CN111925406B - Preparation method and application of 7-ketocholesterol acetate - Google Patents
Preparation method and application of 7-ketocholesterol acetate Download PDFInfo
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Abstract
The invention relates to a preparation method of 7-ketocholesterol acetate, which comprises the following steps: (1) dissolving cholesterol acetate, a catalyst, an initiator and an antioxidant in a mixed solvent to obtain a first mixed solution, and introducing oxygen into the first mixed solution to perform an oxidation reaction on the cholesterol acetate and the oxygen to obtain a second mixed solution; (2) and treating the second mixed solution to obtain the 7-ketocholesterol acetate. The invention also relates to application of the 7-ketocholesterol acetate obtained by the preparation method in preparation of 7-dehydrocholesterol. The antioxidant is added in the preparation method, so that the polymerization reaction of the free radicals of reactants in a reaction system can be effectively prevented, the reaction selectivity can be improved, and the yield and the purity of the target product 7-ketocholesterol acetate can be improved.
Description
Technical Field
The invention belongs to the technical field of vitamin preparation, and particularly relates to a preparation method and application of 7-ketocholesterol acetate.
Background
The 7-ketocholesterol acetate is a key intermediate for synthesizing vitamin D3 and is mainly prepared by the oxidation reaction of the allylic position of the cholesterol acetate.
The traditional preparation method comprises the following steps: (1) the cholesterol acetate allyl is subjected to oxidation reaction by transition metals such as Cr, Fe, Cu, Co and the like and complexes thereof, the common oxidant is chromium salt or oxides thereof, mainly comprising chromium oxide, potassium dichromate, sodium dichromate and the like, but when the chromium salt is the oxidant, the dosage of the oxidant is large, heavy metal pollution to the environment is easy to cause, and the oxidant is difficult to be applied to the development direction of green industry; (2) the oxidation reaction of the allyl position of the cholesterol acetate is carried out by using a catalytic amount of selenide as an oxidant, and the method has the disadvantages of more selenide dosage, serious environmental pollution and difficult wide application.
In recent years, a method of oxidizing an allylic position of cholesterol acetate with oxygen using an oxynitride as a catalyst has been attracting much attention. Chinese patent application publication No. CN 105669813 a discloses a method for synthesizing 7-ketocholesterol acetate, which uses oxygen as an oxidant, and then adds a main catalyst N-hydroxyphthalimide (NHPI), and a cocatalyst consisting of benzoyl peroxide and quaternary ammonium salt to catalyze allylic position of cholesterol acetate to perform oxidation reaction, but the method has low yield of the product, and requires continuous distillation of tetrahydrofuran to carry water in the reaction process, which is high in energy consumption, complex in operation, and not easy to control, thus not beneficial to industrial production.
Disclosure of Invention
In view of the above, it is necessary to provide a method for producing 7-ketocholesterol acetate with high reaction selectivity and high yield and use thereof.
A method of preparing 7-keto-cholesterol acetate, comprising:
(1) dissolving cholesterol acetate, a catalyst, an initiator and an antioxidant in a mixed solvent to obtain a first mixed solution, and introducing oxygen into the first mixed solution to perform an oxidation reaction on the cholesterol acetate and the oxygen to obtain a second mixed solution; and
(2) and treating the second mixed solution to obtain the 7-ketocholesterol acetate.
In one embodiment, the antioxidant in step (1) is a phenolic compound containing a phenol structure.
In one embodiment, the antioxidant comprises at least one of 2, 6-di-tert-butyl-p-cresol, o-tert-butyl-p-methoxyphenol, tocopherol, and tert-butyl hydroquinone.
In one embodiment, the mass of the antioxidant in step (1) is 0.001% -1% of the mass of the cholesterol acetate.
In one embodiment, the catalyst in step (1) is an N-hydroxy derivative selected from one or more of N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxy-2, 3-naphthalimide, N-hydroxy-3, 4,5, 6-tetraphenylphthalimide, or 3-picolyl-N-hydroxyphthalimide, and the molar ratio of the catalyst to the cholesterol acetate is from 0.1:1 to 1.2: 1.
In one embodiment, the catalyst is N-hydroxyphthalimide.
In one embodiment, the catalyst is recovered when the second mixed solution is treated in step (2).
