CN102030794A - Method for preparing 7-dehydrocholesterol - Google Patents
Method for preparing 7-dehydrocholesterol Download PDFInfo
- Publication number
- CN102030794A CN102030794A CN201010571792XA CN201010571792A CN102030794A CN 102030794 A CN102030794 A CN 102030794A CN 201010571792X A CN201010571792X A CN 201010571792XA CN 201010571792 A CN201010571792 A CN 201010571792A CN 102030794 A CN102030794 A CN 102030794A
- Authority
- CN
- China
- Prior art keywords
- cholesterol
- reaction
- product
- carboxylic acid
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Steroid Compounds (AREA)
Abstract
The invention relates to a method for preparing 7-dehydrocholesterol, which comprises the following steps: 1) protecting hydroxyl on the 3-site of cholesterol; 2) oxidizing carbon on the 7-site of the product obtained in step 1) into carbonyl; 3) carrying out a hydrazone reaction on the product obtained in step 2) and a hydrazine derivative; 4) reacting the product obtained in step 3) with a strongly alkaline reagent; and 5) reacting the product obtained in step 4) with water or an acid. The method has the advantages of simple operation process, less secondary reaction, high yield and less corrosion to equipment, thereby having high industrial production values.
Description
Technical field
The invention belongs to the organic synthesis field, relate to a kind of preparation vitamins D
3The method of precursor 7-dehydrocholesterol.
Background technology
Vitamins D
3Be the requisite liposoluble vitamin that people and domestic animal, domestic animal grow, breed, earn a bare living and keep fit, its main effect is to 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.Vitamins D
3Be mainly used in 3 aspects such as pharmaceutical preparation, foodstuff additive and fodder additives, as pharmaceutical preparation, be mainly used in treatment clinically and arrest illnesss such as building disease, richets, osteoporosis, thyroprivia; As food beverage additive, it can make an addition in milk, milk-product, biscuit, candy and the various beverage, is used to prevent vitamin D deficiency; Vitamins D
3As the fodder additives of livestock and poultry, can increase the output of meat, egg, milk, and can improve its nutritive value.
At present, vitamins D is produced in the whole world per year
350-60t is mainly produced by minority developed country.Annual in the world to vitamins D
3Demand surpasses 100t, the annual vitamins D of China
3Consumption (amounting to into the pure product of ten thousand 1.u./g) has survey data to show that China is to vitamins D more than 6t
3Demand will be very fast surpass 10t.The vitamins D of present China
3With feed additive industry consumption maximum.Vitamins D
3The production key be the production of its precursor 7-dehydrocholesterol, the output of 7-dehydrocholesterol and quality product can determine vitamins D to a great extent
3Situation.
The tradition vitamins D
3The synthetic employing of precursor adds the method that a bromine is eliminated a part hydrogen bromide more earlier on 7 of cholesterol, but this method by product is more, and is harmful to environment, restricted the development of this method.
Summary of the invention
The object of the present invention is to provide that a kind of technology is reasonable, selectivity good, reaction yield is high, cost is low, eco-friendly vitamins D
3The preparation method of precursor (7-dehydrocholesterol).
For achieving the above object, the invention provides following technical scheme:
The invention provides a kind of method of the 7-of preparation dehydrocholesterol, comprise the steps:
1) hydroxyl on 3 of the cholesterol is protected;
2) oxidation of coal that step 1) is made on 7 of the products becomes carbonyl;
3) with step 2) product and the hydrazine derivative that make be carried out to hydrazone reaction;
4) with the product and the strong basicity reagent react of step 3);
5) product that step 4) is made and water or acid-respons.
Wherein, utilize acyl chlorides, carboxylic acid or carboxylic acid anhydride that the hydroxyl on 3 of the described cholesterol of step 1) is protected.
Described acyl chlorides can be Benzoyl chloride, Acetyl Chloride 98Min., propionyl chloride etc., preferred Acetyl Chloride 98Min..
Described carboxylic acid can be that saturated carboxylic acid liquid can be unsaturated carboxylic acid, preferred saturated carboxylic acid, more preferably monocarboxylic acid acetate.
Described carboxylic acid anhydride can be that single acid anhydride liquid can be to mix acid anhydride, can be that aliphatic carboxylic acid acid anhydride liquid can be the aromatic carboxylic acid acid anhydride, preferred diacetyl oxide.
