CN112159449B - Preparation method of 7-p-toluenesulfonylhydrazone-3-cholesterol ester - Google Patents
Preparation method of 7-p-toluenesulfonylhydrazone-3-cholesterol ester Download PDFInfo
- Publication number
- CN112159449B CN112159449B CN202011042826.6A CN202011042826A CN112159449B CN 112159449 B CN112159449 B CN 112159449B CN 202011042826 A CN202011042826 A CN 202011042826A CN 112159449 B CN112159449 B CN 112159449B
- Authority
- CN
- China
- Prior art keywords
- cholesterol ester
- toluenesulfonylhydrazone
- cholesterol
- reaction
- amino 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a preparation method of 7-p-toluenesulfonylhydrazone-3-cholesterol ester, which comprises the following steps: carrying out a hydrazonation reaction on p-toluenesulfonylhydrazide and 7-keto-3-cholesterol ester in a solvent under the catalysis of amino acid, and carrying out post-treatment after the reaction is finished to obtain the 7-p-toluenesulfonylhydrazone-3-cholesterol ester. The product obtained by the preparation method has the yield up to 97 percent, the content of more than or equal to 98 percent, and the preparation method is simple to operate, small in corrosivity of the used catalyst, high in safety and more suitable for industrial production.
Description
Technical Field
The invention belongs to the field of vitamin preparation, and particularly relates to a preparation method of 7-p-toluenesulfonylhydrazone-3-cholesterol ester.
Background
Vitamin D3Is essential for human life and health, and 7-p-toluenesulfonylhydrazone-3-cholesterol ester is vitamin D3Key intermediate for industrial production.
The 7-p-toluenesulfonylhydrazone-3-cholesterol ester is prepared by the hydrazonation reaction of p-toluenesulfonylhydrazine and 7-ketone-3-cholesterol ester. In order to obtain high yield, the hydrazonation reaction is usually carried out under the condition of taking acid as a catalyst, wherein the commonly used catalyst is hydrochloric acid, concentrated sulfuric acid and p-toluenesulfonic acid. Hydrochloric acid is used as a catalyst, and the requirement on equipment materials is high due to strong corrosivity of chloride ions, so that the production cost is high. Concentrated sulfuric acid is used as a catalyst, and the concentrated sulfuric acid not only has high corrosivity, but also has strong oxidizing property, so that reaction raw materials are subjected to complex oxidation reaction, the separation and purification process is complex, and the reaction yield is low. Because the p-toluenesulfonic acid ester compound is a genotoxic impurity, the p-toluenesulfonic acid has potential hazard risk in medical synthesis.
Chinese patent application with publication number CN 101220075A discloses a preparation method of 7-dehydrocholesterol, and in step (c) of example 1, a specific procedure is disclosed for reacting cholest-5-en-7-carbonyl-3-acetate with p-toluenesulfonylhydrazide in anhydrous ethanol to obtain a sulfonylhydrazone product, the patent application states that the yield of the step is 99% and the product purity is 95%, but from the operation process, the purity of the charged raw material cholest-5-ene-7-carbonyl-3-acetate is 87.1%, meanwhile, the feeding amount of the p-toluenesulfonyl hydrazide is excessive, a product is directly obtained through rotary evaporation after the reaction is finished, no purification operation is carried out except for the rotary evaporation, a product with the purity of 95% can not be obtained obviously, and the yield and the purity are difficult to be informed.
C é line Loncle et al reported a preparation method of 7-p-toluenesulfonylhydrazone-3-cholesterol ester analog (European Journal of Medicinal Chemistry 39(2004) 1067-1071) by carrying out a hydrazonation reaction in anhydrous methanol using concentrated hydrochloric acid as a catalyst and p-toluenesulfonylhydrazide and 7-keto-3-cholesterol ester as starting materials. The preparation method has mild reaction conditions, but also uses concentrated hydrochloric acid, has the defect of equipment corrosion, has low reaction yield of about 80 percent, and is not suitable for industrial production.
