CN101220075A - Preparation method for 7-dehydrochol esterol - Google Patents
Preparation method for 7-dehydrochol esterol Download PDFInfo
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- CN101220075A CN101220075A CNA2008100568866A CN200810056886A CN101220075A CN 101220075 A CN101220075 A CN 101220075A CN A2008100568866 A CNA2008100568866 A CN A2008100568866A CN 200810056886 A CN200810056886 A CN 200810056886A CN 101220075 A CN101220075 A CN 101220075A
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Abstract
The invention discloses a preparation method of a 7-dehydrocholesterol, which comprises the following steps: a) protecting a hydroxyl on the 3 position of a cholesterol; b) oxidizing the carbon on the 7 position of the product made in step a) into a carbonyl; c) carrying out hydrazone reaction to the product made in step b) with hydrazine derivatives, and the structure of the hydrazine derivatives is a hydrazine with at most one H is substituted; d) reacting the product made in step c) with a strong basic reagent having stronger alkalinity than a sodium hydroxide; e) reacting the product made in step d) with water or acid. In the preparation method of a 7-dehydrocholesterol, no halogen group elements such as Br element participate, the side effects are less and the yield is high, and the prepared product is safe and innocuous.
Description
Technical field
The present invention relates to the organic synthesis field, relate in particular to the preparation method of 7-dehydrocholesterol.This method can be under the condition of no bromine is that feedstock production goes out the 7-dehydrocholesterol with the cholesterol.
Background technology
Vitamins D (vitamin D) is that a class has the active material of anti-rickets, claims the D vitamin again, belongs to liposoluble vitamin.Vitamins D
3Be a kind of of vitamins D, claim cholecalciferol again, molecular formula is C
27H
43OH, relative molecular mass are 384.65.It is the powder of colourless needle crystal or white crystalline, tasteless, meet light or air all apt to deteriorate; Water insoluble, very easily be dissolved in ethanol, acetone, chloroform or ether, slightly be dissolved in vegetables oil; Fusing point is 84 ℃～88 ℃, and structure is as follows:
Vitamins D is the requisite liposoluble vitamin that people and domestic animal, poultry grow, breed, earn a bare living and keep fit, and its main effect shows the following aspects:
One, as pharmaceutical preparation, regulate alcium and phosphor metabolization, promote that calcium phosphorus absorbs and the sclerotin calcification in the intestines, keep the balance of blood calcium and serium inorganic phosphorus.Be mainly used in illnesss such as treatment rickets, richets, osteoporosis, thyroprivia clinically.Vitamins D in addition
3And some metabolites can suppress hyperplasia and reduce leukemia cell differentiation, report vitamins D in addition
3The treatment malignant tumour there is certain booster action.
Two, as food beverage additive, reinforcer.Vitamins D
3Can be added in milk, milk-product, biscuit, candy and the various beverage, be used for replenishing or forced for vitamins, the prevention vitamin D deficiency.
Three, as the fodder additives of livestock and poultry.Vitamins D
3Be added in the fodder additives of livestock and poultry, can increase the output of meat, egg, milk and improve the nutritive value of meat, egg, milk.
Four, as cosmetics additive.VITAMIN is added in trophicity or the curative makeup as effective constituent, can improves skin quality and delaying decrepitude of skin.
Vitamins D
3Transformed and obtain through UV-irradiation by its precursor 7-dehydrocholesterol, reaction formula is as follows:
The synthetic of 7-dehydrocholesterol all is the restriction vitamins D all the time
3The bottleneck of producing.The method of used synthetic 7-dehydrocholesterol is to add a bromine earlier and then remove a part hydrogen bromide by the elimination reaction promptly can obtain vitamins D on the 7-position of cholesterol basically in producing at present
3Precursor 7-dehydrocholesterol, reaction formula is as follows:
This method is proposed in nineteen forty-two by Ziegler (Ziegler), and after this scientists has been spent a lot of painstaking effort to be devoted to the research of this method and finally realized this method industrialization.This method seems simply, but still has following shortcoming: 1. in the process of bromination, the α position of the pendant double bonds of the cholesterol after the esterification also can be by bromination; Mainly be because bromination reaction belongs to free radical reaction, so the position of two keys might be shifted; 2. in the process of dehydrobromination, be difficult for generating the conjugated diolefine structure of expectation; 3. also have other unwanted by products when preparing the 7-dehydrocholesterol with this method and form, this just needs to increase many steps to remove brominated by products and other corresponding by products; 4. bromine is harmful to environment, is difficult for removing; 5. bromine is influential to the photoresponse in later stage.