Utilize Acetyl Chloride 98Min. as reactant, concrete grammar can for: with cholesterol and Acetyl Chloride 98Min. according to 1: 1.15-1: 1.40 molar feed ratio feeds intake, then 70 ℃-120 ℃ of temperature, preferred 70 ℃-100 ℃, more preferably 80 ℃-90 ℃, reaction 7h-10h.Hydroxyl reaction by acid chloride functional groups and cholesterol generates the ester bond structure, thereby can prevent the destruction of oxidized or some other form in the follow-up reaction process.
Step 2) in, utilize the oxidation of coal on 7 of product that oxygenant makes step 1) to be carbonyl, described oxygenant is selected from tin anhydride, cobalt sesquioxide/oxygen, potassium hydroxide/oxygen, chromium trioxide/acetate or potassium permanganate.
Preferably, described oxygenant is a tin anhydride, and temperature of reaction is 50 ℃-55 ℃.
Preferably, described oxygenant is a potassium permanganate, and temperature of reaction is 70 ℃-80 ℃.
In the step 3), described hydrazine derivative is to the Methyl benzenesulfonyl hydrazine.
In the step 3), described one-tenth hydrazone reaction carries out in polar solvent, and described polar solvent can be methyl alcohol, ethanol, acetone ether, normal hexane etc.Preferably, described polar solvent is methyl alcohol or normal hexane.
Strong basicity reagent described in the step 4) is selected from sodium hydride, lithium hydride, lithium methide or Lithamide.
Preferably, the strong basicity reagent described in the step 4) is Lithamide, and temperature of reaction is 70 ℃-120 ℃, preferred 100 ℃-120 ℃.
Being reflected in the non-protonization solvent of step 4) carried out.
Preferably, described non-protonization solvent is dimethyl sulfoxide (DMSO), benzene, toluene or pyridine etc.
Acid described in the step 5) can be hydrochloric acid, and phosphoric acid, Glacial acetic acid etc. are preferably Glacial acetic acid.
The inventive method is simple to operate, and side reaction is few, and the productive rate height is little to equipment corrosion, has very high industrial production and is worth.
Embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.Without departing from the spirit and substance of the case in the present invention, modification or replacement to the inventive method, step or condition are done all belong to scope of the present invention.
If do not specialize the conventional means that used technique means is well known to those skilled in the art among the embodiment.
Embodiment 1
1) get the 5g cholesterol and join in the 40ml Acetyl Chloride 98Min., at 100 ℃ of backflow 8h, reaction generates cholesterol acetate.Utilizing the purity of the cholesterol acetate of internal mark method determination reaction generation is 94%, and productive rate is 90%.
2) get the 5g cholesterol acetate and be dissolved in the 70ml pimelinketone, shake up under the room temperature, be heated to 50 ℃.Get the 0.3g tin anhydride and add in the reaction solution in batches, 30min adds.React 8h down at 80 ℃, reduce to room temperature, use 3 ℃ water cooling again, crystal is separated out, suction filtration, 50 ℃ of vacuum-drying 6h.The 7-carbonyl cholesterol acetate purity 86% that obtains after testing, productive rate 65%.
3) get 7-carbonyl cholesterol acetate 5g and 8g the Methyl benzenesulfonyl hydrazine is dissolved in the 50ml dehydrated alcohol together, stir under the room temperature with the thin layer chromatography monitoring, stopped reaction behind the 15h obtains product 7-to Methyl benzenesulfonyl hydrazone cholesterol acetate after concentrating.Purity is 96% after testing, productive rate 98%.
4,5) get 7-Methyl benzenesulfonyl hydrazone cholesterol acetate 5g is dissolved in the 50ml Benzene Chloride, add the 0.4g Lithamide in batches, stir 5h at 100 ℃.Be cooled to room temperature, 10ml is washed till slightly acidic with Glacial acetic acid, is washed till neutrality with deionized water again.Enriched product obtains faint yellow solid, and 7-dehydrocholesterol purity is 57% after testing, and productive rate is 75%.
Embodiment 2
1) get the 5g cholesterol and join in the 40ml Benzoyl chloride, at 80 ℃ of backflow 6h, reaction generates cholesterol benzoate.Utilizing the purity of the cholesterol benzoate of internal mark method determination reaction generation is 96%, and productive rate is 93%.