In one embodiment, the catalyst recovered in step (2) is recycled to step (1) for further use.
In one embodiment, in step (1), the initiator comprises at least one of benzoyl peroxide and transition metal salt, and the mass of the initiator is 0.1-1% of the mass of the cholesterol acetate.
In one embodiment, the mixed solvent in step (1) comprises a hydrocarbon solvent and a polar solvent, the molar ratio of the hydrocarbon solvent to the cholesterol acetate is 5:1-20:1, and the molar ratio of the polar solvent to the cholesterol acetate is 20:1-40: 1.
In one embodiment, the temperature of the oxidation reaction in step (1) is from 20 ℃ to 100 ℃.
In the preparation method of the 7-ketocholesterol acetate, the added antioxidant can effectively prevent the free radical of the cholesterol acetate in a reaction system from generating a polymerization reaction, so that the selectivity of the reaction can be effectively improved, the yield and the purity of the target product 7-ketocholesterol acetate can be improved, and the purity can reach more than 97%.
The application of the 7-ketocholesterol acetate obtained by the preparation method of the 7-ketocholesterol acetate in preparing 7-dehydrocholesterol.
Detailed Description
The preparation method and application of the 7-ketocholesterol acetate provided by the invention are further explained below.
The preparation method of the 7-ketocholesterol acetate provided by the invention comprises the following steps:
(1) dissolving cholesterol acetate, a catalyst, an initiator and an antioxidant in a mixed solvent to obtain a first mixed solution, and introducing oxygen into the first mixed solution to perform an oxidation reaction on the cholesterol acetate and the oxygen to obtain a second mixed solution; and
(2) and treating the second mixed solution to obtain the 7-ketocholesterol acetate.
Generally, the existence of the antioxidant is not beneficial to the oxidation reaction, but in the step (1) of the invention, the addition of the antioxidant can effectively prevent the free radical of the cholesterol acetate in the reaction system from generating a polymerization reaction, so that the selectivity of the reaction can be effectively improved, the yield and the purity of the target product 7-ketocholesterol acetate can be further improved, and the purity can reach more than 97%.
Of course, in order to avoid the influence of the excessive amount of the antioxidant on the progress of the oxidation reaction, the amount of the antioxidant added is preferably not less than 0 and not more than 1% by mass of the cholesterol acetate, more preferably 0.001% to 1% by mass of the cholesterol acetate, and still more preferably 0.01% to 0.1% by mass of the cholesterol acetate.
Specifically, the antioxidant may be preferably a phenolic compound containing a phenol structure, and more preferably a phenolic antioxidant including at least one of 2, 6-di-tert-butyl-p-cresol, o-tert-butyl-p-methoxyphenol, tocopherol, and tert-butyl hydroquinone.
Specifically, the catalyst is an N-hydroxy derivative, and the N-hydroxy derivative is selected from one or more of N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxy-2, 3-naphthalimide, N-hydroxy-3, 4,5, 6-tetraphenylphthalimide or 3-picolyl-N-hydroxyphthalimide; n-hydroxyphthalimide is preferable, and in order to ensure the catalytic effect, the molar ratio of the catalyst to the cholesterol acetate is preferably 0.1:1 to 1.2:1, and more preferably 0.1:1 to 0.5: 1.
The applicant finds that in a system in which an N-hydroxy derivative is used as a catalyst to catalyze the allylic oxidation reaction of cholesterol acetate, the free radicals formed by the N-hydroxy derivative can generate a polymerization reaction to generate a polymer, or can generate other complex polymers by the polymerization reaction with the free radicals of cholesterol acetate, and the faster the rate of the free radicals formed by the N-hydroxy derivative is, the more the polymers are formed, and the polymers have the characteristic of viscosity and are difficult to filter, so that the recovered N-hydroxy derivative has the phenomenon of viscosity and is difficult to apply mechanically.
The antioxidant can effectively improve the selectivity of the reaction, and can also effectively prevent the free radical formed by the N-hydroxyl derivative from generating polymerization reaction and effectively prevent the free radical formed by the N-hydroxyl derivative from generating polymerization reaction with the free radical of the cholesterol acetate, thereby effectively avoiding the adhesion phenomenon of the recovered catalyst, enabling the recovered N-hydroxyl derivative to be recycled and having no influence on the catalytic activity.