The country that can produce Vitamin D3 500,000 I.U/GM at present in the world has only a few, mainly concentrates on several companies, as: Luo Si (Rose), BASF (BASF) and An Wante animal nutrition companies such as (AAN).Vitamins D
3Annual output is at 50t～60t, but demand surpasses 100t.Therefore a lot of countries and regions D that is deficient in vitamin
3, the especially most African country D that then is deficient in vitamin more
3And vitamins D
3The production key be the production of its precursor 7-dehydrocholesterol.The output of 7-dehydrocholesterol and the quality of product can determine vitamins D to a great extent
3Situation.
In summary, need to improve vitamins D
3The perhaps output of its precursor 7-dehydrocholesterol and the quality of product are to meet the need of market.
Summary of the invention
The present invention is directed to the deficiency of existing production technique, propose a kind of preparation method of 7-dehydrocholesterol.Among this preparation method, do not have the participation of haloid elements such as bromo element, side reaction is few, the productive rate height, and the product safety of preparation is nontoxic.
In order to realize the foregoing invention purpose, the invention provides following technical scheme:
1, the preparation method of 7-dehydrocholesterol may further comprise the steps:
A) with the hydroxyl protection on 3 of the cholesterol;
B) oxidation of coal on 7 of the product that step a) is made becomes carbonyl;
C) product that step b) is made and hydrazine derivative are carried out to hydrazone reaction, and the structure of described hydrazine derivative is that a hydrogen is replaced later hydrazine at the most;
D) product that step c) is made and the strong basicity reagent react stronger than sodium hydroxide alkalescence;
E) product that step d) is made and water or acid-respons.
The 7-dehydrocholesterol has following structural formula:
Marked 1-7 bit position in the structural formula, in the present invention, 1-7 is constant in the reaction process, can not change because of the variation of functional group.For example, if hydrogenation on the carbon on 7, this carbon still is 7 carbon so.
Below each step is set forth respectively:
Step a): with the hydroxyl protection on 3 of the cholesterol
Cholesterol claims cholesterol again.
Hydroxyl protection is means commonly used in the chemosynthesis, and the method for hydroxyl protection is a lot, specifically can be referring to the chapter 2 of " protecting group in the organic synthesis " (press of East China University of Science, first version in 2004) book.The preferred use by after the reaction hydroxyl on 3 of the cholesterol being generated the guard method of ester group.
The method that generates ester bond can be cholesterol and carboxylic acid, carboxylic acid anhydride or acyl chloride reaction.
Described carboxylic acid can be that saturated carboxylic acid also can be a unsaturated carboxylic acid, preferred saturated carboxylic acid; Carboxylic acid can be that monocarboxylic acid also can be the above carboxylic acid of binary or binary, preferred monocarboxylic acid.Can select C in the monocarboxylic acid
2Above monocarboxylic acid is preferably acetate, propionic acid, butyric acid, valeric acid, caproic acid, laurostearic acid, TETRADECONIC ACID, phenylformic acid, more preferably acetate.
Described carboxylic acid anhydride can be single acid anhydride, also can be to mix acid anhydride; Can be the aliphatic carboxylic acid acid anhydride, also can be the aromatic carboxylic acid acid anhydride.Concrete acid anhydrides can be selected: diacetyl oxide, propionic anhydride, butyryl oxide, valeric anhydride, benzoyl oxide, Succinic anhydried, Tetra hydro Phthalic anhydride etc., preferably use diacetyl oxide.
Described acyl chlorides can be Acetyl Chloride 98Min., propionyl chloride, butyryl chloride, Benzoyl chloride etc.; Preferred Acetyl Chloride 98Min..
Use the method for carboxylic acid or carboxylic acid anhydride protection hydroxyl can adopt following two kinds:
(1) utilize diacetyl oxide not only as solvent but also as reactant, concrete grammar can for: cholesterol and the diacetyl oxide molar feed ratio according to 1: 10～1: 30 is fed intake, and is 100 ℃～160 ℃ in temperature then, reaction 2h (hour)～4h.Hydroxyl reaction by anhydride functional group and cholesterol generates the ester bond structure, thereby can prevent the destruction of oxidized or some other form in the follow-up reaction process.Temperature of reaction is preferably 115 ℃～155 ℃, more preferably 135 ℃～145 ℃.