Disclosure of Invention
The technical problem to be solved by the invention is to provide the preparation method of the 7-p-toluenesulfonylhydrazone-3-cholesterol ester, the product obtained by the preparation method has high yield and purity, the operation is simple, the used catalyst has low corrosivity and high safety, and the preparation method is more suitable for industrial production.
The technical scheme provided by the invention is as follows:
a preparation method of 7-p-toluenesulfonylhydrazone-3-cholesterol ester comprises the following steps:
carrying out a hydrazonation reaction on p-toluenesulfonylhydrazide and 7-keto-3-cholesterol ester in a solvent under the catalysis of amino acid, and carrying out post-treatment after the reaction is finished to obtain the 7-p-toluenesulfonylhydrazone-3-cholesterol ester.
The amino acid molecule contains amino with certain alkalinity and carboxyl and sulfonic functional group with certain acidity, the special structure ensures that the amino acid has the characteristics of acidity and alkalinity, and the amino acid can form inner salt with certain phase transfer catalysis. In the research process, the amino acid is found to show excellent catalytic activity in catalyzing the hydrazonation reaction of p-toluenesulfonyl hydrazide and 7-keto-3-cholesterol ester.
The amino acid, preferably an acidic amino acid, particularly preferably one or more of aspartic acid, glutamic acid, taurine and cysteine, has a large influence on the reaction result. The dosage of the amino acid is 0.1 to 100 percent of the mass of the 7-ketone-3-cholesterol ester, and preferably 0.1 to 20 percent.
The 7-keto-3-cholesterol ester is preferably 7-keto-3-cholesterol acetate, 7-keto-3-cholesterol benzoate or 7-keto-3-cholesterol pivalate.
In the invention, the price of the p-toluenesulfonyl hydrazide is cheaper, and compared with the feeding amount of the 7-keto-3-cholesterol ester, the p-toluenesulfonyl hydrazide is slightly excessive without particularly strict requirements.
Specifically, in the present invention, the hydrazonation reaction of p-toluenesulfonylhydrazide and 7-keto-3-cholesterol ester is carried out in a mixed solvent of an alcohol and an alkane. The main reason is that the reactant of 7-ketone-3-cholesterol ester is easily dissolved in alkane solvent, and p-toluenesulfonyl hydrazide is easily dissolved in alcohol solvent. If a single kind of solvent is used, the solubility of the reactants is poor, resulting in a slow reaction rate.
Preferably, the solvent is a mixture of water, an alcohol solvent and a hydrocarbon solvent; more preferably, the alcohol solvent is one or two of methanol and ethanol;
the hydrocarbon solvent is one or more of petroleum ether, n-hexane and cyclohexane.
Preferably, the volume ratio of the alcohol solvent to the hydrocarbon solvent to the water is 1-6: 1: 0.1 to 1; more preferably, the volume ratio of the alcohol solvent to the hydrocarbon solvent to the water is 3-6: 1: 0.2 to 1.
Preferably, the temperature of the hydrazonation reaction is 30 to 60 ℃, and more preferably, the temperature of the hydrazonation reaction is 35 to 50 ℃.
Preferably, the post-treatment process is as follows: after the reaction is finished, crystallizing the reaction mixture at-20-15 ℃ overnight, filtering, washing and drying to obtain a white solid product. The crystallization temperature of the reaction mixture is more preferably-10 to 5 ℃.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention adopts amino acid as an acid catalyst, has higher yield and purity compared with hydrochloric acid or sulfuric acid, has small corrosion to equipment and is convenient for industrial production.
(2) The invention adopts a mixed system of water, alcohol solvent and hydrocarbon solvent to carry out reaction, can better dissolve the two raw materials, simultaneously has a certain phase transfer catalyst effect on amino acid, further promotes the reaction and improves the reaction yield.
Detailed Description
The invention is described in detail below with reference to non-limiting examples.