Specifically, the initiator comprises at least one of benzoyl peroxide and transition metal salt, and the mass of the initiator is 0.1-1% of that of the cholesterol acetate.
Wherein the transition metal salt comprises ferric triacetylacetone (Fe (acac)3) Cobalt (III) acetylacetonate (Co (acac)3) Manganese acetate (Mn (OAc))2) Cobalt acetylacetonate (Co (acac)2) Cobalt (II) acetate (Co (OAc)2) Cobalt (III) acetate (Co (OAc)3) Preferably comprises Mn (OAc)2、Co(acac)2、Co(OAc)2At least one of (1).
Specifically, the mixed solvent comprises a hydrocarbon solvent for dissolving cholesterol acetate and a polar solvent for dissolving a catalyst, wherein the molar ratio of the hydrocarbon solvent to the cholesterol acetate is 5:1-20:1, and the molar ratio of the polar solvent to the cholesterol acetate is 20:1-40: 1.
The hydrocarbon solvent comprises at least one of n-hexane, petroleum ether and heptane, preferably n-hexane, and the polar solvent comprises at least one of ethanol, methyl ethyl ketone, acetone, cyclopentanone, isophorone and cyclohexanone, preferably at least one of cyclopentanone, cyclohexanone and isophorone.
Specifically, when oxygen is introduced into the first mixed solution, high-purity oxygen or a mixed gas containing oxygen may be used, and oxygen is preferably introduced so that the cholesterol acetate and the oxygen undergo an oxidation reaction.
In order to ensure that the cholesterol acetate, the catalyst, the initiator and the antioxidant can be completely dissolved in the mixed solvent and ensure the progress of the oxidation reaction, the temperature of the oxidation reaction is maintained between 20 and 100 ℃.
In the step (2), the step of treating the second mixed solution includes: removing or recovering the mixed solvent by distillation or the like to obtain a solid first intermediate product, and adding the above nonpolar hydrocarbon solvent to dissolve the first intermediate product to obtain a mixture. And the catalyst N-hydroxy derivative in the first intermediate product is insoluble in a non-polar hydrocarbon solvent, so that the mixture can be filtered to recover the white crystalline solid catalyst, and the recovered catalyst can be recycled to the step (1) for continuous use.
And adding triethylamine and acetic anhydride into filtrate obtained by filtering the mixture to react, washing with water to obtain a second intermediate product, concentrating the second intermediate product, and crystallizing with methanol to obtain the final product, namely the 7-ketocholesterol acetate.
7-ketocholesterol acetate is an important precursor of 7-dehydrocholesterol as an intermediate for synthesizing vitamin D3, and 7-ketocholesterol acetate can be obtained in high yield by a plurality of steps of hydrazonation, dehydrozone, saponification and the like.
Therefore, the 7-ketocholesterol acetate obtained by the preparation method of the 7-ketocholesterol acetate can be used for preparing 7-dehydrocholesterol.
Hereinafter, the preparation method of the 7-ketocholesterol acetate and its application will be further described by the following specific examples.
In the following examples, the content of 7-ketocholesterol acetate was determined by High Performance Liquid Chromatography (HPLC) using an Agilent HC-C18 column, 5 μm 4.6 mm 250mm, mobile phase acetonitrile, methanol 5:95, flow rate 1.5 mL/min.
Example 1
Into the autoclave were charged 85.7g (0.2mol) of cholesterol acetate, 24.4g (0.15mol) of N-hydroxyphthalimide (NHPI), Mn (OAc)217.3mg, 8.6mg of 2, 6-di-tert-butyl-p-phenol, 500mL of n-hexane, 450mL of cyclohexanone, heating to 20 ℃ to dissolve, introducing oxygen at normal pressure to react for 7 hours, detecting by HPLC that cholesterol acetate residue is 0.5% (area normalization method), and stopping introducing oxygen. And then recovering the solvent under reduced pressure until the solvent is dried to obtain a first intermediate product, adding 550mL of normal hexane into the first intermediate product for dissolving, filtering to obtain white crystal powder NHPI, and cleaning the NHPI with the normal hexane for recycling.
Adding 25.7g of triethylamine and 22.0g of acetic anhydride into the filtrate in sequence at 35 ℃ for reacting for 12 hours, heating to 50 ℃, adding 100mL of pure water for washing and layering to obtain a second intermediate product, removing n-hexane from the second intermediate product by using a rotary evaporator, adding 350mL of methanol for crystallizing at-5 ℃ for 4 hours, filtering and drying to obtain 85.0g of 7-ketocholesterol acetate (white crystal powder, the yield is 96.0%), and the purity is 97.5% by detection.
Example 2
85.7g (0.2mol) of cholesterol acetate, 12.2g (0.075mol) of NHPI, 25mg of benzoyl peroxide and 35.0mg of tocopherol were put into a reaction vessel, and then 700mL of cyclohexanone and 350mL of petroleum ether were added, the mixture was heated to 50 ℃ to dissolve, oxygen was introduced at normal pressure to react for 22 hours, and the cholesterol acetate residue was found to be 0.5% by HPLC (area normalization method) and the introduction of oxygen was stopped. And then recovering the solvent under reduced pressure until the solvent is dried to obtain a first intermediate product, adding 550mL of normal hexane into the first intermediate product for dissolving, filtering to obtain white crystal powder NHPI, and cleaning the NHPI with the normal hexane for recycling.
Adding 25.7g of triethylamine and 22.0g of acetic anhydride into the filtrate in sequence at 35 ℃ for reacting for 12 hours, heating to 50 ℃, adding 100mL of pure water for washing and layering to obtain a second intermediate product, removing n-hexane from the second intermediate product by using a rotary evaporator, adding 350mL of methanol for crystallizing at-5 ℃ for 4 hours, filtering and drying to obtain 82.0g of 7-ketocholesterol acetate (white crystal powder, the yield is 92.9%), and the purity is 98.0% by detection.
Example 3
Into the reaction vessel, 85.7g (0.2mol) of cholesterol acetate, 24.4g (0.15mol) of NHPI, and Co (OAc)210mg, 4.0mg of 2, 6-di-tert-butyl-p-phenol, 700mL of cyclopentanone and 150mL of heptane were added, the mixture was heated to 45 ℃ to dissolve, oxygen was introduced at normal pressure for 20 hours, and the cholesterol acetate was found to remain 0.5% (area normalization) by HPLC detection, and oxygen introduction was stopped. And then recovering the solvent under reduced pressure until the solvent is dried to obtain a first intermediate product, adding 550mL of normal hexane into the first intermediate product for dissolving, filtering to obtain white crystal powder NHPI, and cleaning the NHPI with the normal hexane for recycling.
Adding 25.7g of triethylamine and 22.0g of acetic anhydride into the filtrate in sequence at 35 ℃ for reacting for 12 hours, heating to 50 ℃, adding 100mL of pure water for washing and layering to obtain a second intermediate product, removing n-hexane from the second intermediate product by using a rotary evaporator, adding 350mL of methanol for crystallizing at-5 ℃ for 4 hours, filtering and drying to obtain 85.5g of 7-ketocholesterol acetate (white crystal powder, the yield is 96.5%), and the purity is 98.0% by detection.
Example 4
85.7g (0.2mol) of cholesterol acetate, 12.2g (0.075mol) of NHPI, 25mg of benzoyl peroxide and 35.0mg of tert-butylhydroquinone were charged into a reaction vessel, 800mL of isophorone and 150mL of heptane were added, the mixture was heated to 60 ℃ to dissolve, oxygen was introduced at normal pressure for 8 hours to react, and HPLC showed that cholesterol acetate remained at 0.5% (area normalization), and oxygen introduction was stopped. And then recovering the solvent under reduced pressure until the solvent is dried to obtain a first intermediate product, adding 550mL of normal hexane into the first intermediate product for dissolving, filtering to obtain white crystal powder NHPI, and cleaning the NHPI with the normal hexane for recycling.
Adding 25.7g of triethylamine and 22.0g of acetic anhydride into the filtrate in sequence at 35 ℃ for reacting for 12 hours, heating to 50 ℃, adding 100mL of pure water for washing and layering to obtain a second intermediate product, removing n-hexane from the second intermediate product by using a rotary evaporator, adding 350mL of methanol for crystallizing at-5 ℃ for 4 hours, filtering and drying to obtain 83.5g of 7-ketocholesterol acetate (white crystal powder, the yield is 94.3%), and the purity is 98.5% by detection.
