CN109761867A - One kind producing vitamin D by raw material of lanolin3New industrial process - Google Patents
One kind producing vitamin D by raw material of lanolin3New industrial process Download PDFInfo
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Abstract
The present invention provides a kind of using lanolin as raw material production vitamin D3New industrial process; lanolin is first obtained into cholesterol crude product through saponification, preliminary purification in low-alcohol solution; the crude product directly obtains high-purity cholesterol acetate through acetylation, then successively through oxidation, hydrazone, de- hydrazone, hydrolysis, illumination and etc. obtain vitamin D3.Production technology of the present invention efficiently, green, environmental protection, product yield high, be suitable for industrialized production, greatly reduce vitamin D3Manufacturing cost；The processing of saponification process filtrate is ingenious, generates without waste liquid and waste, is more advantageous to environmental protection.
Description
Technical field
The present invention relates to a kind of vitamin Ds3Industrialized preparing process, belong to chemicals preparation field.
Background technique
Vitamin D3Also known as cholecalciferol, No. CAS: 67-97-0, be white powder, chemical name 9,10- open loop cholesteric -5,
- 3 β -ol of 7,10 (19)-triolefin, molecular formula C27H44O, molecular weight 384.64, fusing point is at 84-85 DEG C, easy oxygen in air
Change, it is heat-resist, but light-exposed easy decomposition, it is highly soluble in chloroform, is soluble in ethyl alcohol, ether, hexamethylene and acetone, it is not soluble in water,
It is transformed by epidermis 7-DHC through illumination in human body.Vitamin D3It is that the mankind, animal normal growth and breeding must not
It can the highest a kind of active form of biological metabolism rate in a kind of substance and vitamin D less.Work as vitamin D3Successively in liver
With activated vitamin D is converted into kidney3Afterwards, there is regulation Ca,P metabolism, adjust cell differentiation and adjust immune system
Effect.Human body is deficient in vitamin D3When, the ability reduction of calcium, phosphorus is absorbed, calcium, phosphorus cannot deposit in bone tissue, or even can also
Dissolve bone salts, the consumption of hindering bone lattice.Children, which lack, can obtain rickets, adult then obtain osteomalacia.Vitamin D3It is often used as
Drug and food additives, due to its efficient and low toxicity therapeutic index, activated vitamin D3And its homologue can be used as treating
Secondary hyperparathyroidism, the drug of the diseases such as osteoporosis, psoriasis, kidney failure.
In recent years, about vitamin D3Research have received widespread attention.Scientific research personnel has found vitamin D3And its it is derivative
Object also has other than known promotion Calcium and phosphorous absorption, maintaining the balanced action of blood calcium and serium inorganic phosphorus and increases insulin secretion, induction
The pharmacological activity such as cell differentiation, immune and treatment and prevention cancer, obesity, hypertension.These new researchs discoveries will be after
It is continuous to push scientific research personnel to vitamin D3And its pharmacological activity and synthetic method of derivative are further furtherd investigate.
Vitamin D3Structure is complicated, currently, industrial synthesis of vitamin d3Method, be by acylation, upper bromine, debrominate,
Hydrolysis, illumination are heated, but since the reagent toxicity used is larger, cost increases, and are difficult to control, there are many problems
It needs to research and solve.Although some method yields increase, that there are purification steps is more, complicated for operation, at high cost, is unfavorable for
The problems such as industrial production.Therefore industrially it is badly in need of a kind of vitamin D easy to operate, yield is high, at low cost3Production method.
Cholesterol is vitamin D3The most critical raw material of production.Cholesterol not only has important physiological function to human body,
Also there is very important application in industries such as medicine, cosmetics, liquid crystal materials, but the source method of cholesterol is less, biology
The yield of cholesterol obtained in method report is too low, and fermentation condition is too difficult to control, can not achieve industrialized production；From animal
Cholesterol is extracted in tissue, it is with high costs, not environmentally, be not suitable for sustainable development, therefore be highly desirable to seek new production
The method of cholesterol.
China's lanolin resource is very rich, but utilization rate only has 10% or so, is applied to cosmetic industry except a small number of
Or purchased by foreign countries, other not only cause huge resources loss by direct emission, also cause pollution to environment, because
This need to reinforce the comprehensive utilization that lanolin and lanolin are extracted from wool waste water.Lanolin is cheap, and only 10,000 yuan/ton
Left and right, but wherein contain the cholesterol of a large amount of high value, thus can separation and Extraction gallbladder is solid liquor-saturated from lanolin, both can solve
The lesser problem of the utilization rate of lanolin, can also complete the industrialization of cholesterol.
Both at home and abroad a long time ago just to how from lanolin separation and Extraction cholesterol has made many researchs, but occur respectively
The problem of kind of various kinds, for example, yield and purity it is lower, pollution environment, economic cost are uneconomical etc., so do not carry out industrialization,
Therefore suitable method separation and Extraction cholesterol from lanolin is selected to be necessary.
Summary of the invention
Aiming at the problems existing in the prior art, the present invention provides one kind produces vitamin D by raw material of lanolin3's
New industrial process.
The technical scheme is that
A kind of vitamin D is provided3Preparation method, successively include following 7 steps: (1) cholesterol (VII) crude product prepare,
(2) preparation of cholesterol acetate (VI), (3) oxidation preparation 7- ketone group-cholesterol acetate (V), (4) hydrazone are combined to 7- pairs
Tosylhydrazone-cholesterol acetate (IV), (5) take off hydrazone and prepare 7-DHC acetate (III), and (6) hydrolysis preparation 7- is gone
Hydrogen cholesterol (II), (7) illumination synthesis of vitamin d3(Ⅰ)；Route is as follows:
Wherein step (1) includes: to dissolve lanolin methanol or ethyl alcohol or butanol, and sodium hydroxide or hydroxide is added
Potassium, reflux saponification 5-10 hours, cooled and filtered must be saponified filtrate and saponification filter cake；Saponification filtrate adds sodium hydroxide or hydrogen
Apply after potassium oxide as saponification liquor next time (it is added in next time new lanolin saponification step and is saponified together, under
Together)；It is saponified filter cake petroleum ether-acetone mixed solution dissolution, crystallization, filters to obtain lanonol filter cake, the concentration of filtrate recycling design
It is dissolved to after doing with lower alcohol, lanosterol, filtering is precipitated, filtrate continues substep concentration, thin-layer chromatography monitor and detection, until filter
Liquid only remains the single spot of cholesterol and is concentrated to dryness, and obtains cholesterol crude product.
In one embodiment, the step (1) includes: by 1 parts by weight lanolin 5-15 parts by weight 60-90% methanol
Or ethyl alcohol dissolution, the sodium hydroxide or potassium hydroxide of 0.1-0.5 parts by weight is added, reflux saponification 8 hours, cooled and filtered obtains
It is saponified filtrate and saponification filter cake；Saponification filtrate is used as next time after adding 0.03-0.15 parts by weight of sodium hydroxide or potassium hydroxide
Saponification liquor is applied；It is molten to be saponified filter cake 5-10 times of the filter cake weight, petroleum ether-acetone mixed solution of volume ratio 1:0.5-2
Solution, crystallization filter to obtain lanonol filter cake, and filtrate recycling design is dissolved after being concentrated to dryness with methanol or ethyl alcohol or butanol, and sheep is precipitated
Hair sterol, filtering, filtrate are continued substep and are concentrated, thin-layer chromatography monitor and detection, until filtrate only remains the single spot of cholesterol, that is, dense
It is reduced to dry, obtains cholesterol crude product.
In one embodiment, the step (1) includes: by 1 parts by weight lanolin 8-12 parts by weight 60-90% methanol
Or ethyl alcohol dissolution, the sodium hydroxide or potassium hydroxide of 0.2 parts by weight is added, reflux saponification 8 hours, cooled and filtered must be saponified
Filtrate and saponification filter cake；Saponification filtrate is used as saponification liquor set next time after adding 0.06 parts by weight of sodium hydroxide or potassium hydroxide
With；It is saponified petroleum ether-acetone mixed solution dissolution, crystallization of filter cake 5-10 times of the filter cake weight, volume ratio 1:1, filtering
Lanonol filter cake is obtained, filtrate recycling design is dissolved with methanol or ethyl alcohol or butanol after being concentrated to dryness, lanosterol is precipitated, filters,
Filtrate is continued substep and is concentrated, thin-layer chromatography monitor and detection, until filtrate only remains the single spot of cholesterol and is concentrated to dryness, it is solid to obtain gallbladder
Alcohol crude product.
