step 3) in the refrigerator and cooled of-15 ℃, freeze and within 8 hours, carry out recrystallization.
Obviously, the above embodiment of the present invention is only for example of the present invention is clearly described, and is not the 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 cannot give all embodiments exhaustive.Every still row in protection scope of the present invention of apparent variation that technical scheme of the present invention extends out or change that belong to.

Claims (16)

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, wherein, the volume ratio of polar solvent and non-polar solvent is 9~4:1, adds oxidation inhibitor, and illumination is reacted; Use high performance liquid chromatography monitoring reaction course, controlling feed stock conversion is 32~39%;
Separation and Recovery 25-hydroxyl-7-DHC after reaction;
Remaining reactant after separated 25-hydroxyl-7-DHC is added to thermal isomerization, the more freezing recrystallization that carries out, 25-hydroxy-vitamin D obtained 3crystal; Or remaining reactant after separated 25-hydroxyl-7-DHC is dissolved in and in treated oil, adds thermal isomerization, then be cooled to 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, be uniformly mixed, obtain photochemical reaction liquid; Photochemical reaction liquid is poured in the photochemical reactor of protection of inert gas, utilized lamp and high pressure mercury reaction system to react, make 25-hydroxyl-7-DHC generation photo cleavage reaction; Use high performance liquid chromatography monitoring reaction course, controlling feed stock conversion is 32~39%;
2) reclaim 25-hydroxyl-7-DHC
By step 1) reaction solution after illumination is except desolventizing, in residue solid substance, adds polar solvent, and quantity of solvent is as the criterion with complete solubilizing reaction thing just, through freezing, obtains suspension liquid; This suspension liquid is filtered, make unreacted 25-hydroxyl-7-DHC separated with reaction product; Filter residue is unreacted 25-hydroxyl-7-DHC;
3) 25-hydroxyvitamin D3 crystallization or finish are prepared in thermal isomerization reaction
By step 2) filtrate, under protection of inert gas, 60~70 ℃ of heated and stirred 3~5 hours, after cool to room temperature, add the non-polar solvent of filtrate volume 1/5~1/2, carry out at low temperatures recrystallization, obtain 25-hydroxy-vitamin D 3xln; Or by step 2) filtrate is concentrated, obtains solid product, this solid product is dissolved in treated oil; under protection of inert gas, be heated to 60~70 ℃, and keep 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: described polar solvent is selected from one or more in following material: methyl alcohol, ethanol, propyl alcohol, Virahol.
4. synthesize as claimed in claim 1 or 2 25-hydroxy-vitamin D 3method, it is characterized in that: described non-polar solvent is one or more in following material: boiling point is the sherwood oil of 30-60 ℃, sherwood oil, octane, normal heptane, normal hexane, hexanaphthene, pentamethylene, Skellysolve A, the iso-pentane that boiling point is 60-90 ℃.
5. 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.
6. 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.
7. synthesize as claimed in claim 1 or 2 25-hydroxy-vitamin D 3method, it is characterized in that: in step 1) in, control the temperature of photochemical reaction liquid and carry out at ambient temperature.
8. 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.
9. 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 the condition of-15~-10 ℃.
10. 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: at the temperature of-10~-20 ℃, carry out recrystallization.
11. synthesize 25-hydroxy-vitamin D as claimed in claim 1 or 2 3method, it is characterized in that: synthetic method institute all under protection of inert gas, carry out in steps; Described rare gas element is nitrogen or argon gas.
12. synthesize 25-hydroxy-vitamin D as claimed in claim 1 or 2 3method, it is characterized in that: in step 3) in, the weight ratio of described solid product and treated oil is 1:8~10.
13. synthesize 25-hydroxy-vitamin D as claimed in claim 14 3method, it is characterized in that: described treated oil is refining salad oil or refining peanut oil.
14. synthesize 25-hydroxy-vitamin D as claimed in claim 1 3method, it is characterized in that: concrete steps are as follows:
1) illumination reaction of 25-hydroxyl-7 dehydrocholesterol
In 500 milliliters of round-bottomed flasks, 10 grams of 25-hydroxyl-7 dehydrocholesterols are at room temperature dissolved in to 280 ml volumes than in the Methanol/hexane mixed solvent for 4:1, add 20 milligram 2,6-di-t-butyl-p methoxy phenol, mix, be configured to photochemical reaction liquid; Reaction solution is inserted and put 500W high voltage mercury lamp well and lead in the built-in optical chemical reactor of nitrogen; Regulate flow and the condensate flow of nitrogen; Start mercury lamp, and timing; Whole photochemical reaction device is placed in the stink cupboard of lucifuge, and promotes photothermal dispersion with a small-sized fans, to guarantee that the temperature of photochemical reaction liquid is no more than 25 ℃, avoids generating too early 25-hydroxy-vitamin D 3; With high-efficient liquid phase chromatogram HPLC monitoring reaction, react feed stock conversion 39% 10 minutes;
2) reclaim 25-hydroxyl-7 dehydrocholesterol
After above-mentioned photochemical reaction finishes, reaction solution is transferred in 500 milliliters of round-bottomed flasks except desolventizing, then toward remaining solid substance in, added 50 ml methanol, and after suitable heating for dissolving, cool to room temperature and insert the refrigerator and cooled of-15 ℃ and freeze 10 hours; Freezing rear fast filtering, 6.1 grams of the 25-being recycled hydroxyl-7-DHC solids, Liquid Detection substantially pure;
3) crystallization and the finish of thermal isomerization reaction 25-hydroxyvitamin D3 processed
By step 2) filtrate by Liquid Detection, raw material is removed completely, 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, and 22 milliliters every part, under a copy of it nitrogen protection, reflux is concentrated into 10 milliliters after 3 hours, and add 5 ml n-hexanes, be placed in the refrigerator and cooled of-20 ℃ and freeze and within 10 hours, carry out recrystallization, freezing rear fast filtering, obtains 0.84 gram, off-white color crystal; Another part of concentrated evaporate to dryness, obtains solids, and this solids is dissolved in to 10 grams of refining salad oils, is heated to 65 ℃ and keep 3 hours under nitrogen protection, naturally cools to 35 ℃, with nitrogen-sealed, obtains the 25-hydroxy-vitamin D of limpid high-quality 3finish.
15. synthesize 25-hydroxy-vitamin D as claimed in claim 1 3method, it is characterized in that: concrete steps are as follows:
1) illumination reaction of 25-hydroxyl-7 dehydrocholesterol
In 500 milliliters of round-bottomed flasks, 10 grams of 25-hydroxyl-7 dehydrocholesterols are at room temperature dissolved in to 280 ml volumes than in 9:1 Virahol/octane mixed solvent, add 20 milligram 2,6-di-t-butyl-p methoxy phenol, mix, be configured to photochemical reaction liquid; Reaction solution is inserted and put 500W high voltage mercury lamp well and lead in the built-in optical chemical reactor of nitrogen; Regulate flow and the condensate flow of nitrogen; Start mercury lamp, and timing; Whole photochemical reaction device is placed in the stink cupboard of lucifuge, and promotes photothermal dispersion with a small-sized fans, to guarantee that the temperature of photochemical reaction liquid is no more than 25 ℃, avoids generating too early 25-hydroxy-vitamin D 3; With high-efficient liquid phase chromatogram HPLC monitoring reaction, react transformation efficiency 32% 10 minutes;
2) reclaim 25-hydroxyl-7 dehydrocholesterol
After above-mentioned photochemical reaction finishes, reaction solution is transferred to rotation in 500 milliliters of round-bottomed flasks to be dried except desolventizing, in remaining solid substance, add approximately 50 milliliters of Virahols, and suitably after heating for dissolving, cool to room temperature and insert the refrigerator and cooled of-15 ℃ and freeze 10 hours; Freezing rear fast filtering, 6.8 grams of the 25-being recycled hydroxyl-7-DHC solids, Liquid Detection substantially pure;
3) crystallization and the finish of thermal isomerization reaction 25-hydroxyvitamin D3 processed
By step 2) filtrate by Liquid Detection, raw material is removed completely, 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, and 22 milliliters every part, a copy of it reflux under nitrogen protection is concentrated into 10 milliliters after 3 hours, and add 5 milliliters of octanes, be placed in the refrigerator and cooled of-20 ℃ and freeze and within 8 hours, carry out recrystallization, freezing rear fast filtering, obtains 0.66 gram, off-white color crystal; Another part of concentrated evaporate to dryness, obtains solids, and this solids is dissolved in 10 grams of refining peanut oil, is heated to 65 ℃ and keep 4 hours under nitrogen protection, cools to 35 ℃, with nitrogen-sealed, obtains the 25-hydroxy-vitamin D of limpid high-quality 3finish.
16. synthesize 25-hydroxy-vitamin D as claimed in claim 1 3method, it is characterized in that: concrete steps are as follows:
1) illumination reaction of 25-hydroxyl-7 dehydrocholesterol
In 500 milliliters of round-bottomed flasks, 10 grams of 25-hydroxyl-7 dehydrocholesterols are at room temperature dissolved in to 280 ml volumes than in 6:1 ethanol/Skellysolve A mixed solvent, add 20 milligram 2,6-di-t-butyl-p methoxy phenol, mix, be configured to photochemical reaction liquid; Reaction solution is inserted in the built-in optical chemical reactor of putting 500W high voltage mercury lamp logical nitrogen well; Regulate flow and the condensate flow of nitrogen; Start mercury lamp, and timing; Whole photochemical reaction device is placed in the stink cupboard of lucifuge, and promotes photothermal dispersion with a small-sized fans, to guarantee that the temperature of photochemical reaction liquid is no more than 25 ℃, avoids generating too early 25-hydroxy-vitamin D 3; With high-efficient liquid phase chromatogram HPLC monitoring reaction, react transformation efficiency 37% 10 minutes;
2) reclaim 25-hydroxyl-7 dehydrocholesterol
After above-mentioned photochemical reaction finishes, reaction solution is transferred in 500 milliliters of round-bottomed flasks to rotation and dry except desolventizing, toward remaining solid substance in, add 50 milliliters of ethanol, and after suitable heating for dissolving, cool to room temperature and insert the refrigerator and cooled of-15 ℃ and freeze 8 hours; Freezing rear fast filtering, reclaims 6.3 grams of 25-hydroxyl-7-DHC solids, Liquid Detection substantially pure;
3) crystallization and the finish of thermal isomerization reaction 25-hydroxyvitamin D3 processed
By step 2) filtrate by Liquid Detection, raw material is removed completely, 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, and approximately 21 milliliters every part, a copy of it reflux under nitrogen protection is concentrated into 10 milliliters after 4 hours, and add 5 milliliters of pentanes, be placed in the refrigerator and cooled of-20 ℃ and freeze and within 8 hours, carry out recrystallization, freezing rear fast filtering, obtains 0.80 gram, off-white color crystal; Another part of concentrated evaporate to dryness, obtains solids, and this solids is dissolved in 10 grams of refining salad oils, is heated to 65 ℃ and keep 4 hours under nitrogen protection, naturally cools to 35 ℃, with nitrogen-sealed, obtains the 25-hydroxy-vitamin D of limpid high-quality 3finish.
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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
EP3383885B1 (en) * 2015-11-30 2021-10-13 DSM IP Assets B.V. Crystallization of 25-hydroxy-7-dehydrocholsterol
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
CN109081796B (en) * 2018-09-06 2020-06-12 山东清创化工有限公司 Photochemical synthesis of vitamin D in tubular reactor2、D3Method (2)
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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

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