Example 5
Into the reaction vessel, 85.7g (0.2mol) of cholesterol acetate, 24.4g (0.15mol) of NHPI, and Co (OAc)210mg, 2, 6-di-tert-butyl-p-phenol 4.0mg, followed by addition of cyclohexanone 700mL and heptane 150mL, heating to 35 ℃ to dissolve, introducing oxygen at normal pressure for 16 hours, and detecting by HPLC that cholesterol acetate residue is 0.5% (area normalization method), and stopping introduction of oxygen. And then recovering the solvent under reduced pressure until the solvent is dried to obtain a first intermediate product, adding 550mL of normal hexane into the first intermediate product for dissolving, filtering to obtain white crystal powder NHPI, and cleaning the NHPI with the normal hexane for recycling.
Adding 25.7g of triethylamine and 22.0g of acetic anhydride into the filtrate in sequence at 35 ℃ for reacting for 12 hours, heating to 50 ℃, adding 100mL of pure water for washing and layering to obtain a second intermediate product, removing n-hexane from the second intermediate product by using a rotary evaporator, adding 350mL of methanol for crystallizing at-5 ℃ for 4 hours, filtering and drying to obtain 85.5g of 7-ketocholesterol acetate (white crystal powder, the yield is 96.5%), and the purity is 98.0% by detection.
Comparative example 1
Into the reaction vessel, 85.7g (0.2mol) of cholesterol acetate, 24.4g (0.15mol) of NHPI, and Co (OAc)210mg, then adding 700mL of cyclohexanone and 150mL of heptane, heating to 55 ℃ for dissolution, introducing oxygen at normal pressure for reaction for 14 hours, detecting by HPLC that cholesterol acetate residue is 0.5% (area normalization method), and stopping introducing oxygen. Then, the solvent is recovered under reduced pressure until the solvent is dried to obtain a first intermediate product, the first intermediate product is dissolved by adding 550mL of normal hexane, and a whitish sticky solid is obtained by filtration and mainly becomes NHPI by detection.
Adding 25.7g of triethylamine and 22.0g of acetic anhydride into the filtrate in sequence at 35 ℃ for reacting for 12 hours, heating to 50 ℃, adding 100mL of pure water for washing and layering to obtain a second intermediate product, removing n-hexane from the second intermediate product by using a rotary evaporator, adding 350mL of methanol for crystallizing at-5 ℃ for 4 hours, filtering and drying to obtain 77.0g of 7-ketocholesterol acetate (white crystal powder, the yield is 86.7%), and detecting that the purity is 95.0%.
Examples 1-5 and comparative example 1 show that the catalyst NHPI recovered after the addition of the antioxidant was a white crystalline powder and did not become sticky, and that the yield of the product 7-ketocholesterol acetate was increased to 90% or more and the purity was increased to 97% or more.
Catalyst NHPI use example:
examples 6 to 14
The catalyst NHPI recovered in the example was recycled, the operation was the same as that of example 5, and the results are shown in Table 1.
TABLE 1
| Examples | Number of times of catalyst application | Product/g | Product yield/% | External standard content of the product/%) |
| 6 | 1 | 85.5 | 96.8 | 98.0 |
| 7 | 2 | 85.5 | 96.8 | 98.1 |
| 8 | 3 | 85.7 | 97.0 | 98.0 |
| 9 | 4 | 85.5 | 96.8 | 98.0 |
| 10 | 5 | 85.5 | 96.8 | 97.8 |
| 11 | 6 | 85.3 | 96.6 | 98.0 |
| 12 | 7 | 85.5 | 96.8 | 97.8 |
| 13 | 8 | 85.6 | 96.9 | 97.5 |
| 14 | 9 | 85.3 | 96.6 | 97.0 |
As can be seen from Table 1, the good catalytic activity is still maintained after the catalyst NHPI is used for 9 times, the yield of the product is more than 96%, and the purity is more than or equal to 97%.
Example 15
85.7g (0.2mol) of cholesterol acetate, 17.3g (0.15mol) of N-hydroxysuccinimide, 217.3mg of Mn (OAc), and 8.6mg of 2, 6-di-t-butyl-p-phenol were put into a reaction vessel, 450mL of N-hexane and 500mL of cyclohexanone were added, the mixture was heated to 20 ℃ to dissolve the compounds, oxygen was introduced into the reaction vessel at normal pressure for reaction for 11 hours, and HPLC analysis showed that cholesterol acetate remained at 0.5% (area normalization method) and oxygen introduction was stopped. And then recovering the solvent under reduced pressure until the solvent is dried to obtain a first intermediate product, adding 550mL of normal hexane into the first intermediate product for dissolving, filtering to obtain white crystal powder N-hydroxysuccinimide, and cleaning the N-hydroxysuccinimide with the normal hexane for recycling.
Adding 25.7g of triethylamine and 22.0g of acetic anhydride into the filtrate in sequence at 35 ℃ for reacting for 12 hours, heating to 50 ℃, adding 100mL of pure water for washing and layering to obtain a second intermediate product, removing n-hexane from the second intermediate product by using a rotary evaporator, adding 350mL of methanol for crystallizing at-5 ℃ for 4 hours, filtering and drying to obtain 80.0g of 7-ketocholesterol acetate (white crystal powder, the yield is 90.3%), and the purity is 97.5% by detection.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (6)
1. A method for preparing 7-ketocholesterol acetate, which is characterized by comprising the following steps:
(1) dissolving cholesterol acetate, a catalyst, an initiator and an antioxidant in a mixed solvent to obtain a first mixed solution, and introducing oxygen into the first mixed solution to perform an oxidation reaction on the cholesterol acetate and the oxygen to obtain a second mixed solution; and
(2) treating the second mixed solution to obtain 7-ketocholesterol acetate;
wherein the catalyst is selected from one or more of N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxy-2, 3-naphthalimide, N-hydroxy-3, 4,5, 6-tetraphenylphthalimide or 3-picolyl-N-hydroxyphthalimide, and the molar ratio of the catalyst to the cholesterol acetate is 0.1:1-1.2: 1;
the initiator is selected from benzoyl peroxide, Mn (OAc)2、Co(acac)2、Co(OAc)2At least one of;
the antioxidant is selected from at least one of 2, 6-di-tert-butyl-p-cresol, o-tert-butyl-p-methoxyphenol, tocopherol and tert-butyl hydroquinone, and the mass of the antioxidant is 0.001-1% of that of the cholesterol acetate.
2. The method according to claim 1, wherein the catalyst is further recovered in the step (2) of treating the second mixed solution.
3. The process according to claim 2, wherein the recovered catalyst is recycled to step (1) for further use.
4. The method according to claim 1, wherein the mass of the initiator is 0.1 to 1% o of the mass of the cholesterol acetate.
5. The process according to claim 1, wherein the mixed solvent in the step (1) is selected from the group consisting of hydrocarbon solvents and polar solvents, the molar ratio of the hydrocarbon solvents to the cholesterol acetate is 5:1 to 20:1, and the molar ratio of the polar solvents to the cholesterol acetate is 20:1 to 40: 1.
6. The method for producing 7-ketocholesterol acetate as claimed in claim 1, wherein the temperature of the oxidation reaction in the step (1) is 20 ℃ to 100 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105669813A (en) * | 2015-12-31 | 2016-06-15 | 厦门金达威维生素有限公司 | Synthesis method of vitamin D3 intermediate 7-ketocholesteryl acetate |
| CN107936077A (en) * | 2016-10-12 | 2018-04-20 | 浙江天新药业有限公司 | A kind of preparation method of 7 oxo cholesterol acetate |
| CN110885354A (en) * | 2019-11-14 | 2020-03-17 | 浙江新和成股份有限公司 | Preparation method of 7-ketone-cholesterol acetate |
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| US8163944B2 (en) * | 2007-10-08 | 2012-04-24 | University Of Maryland College Park | Allylic oxidations catalyzed by dirhodium catalysts under aqueous conditions |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105669813A (en) * | 2015-12-31 | 2016-06-15 | 厦门金达威维生素有限公司 | Synthesis method of vitamin D3 intermediate 7-ketocholesteryl acetate |
| CN107936077A (en) * | 2016-10-12 | 2018-04-20 | 浙江天新药业有限公司 | A kind of preparation method of 7 oxo cholesterol acetate |
| CN110885354A (en) * | 2019-11-14 | 2020-03-17 | 浙江新和成股份有限公司 | Preparation method of 7-ketone-cholesterol acetate |
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