Example 1
Adding 50g of 7-ketone-3-cholesterol acetate, 22g of p-toluenesulfonylhydrazide, 10g of taurine, 300mL of methanol, 100mL of cyclohexane and 20mL of water into a 1000mL reaction bottle in sequence, reacting at 50 ℃ for 18 hours, detecting by high performance liquid chromatography that 0.1% of 7-ketone-3-cholesterol acetate raw material is remained (the detection wavelength is 205nm, the relative peak area accounts for the ratio), stopping the reaction, cooling the reaction mixed solution to-5 ℃ for crystallization for 4 hours, filtering while the solution is cold, washing a filter cake by using cold water, and drying to obtain 67g of a white solid product (the yield is 97%, and the external standard content is 98.5%).
The obtained white solid and the 7-p-toluenesulfonylhydrazone-3-cholesterol acetate have the same retention time in the high performance liquid chromatography, and the white solid is the 7-p-toluenesulfonylhydrazone-3-cholesterol acetate.
Example 2
Adding 50g of 7-ketone-3-cholesterol acetate, 22g of p-toluenesulfonyl hydrazide, 5g of aspartic acid, 300mL of methanol, 100mL of cyclohexane and 20mL of water into a 1000mL reaction bottle in sequence, reacting at 35 ℃ for 24 hours, detecting by high performance liquid chromatography that 0.1% of 7-ketone-3-cholesterol acetate raw material remains (the detection wavelength is 205nm, the relative peak area accounts for the ratio), stopping the reaction, cooling the reaction mixed solution to-5 ℃ for crystallization for 4 hours, filtering while the solution is cold, washing a filter cake by cold water, and drying to obtain 65g of a white solid product (the yield is 94%, and the external standard content is 98.0%).
The obtained white solid and the 7-p-toluenesulfonylhydrazone-3-cholesterol acetate have the same retention time in the high performance liquid chromatography, and the white solid is the 7-p-toluenesulfonylhydrazone-3-cholesterol acetate.
Example 3
Adding 50g of 7-ketone-3-cholesterol acetate, 22g of p-toluenesulfonyl hydrazide, 5g of glutamic acid, 300mL of methanol, 50mL of cyclohexane and 50mL of water into a 1000mL reaction bottle in sequence, reacting at 40 ℃ for 10 hours, detecting by high performance liquid chromatography that 0.1% of 7-ketone-3-cholesterol acetate raw material is remained (the detection wavelength is 205nm, the relative peak area is in proportion), stopping the reaction, cooling the reaction mixed solution to-5 ℃ for crystallization for 4 hours, filtering while the solution is cold, washing a filter cake by using cold water, and drying to obtain 66g of a white solid product (the yield is 96%, and the external standard content is 99.2%).
The obtained white solid and the 7-p-toluenesulfonylhydrazone-3-cholesterol acetate have the same retention time in the high performance liquid chromatography, and the white solid is the 7-p-toluenesulfonylhydrazone-3-cholesterol acetate.
Example 4
Adding 57g of 7-ketone-3-cholesterol benzoate, 22g of p-toluenesulfonylhydrazide, 10g of taurine, 300mL of methanol, 100mL of petroleum ether and 20mL of water in a 1000mL reaction bottle in sequence, reacting at 50 ℃ for 18 hours, detecting by high performance liquid chromatography that 0.1% of 7-ketone-3-cholesterol benzoate raw material is remained (the detection wavelength is 205nm, the relative peak area is in proportion), stopping the reaction, cooling the reaction mixed solution to-5 ℃ for crystallization for 4 hours, filtering while the solution is cold, washing a filter cake by cold water, and drying to obtain 70g of a white solid product (the yield is 92%, and the external standard content is 99.0%).
The obtained white solid and the 7-p-toluenesulfonylhydrazone-3-cholesterol benzoate have the same retention time in the high performance liquid chromatography, and the white solid is the 7-p-toluenesulfonylhydrazone-3-cholesterol acetate.