(2) utilize acetate or diacetyl oxide as reactant, concrete grammar can for: cholesterol and the diacetyl oxide molar feed ratio according to 1: 1.2～1: 2.0 is fed intake, be 60 ℃～90 ℃ reactions in temperature of reaction then, the reaction times can be 2h～8h, is reflected in the non-protonization solvent and carries out.Described non-protonization solvent is a benzene.The proton that non-protonization solvent is called aprotonic solvent, non-protonic solvent, aprotic solvent, deionization solvent or deionization kind solvent again reacts extremely faint or does not transmit tendency certainly from transmitting.According to non-protonization solvent solvent, this type can be divided into nonpolar aprotic solvent and aprotic, polar solvent.For example benzene, ether, tetracol phenixin etc. belong to nonpolar solvent, methyl-sulphoxide, N, and dinethylformamide, acetone etc. belongs to the polar solvent.Because the polar solvent molecule has polarity, so understand influential and the generation solvation effect to solute molecule.The preferred nonpolar aprotic solvent that uses in this step, more preferably benzene is as solvent.
Step b): the oxidation of coal on 7 of the product that step a) is made becomes carbonyl
Oxidation of coal on the 7-position is become carbonyl.
Can utilize the oxidation of coal on 7 of product that oxygenant makes step a) to become carbonyl, described oxygenant is selected from: chromium trioxide, chromium trioxide/peroxy tert-butyl alcohol composite oxidant, tertbutyl peroxide/Chromium hexacarbonyl composite oxidant, ammonium chloride/chromium trioxide composite oxidant, tertbutyl peroxide/CuI
2Composite oxidant, chromium trioxide/3,5-lutidine composite oxidant.Preferred use chromium trioxide is 55 ℃～65 ℃ reactions in temperature, and perhaps preferably using peroxy tert-butyl alcohol is 25 ℃～45 ℃ reactions in temperature.
Step c) is incited somebody to action: product that step b) makes and hydrazine derivative are carried out to hydrazone reaction, and the structure of described hydrazine derivative is that a hydrogen is replaced later hydrazine at the most
Described hydrazine derivative has following structure:
The hydrazine derivative of above-mentioned structure can become hydrazone reaction with the product that step b) makes, and reaction formula is:
In above-mentioned reaction formula, be directed to the present invention, R
2And R
3Determine that the nitrogen-atoms that is connected with two hydrogen of described hydrazine derivative is connected with the two keys of carbonyl carbon at last.Described hydrazine derivative is preferably to the Methyl benzenesulfonyl hydrazine.
Being reflected at of step c) carried out in the polar solvent better.Polar solvent can be methyl alcohol, ethanol, propyl alcohol, propyl carbinol, acetone, ether, isopropyl ether, chloroform, monobromethane etc., preferably uses methyl alcohol or ethanol.
Step d): the product that step c) is made with than the strong strong basicity reagent react of sodium hydroxide alkalescence
The reaction the present invention who takes place for this step does not wish to be limited to a certain theory.
Strong basicity reagent described in the step d) can be sodium hydride, lithium hydride, lithium methide, preferably uses sodium hydride, and speed of response is comparatively suitable when using sodium hydride.When selecting sodium hydride for use, temperature of reaction is 80 ℃～150 ℃, is preferably 140 ℃～150 ℃.
The reaction of this step is preferably carried out in non-protonization solvent, and described non-protonization solvent can be N, dinethylformamide, methyl-sulphoxide, benzene, toluene, pyridine and derivative thereof, acetonitrile.
Step e): product and water or acid-respons that step d) is made.
The reaction the present invention who takes place for this step does not wish to be limited to a certain theory.
The described acid of this step can be hydrochloric acid, preferably uses dilute hydrochloric acid, and more preferably concentration is 1%～2% hydrochloric acid.
Embodiment
Below in conjunction with embodiment, further set forth the present invention:
The amount of reaction product does not influence the use of other steps in each step of embodiment, if the amount of reaction product can not satisfy other steps when using, can repeatedly prepare to satisfy the required amount of other steps.
Embodiment 1
A) get 5g (gram) cholesterol and join in 36.8ml (milliliter) diacetyl oxide, add two zeolites at 140 ℃ ± 5 ℃ backflow 3h, reaction generates courage steroid-5 alkene-3-acetic ester.Described diacetyl oxide is an analytical pure, and density is 540g/500ml.
Utilize the purity of the courage steroid-5 alkene-3-acetic ester of internal mark method determination reaction generation, productive rate is 87%.
B) get 5g courage steroid-5-alkene-3-acetic ester and 4 normal anhydrous sodium acetates and be dissolved in the 40ml Glacial acetic acid, shake up, then be heated to 59 ℃ ± 1 ℃ in the water-bath at 25 ℃.Get 2 normal CrO
3(chromium trioxide) gradation adds in the reaction solution, and few earlier back is many, and slow earlier back is fast, 30min (minute) in add.Stir down 4.5h at 59 ℃ ± 1 ℃, be cooled to 25 ℃, and then have crystal with 4 ℃ water cooling 12h and separate out, filter with the glass sand core funnel, with deionized water crystal is washed till again colourless, 50 ℃ of vacuum-drying 8h in baking oven.
Obtaining courage steroid-5-alkene-7-carbonyl-3-acetic ester solid 2.8g, is 87.1% through check purity, and productive rate is 60%.
C) getting courage steroid-5-alkene-7-carbonyl-3-acetic ester 0.174g, 2 normally is dissolved in the 40ml dehydrated alcohol together to the Methyl benzenesulfonyl hydrazine, 25 ℃ are stirred down with TLC monitoring (thin-layer chromatography monitoring), stopped reaction behind the 20h, revolve after the steaming product 3-courage steroid-5-alkene-7-to Methyl benzenesulfonyl hydrazone-3-acetic ester 0.251g.
Through check purity is 95%, productive rate 99%.
D e) gets 3-courage steroid-5-alkene-7-Methyl benzenesulfonyl hydrazone-3-acetic ester 0.1787g is dissolved in the 25ml dimethyl sulfoxide (DMSO), adds 7 normal NaH (sodium hydride), stirring reaction 6h at 150 ℃ in batches.Be cooled to 25 ℃, the dilute hydrochloric acid 25ml with 1% is washed till slightly acidic, is washed till neutrality with deionized water again, adds the 5ml deionized water then, shakes up.With ethyl acetate extraction three times, use ethyl acetate 30ml at every turn.Merge three times the extraction after ethyl acetate layer and use anhydrous Na
2SO
4Drying, normal pressure elimination Na
2SO
4After revolve to steam and obtain tawny solid 0.1843g, content is 0.0787g.
It is the 7-dehydrocholesterol after testing, and purity is 42.72%, and productive rate is 70%.
The amount of the reactant that takes by weighing in each step is the net content through converting.For example: get courage steroid-5-alkene-7-carbonyl-3-acetic ester 0.174g described in the step c), from step b) as can be seen its purity be 87.1%, the so actual purity that takes by weighing is that courage steroid-5-alkene-7-carbonyl-3-acetic ester of 87.1% is 0.200g.The reactant that takes by weighing in each step in following embodiment also all is net contents.
Embodiment 2
A) get the 5g cholesterol and be dissolved in the dry benzene of crossing of 40ml, then add 2 normal diacetyl oxides, at 80 ℃ of condensing reflux 3h.Question response liquid is cooled to after 25 ℃ earlier and is washed till slightly acidic with 1% dilute hydrochloric acid and uses 5% NaHCO again
3(sodium bicarbonate) aqueous solution is washed till weakly alkaline, is washed till neutrality with deionized water at last.With an amount of extracted with diethyl ether water 3 times, merge three times after the extraction the benzene layer and use anhydrous Na
2SO
4Dry.Benzene-diethyl ether solution that drying is good revolves to steam and obtains 5.44g courage steroid-5 alkene-3-acetic ester.
97%, courage steroid-5 alkene-3-acetic ester productive rate is greater than 95% through check purity.
B) with the 4ml volume fraction be 70% tertbutanol peroxide and courage steroid-5-alkene-3-acetic ester of 1.71g (4mmol), be dissolved in the 16ml methylene dichloride, under 25 ℃, stir 24h, then solvent is revolved steaming and obtain solid courage steroid-5-alkene-7-carbonyl-3-acetic ester 2.61g.
Purity is 51% after testing, and courage steroid-5-alkene-7-carbonyl-3-acetic ester productive rate is 70%.
Step c among following steps and the embodiment 1, d is e) identical.
Embodiment 3
Among this embodiment, step b) is different with embodiment 1, and other steps are identical with the step of embodiment 1.The step b) of present embodiment is:
Get cholesterol acetate 2.0 gram and 0.029 normal cuprous iodides, it is dissolved in the benzene of 30ml, add 5.6 normal tertbutyl peroxides at last.70 ℃ of stirring reaction 26h under protection of nitrogen gas.
Obtain courage steroid-5-alkene-7-carbonyl-3-acetic ester solid, through check purity, calculating productive rate is 30%.
Embodiment 4
Among this embodiment, step b) is different with embodiment 2, and other steps are identical with the step of embodiment 2.The step b) of present embodiment is:
Get 0.2g courage steroid-5-alkene-3-acetic ester, 0.101g 4A molecular sieve, 1.0g PCC-Al
2O
3With 40ml benzene.Earlier courage steroid-5-alkene-3-acetic ester is dissolved in the benzene, then with 4A molecular sieve and PCC-Al
2O
3Pour into wherein fast.70 ℃ down stir 24h after stopped reaction, filtration, wash filter residue, combined ethyl acetate and benzene repeatedly with ethyl acetate, use anhydrous Na at last
2SO
4Dry.
Obtain courage steroid-5-alkene-7-carbonyl-3-acetic ester solid, through check purity, calculating productive rate is 15%.
Described PCC is pyridinium chlorochromate a drone salt, Al
2O
3Be aluminum oxide, every 2.5g PCC-Al
2O
3In contain PCC1.0g, the 4A molecular sieve is a sodium A molecular sieve.
Embodiment 5
Among this embodiment, step b) is different with embodiment 1, and other steps are identical with the step of embodiment 1.The step b) of present embodiment is:
Get 0.5g courage steroid-5-alkene-3-acetic ester and 0.058g Bi (NO
3)
35H
2O is dissolved in the 40ml acetonitrile, adds 2.264gt-BuOOH then, revolves steaming with the acetonitrile evaporate to dryness behind 70 ℃ of following stirring reaction 22h.With ethyl acetate product is dissolved, normal pressure filters, the NaHCO with 5%
3Solution is washed till weakly alkaline with organic phase earlier, with deionized water organic phase is washed till neutrality again, uses the ethyl acetate extraction water at last again 2 times, merges organic phase.Obtain white solid 0.531g after revolving steaming.
Obtain courage steroid-5-alkene-7-carbonyl-3-acetic ester solid, through check purity, calculating productive rate is 10%.
Described Bi (NO
3)
35H
2O is five water Bismuth trinitrates, and t-BuOOH is a tertbutyl peroxide.
Embodiment 6
Among this embodiment, steps d, e) different with embodiment 1, other steps are identical with the step of embodiment 1.The steps d of present embodiment, e) difference from Example 1 is: utilize benzene to make solvent and without dimethyl sulfoxide (DMSO), temperature of reaction is 80 ℃.
Final reacting product is the 7-dehydrocholesterol after testing, and productive rate is 15%.
Embodiment 7
Among this embodiment, steps d, e) different with embodiment 6, other steps are identical.Difference is: utilize toluene to make solvent, temperature of reaction is 80 ℃.
Final reacting product is the 7-dehydrocholesterol after testing, and productive rate is 15%.
Embodiment 8
The final product of embodiment 1～7 gained is carried out infrared spectrometer and nuclear magnetic resonance analyser detection, and the gained result is:
The ownership at infrared principal character peak: 3294cm
-1The O-H stretching vibration, 1657cm
-1The cyclic olefinic bond stretching vibration, 1066 and 1034cm
-1The C-OH stretching vibration, 984 and 946cm
-1=CH stretching vibration.
The ownership at nuclear-magnetism principal character peak: 5.559 and 5.378 (d, 2H, 6-CH and 8-CH), 3.628 (m, 1H, 3 α-CH).
As can be seen: its final product is the 7-dehydrocholesterol.
The testing method explanation
What the method for the detection purity of the reaction product of addressing in each step adopted in the above-described embodiments is marker method, concrete testing method is: getting standard substance is the standardized solution that internal standard substance is made into different concns, under certain ultraviolet wavelength, measure the peak area of different concns standardized solution with liquid Hunan, make typical curve with the peak area normalization method.To treat that then the thing survey is made into certain density solution and measures its peak area with liquid Hunan, and then contrast, through calculating degree of purity of production to be measured with typical curve.Is example with 3 courages steroid-5-alkene-7-to Methyl benzenesulfonyl hydrazone-3-acetic ester: get 3 courages steroid-5-alkene-7-Methyl benzenesulfonyl hydrazone-3-acetic ester is got pure product 0.0387 gram with dissolve with methanol and fixed moltenly get 8 10ml volumetric flasks numbering 1-8 in the 25ml volumetric flask and pipette 400,800,1200,1600,2000,2400,2800,3200 μ l (microlitre) mother liquors and fixed molten to the each sample introduction 20 μ l of 10ml respectively, under the ultraviolet wavelength of 235nm, record the absorption peak area of different concns standardized solution with high performance liquid phase, draw typical curve with the peak area normalization method then.