2) get the 5g cholesterol benzoate and be dissolved in the 70ml pimelinketone, shake up under the room temperature, be heated to 50 ℃.Get 0.5g potassium permanganate and add in the reaction solution in batches, 30min adds.React 5h down at 50 ℃, reduce to room temperature, use 3 ℃ water cooling again, crystal is separated out, suction filtration, 50 ℃ of vacuum-drying 6h.The 7-carbonyl cholesterol benzoate purity 87% that obtains after testing, productive rate 69%.
Step 3 among following steps and the embodiment 1,4,5) identical.
Embodiment 3
Among this embodiment, step 2) different with embodiment 1, other step is identical with embodiment 1 step.The step 2 of present embodiment) be:
2) get the 5g cholesterol acetate and be dissolved in the 70ml pimelinketone, shake up under the room temperature, be heated to 50 ℃.Get the 0.2g cobalt sesquioxide and add in the reaction solution in batches, 30min adds, and continues aerating oxygen.React 6h down at 90 ℃, reduce to room temperature, use 3 ℃ water cooling again, crystal is separated out, suction filtration, 50 ℃ of vacuum-drying 6h.The 7-carbonyl cholesterol acetate purity 91% that obtains after testing, productive rate 75%.
Embodiment 4
Among this embodiment, step 2) different with embodiment 1, other step is identical with embodiment 1 step.The step 2 of present embodiment) be:
2) get the 5g cholesterol acetate and be dissolved in 70ml acetate, shake up under the room temperature, be heated to 50 ℃.Get the 0.2g chromium trioxide and add in the reaction solution in batches, 30min adds.React 6h down at 80 ℃, reduce to room temperature, use 3 ℃ water cooling again, crystal is separated out, suction filtration, 50 ℃ of vacuum-drying 6h.The 7-carbonyl cholesterol acetate purity 76% that obtains after testing, productive rate 73%.
Embodiment 5
Among this embodiment, step 4,5) different with embodiment 1, other step is identical with embodiment 1 step.The step 4 of present embodiment, 5) be:
4,5) get 7-Methyl benzenesulfonyl hydrazone cholesterol acetate 6g is dissolved in the 50ml Benzene Chloride, add the 0.4g lithium methide in batches, stir 0.5h, be warmed up to 20 ℃, reaction 2h at-20 ℃.Be cooled to room temperature, 10ml is washed till slightly acidic with hydrochloric acid, is washed till neutrality with deionized water again.Enriched product obtains faint yellow solid, and 7-dehydrocholesterol purity is 67% after testing, and productive rate is 76%.Embodiment 6
Among this embodiment, step 4,5) different with embodiment 1, other step is identical with embodiment 1 step.The step 4 of present embodiment, 5) be:
4,5) get 7-Methyl benzenesulfonyl hydrazone cholesterol acetate 6g is dissolved in the 50ml Benzene Chloride, add the 0.3g lithium diisopropylamine in batches, stir 0.5h, be warmed up to 110 ℃, reaction 2h at-20 ℃.Be cooled to room temperature, 10ml is washed till slightly acidic with hydrochloric acid, is washed till neutrality with deionized water again.Enriched product obtains faint yellow solid, and 7-dehydrocholesterol purity is 77% after testing, and productive rate is 80%.
Embodiment 7
Among this embodiment, step 4,5) different with embodiment 1, other step is identical with embodiment 1 step.The step 4 of present embodiment, 5) be:
4,5) get 7-Methyl benzenesulfonyl hydrazone cholesterol acetate 6g is dissolved in the 50ml Benzene Chloride, add 0.6g tertiary butyl Lithamide in batches, stir 0.5h, be warmed up to 110 ℃, reaction 2h at-20 ℃.Be cooled to room temperature, 10ml is washed till slightly acidic with hydrochloric acid, is washed till neutrality with deionized water again.Enriched product obtains faint yellow solid, and 7-dehydrocholesterol purity is 75% after testing, and productive rate is 81%.
Embodiment 8
Among this embodiment, step 4,5) different with embodiment 1, other step is identical with embodiment 1 step.The step 4 of present embodiment, 5) be:
4,5) get 7-Methyl benzenesulfonyl hydrazone cholesterol acetate 6g is dissolved in the 50ml Benzene Chloride, add the 0.2g sodium methylate in batches, stir 0.5h, be warmed up to 110 ℃, reaction 2h at-20 ℃.Be cooled to room temperature, 10ml is washed till slightly acidic with hydrochloric acid, is washed till neutrality with deionized water again.Enriched product obtains faint yellow solid, and 7-dehydrocholesterol purity is 74% after testing, and productive rate is 79%.