Example 5
Adding 55g of 7-ketone-3-cholesterol pivalate, 22g of p-toluenesulfonylhydrazide, 0.6g of glutamic acid, 450mL of methanol, 100mL of n-hexane and 100mL of water into a 1000mL reaction bottle in sequence, reacting at 45 ℃ for 36 hours, detecting by high performance liquid chromatography that 0.1% of 7-ketone-3-cholesterol pivalate remains (the detection wavelength is 205nm, the relative peak area is in proportion), stopping the reaction, cooling the reaction mixed solution to-5 ℃ for crystallization for 4 hours, filtering while the solution is cold, washing a filter cake by cold water, and drying to obtain 70g of a white solid product (the yield is 94%, and the external standard content is 98.5%).
The obtained white solid and the 7-p-toluenesulfonylhydrazone-3-cholesterol pivalate are kept for the same time in the high performance liquid chromatography, and the white solid is the 7-p-toluenesulfonylhydrazone-3-cholesterol acetate.
Comparative example 1
Adding 50g of 7-ketone-3-cholesterol acetate, 22g of p-toluenesulfonylhydrazide, 12.4mL of concentrated hydrochloric acid and 650mL of methanol into a 1000mL reaction bottle in sequence, reacting at 30 ℃ for 16 hours, detecting by high performance liquid chromatography that 0.1% of 7-ketone-3-cholesterol acetate raw material remains (the detection wavelength is 205nm, the relative peak area accounts for the ratio), stopping the reaction, cooling the reaction mixed solution to-5 ℃ for crystallization for 4 hours, filtering while the solution is cold, washing a filter cake by using cold water, and drying to obtain 58g of a white solid product (the yield is 84%, and the external standard content is 97.3%).
Claims (7)
1. A preparation method of 7-p-toluenesulfonylhydrazone-3-cholesterol ester is characterized by comprising the following steps:
carrying out a hydrazonation reaction on p-toluenesulfonylhydrazide and 7-keto-3-cholesterol ester in a solvent under the catalysis of amino acid, and carrying out post-treatment after the reaction is finished to obtain the 7-p-toluenesulfonylhydrazone-3-cholesterol ester;
the amino acid is acidic amino acid;
the solvent is a mixture of water, an alcohol solvent and a hydrocarbon solvent;
the 7-ketone-3-cholesterol ester is 7-ketone-3-cholesterol acetate, 7-ketone-3-cholesterol benzoate or 7-ketone-3-cholesterol pivalate.
2. The method of claim 1, wherein the amino acid is one or more of aspartic acid, glutamic acid, and taurine.
3. The method for preparing 7-p-toluenesulfonylhydrazone-3-cholesterol ester according to any one of claims 1 to 2, wherein the amount of the amino acid used is 0.1% to 100% by mass of the 7-keto-3-cholesterol ester.
4. The method for preparing 7-p-toluenesulfonylhydrazone-3-cholesterol ester according to claim 3, wherein said amino acid is used in an amount of 0.1% to 20% by mass of 7-keto-3-cholesterol ester.
5. The method for preparing 7-p-toluenesulfonylhydrazone-3-cholesterol ester according to claim 1, wherein said alcohol solvent is one or both of methanol and ethanol;
the hydrocarbon solvent is one or more of petroleum ether, n-hexane and cyclohexane.
6. The method for preparing 7-p-toluenesulfonylhydrazone-3-cholesterol ester according to claim 1, wherein said post-treatment process is as follows: after the reaction is finished, crystallizing the reaction mixture at the temperature of minus 20-15 ℃, and filtering, washing and drying to obtain a white solid;
the white solid is the 7-p-toluenesulfonylhydrazone-3-cholesterol ester.