Can calculate the productive rate of reaction product by the purity of reaction product.
The reaction formula of preparation method described in the embodiment of the invention 1 is as follows; from formula as can be seen; this kind prepares the method for 7-dehydrocholesterol; from cholesterol is that raw material begins reaction; at first experience hydroxyl protection, specific carbon potential be oxidized to carbonyl, carry out then becoming hydrazone reaction in the carbonyl position; at last with than the strong strong basicity reagent react of sodium hydroxide alkalescence, obtain the 7-dehydrocholesterol with water or acid-respons then.
The above only is a preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (21)
1.7-the preparation method of dehydrocholesterol may further comprise the steps:
A) with the hydroxyl protection on 3 of the cholesterol;
B) oxidation of coal on 7 of the product that step a) is made becomes carbonyl;
C) product that step b) is made and hydrazine derivative are carried out to hydrazone reaction, and the structure of described hydrazine derivative is that a hydrogen is replaced later hydrazine at the most;
D) product that step c) is made and strong basicity reagent react;
E) product that step d) is made and water or acid-respons.
2. method according to claim 1, wherein, step a) with the hydroxyl protection on 3 of the cholesterol is: cholesterol and carboxylic acid, carboxylic acid anhydride or acyl chloride reaction.
3. method according to claim 2, wherein said carboxylic acid, carboxylic acid anhydride or acyl chlorides are acetate, diacetyl oxide or Acetyl Chloride 98Min..
4. method according to claim 3, wherein, the mol ratio of described cholesterol and diacetyl oxide is 1: 10～1: 30, and the temperature of reaction is 100 ℃～160 ℃, and the reaction times is 2h～4h.
5. method according to claim 4, wherein, temperature of reaction is 115 ℃～155 ℃.
6. method according to claim 5, wherein, temperature of reaction is 125 ℃～145 ℃.
7. method according to claim 3, wherein, the mol ratio of cholesterol and acetate or diacetyl oxide is: 1: 1.2～1: 2.0, temperature of reaction was 60 ℃～90 ℃, was reflected in the non-protonization solvent and carried out.
8. method according to claim 7, wherein said non-protonization solvent is a benzene.
9. method according to claim 1, wherein, oxidation of coal on 7 of the product that step b) makes step a) becomes carbonyl to be: utilize the oxidation of coal on 7 of product that oxygenant makes step a) to become carbonyl, described oxygenant is selected from: chromium trioxide, peroxy tert-butyl alcohol, tertbutyl peroxide/Chromium hexacarbonyl composite oxidant, ammonium chloride/chromium trioxide composite oxidant, tertbutyl peroxide/CuI
2Composite oxidant, chromium trioxide/3,5-lutidine composite oxidant.
10. method according to claim 9, wherein, described oxygenant is a chromium trioxide, temperature of reaction is 55 ℃～65 ℃.
11. method according to claim 9, wherein, described oxygenant is a peroxy tert-butyl alcohol, and temperature of reaction is 25 ℃～45 ℃.
12. method according to claim 1, wherein, described hydrazine derivative is to the Methyl benzenesulfonyl hydrazine.
13. method according to claim 1, being reflected in the polar solvent of step c) carried out.
14. method according to claim 13, described polar solvent are methyl alcohol or ethanol.
15. method according to claim 1, wherein, the strong basicity reagent described in the step d) is selected from: sodium hydride, lithium hydride, lithium methide.
16. method according to claim 15, wherein, the strong basicity reagent described in the step d) is sodium hydride, and temperature of reaction is 80 ℃～150 ℃.
17. method according to claim 16, wherein, the temperature of the reaction of step d) is 140 ℃～150 ℃.
18. method according to claim 1, wherein, being reflected in the non-protonization solvent of step d) carried out.
19. method according to claim 18, wherein, the non-protonization solvent described in the step d) is N, dinethylformamide, methyl-sulphoxide, benzene, toluene, pyridine and derivative thereof, acetonitrile.
20. method according to claim 1, wherein, the acid described in the step e) is hydrochloric acid.
21. method according to claim 20, wherein said hydrochloric acid are concentration is 1%～2% hydrochloric acid.
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2008
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| 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 |
| 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 |
| CN115594727A (en) * | 2022-10-09 | 2023-01-13 | 南通励成生物工程有限公司（Cn） | Purification method of 7-dehydrocholesterol fermentation broth and purification intermediate thereof |
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