CN103626822A - Synthetic method of 25-hydroxycholesterol - Google Patents
Synthetic method of 25-hydroxycholesterol Download PDFInfo
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- CN103626822A CN103626822A CN201310548969.8A CN201310548969A CN103626822A CN 103626822 A CN103626822 A CN 103626822A CN 201310548969 A CN201310548969 A CN 201310548969A CN 103626822 A CN103626822 A CN 103626822A
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Abstract
The invention discloses a synthetic method of 25-hydroxycholesterol. The synthetic method comprises the following steps: (1) protecting 3-hydroxy of 24-dehydrocholesterol so a to obtain acylated 24-dehydrocholesterol; (2) carrying out hydroxyhalogenation reaction on double bonds on the 24th site of the product obtained in the step (1), namely reacting the acylated 24-dehydrocholesterol with deionized water and a halogenated agent for 2-4 hours in a solvent at the temperature of -20 DEG C to -1 DEG C; and carrying out aftertreatment on reaction liquid so as to obtain a hydroxyhalogenation product; and (3) reacting the hydroxyhalogenation product with an aluminium hydrogenation reagent for 3-8 hours in the solvent at the temperature of 20-70 DEG C, wherein the molar ratio of the aluminium hydrogenation reagent to the hydroxyhalogenation product is (2-6): 1, and carrying out aftertreatment on reaction liquid, thus obtaining the 25-hydroxycholesterol. The synthetic method of the 25-hydroxycholesterol has the characteristics of simple process, environmental protection, few side reactions and high yield.
Description
Technical field
The present invention relates to a kind of method of being prepared 25-HYDROXY CHOLESTEROL by desmesterol, belong to a kind of method of preparing 25-HYDROXY CHOLESTEROL based on hydroxyl halogenation and reductive dehalogenation.
Background technology
Vitamins D
3belong to steroid derivative, for the formation of bone, have great significance.It can promote the absorption in enteron aisle of calcium, phosphorus, guarantees the content of these two kinds of elements in body fluid, promotes the normal calcification of bone.The human body D that is deficient in vitamin
3, can there is rickets in children's, can there is osteomalacia in adult.Vitamins D
3anti-rachitic effect be mainly by 1,25-(OH)
2d
3realize, its biological activity intensity is vitamins D
310000 times.Through a series of research, find, the hydroxyl of 25-position is vitamins D
3the feature that meta-bolites has jointly, therefore, as synthetic 1,25-(OH)
2d
3important as precursors, the synthetic of 25-HYDROXY CHOLESTEROL can determine its condition of production to a great extent.
In the synthetic method of bibliographical information, comprise following 2 classes at present:
1), the synthetic 25-HYDROXY CHOLESTEROL (C.R.Chimie, 6,79-82,2003.) of hydroxyl mercury method.The method is usingd desmesterol as raw material, adopts mercuric acetate and water to carry out oxymercuration reaction, and the temperature of reaction of oxymercuration reaction is room temperature, and yield is 85%, and hydroxyl mercury method relates to heavy metal Hg, has toxicity, pollutes large.
2), adopt epoxidation again the method for open loop react.The method is usingd desmesterol as starting raw material, at metachloroperbenzoic acid, as epoxidation reagent, chloroform, carries out epoxidation reaction under as the condition of solvent.After finishing, epoxidation reaction utilize Lithium Aluminium Hydride to carry out open loop (Chem.Pharm.Bull.21 (2), 457-458,1973.).Epoxidation reaction temperature is 0 ℃ of left and right, and ultimate yield is 50%, and epoxidation step yield is 60%.The major defect of the method is: selectivity is poor, and yield is relatively low.
So, need at present a rational alternative route badly and carry out the production of 25-HYDROXY CHOLESTEROL.
Summary of the invention
The technical problem to be solved in the present invention is to provide that a kind of technique is reasonable, reaction conditions is gentle, and selectivity is high, simple to operate, the preparation method of eco-friendly 25-HYDROXY CHOLESTEROL.
In order to solve the problems of the technologies described above, the invention provides a kind of preparation method of 25-HYDROXY CHOLESTEROL, comprise the following steps:
1), the hydroxyl of compound 3-shown in formula II is protected:
In solvent I, under the katalysis of DMAP (DMAP), under the condition existing at acid binding agent, desmesterol and carboxylic acid anhydride or acyl chlorides under 10 ℃～reflux state (that is, approximately 10～40 ℃) react 10～24h; The mol ratio of described desmesterol and carboxylic acid anhydride or acyl chlorides is 1:1.2～2; DMAP (DMAP) is 0.005～0.05:1 with the mass ratio of desmesterol consumption; The mol ratio of acid binding agent and desmesterol is 1.8～10:1;
The reaction solution of gained, through aftertreatment, obtains acidylate desmesterol;
The structural formula of described desmesterol is as shown in following formula II:
2) the two keys that, step 1) made on 24 of products carry out hydroxyl halogenating reaction:
In solvent II, step 1) preparation and acidylate desmesterol, deionized water and halide reagent at the temperature of-20～-1 ℃, react 2～4h; The mol ratio of described acidylate desmesterol and halide reagent is 1:1～1.5; Acidylate desmesterol adapted 8～12mL(of described every 1mmol is preferably 10mL) deionized water;
Extraction after the reaction solution dilution of gained, dry after the extraction liquid washing of gained, the dried product exhibited of gained is separated through column chromatography, obtains hydroxyl halogenated products;
3), by step 2) make product and carry out the dehalogenation reaction, can obtain compound shown in formula I:
In solvent III, step 2) preparation and hydroxyl halogenated products at the temperature of 20～70 ℃, react 3～8h with aluminium hydroborating reagent; The mol ratio of described aluminium hydroborating reagent and hydroxyl halogenated products is 2～6:1;
The reaction solution of gained is cooled to and utilizes the shrend excessive aluminium hydroborating reagent in reaction solution that goes out after room temperature, then successively through pickling and extraction; Dry after the extraction liquid washing of gained, obtain 25-HYDROXY CHOLESTEROL crude product; Described 25-HYDROXY CHOLESTEROL crude product, through recrystallization, obtains 25-HYDROXY CHOLESTEROL;
The structural formula of described 25-HYDROXY CHOLESTEROL is as shown in following formula I:
Improvement as the preparation method of 25-HYDROXY CHOLESTEROL of the present invention: in step 1):
Carboxylic acid anhydride is diacetyl oxide (aceticanhydride), propionic anhydride, butyryl oxide, valeric anhydride, benzoyl oxide, Succinic anhydried or Tetra hydro Phthalic anhydride;
Acyl chlorides is Acetyl Chloride 98Min., propionyl chloride, butyryl chloride or Benzoyl chloride.
Further improvement as the preparation method of 25-HYDROXY CHOLESTEROL of the present invention:
In step 1):
Acid binding agent is triethylamine, diethylamine, quadrol, ammonia, pyridine or piperidines.
Further improvement as the preparation method of 25-HYDROXY CHOLESTEROL of the present invention: step 2):
Halide reagent is N-halogenated succinimide imide, N, N-dibromo para toluene sulfonamide (TsNBr
2), C5H6Br2N2O2 (DBDMH) or tribromo tricarbimide (TBCA).
Further improvement as the preparation method of 25-HYDROXY CHOLESTEROL of the present invention:
Described N-halogenated succinimide imide is N-chlorosuccinimide (NCS) or N-bromo-succinimide (NBS).
Further improvement as the preparation method of 25-HYDROXY CHOLESTEROL of the present invention: described aluminium hydroborating reagent is Lithium Aluminium Hydride, three (tert.-butoxy) lithium aluminum hydride, two (methoxy ethoxy) sodium aluminum hydride (that is, two (methoxy ethoxy) sodium alanate).
In the present invention:
In step 1), solvent I used is pyridine, methylene dichloride, tetrahydrofuran (THF), toluene etc.; Generally speaking, the solvent I of desmesterol adapted 100～200ml of every 0.052mol.
In step 1),
When selecting pyridine, tetrahydrofuran (THF) as solvent I; aftertreatment is: the reaction solution of gained, successively through washing, is extracted after pickling (5% dilute hydrochloric acid), and described extraction liquid alkali cleaning (utilizing saturated sodium bicarbonate solution to wash) is to neutral; dry, obtain acidylate desmesterol.
When selecting methylene dichloride, toluene as solvent I; aftertreatment is: the reaction solution of gained is washed after (saturated nacl aqueous solution) through pickling (5% dilute hydrochloric acid), alkali cleaning (saturated sodium bicarbonate solution), salt successively; dry, obtain acetylize desmesterol.
Step 2) in, solvent II used is tetrahydrofuran (THF), acetone, butanone, ethyl acetate, methylene dichloride, toluene, the trimethyl carbinol, diglyme; Generally speaking, the solvent II of acidylate desmesterol adapted 20～100mL of every 1mmol.
By step 3) solvent III used, it is tetrahydrofuran (THF); Generally speaking, the solvent of hydroxyl halogenated products adapted 20～100mL of every 1mmol.
The invention belongs to a kind of method of preparing 25-HYDROXY CHOLESTEROL based on hydroxyl halogenation and reductive dehalogenation.
In step 1): utilize carboxylic acid anhydride or acyl chlorides to protect the hydroxyl on 3 of desmesterols.
In step 2) in: N-halogenated succinimide imide, N utilized, N-dibromo para toluene sulfonamide (TsNBr
2), the halide reagent such as C5H6Br2N2O2 (DBDMH), tribromo tricarbimide (TBCA) and deionized water to step 1) preparation and product---the two keys on 24 of acidylate desmesterol carry out hydroxyl halogenating reaction.
In step 3): utilize and to go back original reagent---aluminium hydroborating reagent is to step 2) preparation and product---hydroxyl halogenated products is carried out reduction dehalogenation reaction.
The preparation method of 25-HYDROXY CHOLESTEROL of the present invention has following technical superiority:
The present invention utilizes N-halogenated succinimide imide, N, N-dibromo para toluene sulfonamide (TsNBr
2), C5H6Br2N2O2 (DBDMH), tribromo tricarbimide (TBCA) etc. be as halide reagent, side reaction is few; Reaction is carried out at low temperatures, and selectivity is high.Adopt the inventive method to prepare 25-HYDROXY CHOLESTEROL, have that technique is simple, an environmental friendliness, side reaction is few, yield is high feature.
Embodiment
Room temperature in following examples refers to 10～25 ℃.
The preparation method of embodiment 1, a kind of 25-HYDROXY CHOLESTEROL, carries out following steps successively:
1), using 120mL pyridine as solvent, using 30mL pyridine (about 0.372mol) as acid binding agent, the desmesterol (about 0.052mol), the 0.2g4-Dimethylamino pyridine (DMAP) that add 20g, drip the about 0.097mmol of 10g(under room temperature) diacetyl oxide (dripping off for approximately 30 minutes).Reaction process utilizes TLC to monitor, and continues reaction 10h after dropping finishes under room temperature, and reaction finishes.
Reaction solution washing (consumption of water is 50ml * 2); (utilizing volumetric concentration is 5% dilute hydrochloric acid solution in pickling; consumption is 50ml * 2) after utilize methylene dichloride (consumption is 30ml * 3) extraction; extraction liquid utilizes saturated sodium bicarbonate solution to be washed till neutrality; after anhydrous sodium sulphate (about 5g) is dry, de-dry solvent (; methylene dichloride), obtain acetylize desmesterol 19.1g, yield is 90.0%.
Yield=actual theoretical amount that obtains quality product/product.
2), take 40mL tetrahydrofuran (THF) as solvent, add the about 1mmol of 0.4226g() acetylize desmesterol, 10mL deionized water, 0.213g(1.2mmol) N-bromo-succinimide (NBS) slowly adds in (add in four batches, about 1h left and right adds) reaction flask at-10 ℃ in batches; Reaction process utilizes TLC to monitor, insulation (10 ℃) reaction 2h.
Reaction solution water (30ml * 2) dilution of gained, add methylene dichloride (30ml * 3) extraction, gained extraction liquid is dried by anhydrous sodium sulphate (about 5g) after using successively saturated sodium bisulfite solution (30ml * 2), saturated sodium bicarbonate solution (30ml * 2), saturated nacl aqueous solution (30ml) washing, (decompression (0.1MPa) rotary evaporation removes desolventizing, methylene dichloride), obtain white solid (0.52g), this white solid is carried out to column chromatography separation.
The particular content of column chromatography separation is: adopt the glass column that internal diameter is 2cm, 200-300 object silica gel dress post, dry method loading, adopt n-hexane/ethyl acetate=8:1(volume ratio) eluent carry out wash-out, elutriant adopts TLC to detect, and in elutriant being detected now, collects during for hydroxyl bromination solid pure product, the effluent liquid of collecting is removed to desolventizing through decompression (0.1MPa) rotary evaporation, can obtain hydroxyl bromination solid (that is, hydroxyl brominated product), yield 85%.
3), take 30mL tetrahydrofuran (THF) as solvent, add the about 1mmol of 0.52g() hydroxyl brominated product, under room temperature, slowly add 0.15g(4mmol) be warming up to 70 ℃ after Lithium Aluminium Hydride, reaction process utilizes TLC to monitor, stopped reaction after 70 ℃ of reaction 4h.
The reaction solution of gained utilizes the excessive Lithium Aluminium Hydride of water (100ml) cancellation after being cooled to room temperature, then (utilizing volumetric concentration is 5% dilute hydrochloric acid solution directly to carry out pickling, consumption is 50ml * 2), methylene dichloride (30ml * 3) extraction, extraction liquid utilizes saturated sodium bicarbonate solution (30ml * 2) successively, dry by anhydrous sodium sulphate (about 5g) after saturated nacl aqueous solution (30ml) washing, (decompression (0.1MPa) rotary evaporation removes desolventizing, methylene dichloride), obtain 25-HYDROXY CHOLESTEROL crude product (0.40g), crude product utilizes toluene (10ml) recrystallization, obtain the finished product 25-HYDROXY CHOLESTEROL 0.33g, yield 88%.
The preparation method of embodiment 2, a kind of 25-HYDROXY CHOLESTEROL,
In this embodiment 2, step 1), 2) different from embodiment 1, difference is:
1), using 100mL methylene dichloride as solvent, add desmesterol (about 0.052mol), the 0.2gDMAP of 20g, the about 0.1mmol of 10.1g() triethylamine, under room temperature, drip the about 0.097mmol of 10g() aceticanhydride.Reaction process utilizes TLC to monitor, and after dropping finishes, continues under room temperature and reacts 10h, and reaction finishes.
Reaction solution is used dilute hydrochloric acid successively, and (volumetric concentration is 5%; consumption 50ml * 2), dry by anhydrous sodium sulphate (about 5g) after saturated sodium bicarbonate solution (30ml * 2), saturated nacl aqueous solution (30ml) washing; decompression (0.1MPa) rotary evaporation is except desolventizing (being methylene dichloride); obtain acetylize desmesterol 19.0g, yield is 90.0%.
2), by 0.213g(1.2mmol) N-bromo-succinimide (NBS) makes the about 1.5mmol of 0.2g(into) N-chlorosuccinimide (NCS), by-10 ℃, make temperature of reaction into-1 ℃; All the other are equal to the step 2 of embodiment 1); Yield is 60%.
The preparation method of embodiment 3, a kind of 25-HYDROXY CHOLESTEROL,
In this embodiment 3, step 1), 2) different from embodiment 1, difference is:
1), using 100mL methylene dichloride as solvent, the desmesterol (about 0.052mol), the 0.2gDMAP that add 20g, the about 0.1mmol of 10.1g() triethylamine, under room temperature, drip the about 0.1mol of 14.1g() Benzoyl chloride, after finishing, dropping is warming up to backflow (approximately 40 ℃), reaction process utilizes TLC to monitor, and finishes reaction after back flow reaction 24h.
Reaction solution is successively with using anhydrous sodium sulfate drying after dilute hydrochloric acid, saturated sodium bicarbonate solution, saturated nacl aqueous solution washing, and decompression rotary evaporation, except desolventizing, obtains benzoylation desmesterol 23.2g, and yield is 95.0%.
2), by 0.213g(1.2mmol) N-bromo-succinimide (NBS) makes the about 1.0mmol of 0.29g(into) C5H6Br2N2O2, by-10 ℃, make temperature of reaction into-20 ℃; All the other are equal to the step 2 of embodiment 1); Yield is 58%.
The preparation method of embodiment 4, a kind of 25-HYDROXY CHOLESTEROL,
In this embodiment 4, step 2) different from embodiment 1, difference is:
By 0.213g(1.2mmol) N-bromo-succinimide (NBS) makes the about 1.1mmol of 0.40g(into) N, N-dibromo para toluene sulfonamide, makes solvent into methylene dichloride by tetrahydrofuran (THF); All the other are equal to the step 2 of embodiment 1); Yield is 80%.
The preparation method of embodiment 5, a kind of 25-HYDROXY CHOLESTEROL,
In this embodiment 5, step 2) different from embodiment 1, difference is:
By 0.213g(1.2mmol) N-bromo-succinimide (NBS) makes the about 1.0mmol of 0.365g(into) tribromo tricarbimide, by tetrahydrofuran (THF), make solvent into acetone; All the other are equal to the step 2 of embodiment 1); Yield is 52%.
The preparation method of embodiment 6, a kind of 25-HYDROXY CHOLESTEROL,
In this embodiment 6, step 3) is different from embodiment 1, and difference is:
By 0.15g(4mmol) Lithium Aluminium Hydride makes three (tert.-butoxy) lithium aluminum hydrides (1.5g, 6mmol) into; By 70 ℃, make temperature of reaction into 40 ℃, the reaction times is made 6h into by 4h; All the other are equal to the step 3) of embodiment 1; Yield is 85%.
The preparation method of embodiment 7, a kind of 25-HYDROXY CHOLESTEROL,
In this embodiment 7, step 3) is different from embodiment 1, and difference is:
By 0.15g(4mmol) Lithium Aluminium Hydride makes two (methoxy ethoxy) sodium aluminum hydrides (0.61g, 3mmol) into; By 70 ℃, make temperature of reaction into 30 ℃, the reaction times is made 8h into by 4h; All the other are equal to the step 3) of embodiment 1; Yield is 87%.
Comparative example 1, with respect to the step 2 of embodiment 1) do to change as follows:
Temperature of reaction is risen to 20 ℃ by-10 ℃, and all the other are equal to the step 2 of embodiment 1); The yield of this step is only 40%.
Comparative example 2, with respect to the step 2 of embodiment 1) do to change as follows:
In step 2) in, the consumption of deionized water is reduced to 1mL by 10mL, all the other are equal to the step 2 of embodiment 1); The yield of this step is only for yield is 49%.
Comparative example 3, with respect to the step 3) of embodiment 1, do following change:
In step 3), Lithium Aluminium Hydride is changed into sodium borohydride (molar weight is constant), all the other are all same as the step 3) of embodiment 1; Finally cannot obtain product.
Comparative example 4, with respect to the step 2 of embodiment 1) do to change as follows:
In step 2) in, NBS is replaced by bromine water (molar weight is constant), all the other are equal to the step 2 of embodiment 1); The yield of this step is only 23%.
Finally, it is also to be noted that, what more than enumerate is only some specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, can also have many distortion.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention, all should think protection scope of the present invention.
Claims (7)
- The preparation method of 1.25-hydroxycholesterol, is characterized in that comprising the following steps:1), the hydroxyl of compound 3-shown in formula II is protected:In solvent I, under the katalysis of DMAP, under the condition existing at acid binding agent, desmesterol reacts 10～24h with carboxylic acid anhydride or acyl chlorides under 10 ℃～reflux state; The mol ratio of described desmesterol and carboxylic acid anhydride or acyl chlorides is 1:1.2～2; The mass ratio of DMAP and desmesterol consumption is 0.005～0.05:1; The mol ratio of acid binding agent and desmesterol is 1.8～10:1;The reaction solution of gained, through aftertreatment, obtains acidylate desmesterol;The structural formula of described desmesterol is as shown in following formula II:
2) the two keys that, step 1) made on 24 of products carry out hydroxyl halogenating reaction:In solvent II, step 1) preparation and acidylate desmesterol, deionized water and halide reagent at the temperature of-20～-1 ℃, react 2～4h; The mol ratio of described acidylate desmesterol and halide reagent is 1:1～1.5; Acidylate desmesterol adapted 8～12mL deionized water of described every 1mmol;Extraction after the reaction solution dilution of gained, dry after the extraction liquid washing of gained, the dried product exhibited of gained is separated through column chromatography, obtains hydroxyl halogenated products;3), by step 2) make product and carry out the dehalogenation reaction, can obtain compound shown in formula I:In solvent III, step 2) preparation and hydroxyl halogenated products at the temperature of 20～70 ℃, react 3～8h with aluminium hydroborating reagent; The mol ratio of described aluminium hydroborating reagent and hydroxyl halogenated products is 2～6:1;The reaction solution of gained is cooled to and utilizes the shrend excessive aluminium hydroborating reagent in reaction solution that goes out after room temperature, then successively through pickling and extraction; Dry after the extraction liquid washing of gained, obtain 25-HYDROXY CHOLESTEROL crude product; Described 25-HYDROXY CHOLESTEROL crude product, through recrystallization, obtains 25-HYDROXY CHOLESTEROL;The structural formula of described 25-HYDROXY CHOLESTEROL is as shown in following formula I:
- 2. the preparation method of 25-HYDROXY CHOLESTEROL according to claim 1, is characterized in that in described step 1):Carboxylic acid anhydride is diacetyl oxide, propionic anhydride, butyryl oxide, valeric anhydride, benzoyl oxide, Succinic anhydried or Tetra hydro Phthalic anhydride;Acyl chlorides is Acetyl Chloride 98Min., propionyl chloride, butyryl chloride or Benzoyl chloride.
- 3. the preparation method of 25-HYDROXY CHOLESTEROL according to claim 2, is characterized in that in described step 1):Acid binding agent is triethylamine, diethylamine, quadrol, ammonia, pyridine or piperidines.
- 4. the preparation method of 25-HYDROXY CHOLESTEROL according to claim 3, is characterized in that described step 2) in:Halide reagent is N-halogenated succinimide imide, N, N-dibromo para toluene sulfonamide, C5H6Br2N2O2 or tribromo tricarbimide.
- 5. the preparation method of 25-HYDROXY CHOLESTEROL according to claim 4, is characterized in that:Described N-halogenated succinimide imide is N-chlorosuccinimide or N-bromo-succinimide.
- 6. the preparation method of 25-HYDROXY CHOLESTEROL according to claim 5, is characterized in that in described step 3):Described aluminium hydroborating reagent is Lithium Aluminium Hydride, three (tert.-butoxy) lithium aluminum hydride, two (methoxy ethoxy) sodium aluminum hydride.
- 7. the preparation method of 25-HYDROXY CHOLESTEROL according to claim 6, is characterized in that described step 2) in:The acidylate desmesterol adapted 10mL deionized water of every 1mmol, the N-bromo-succinimide of 1.2mmol; Temperature of reaction is-10 ℃, and the reaction times is 2～3 hours.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104961788A (en) * | 2015-06-25 | 2015-10-07 | 湖南科瑞生物科技股份有限公司 | Synthetic method of cholesterol |
| WO2016015512A1 (en) * | 2014-07-30 | 2016-02-04 | 浙江工业大学 | Method for synthesizing 25-hydroxy cholesterol |
| WO2020095888A1 (en) * | 2018-11-05 | 2020-05-14 | 日本精化株式会社 | Method for producing high-purity cholesterol |
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| US3868396A (en) * | 1973-02-16 | 1975-02-25 | Eisai Co Ltd | Preparation of 25-hydroxycholesterol and esters thereof |
| CN102060902A (en) * | 2011-01-21 | 2011-05-18 | 郑州大学 | Chenodeoxycholic acid synthesis method |
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| US3868396A (en) * | 1973-02-16 | 1975-02-25 | Eisai Co Ltd | Preparation of 25-hydroxycholesterol and esters thereof |
| CN102060902A (en) * | 2011-01-21 | 2011-05-18 | 郑州大学 | Chenodeoxycholic acid synthesis method |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016015512A1 (en) * | 2014-07-30 | 2016-02-04 | 浙江工业大学 | Method for synthesizing 25-hydroxy cholesterol |
| CN104961788A (en) * | 2015-06-25 | 2015-10-07 | 湖南科瑞生物科技股份有限公司 | Synthetic method of cholesterol |
| WO2020095888A1 (en) * | 2018-11-05 | 2020-05-14 | 日本精化株式会社 | Method for producing high-purity cholesterol |
| JP7361715B2 (en) | 2018-11-05 | 2023-10-16 | 日本精化株式会社 | Method for producing high purity cholesterol |
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