In one embodiment, optionally, first a large amount of lanolin fatty acids are precipitated through appropriate concentration in saponification filtrate described in step (1)
Sodium, is filtered to remove that gained filtrate after lanolin fatty acid sodium adds sodium hydroxide again or potassium hydroxide is used as saponification liquor next time and applies.
In one embodiment, the step (2) includes: that the cholesterol crude product after the dry water removal of 1 parts by weight is dissolved in 5-
In 10 parts by weight of cyclohexane or petroleum ether, DMAP (i.e. 4-dimethylaminopyridine), the 0.5-0.7 weight of 0.005 parts by weight is added
Part sodium carbonate or sodium bicarbonate are added 0.6-0.8 parts by weight acetic acid acid anhydride after stirring and dissolving, react 1.5-3 hours at 55 DEG C, thin layer
Chromatography detection monitoring, is quenched extra acetic anhydride with methanol after fully reacting, filters, cholesterol acetate crude product is concentrated under reduced pressure to obtain,
Cholesterol acetate (VI) highly finished product are recrystallized to obtain in methanol or ethyl alcohol.
In one embodiment, the step (3) includes: that 1 parts by weight cholesterol acetate (VI) is dissolved in 7-13 weight
In part dichloroethanes or acetone or acetonitrile, the catalyst of 0.5~1% parts by weight is added, the catalyst is selected from copper powder, chlorination
Copper, stannous chloride, chromium trioxide, NHPI or benzoyl peroxide；Add the phase that equivalents is 2-4 times of cholesterol acetate (VI)
Transfering reagent, the phase transfer reagent are selected from tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammoinium chloride；45~50
At DEG C, while stirring be added 1-2 parts by weight tert-butyl hydroperoxide, isothermal reaction 8 hours；It is concentrated under reduced pressure after reaction, it is residual
Excess is added in ice water, and with n-hexane extraction, organic phase is further washed with saturated sodium-chloride water solution, anhydrous sodium sulfate is dry
Dry, filtering, filtrate decompression concentration obtains 7- ketone group-cholesterol acetate (V).
In one embodiment, the step (4) includes: that 1 parts by weight 7- ketone group-cholesterol acetate (V) is dissolved in 7-
In 10 parts by weight Methanol, addition equivalents be 7- ketone group -1.2 times of equivalents of cholesterol acetate (V) unifor,
The concentrated hydrochloric acid of 0.01-0.025 parts by weight, back flow reaction 3 hours to fully reacting, filtering, filter cake are washed with methanol, dry 7-
Tosylhydrazone-cholesterol acetate (IV).
In one embodiment, the step (5) includes: by 1 parts by weight 7- Tosylhydrazone-cholesterol acetate
(IV) it is dissolved in the toluene dry with anhydrous calcium chloride of 8-10 parts by weight, the addition parts by weight of hydrogenated lithium of 0.06-0.08,120 DEG C
To fully reacting, filtering uses petroleum ether dissolution after filtrate concentration, and lysate is filtered through silicagel column, filtrate warp within back flow reaction 8 hours
Solid is obtained after concentration, then 7-DHC acetate (III) is recrystallized to obtain in methanol or ethyl alcohol or butanol.
In one embodiment, the step (6) includes: that 1 parts by weight 7-DHC acetate (III) is dissolved in 3-5
In parts by weight Methanol, the potassium hydroxide or sodium hydroxide of addition equivalents identical as 7-DHC acetate (III), 50 DEG C
Lower reaction；After reaction with acetic acid tune pH to neutrality, solid is precipitated, filters to obtain 7-DHC (II) solid.
In one embodiment, the step (7) includes: that 1 parts by weight 7-DHC (II) is dissolved in 110-130
In the hexamethylene of parts by weight-methanol (volume ratio 10:1) mixed solution, solution temperature maintains 30~35 DEG C；It will reaction original with pump
Liquid pump, which enters in 20KW high-pressure sodium lamp photochemical reaction equipment, carries out photochemical reaction, 15~20L/min of flow velocity；Collect reaction solution, 2-8
DEG C, decompression low temperature is concentrated into the 1/60-1/15 of initial volume under nitrogen protection, is placed 24 hours at 2-8 DEG C, precipitation 7- dehydrogenation gallbladder
Sterol raw material, filtering, the 7-DHC raw material filtered out may be repeated photochemical reaction, and filtrate is concentrated under reduced pressure up to dimension life
Plain D3Product.
Vitamin D provided by the invention3Industrialized production new method have the advantage that
(1) lanolin saponification, cholesterol purification process step succinctly facilitate, and saponification liquor is crystallized twice just to be eliminated absolutely greatly
Partial impurities (lanonol, lanosterol), filtrate obtain cholesterol through substep concentration；Target product recovery rate is high, and 50 kilograms
7 kilograms of cholesterol can be made in lanolin.
(2) processing of saponification filtrate is ingenious.The present invention will be saponified filtrate and add after sodium hydroxide or potassium hydroxide as next
Secondary saponification liquor is applied, and saponification is made to improve yield more thoroughly, completely, reduce costs and generate without waste liquid and waste, make
Production technology is more efficient, green, environmentally friendly.
(3) saponification gained cholesterol crude product is directly used in the preparation of subsequent synthetic processes cholesterol acetate without purifying,
The cholesterol acetate intermediate that high-purity can equally be prepared, this invention simplifies technique, reduce reagent consumption, improve
Product yield.
(4) in 7- ketone group-cholesterol acetate (V) preparation step, by the way that phase transfer reagent is added, make product yield
It is improved by 48% to 92%, greatly improves 7- ketone group-cholesterol acetate (V) recovery rate, reduce production cost.
(5) vitamin D is shortened3Preparation process route reduces energy consumption, simple process and low cost, and environmental pollution
Small, industrial strong operability, it is easy to accomplish industrialization large-scale production.
Specific embodiment
The present invention is described in further detail with reference to embodiments, but not limitation of the present invention, it is all according to
The equivalent replacement of any this field, all belongs to the scope of protection of the present invention made by the disclosure of invention.
The saponification of 1 lanolin of embodiment
50 kilograms of lanolin are added in reaction kettle, 500L (about 420 kilograms) 80% methanol, 10 kilograms of hydroxides are added
Sodium, reflux saponification 8 hours.Natural cooling after saponification, filtering；It is used as down after the sodium hydroxide 3kg that filtrate supplement consumes
One time saponification liquor is applied.
Or: above-mentioned filtrate is first concentrated under reduced pressure into about 50L, a large amount of lanolin fatty acid sodium are precipitated, is filtered to remove lanolin fatty acid sodium, is filtered
Liquid is applied after adding sodium hydroxide 3Kg again as saponification liquor next time.
The crystallization of embodiment 2 removes lanonol
By 1 gained filtration cakes torrefaction of embodiment, 15 kilograms are obtained, it is molten with 75-150 kilograms of petroleum mystery-acetone (volume ratio 1:1)
Solution, crystallisation by cooling go out lanonol, filter, and filtrate decompression is concentrated to dryness to be handled in next step wait enter, and filtration cakes torrefaction obtains lanonol
4Kg。
The crystallization of embodiment 3 removes lanosterol and obtains cholesterol crude product
50 times of weight percent methanols are added in filtrate concentrate in embodiment 2, and lanosterol, filtering, dry lanosterol is precipitated
Solid about 4Kg；Filtrate is continued a point multistep and is concentrated, and every a certain amount of lanosterol of precipitation is filtered to remove, and filtrate continues concentration, filtering
Except lanosterol, thin-layer chromatography monitor and detection obtains cholesterol crude product until filtrate only remains the single spot of cholesterol and is concentrated to dryness
7 kilograms.
The preparation of 4 cholesterol acetate (VI) of embodiment
50L hexamethylene (39Kg) or petroleum ether will be dissolved in after the dry water removal of 3 gained 7Kg cholesterol crude product of embodiment
In (32.5Kg), adds 35 grams of DMAP, 4kg sodium carbonate or sodium bicarbonate, be pumped into after stirring and dissolving with peristaltic pump 100ml/min speed
4.5~5L of acetic anhydride (4.8~5.4Kg)；It is reacted 1.5-3 hours at 55 DEG C, thin-layer chromatography detection monitoring uses first after fully reacting
Extra acetic anhydride is quenched in alcohol, and cholesterol acetate crude product about 8Kg is concentrated under reduced pressure to obtain, through recrystallizing in methanol or ethyl alcohol in filtering
Cholesterol acetate (VI) highly finished product about 5Kg, yield 64%.
The oxidation preparation 7- ketone group-cholesterol acetate (V) of embodiment 5
5Kg cholesterol acetate (VI) made from embodiment 4 is dissolved in (weight in 50L dichloroethanes or acetone or acetonitrile
39~62Kg), catalyst copper powder or copper chloride or chromium trioxide 38g is added；Add phase transfer reagent tetrabutylammonium bromide
At 45~50 DEG C, 6.75L (about 6.1Kg) tert-butyl hydroperoxide is added in 11Kg while stirring, and isothermal reaction 8 hours；Reaction knot
It is concentrated under reduced pressure after beam, residue is added in 25L ice water, adds 25L n-hexane, filters, separating in filtrate has several layers of, water layer
It is stripped again with n-hexane 12.5L × 2, merges organic phase, washed with saturated sodium-chloride water solution 8L × 2, anhydrous sodium sulfate is dry；
Filtering, filtrate decompression concentration, obtains (V) 4.75 kilogram of 7- ketone group-cholesterol acetate, yield 92%.
The case where phase transfer reagent is not added: 5Kg cholesterol acetate (VI) is dissolved in 50L dichloroethanes or acetone or acetonitrile
In, it is added catalyst copper powder or copper chloride or chromium trioxide 38g, at 45~50 DEG C, 6.75L (about 6.1Kg) is added while stirring
Tert-butyl hydroperoxide, isothermal reaction 8 hours；After reaction, it is concentrated to dryness, cooling knot after the dissolution of 25L methanol is added
Crystalline substance obtains 2.5Kg 7- ketone group-cholesterol acetate (V), yield 48%.
6 hydrazone of embodiment is combined to 7- Tosylhydrazone-cholesterol acetate (IV)
2.5Kg 7- ketone group-cholesterol acetate (V) is dissolved in 25L (about 19.8Kg) methanol, addition equivalents is 7-
Ketone group -1.2 times of equivalents of cholesterol acetate (V) unifor, adds 50mL (about 59g) concentrated hydrochloric acid, at 65 DEG C
To fully reacting, solution goes to paste by transparent within back flow reaction 3 hours；Filtering, filter cake washs with methanol, be dried to no moisture and
Solvent obtains 2.8Kg 7- Tosylhydrazone-cholesterol acetate (IV), yield 81%.
Embodiment 7 takes off hydrazone and prepares 7-DHC acetate (III)
2.8Kg 7- Tosylhydrazone made from embodiment 6-cholesterol acetate (IV) is dissolved in 28L (24.25Kg)
With in the dry toluene of anhydrous calcium chloride, 200g lithium hydride is taken to be scattered in dry toluene, addition to reaction system, 120 DEG C
Back flow reaction 8 hours is to complete；The salinities such as calcium chloride are filtered to remove, filter cake is cleaned with toluene, and combining methylbenzene liquid is concentrated under reduced pressure
To grease, grease petroleum ether dissolution is pumped into silicagel column filtering, faint yellow solid 1.9Kg is obtained after concentrating filter liquor, by it
After reflux is dissolved in 15L methanol or ethyl alcohol or butanol, it is concentrated under reduced pressure into 10L, it is cooling, white-yellowish crystal 7- is precipitated
Dehydrocholesterol acetate (III) 1.6Kg, yield 82%.
8 hydrolysis of embodiment prepares 7-DHC (II)
(3.756eq) the 7-DHC acetate of 1.6Kg made from embodiment 7 (III) is dissolved in 8L (about 6.3Kg)
In methanol, the potassium hydroxide or sodium hydroxide of 3.756eq is added, is reacted at 50 DEG C；After reaction with acetic acid tune pH to neutrality,
Solid is precipitated, filters to obtain 7-DHC (II) solid 1.3Kg, yield 90%.
9 illumination synthesis of vitamin d of embodiment3(Ⅰ)
It is mixed that 20Kg 7-DHC (II) is dissolved in 3000L (about 2340Kg) hexamethylene-methanol (volume ratio 10:1)
It closes in solution, it is ensured that 30~35 DEG C of solution temperature；Reaction stoste 20KW high-pressure sodium lamp photochemical reaction equipment is pumped into pump to carry out,
15~20L/min of flow velocity；It collects reaction solution, 2-8 DEG C, decompression low temperature is concentrated into 50~200L under nitrogen protection, is placed at 2-8 DEG C
24 hours, 7-DHC raw material is precipitated, is filtered at 2-8 DEG C, the 7-DHC raw material filtered out may be repeated photochemical
Reaction, filtrate are concentrated under reduced pressure up to vitamin D3Oily 6.4Kg.
The above-mentioned vitamin D directly obtained3Oil can be directly used as feed addictive and food additives, if the dimension is raw
Plain D3Oil obtains vitamin D through repeated recrystallize3Crystalline product can be used in medical product.
Claims (10)
1. a kind of vitamin D3Preparation method, it is characterised in that successively include following 7 steps: (1) cholesterol (VII) crude product system
Standby, the preparation of (2) cholesterol acetate (VI), (3) oxidation prepares 7- ketone group-cholesterol acetate (V), and (4) hydrazone is combined to 7-
Tosylhydrazone-cholesterol acetate (IV), (5) take off hydrazone and prepare 7-DHC acetate (III), (6) hydrolysis preparation 7-
Dehydrocholesterol (II), (7) illumination synthesis of vitamin d3(Ⅰ)；Route is as follows:
Wherein step (1) includes: to dissolve lanolin methanol or ethyl alcohol or butanol, and sodium hydroxide or potassium hydroxide is added, and is returned
Stream saponification 5-10 hours, cooled and filtered must be saponified filtrate and saponification filter cake；Saponification filtrate adds sodium hydroxide or potassium hydroxide
It is applied afterwards as saponification liquor next time；It is saponified filter cake petroleum ether-acetone mixed solution dissolution, crystallization, filters to obtain lanonol filter
Cake, filtrate recycling design are dissolved after being concentrated to dryness with lower alcohol, and lanosterol, filtering is precipitated, and filtrate is continued substep and is concentrated, thin layer
Chromatography monitor and detection obtains cholesterol crude product until filtrate only remains the single spot of cholesterol and is concentrated to dryness.
2. vitamin D as described in claim 13Preparation method, which is characterized in that the step (1) includes: by 1 parts by weight
Lanolin 5-15 parts by weight 60-90% methanol or ethyl alcohol dissolution, are added the sodium hydroxide or hydroxide of 0.1-0.5 parts by weight
Potassium, reflux saponification 8 hours, cooled and filtered must be saponified filtrate and saponification filter cake；Saponification filtrate adds 0.03-0.15 parts by weight
It is applied after sodium hydroxide or potassium hydroxide as saponification liquor next time；It is saponified filter cake 5-10 times of the filter cake weight, volume ratio
The petroleum ether of 1:0.5-2-acetone mixed solution dissolution, crystallization, filters to obtain lanonol filter cake, after filtrate recycling design is concentrated to dryness
It is dissolved with methanol or ethyl alcohol or butanol, lanosterol, filtering is precipitated, filtrate is continued substep and is concentrated, thin-layer chromatography monitor and detection, directly
The single spot of cholesterol is only remained to filtrate to be concentrated to dryness, and obtains cholesterol crude product.
3. vitamin D as claimed in claim 23Preparation method, which is characterized in that the step (1) includes: by 1 parts by weight
Lanolin 8-12 parts by weight 60-90% methanol or ethyl alcohol dissolution, are added the sodium hydroxide or potassium hydroxide of 0.2 parts by weight, return
Stream saponification 8 hours, cooled and filtered must be saponified filtrate and saponification filter cake；Saponification filtrate add 0.06 parts by weight of sodium hydroxide or
It is applied after potassium hydroxide as saponification liquor next time；It is saponified filter cake 5-10 times of the filter cake weight, the petroleum of volume ratio 1:1
Ether-acetone mixed solution dissolution, crystallization, filters to obtain lanonol filter cake, and filtrate recycling design uses methanol or ethyl alcohol after being concentrated to dryness
Or butanol dissolution, lanosterol, filtering is precipitated, filtrate is continued substep and is concentrated, thin-layer chromatography monitor and detection, until filtrate only remains gallbladder
The single spot of sterol is concentrated to dryness, and obtains cholesterol crude product.
4. vitamin D as claimed in any one of claims 1-33Preparation method, which is characterized in that optionally, the saponification
First a large amount of lanolin fatty acid sodium are precipitated through appropriate concentration in filtrate, and gained filtrate adds sodium hydroxide or hydrogen again after being filtered to remove lanolin fatty acid sodium
Potassium oxide is used as saponification liquor next time and applies.
5. vitamin D as claimed in any one of claims 1-33Preparation method, which is characterized in that the step (2) packet
It includes: the cholesterol crude product after the dry water removal of 1 parts by weight being dissolved in 5-10 parts by weight of cyclohexane or petroleum ether, 0.005 weight is added
DMAP, 0.5-0.7 parts by weight sodium carbonate or sodium bicarbonate of part are measured, addition 0.6-0.8 parts by weight acetic acid acid anhydride after stirring and dissolving, 55
It is reacted 1.5-3 hours at DEG C, thin-layer chromatography detection monitoring is quenched extra acetic anhydride with methanol after fully reacting, filters, depressurizes dense
Contract to obtain cholesterol acetate crude product, and cholesterol acetate (VI) highly finished product are recrystallized to obtain in methanol or ethyl alcohol.
6. vitamin D as claimed in any one of claims 1-33Preparation method, which is characterized in that the step (3) packet
It includes: 1 parts by weight cholesterol acetate (VI) is dissolved in 7-13 parts by weight dichloroethanes or acetone or acetonitrile, be added 0.5~1%
The catalyst of parts by weight, the catalyst are selected from copper powder, copper chloride, stannous chloride, chromium trioxide, NHPI or benzoyl peroxide；
The phase transfer reagent that equivalents is 2-4 times of cholesterol acetate (VI) is added, the phase transfer reagent is selected from tetrabutyl phosphonium bromide
Ammonium, tetrabutylammonium chloride, benzyltriethylammoinium chloride；At 45~50 DEG C, 1-2 parts by weight tert-butyl hydroperoxide is added while stirring
Hydrogen, isothermal reaction 8 hours；It is concentrated under reduced pressure after reaction, residue is added in ice water, and with n-hexane extraction, organic phase is into one
Step is washed with saturated sodium-chloride water solution, anhydrous sodium sulfate dries, filters, and filtrate decompression concentration obtains 7- ketone group-cholesterol acetic acid
Ester (V).
7. vitamin D as claimed in any one of claims 1-33Preparation method, which is characterized in that the step (4) packet
It includes: 1 parts by weight 7- ketone group-cholesterol acetate (V) is dissolved in 7-10 parts by weight Methanol, addition equivalents is 7- ketone group-gallbladder
The concentrated hydrochloric acid of the unifor, 0.01-0.025 parts by weight that 1.2 times of equivalents of sterol acetate (V), back flow reaction 3 are small
Up to fully reacting, filtering, filter cake is washed with methanol, dry 7- Tosylhydrazone-cholesterol acetate (IV).
8. vitamin D as claimed in any one of claims 1-33Preparation method, which is characterized in that the step (5) packet
It includes: 1 parts by weight 7- Tosylhydrazone-cholesterol acetate (IV) is dissolved in the dry with anhydrous calcium chloride of 8-10 parts by weight
In toluene, it is added the parts by weight of hydrogenated lithium of 0.06-0.08,120 DEG C of back flow reactions 8 hours to fully reacting, filtering, after filtrate concentration
With petroleum ether dissolution, lysate is filtered through silicagel column, solid is obtained after concentrating filter liquor, then through tying in methanol or ethyl alcohol or butanol again
It is brilliant to obtain 7-DHC acetate (III).
9. vitamin D as claimed in any one of claims 1-33Preparation method, which is characterized in that the step (6) packet
It includes: 1 parts by weight 7-DHC acetate (III) is dissolved in 3-5 parts by weight Methanol, be added and 7-DHC acetic acid
The potassium hydroxide or sodium hydroxide of the identical equivalents of ester (III) react at 50 DEG C；After reaction with acetic acid tune pH to neutrality, analysis
Solid out filters to obtain 7-DHC (II) solid.
10. vitamin D as claimed in any one of claims 1-33Preparation method, which is characterized in that the step (7) packet
It includes: hexamethylene-methanol that 1 parts by weight 7-DHC (II) is dissolved in 110-130 parts by weight volume ratio 10:1 being mixed molten
In liquid, solution temperature maintains 30~35 DEG C；Reaction stoste is pumped into 20kw high-pressure sodium lamp photochemical reaction equipment with pump and is carried out
Photochemical reaction, 15~20L/min of flow velocity；Collect reaction solution, 2-8 DEG C, decompression low temperature is concentrated into initial volume under nitrogen protection
, place 24 hours at 2-8 DEG C, 7-DHC raw material, filtering, the 7-DHC raw material filtered out be precipitated
It may be repeated photochemical reaction, filtrate is concentrated under reduced pressure up to vitamin D3Product.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112159449A (en) * | 2020-09-28 | 2021-01-01 | 浙江新和成药业有限公司 | Preparation method of 7-p-toluenesulfonylhydrazone-3-cholesterol ester |
| CN112608264A (en) * | 2020-12-12 | 2021-04-06 | 弘健制药(上海)有限公司 | Preparation method of vitamin D3 intermediate |
| CN112745253A (en) * | 2021-02-07 | 2021-05-04 | 成都健腾生物技术有限公司 | Preparation of vitamin D from stigmasterol3Is a new method for industrialization |
| WO2021213984A1 (en) * | 2020-04-23 | 2021-10-28 | Dsm Ip Assets B.V. | Preparation of 7-dehydrocholesterol using specific aromatic solvents |
| CN113621015A (en) * | 2021-08-11 | 2021-11-09 | 浙江新和成药业有限公司 | 7-dehydrocholesterol and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1445215A (en) * | 2002-03-18 | 2003-10-01 | 中国科学院理化技术研究所 | Photochemical method for synthesizing vitamine D3 |
| CN1594350A (en) * | 2004-06-24 | 2005-03-16 | 浙江大学 | Method for separating and extracting cholesterol from lanolin |
| US6900191B1 (en) * | 1997-02-25 | 2005-05-31 | Oncquest, Inc. | 1α-Hydroxyvitamin D5, its synthesis and use in cancer prevention |
| CN101220075A (en) * | 2008-01-25 | 2008-07-16 | 北京化工大学 | Preparation method for 7-dehydrochol esterol |
| CN103113446A (en) * | 2013-03-15 | 2013-05-22 | 北京化工大学 | Method for separating and extracting sterol from wool fat |
| CN105131071A (en) * | 2015-07-14 | 2015-12-09 | 浙江花园生物高科股份有限公司 | Synthesis method of 25-hydroxycholesteryl acetate-7-p-toluenesulfonylhydrazone |
-
2019
- 2019-02-28 CN CN201910153505.4A patent/CN109761867B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6900191B1 (en) * | 1997-02-25 | 2005-05-31 | Oncquest, Inc. | 1α-Hydroxyvitamin D5, its synthesis and use in cancer prevention |
| CN1445215A (en) * | 2002-03-18 | 2003-10-01 | 中国科学院理化技术研究所 | Photochemical method for synthesizing vitamine D3 |
| CN1594350A (en) * | 2004-06-24 | 2005-03-16 | 浙江大学 | Method for separating and extracting cholesterol from lanolin |
| CN101220075A (en) * | 2008-01-25 | 2008-07-16 | 北京化工大学 | Preparation method for 7-dehydrochol esterol |
| CN103113446A (en) * | 2013-03-15 | 2013-05-22 | 北京化工大学 | Method for separating and extracting sterol from wool fat |
| CN105131071A (en) * | 2015-07-14 | 2015-12-09 | 浙江花园生物高科股份有限公司 | Synthesis method of 25-hydroxycholesteryl acetate-7-p-toluenesulfonylhydrazone |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021213984A1 (en) * | 2020-04-23 | 2021-10-28 | Dsm Ip Assets B.V. | Preparation of 7-dehydrocholesterol using specific aromatic solvents |
| CN115427424A (en) * | 2020-04-23 | 2022-12-02 | 帝斯曼知识产权资产管理有限公司 | Preparation of 7-dehydrocholesterol using specific aromatic solvents |
| CN112159449A (en) * | 2020-09-28 | 2021-01-01 | 浙江新和成药业有限公司 | Preparation method of 7-p-toluenesulfonylhydrazone-3-cholesterol ester |
| CN112608264A (en) * | 2020-12-12 | 2021-04-06 | 弘健制药(上海)有限公司 | Preparation method of vitamin D3 intermediate |
| CN112745253A (en) * | 2021-02-07 | 2021-05-04 | 成都健腾生物技术有限公司 | Preparation of vitamin D from stigmasterol3Is a new method for industrialization |
| CN112745253B (en) * | 2021-02-07 | 2023-03-14 | 成都健腾生物技术有限公司 | Preparation of vitamin D from stigmasterol 3 Is a new method for industrialization |
| CN113621015A (en) * | 2021-08-11 | 2021-11-09 | 浙江新和成药业有限公司 | 7-dehydrocholesterol and preparation method thereof |
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