Embodiment 9
Among this embodiment, step 4,5) different with embodiment 1, other step is identical with embodiment 1 step.The step 4 of present embodiment, 5) be:
4,5) get 7-Methyl benzenesulfonyl hydrazone cholesterol acetate 6g is dissolved in the 50ml Benzene Chloride, add the 0.4g sodium ethylate in batches, stir 0.5h, keep 20 ℃, reaction 2h at 20 ℃.Be cooled to room temperature, 10ml is washed till slightly acidic with hydrochloric acid, is washed till neutrality with deionized water again.Enriched product obtains faint yellow solid, and 7-dehydrocholesterol purity is 79% after testing, and productive rate is 82%.
Embodiment 10
Among this embodiment, step 4,5) different with embodiment 1, other step is identical with embodiment 1 step.The step 4 of present embodiment, 5) be:
4,5) get 7-Methyl benzenesulfonyl hydrazone cholesterol acetate 6g is dissolved in the 50ml Benzene Chloride, add the 0.3g potassium tert.-butoxide in batches, stir 0.5h, keep 20 ℃, reaction 2h at 20 ℃.Be cooled to room temperature, 10ml is washed till slightly acidic with hydrochloric acid, is washed till neutrality with deionized water again.Enriched product obtains faint yellow solid, and 7-dehydrocholesterol purity is 77% after testing, and productive rate is 78%.
Though above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this is to show and Yi Fengjian to those skilled in the art.Therefore, this modification of this that made or improvement without departing from theon the basis of the spirit of the present invention all belongs to the scope of protection of present invention.
Claims (10)
1. a method for preparing the 7-dehydrocholesterol comprises the steps:
1) hydroxyl on 3 of the cholesterol is protected;
2) oxidation of coal that step 1) is made on 7 of the products becomes carbonyl;
3) with step 2) product and the hydrazine derivative that make be carried out to hydrazone reaction;
4) with the product and the strong basicity reagent react of step 3);
5) product that step 4) is made and water or acid-respons.
2. method according to claim 1 is characterized in that, utilizes acyl chlorides, carboxylic acid or carboxylic acid anhydride that the hydroxyl on 3 of the described cholesterol of step 1) is protected.
3. method according to claim 2 is characterized in that, described acyl chlorides, carboxylic acid or carboxylic acid anhydride are Acetyl Chloride 98Min., acetate or diacetyl oxide.
4. method according to claim 3 is characterized in that, the mol ratio of cholesterol and Acetyl Chloride 98Min. is 1: 1.15-1: 1.40, and temperature of reaction is 70 ℃-120 ℃, the reaction times is 7h-10h.
5. method according to claim 1, it is characterized in that, step 2) in, utilize the oxidation of coal on 7 of product that oxygenant makes step 1) to be carbonyl, described oxygenant is selected from tin anhydride, cobalt sesquioxide/oxygen, potassium hydroxide/oxygen, chromium trioxide/acetate or potassium permanganate.
6. method according to claim 1 is characterized in that, in the step 3), described hydrazine derivative is to the Methyl benzenesulfonyl hydrazine.
7. method according to claim 1 is characterized in that, in the step 3), described one-tenth hydrazone reaction carries out in polar solvent.
8. method according to claim 1 is characterized in that, the strong basicity reagent described in the step 4) is selected from sodium hydride, lithium hydride, lithium methide or Lithamide.
9. method according to claim 1 is characterized in that, being reflected in the non-protonization solvent of step 4) carried out.
10. method according to claim 1 is characterized in that, the acid described in the step 5) is Glacial acetic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010571792 CN102030794B (en) | 2010-12-01 | 2010-12-01 | Method for preparing 7-dehydrocholesterol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010571792 CN102030794B (en) | 2010-12-01 | 2010-12-01 | Method for preparing 7-dehydrocholesterol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102030794A true CN102030794A (en) | 2011-04-27 |
| CN102030794B CN102030794B (en) | 2013-07-24 |
Family
ID=43884299
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010571792 Active CN102030794B (en) | 2010-12-01 | 2010-12-01 | Method for preparing 7-dehydrocholesterol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102030794B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702295A (en) * | 2012-05-24 | 2012-10-03 | 河南利伟生物药业股份有限公司 | Preparation method of 7-dehydrocholesterol |
| CN110143993A (en) * | 2018-02-13 | 2019-08-20 | 江西天新药业股份有限公司 | The method for preparing acetyl cholesterol -7- ketone Tosylhydrazone |
| 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 |
| WO2021121239A1 (en) | 2019-12-19 | 2021-06-24 | 湖南科瑞生物制药股份有限公司 | Method for preparing cholesterol, derivative thereof, and analog thereof |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB537030A (en) * | 1938-09-02 | 1941-06-05 | Du Pont | Sterol compounds and process for their preparation |
| CN1795201A (en) * | 2003-04-24 | 2006-06-28 | 姜宪中 | Process for preparing guggulsterones and guggulsterol |
| CN101220075A (en) * | 2008-01-25 | 2008-07-16 | 北京化工大学 | Preparation method for 7-dehydrochol esterol |
-
2010
- 2010-12-01 CN CN 201010571792 patent/CN102030794B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB537030A (en) * | 1938-09-02 | 1941-06-05 | Du Pont | Sterol compounds and process for their preparation |
| CN1795201A (en) * | 2003-04-24 | 2006-06-28 | 姜宪中 | Process for preparing guggulsterones and guggulsterol |
| CN101220075A (en) * | 2008-01-25 | 2008-07-16 | 北京化工大学 | Preparation method for 7-dehydrochol esterol |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702295A (en) * | 2012-05-24 | 2012-10-03 | 河南利伟生物药业股份有限公司 | Preparation method of 7-dehydrocholesterol |
| CN110143993A (en) * | 2018-02-13 | 2019-08-20 | 江西天新药业股份有限公司 | The method for preparing acetyl cholesterol -7- ketone Tosylhydrazone |
| WO2021121239A1 (en) | 2019-12-19 | 2021-06-24 | 湖南科瑞生物制药股份有限公司 | Method for preparing cholesterol, derivative thereof, and analog thereof |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102030794B (en) | 2013-07-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102030794B (en) | Method for preparing 7-dehydrocholesterol | |
| CN108503531B (en) | Preparation method of 3, 3-dimethyl-2-oxobutyric acid | |
| CN101607888B (en) | Alpha-keto-leucine-calcium preparation method | |
| CN101220075A (en) | Preparation method for 7-dehydrochol esterol | |
| CN106699774A (en) | Sulbactam sodium preparation method | |
| US20130253001A1 (en) | Highly soluble salt of pyrroloquinoline quinone and method for producing the same | |
| CN109384660B (en) | Synthetic method of 2-methyl-1, 4-naphthoquinone | |
| CN102690194B (en) | Preparation method of 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid | |
| CN102827015B (en) | Preparation method of 5-aminolevulinic acid (ALA) hydrochloride | |
| CN101671286B (en) | Method for preparing benzoyl-1,3-cyclohexanedione compound | |
| US9802977B2 (en) | Method of synthesizing 25-hydroxy cholesterol | |
| US3362988A (en) | Alkanoylnaphthyloxy-carboxylic acids | |
| CN104672155B (en) | A kind of synthetic method for improving quinocetone | |
| PAYNE | Reactions of hydrogen peroxide. IX. oxidation of cyanopyridines | |
| Rohrmann et al. | The use of chalcones in the synthesis of medicinal intermediates | |
| CN111187146B (en) | Process for producing 2-methyl-3-buten-2-ol | |
| CN102702295A (en) | Preparation method of 7-dehydrocholesterol | |
| CN104402690B (en) | The preparation method of method Buddhist nun's aldehyde and accompany the preparation method of auspicious tretinoin | |
| CN108997165B (en) | Method for synthesizing balsalazide disodium | |
| CN107868054A (en) | A kind of preparation method of azoxystrobin intermediate | |
| Hardman | The Preparation and Some Reactions of α-(ι-Cyanoethyl)-β-naphthol | |
| CN109836311B (en) | Method for controlling lignin model molecule fracture by amine at room temperature | |
| CN109384659B (en) | Preparation method of 2-methyl-1, 4-naphthoquinone | |
| CN101973874B (en) | Preparation method of 3-dehydroshikimic ester compound | |
| CN109336810A (en) | A kind of preparation method of haloperidid class nitrogen oxides |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |