CN114315947B - New method for synthesizing cholesterol and 25-hydroxycholesterol by using 22-sterol as raw material - Google Patents
New method for synthesizing cholesterol and 25-hydroxycholesterol by using 22-sterol as raw material Download PDFInfo
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Abstract
The invention provides a method for synthesizing cholesterol and 25-hydroxy cholesterol, which comprises the steps of 1) reacting 22-hydroxy-20-methyl pregna-4-en-3-one with tetrahydropyrrole or ethylene glycol to protect 3-carbonyl, then performing 22-hydroxy sulfonylation, performing a Grignard reagent substitution reaction catalyzed by copper, and performing a sodium borohydride reduction reaction to obtain cholesterol or 25-hydroxy cholesterol. The synthesis method has the advantages of simple process, high yield, low cost and environment-friendly process, and is suitable for industrial production.
Description
Technical Field
The invention relates to a method for synthesizing steroid compounds, in particular to a method for synthesizing cholesterol and 25-hydroxycholesterol.
Background
Cholesterol, also known as cholesterol, is a derivative of cyclopentane polyhydrophenanthrene and is widely found in animals. It is an essential substance indispensable to animal tissue cells. It is not only involved in the formation of cell membranes, but also a raw material for the synthesis of bile acids, vitamin D and steroid hormones.
At present, cholesterol is derived from animals, mainly by saponifying brains and spinal tendons of pigs, cattle and sheep and then extracting the brains and the spinal tendons by using an organic solvent. Since many of the diseases found today are transmitted by animals to humans, especially the occurrence of the last European mad cow disease of the last reagent, and Streptococcus suis infection at the beginning of the century, people are doubted about the safety of cholesterol in the traditional preparation, and a safer cholesterol synthesis method is needed.
Patent number CN1772760a adopts a method for synthesizing cholesterol by taking dioscorea unit as raw material, and the synthetic route is as follows:
the synthesis route has low yield, high consumption of raw materials and auxiliary materials, high pollution and uneconomical.
The patent number CN105218610A adopts a method for synthesizing cholesterol by taking stigmasterol degradation products as raw materials, and the synthetic route is as follows:
in the synthesis technology, 3-carbonyl-4-pregna-22-aldehyde is used as a raw material to synthesize cholesterol, a palladium-carbon catalyst is adopted in hydrogenation reaction, so that the cost is high, the selective reduction is poor, the product is not purified well, and the yield is low.
Patent WO2021120127 discloses a method for synthesizing cholesterol using BA as a raw material, which is synthesized as follows:
in the synthetic route, the Euclidean reaction of the Grignard reagent needs 10 times of Grignard reagent to react under the influence of 3-position hydroxyl, so that the reaction is very dangerous and does not accord with the atom economy.
Disclosure of Invention
The invention aims to provide a synthesis method of cholesterol and 25-hydroxycholesterol with simple process and high yield, which takes 22-hydroxy-20-methyl pregna-4-en-3-one (4-BA) as a raw material to synthesize the cholesterol and the 25-hydroxycholesterol, and the synthesis route is as follows:
a method for synthesizing cholesterol and 25-hydroxycholesterol by using 22-hydroxy-20-methyl pregna-4-en-3-one (4-BA) as raw material, comprising the steps of:
1) Protection of 3-carbonyl group: the 22 hydroxy-20-methyl pregna-4-en-3-one is catalyzed by p-toluenesulfonic acid, reacts with tetrahydropyrrole or ethylene glycol at the reaction temperature of 10-120 ℃ for 3-5 hours, then stops the reaction by sodium bicarbonate, and is subjected to water separation and filtration to obtain the 22-hydroxy-20-methyl pregna-3-tetrahydropyrrole-3, 5-diene or 22-hydroxy-20-methyl pregna-3-ethylene glycol-5-ene.
2) Sulfonation reaction: the 22-hydroxy-20-methyl pregna-3-tetrahydropyrrole-3, 5-diene or 21-hydroxy-20-methyl pregna-3-glycol-5-alkene reacts with p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride and fluoro sulfonyl fluoride in dichloromethane or dichloroethane under the condition of triethylamine or diisopropylethylamine, and the 22-sulfonyl compound is obtained by washing, extracting and concentrating.
3) Substitution reaction: the 22-sulfonyl compound and the formative reagent isopentylmagnesium bromide are added in tetrahydrofuran solvent for reaction, then are quenched by acid, separated into liquid and concentrated to obtain 3-site protected cholestane or 3-site protected 25-hydroxy cholestane.
4) Acetylation reaction: cholestanes protected in the 3-position or cholestanes protected in the 3-position with 25-hydroxy groups. Under the condition of acetic acid and acetic anhydride, 3-site protecting group exchange reaction is carried out, ethanol is evaporated to dryness and crystallization is carried out, thus obtaining 3-acetyl-3, 5-diene cholestane and 3-acetyl-25 hydroxy-3, 5-diene cholestane.
5) Reduction reaction: 3-acetyl-3, 5-diene cholestane or 3-acetyl-25-hydroxy-3, 5-diene cholestane is dissolved in ethylene glycol dimethyl ether and tetrahydrofuran to react with sodium borohydride, potassium borohydride, zinc borohydride, calcium borohydride or reductase to obtain cholesterol or 25-hydroxy cholesterol.
Further, in the above method, the weight ratio of each reactant in the 3 carbonyl protection reaction in the step 1) is: 21-hydroxy-20-methylpregna-4-en-3-one: tetrahydropyrrole or ethylene glycol = 1.0:1.0 to 5.0:1.0 to 5.0.
Further, in the above method, the 3-carbonyl protection reaction in step 1) is performed in an organic solvent, and the solvent is one of ethanol, methanol and toluene.
Further, in the above method, in the sulfonation reaction in the step 2), triethylamine, diisopropylethylamine, or the like is used as a base, and the sulfonation reaction is carried out with p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride, fluorosulfonyl fluoride in a dichloromethane solvent to obtain 22-sulfonate.
In the above method, the substitution reaction in the step 3) is performed with a reagent such as isoamyl magnesium bromide, isoamyl lithium bromide, 3-trimethylsiloxy-3-methylbutyl magnesium bromide, etc. The molar ratio of the reactants is as follows: 22-sulfonate: isopentylmagnesium bromide = 1:3 to 10.
Further, in the above method, in the substitution reaction with the grignard reagent in the step 3), cuprous salt is used as a catalyst, cuprous bromide, cuprous dimethyl sulfide, cuprous chloride, cuprous iodide and cupric salt lithium copper tetrachloride are used as cuprous salts, and the reaction molar ratio is 1:0.1 to 1.
In the above method, in the step 5), 3-acetyl-3, 5-diene cholestane or 3-acetyl-25-hydroxy-3, 5-diene cholestane is dissolved in ethylene glycol dimethyl ether and tetrahydrofuran, sodium borohydride is added, and the reaction product is extracted and ethanol is crystallized to obtain cholesterol or 25-hydroxy cholesterol. 3-acetyl-3, 5-diene cholestane: sodium borohydride molar ratio = 1.0:0.25 to 1.
In the above method, in the step 5), 3-acetyl-25 hydroxy-3, 5-diene cholestane or 3-acetyl-3, 5-diene cholestane is reduced in methyl tertiary butyl ether phosphate buffer solution by carbonyl reductase to obtain cholesterol or 25-hydroxy cholesterol, and calcium hydroxide suspension is added dropwise during the reduction reaction to maintain the pH of the reaction solution to be about 7-7.5.
Further, cholesterol or 25-hydroxycholesterol obtained by the above method.
The invention has the following beneficial effects:
compared with the method which takes dioscin as the initial raw material, the method has the defects of large consumption, large pollution and uneconomical caused by ring-opening reaction of a large amount of concentrated hydrochloric acid and zinc powder; and the defects of high raw material cost, poor selective reduction effect, difficult purification of products and low yield in the reaction taking stigmasterol as a raw material. The invention takes 21-hydroxy-20-methyl pregna-4-ene-3-ketone (4-BA) as an initial raw material to synthesize cholesterol or 25-hydroxy cholesterol, and obtains the cholesterol or 25-hydroxy cholesterol through 3 carbonyl protection, sulfonylation reaction, substitution reaction of isoamyl magnesium bromide format reagent, acetylation reaction and reduction reaction. The synthetic method has simple reaction process and high yield. The production cost is low, the process is environment-friendly, and the method is more suitable for industrial implementation.
Drawings
FIG. 1 is a reaction scheme diagram of a method for synthesizing cholesterol and 25-hydroxycholesterol by using 21-hydroxy-20-methyl pregna-4-en-3-one (4-BA) as a raw material;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the 3-carbonyl tetrahydropyrrole protective compound in the embodiment of the invention;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of the 3-carbonyl glycol protecting compound in the embodiment of the invention;
FIG. 4 is a nuclear magnetic resonance spectrum of 22-p-toluenesulfonate-20-methylpgestrel-3-glycol-5-ene in the example of the present invention;
FIG. 5 is a nuclear magnetic resonance spectrum of 3-acetyl 3, 5-diene cholestane in the examples of the present invention;
FIG. 6 is a nuclear magnetic resonance spectrum of cholesterol in an embodiment of the present invention;
FIG. 7 shows the nuclear magnetic resonance hydrogen spectrum of 25-hydroxycholesterol in the examples of this invention.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The synthesis method of cholesterol and 25-hydroxycholesterol, as shown in figure 1, comprises the following steps:
1. 3-carbonyl tetrahydropyrrole protection
1000g of 22-hydroxy-20-methyl pregna-4-en-3-one and 5000ml of absolute methanol are put into a 10L three-neck flask, 200g of tetrahydropyrrole is added dropwise under the condition of heating and refluxing, the reaction liquid becomes turbid again, the reaction is cooled to room temperature after the dropwise addition, and 1050g of 22-hydroxy-20-methyl pregna-3-tetrahydropyrrole-3, 5-diene is obtained after filtration and drying. The molar yield was 90.4%.
HNMR (500 MHz, CDCl 3) delta 5.09 (m, 1H), 4.78 (m, 1H), 3.13 (m, 4H), 1.87 (m, 4H), 1.04 (d, 3H), 1.00 (d, 3H), 0.72 (s, 3H). The spectrogram is shown in figure 2.
2. 3-carbonyl glycol protection
1000g of 22-hydroxy-20-methyl pregn-4-en-3-one, 2000ml of toluene, 300ml of ethylene glycol, 200g of anhydrous copper sulfate, heating reflux for water diversion, TLC detection of the reaction completion, filtering for removing copper sulfate, evaporating to dryness, and crystallizing the concentrate methanol to obtain 980g of 22-hydroxy-20-methyl pregn-3-ethylene glycol-5-en. The molar yield was 86.5%.
HNMR (400 MHz, CDCl 3) delta 5.34 (m, 1H), 4.0 (m, 2H), 3.95 (m, 2H), 1.04 (d, 3H), 0.97 (d, 3H), 0.65 (s, 3H). The spectrogram is shown in figure 3.
3. 1000g of 22-hydroxy-20-methyl pregna-3-tetrahydropyrrole-3, 5-diene and 2000ml of pyridine are put into a three-neck flask for synthesizing 22-p-toluenesulfonate-20-methyl pregna-3-tetrahydropyrrole-3, 5-diene, the temperature is reduced to 0 ℃ in an ice water bath, 900g of p-toluenesulfonyl chloride is added in batches, stirring is continued for 30min after the addition, and TLC detection reaction is finished. The reaction solution is poured into 4000ml of ice water, a large amount of white solid is separated out, the solution is filtered by suction, and the solid methanol is pulped and dried to obtain 1100g of product. The molar yield was 78.4%.
4. 1000g of 22-hydroxy-20-methyl pregna-3-glycol-5-ene and 2000ml of pyridine are put into a three-neck flask for synthesizing 22-p-toluenesulfonate-20-methyl pregna-3-glycol-5-ene, the temperature of the ice water bath is reduced to 0 ℃, 900g of p-toluenesulfonyl chloride is added in batches, stirring is continued for 30min after the addition is finished, and TLC detection reaction is finished. The reaction solution is poured into 4000ml of ice water, a large amount of white solid is separated out, the solution is filtered by suction, and the solid methanol is pulped and dried to obtain 1000g of product. The molar yield was 70.8%.
HNMR (500 mhz, cdcl 3) δ:7.80 (m, 2H), 7.33 (m, 2H), 5.34 (m, 1H), 4.0 (m, 2H), 3.95 (m, 2H), 1.04 (d, 3H), 0.97 (d, 3H), 0.65 (s, 3H). The spectrogram is shown in figure 4.
5. Synthesis of 3-acetyl 3, 5-diene cholestane
1000ml of 1mol/L isopentylmagnesium bromide is added into a 3000ml three-neck flask, 200ml of 0.5mol/L copper lithium tetrachloride is dropwise added under ice water bath, 270g of solution of 22-p-toluenesulfonate-20-methyl pregna-3-tetrahydropyrrole-3, 5-diene dissolved in tetrahydrofuran is dropwise added under ice water bath, TLC detection reaction is finished, 1mol/L hydrochloric acid is added for quenching reaction, ethyl acetate is added for extraction, and liquid separation is carried out. The organic layer was dried and evaporated to dryness to give 180g of crude product which was directly put into the next reaction.
180g of the crude product is dissolved in 100ml of acetic acid and 100ml of acetic anhydride, and the mixture is heated and refluxed for 3 hours. TLC detection reaction was completed. Evaporating to dryness to recover acetic anhydride, crystallizing the crude product with methanol to obtain 160g of 3-acetyl 3, 5-diene cholestane pure product. The molar yield was 74.6%.
HNMR(500MHz,CDCl3)δ:5.69(m,1H),5.40(m,1H),2.13(s,3H),1.02(d,3H),0.92 (d,3H),0.87(d,3H),0.86(d,3H)，0.70(s,3H)。
6. Synthesis of 3-acetyl 3, 5-diene cholestane
1000ml of 1mol/L isopentylmagnesium bromide is added into a 3000ml three-neck flask, 200ml of 0.5mol/L copper lithium tetrachloride is dropwise added under ice water bath, 270g of solution of 22-p-toluenesulfonate-20-methyl pregna-3-glycol-3, 5-diene dissolved in tetrahydrofuran is dropwise added under ice water bath, TLC detection reaction is finished, 1mol/L hydrochloric acid is added for quenching reaction, ethyl acetate is added for extraction, and liquid separation is carried out. The organic layer was dried and evaporated to dryness to give 173g of crude product which was directly put into the next reaction.
173g of the crude product is dissolved in 100ml of acetic acid and 100ml of acetic anhydride and heated to reflux for reaction for 3h. TLC detection reaction was completed. Evaporating to dryness to recover acetic anhydride, crystallizing crude methanol to obtain 146g of 3-acetyl 3, 5-diene cholestane pure product. The molar yield was 67%.
HNMR (500 mhz, cdcl 3) δ:5.69 (m, 1H), 5.40 (m, 1H), 2.13 (s, 3H), 1.02 (d, 3H), 0.92 (d, 3H), 0.87 (d, 3H), 0.86 (d, 3H), 0.70 (s, 3H). The spectrogram is shown in figure 5.
7. Synthesis of 3-acetyl 3, 5-diene-25-hydroxycholestane
1000ml of 1 mol/L3-trisilyl hydroxy-3-methylbutylmagnesium bromide is added into a 3000ml three-neck flask, 200ml of 0.5mol/L copper lithium tetrachloride is dropwise added under an ice water bath, 270g of solution of 22-p-toluenesulfonate-20-methyl pregna-3-tetrahydropyrrole-3, 5-diene dissolved in tetrahydrofuran is dropwise added under the ice water bath, TLC detection reaction is finished, 1mol/L hydrochloric acid quenching reaction is added, ethyl acetate is added for extraction, and liquid separation is carried out. The organic layer was dried and evaporated to dryness to give 164g of crude product which was directly put into the next reaction.
164g of the crude product was dissolved in 100ml of acetic acid and 100ml of acetic anhydride and reacted under reflux with heating for 3 hours. TLC detection reaction was completed. Evaporating to dryness to recover acetic anhydride, crystallizing crude methanol to obtain 138g of 3-acetyl 3, 5-diene-25 hydroxy cholestane pure product. The molar yield was 62%.
Synthesis of 8, 3-acetyl 3, 5-diene-25-hydroxycholesterane
1000ml of 1 mol/L3-trimethylsiloxy-3-methylbutylmagnesium bromide is added into a 3000ml three-necked flask, 200ml of 0.5mol/L copper lithium tetrachloride is dropwise added under an ice water bath, 270g of solution of 22-p-toluenesulfonate-20-methylpregna-3-glycol-3, 5-diene dissolved in tetrahydrofuran is dropwise added under the ice water bath, and TLC detection reaction is finished. Adding 1mol/L hydrochloric acid to quench the reaction, adding ethyl acetate to extract, and separating the solution. The organic layer was dried and evaporated to dryness to give 151g of crude product which was directly put into the next reaction.
151g of the crude product was dissolved in 100ml of acetic acid and 100ml of acetic anhydride and reacted under reflux with heating for 3 hours. TLC detection reaction was completed. Evaporating to dryness to recover acetic anhydride, crystallizing crude methanol to obtain 119g of 3-acetyl 3, 5-diene-25 hydroxy cholestane pure product. The molar yield was 52.7%.
9. Synthesis of cholesterol
4260g of 3-acetyl 3, 5-diene cholestane was dissolved in 8000ml of tetrahydrofuran, 340g of a freshly prepared calcium borohydride solution was added in portions at room temperature, and the reaction was spotted to completion. Adding 100ml of methanol to decompose residual calcium borohydride, adding 1mol/L hydrochloric acid to adjust pH to be=5, adding ethyl acetate to separate liquid, drying and evaporating an organic layer to obtain a white solid, and crystallizing ethanol to obtain 3670g of a pure product. Purity >99% by HPLC. The molar yield was 95%. HNMR (500 mhz, cdcl 3) δ:5.35 (m, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 1.01 (d, 3H), 0.92 (d, 3H), 0.87 (d, 3H), 0.86 (d, 3H), 0.68 (s, 3H). The spectrum is shown in figure 6.
10. Synthesis of 25-hydroxycholesterol
5140g of 3-acetyl-3, 5-diene 25-hydroxycholesterane was dissolved in 8000ml of tetrahydrofuran, 340g of freshly prepared calcium borohydride solution was added in portions at room temperature, and the reaction was spotted to completion. 100ml of residual calcium borohydride decomposed by methanol is added, 1mol/L hydrochloric acid is added to adjust the PH to be=5, ethyl acetate is added to separate liquid, the organic layer is dried and evaporated to dryness to obtain white solid, and then 4017g of pure product is obtained by ethanol crystallization. Purity >99% by HPLC. The molar yield was 85.82%. HNMR (500 MHz, CDCl 3) delta 5.35 (m, 1H), 3.51 (m, 1H), 1.21 (d, 6H), 1.01 (d, 3H), 0.93 (d, 3H), 0.68 (s, 3H).
11. 25-hydroxycholesterol (enzyme reduction method)
5.14g of 3-acetyl 3, 5-diene 25-hydroxycholesterane were dissolved in 20ml of methyl tert-butyl ether, 20ml of pH=7.0 phosphate buffer solution. 30mg of ketoreductase, 2g of glucose, NAD and NAD (P) were added + 70mg,glucose dehydrogenase (CDX-901, 30mg, 66U/mg) and reacting at 45 ℃ for 48h, wherein calcium hydroxide suspension is added in batches during the reaction to keep pH=7.0, separating liquid after the reaction, adding methyl tertiary butyl ether into a water layer for extraction, combining organic layers, drying and evaporating to dryness to obtain white solid, and crystallizing with ethanol to obtain 3.98g of pure product. HPLC detection of purity>99%. The molar yield was 85%.
HNMR (500 MHz, CDCl 3) delta 5.35 (m, 1H), 3.51 (m, 1H), 1.21 (d, 6H), 1.01 (d, 3H), 0.93 (d, 3H), 0.68 (s, 3H). The spectrogram is shown in figure 7.
The comprehensive experimental result shows that the method for synthesizing cholesterol and 25-hydroxycholesterol by using 22-sterol as the raw material has the advantages of simple reaction process, high yield, low production cost, environment-friendly process and suitability for industrial implementation.
The above embodiments are only preferred embodiments of the present invention, and the scope of the present invention is not limited thereto, i.e. the present invention is not limited to the above embodiments, but is capable of being modified and varied in all ways according to the following claims and the detailed description.
Claims (6)
1. A method for synthesizing cholesterol and 25-hydroxycholesterol by using 22-hydroxy-20-methyl pregna-4-en-3-one as a raw material is characterized by taking a plant sterol fermentation product 22-hydroxy-20-methyl pregna-4-en-3-one as a raw material and comprising the following steps:
1) Protection of 3-carbonyl group: the 22-hydroxy-20-methyl pregna-4-en-3-one is catalyzed by p-toluenesulfonic acid, reacts with tetrahydropyrrole or ethylene glycol at the reaction temperature of 10-120 ℃ for 3-5 hours, then stops the reaction by sodium bicarbonate, and is subjected to water separation and filtration to obtain 21-hydroxy-20-methyl pregna-3-tetrahydropyrrole-3, 5-diene or 21-hydroxy-20-methyl pregna-3-ethylene glycol-5-ene;
2) Sulfonation reaction: reacting 21-hydroxy-20-methyl pregna-3-tetrahydropyrrole-3, 5-diene or 21-hydroxy-20-methyl pregna-3-glycol-5-alkene with p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride and fluoro sulfonyl fluoride in dichloromethane or dichloroethane under the condition of triethylamine or diisopropylethylamine, washing with water, extracting, and concentrating to obtain a 22-sulfonyl compound;
3) Substitution reaction: adding 22-sulfonyl compound and Grignard reagent isopentylmagnesium bromide in tetrahydrofuran solvent, quenching with acid, separating liquid, concentrating to obtain 3-site protected cholestane or 3-site protected 25-hydroxy cholestane;
4) Acetylation reaction: 3-site protected cholestane or 3-site protected cholestane with 25-hydroxy group is subjected to 3-site protecting group exchange reaction under the condition of acetic acid and acetic anhydride, ethanol is evaporated to dryness and crystallized to obtain 3-acetyl-3, 5-diene cholestane or 3-acetyl-25-hydroxy-3, 5-diene cholestane;
5) Reduction reaction: 3-acetyl-3, 5-diene cholestane or 3-acetyl-25-hydroxy-3, 5-diene cholestane is dissolved in ethylene glycol dimethyl ether and tetrahydrofuran to react with sodium borohydride, potassium borohydride, zinc borohydride, calcium borohydride or reductase to obtain cholesterol or 25-hydroxy cholesterol.
2. The method according to claim 1, wherein the weight ratio of each reactant in the 3-carbonyl protection reaction in step 1) is: 21-hydroxy-20-methylpregna-4-en-3-one: tetrahydropyrrole or ethylene glycol = 1.0:1.0 to 5.0:1.0 to 5.0.
3. The method according to claim 1, wherein the 3-carbonyl protection reaction of step 1) is performed in an organic solvent, the solvent being one of ethanol, methanol, toluene.
4. The method of claim 1, wherein the substitution reaction in step 3) uses the grignard reagent isopentylmagnesium bromide with a reactant molar ratio of: 22-sulfonate: isopentylmagnesium bromide = 1: 3-10.
5. The method of claim 1, wherein in step 5) the 3-acetyl-3, 5-diene cholestane or 3-acetyl-25-hydroxy-3, 5-diene cholestane is dissolved in ethylene glycol dimethyl ether, tetrahydrofuran, sodium borohydride is added, and ethanol is extracted from the reaction product for crystallization to obtain cholesterol or 25-hydroxy cholesterol, 3-acetyl-3, 5-diene cholestane: sodium borohydride molar ratio = 1.0:0.25 to 1.
6. The method according to claim 1, wherein in step 5), 3-acetyl-25 hydroxy-3, 5-diene cholestane or 3-acetyl-3, 5-diene cholestane is reduced in methyl tertiary butyl ether phosphate buffer solution by carbonyl reductase to obtain cholesterol or 25-hydroxy cholesterol, and calcium hydroxide suspension is added dropwise during the reduction reaction to maintain the pH of the reaction solution at 7-7.5.
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