7. The method of claim 6, wherein the crystallization temperature of the reaction mixture is-10 to 5 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011042826.6A CN112159449B (en) | 2020-09-28 | 2020-09-28 | Preparation method of 7-p-toluenesulfonylhydrazone-3-cholesterol ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011042826.6A CN112159449B (en) | 2020-09-28 | 2020-09-28 | Preparation method of 7-p-toluenesulfonylhydrazone-3-cholesterol ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112159449A CN112159449A (en) | 2021-01-01 |
| CN112159449B true CN112159449B (en) | 2021-06-18 |
Family
ID=73861847
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011042826.6A Active CN112159449B (en) | 2020-09-28 | 2020-09-28 | Preparation method of 7-p-toluenesulfonylhydrazone-3-cholesterol ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112159449B (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101220075A (en) * | 2008-01-25 | 2008-07-16 | 北京化工大学 | Preparation method for 7-dehydrochol esterol |
| CN102030794B (en) * | 2010-12-01 | 2013-07-24 | 安徽丰原发酵技术工程研究有限公司 | Method for preparing 7-dehydrocholesterol |
| CN105131071B (en) * | 2015-07-14 | 2017-09-12 | 浙江花园生物高科股份有限公司 | A kind of synthetic method of the Tosylhydrazone of 25 hydroxy cholesterol acetate 7 |
| CN110143993B (en) * | 2018-02-13 | 2020-12-11 | 江西天新药业股份有限公司 | Method for preparing acetylcholinesterase-7-ketone p-toluenesulfonylhydrazone |
| CN109761867B (en) * | 2019-02-28 | 2021-02-26 | 四川健腾生物技术有限公司 | Vitamin D production by using lanolin as raw material3Is a new method for industrialization |
-
2020
- 2020-09-28 CN CN202011042826.6A patent/CN112159449B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN112159449A (en) | 2021-01-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114133350B (en) | Preparation method of anti-neocrown drug Paxlovid intermediate | |
| CN104447443A (en) | Preparation method for apremilast and intermediate of apremilast | |
| CN112159449B (en) | Preparation method of 7-p-toluenesulfonylhydrazone-3-cholesterol ester | |
| CN103570601A (en) | Preparation method of optical active medicine intermediate | |
| CN115430418A (en) | Catalyst, preparation method thereof and method for preparing acetic acid by using catalyst | |
| CN114181117A (en) | Preparation method of peramivir intermediate | |
| CN112898307A (en) | Ketorolac impurity C and preparation method and application thereof | |
| CN111908999A (en) | Method for preparing 1, 3-butanediol | |
| KR102080381B1 (en) | Heteropoly Acid Catalysts with Aluminum and Cobalt as Central Atom, Preparation Method Thereof, and Hydration reaction of n-Butene to 2-Butanol Using Said Catalysts | |
| CN111499497B (en) | Preparation method of thymol | |
| CN107540520B (en) | Method for preparing pyromellitic acid or trimellitic acid from pinacol | |
| CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
| WO2023138341A9 (en) | Synthesis method for ertapenem sodium | |
| CN113563166B (en) | Synthesis method of vanillyl alcohol ether | |
| CN103408553B (en) | A kind of process for refining of hydromorphone acid salt | |
| CN115124452B (en) | Preparation method of 2- (4-amino-2-ethoxyphenyl) isoindole-1, 3-dione | |
| JPH04149160A (en) | Production of 1-amino-4-alkoxybenzene compounds | |
| CN110128246A (en) | A kind of preparation method of hydroxytyrosol | |
| CN105820054A (en) | Preparation method of 3-methoxy-2-nitrobenzoate | |
| CN114225929B (en) | Catalyst, application and preparation method of trans-tranexamic acid | |
| CN117800858B (en) | Preparation method for catalytic cyanation of milbelin | |
| CN115814851B (en) | Preparation method and application of ionic liquid gel catalyst for synthesizing n-borneol acetate | |
| CN110845305A (en) | Method for preparing L-menthol by adopting modified homogeneous catalyst | |
| CN110105362B (en) | Safe and green folic acid synthesis method catalyzed by heteropoly acid | |
| CN116003283B (en) | Preparation method of iohexol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |