CN115260266A - Cholesterol synthesis method for constructing cholesterol side chain - Google Patents
Cholesterol synthesis method for constructing cholesterol side chain Download PDFInfo
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- CN115260266A CN115260266A CN202210793255.2A CN202210793255A CN115260266A CN 115260266 A CN115260266 A CN 115260266A CN 202210793255 A CN202210793255 A CN 202210793255A CN 115260266 A CN115260266 A CN 115260266A
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Abstract
The invention discloses a novel method for constructing a cholesterol side chain. The method takes 21-halo-20-methylpregna-5-en-3-ol (BA halide for short) as a raw material, and the raw material and halogenated isopentane carry out coupling reaction under the action of a catalyst to construct a cholesterol side chain. The method is simple, convenient and safe to operate, and improves the reaction yield by adding halogenated inorganic salt, organic alkali, an activating agent and the like. The raw material BA halide can be conveniently prepared from a plant source raw material 21-hydroxy-20-methyl pregn-4-alkene-3 ketone, is cheap and easily available, is safe and simple in reaction feeding, generates less waste and is environment-friendly. The invention has good industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of organic compound preparation, and relates to a method for constructing a cholesterol side chain and preparing cholesterol.
Background
Cholesterol (cholestrol), chemical name: cholesterol-5-ene-3 beta-ol, also known as cholesterol, is a derivative of cyclopentane-phenanthrene. Cholesterol, a lipid-type molecule, is not only an important component of cell membranes, but also can be converted into various physiologically active substances, such as corticosteroids, vitamin D3, bile acids, and the like, by oxidation, reduction, degradation, or the like of side chains. The traditional source of cholesterol is mainly extracted from animal organs, and in recent years, in view of the safety problem of animal source cholesterol, the demand of plant source cholesterol is increased year by year, so that the research on a method for synthesizing cholesterol by using a plant source extract as a starting material has great significance.
The early cholesterol synthesis method mainly uses diosgenin as a raw material and synthesizes the diosgenin through a six-step reaction (patent CN 1772760A).
In recent years, with the diversification of plant-derived raw materials, some new synthetic routes are reported successively, but the methods for constructing cholesterol side chains in the new routes are mostly limited to the application of Wittig reaction and coupling reaction of organometallic reagents.
The Wittig reaction is more applied. For example, patents CN105218609A and CN104961788A report a synthetic route using pregna-5-ene-3 β -hydroxy-20-one as a raw material. However, in order to ensure the stereoselectivity of the methyl group at the 20-position in the catalytic hydrogenation step, a relatively expensive hydrogenation catalyst and a relatively expensive ligand are required.
Phytosterol is a natural organic substance which can be produced in large quantities from byproducts of vegetable oil industry, wherein stigmasterol and degradation products thereof have wide application in steroid synthesis. CN106632565A and CN105237603A report a synthetic route via stigmasterol as starting material. After protecting the 3-hydroxyl of the raw material by using different strategies, the original side chain is cut off by using an ozonization reaction, and then the construction of the cholesterol side chain is completed by a Wittig reaction. But the ozonation reaction presents a greater risk of scaling up the production of such routes.
Similarly, patent CN105218610A reports a route to the use of 20-formylpregn-4-en-3-one as a starting material.
With the development of biodegradation technology, the cost of plant source raw material 21-hydroxy-20-methylpregna-4-en-3-one (BA, or biscarbinol) is greatly reduced in recent years, and the compound becomes an economic and practical synthetic intermediate. CN113248557A reports a new synthetic route based on Wittig reaction using BA as raw material.
Methods of coupling via organometallic reagents have also been reported. CN112608361A uses BA as the starting material, and adopts organic copper lithium reagent to react with 20-methyl pregn-5-ene-3, 21-diol 21-p-toluene sulfonic acid ester to construct the cholesterol side chain.
However, no matter the Wittig reaction or the coupling reaction of the organic metal reagent, the reaction conditions are harsh to different degrees, the hydrogenation reaction has potential safety hazard, the catalyst is expensive, the preparation and the use of the stoichiometric organic metal reagent have potential safety hazard, a large amount of solid wastes (such as triphenyl phosphine oxide) are generated, and the like, so that the research on the novel side chain construction method has important significance for the industrial production of the cholesterol.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a synthesis method for preparing cholesterol by using 21-halogeno-20-methyl pregn-5-ene-3-ol (BA halide for short) as a raw material and performing coupling reaction with halogenated isopentane under the catalysis of a catalyst to construct a cholesterol side chain.
The reaction process of the preparation method of the invention is shown as a reaction formula (I), wherein X1、X2Is any one of I, br and Cl. In the synthesis reaction, 21-halogeno-20-methyl pregn-5-alkene-3-alcohol is used as a raw material, and is subjected to coupling reaction with halogenated isopentane in an organic solvent under the action of a catalyst, a ligand and a reducing agent to construct the cholesterol side chain, so that a reaction product, namely cholesterol:
specifically, the method of the present invention comprises the steps of:
coupling reaction: in an organic solvent, performing coupling reaction on a BA halide, halogenated isopentane, a catalyst, a ligand and a reducing agent under the heating condition to obtain cholesterol; further, the reaction yield can be further improved by adding a halogenated inorganic salt, an organic base and an activator.
Wherein X in the BA halide and the halogenated isopentane1，X2Each group is selected from one of chlorine, bromine and iodine; preferably, X1Is bromine, X2Is bromine.
Wherein the organic solvent is selected from one or more of N, N-dimethylformamide, N, N-dimethyl-acetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene and the like; preferably, it is N, N-dimethylacetamide.
Wherein the catalyst comprises a nickel (II) halide; the catalyst is selected from one or more of anhydrous nickel iodide, hydrated nickel iodide, anhydrous nickel bromide, anhydrous nickel chloride, nickel chloride hexahydrate and the like; preferably, it is anhydrous nickel iodide.
Wherein the ligand is selected from one or more of bipyridyl, 4-dimethoxy bipyridyl, 4-di-tert-butyl bipyridyl, 1, 10-phenanthroline and the like; preferably, it is bipyridine.
Wherein the reducing agent is selected from one or more of zinc powder, manganese powder and the like; preferably manganese powder.
Wherein the mass ratio of the 21-halogenated-20-methylpregna-5-en-3-ol, the halogenated isopentane, the catalyst, the ligand and the reducing agent is 1: (0.4-1.1): (0.02-0.15): (0.01-0.08): (0.14-0.4); preferably, it is 1:0.57:0.08:0.05:0.28.
wherein the temperature of the coupling reaction is 10-80 ℃; preferably, it is 70 ℃.
Wherein the reaction time of the coupling reaction is 10 to 24 hours; preferably, it is 18 hours.
The cholesterol side chain constructed by the reaction has the structure
Has the advantages of high purity of raw materials, low price and less side reaction.
The product cholesterol obtained by the above reaction has the structure
Has the advantages of non-animal source of starting raw materials, better yield and simple feeding.
The invention also provides a synthesis method for constructing the cholesterol side chain and obtaining the cholesterol, wherein the reactivity of the side chain can be further improved by adding halogenated inorganic salt, organic base and an activating agent.
Wherein, the halogenated inorganic salt is selected from one or more of sodium iodide, potassium iodide, sodium bromide, potassium bromide and the like; preferably, it is potassium iodide.
Wherein the organic base is selected from one or more of pyridine, collidine, triethylamine and the like; preferably, pyridine.
Wherein the activating agent is selected from one or more of trimethylchlorosilane, trimethylsilyl trifluoromethanesulfonate and the like; preferably, it is trimethylchlorosilane.
Wherein, preferably, the mass/volume ratio of the BA halide and the organic solvent is: 1: (5-10), such as 1:7.
in the coupling reaction, the mass ratio of the BA halide to the halogenated isopentane to the catalyst to the ligand to the reducing agent to the additive salt to the alkali to the activating agent is 1: (0.4-1.1): (0.02-0.15): (0.01-0.08): (0.14-0.4): (0.04-0.2): (0.01-0.04): (0.02-0.15); preferably, 1:0.57:0.08:0.05:0.28:0.11:0.02:0.06.
wherein the temperature of the coupling reaction is 10-80 ℃; preferably, it is 70 ℃.
Wherein the reaction time of the coupling reaction is 2 to 18 hours; preferably, it is 4 hours.
In the invention, by adding halogenated inorganic salt, organic base and an activating agent, the reaction yield is 80-91%; preferably, the reaction yield is 90.5%.
The structure of the constructed cholesterol side chain is as follows
Has the advantages of high purity of raw materials, low price, less side reaction and the like. The obtained product has the advantages of non-animal source of starting raw materials, high yield, high purity, simple and convenient operation and purification and the like.
The beneficial effects of the invention include: the BA halide raw material can be conveniently prepared from a plant source raw material 21-hydroxy-20-methylpregna-4-en-3-one, is cheap and easy to obtain, is simple to prepare, and can effectively avoid the possible risks of animal source raw materials; the reaction feeding is safe and simple, and no metal reagent needs to be prepared additionally; the used reagents are generally catalytic amounts, generate less waste, avoid a large amount of triphenyl phosphine oxide solid waste generated in the existing Wittig reaction process, are environment-friendly and have better industrial application prospects.
The invention creatively adopts a nickel catalysis method to finish the construction of the cholesterol side chain, avoids the dangerous chemical process (hydrogenation reaction) and the metallorganic synthesis reaction (Grignard reaction) which are strictly monitored in the traditional synthesis process, further improves the reaction yield by adding the iodized inorganic salt and the pyridine organic base, greatly accelerates the reaction rate by adding the trimethylchlorosilane, and improves the industrialization potential of the method; the reaction intermediate is simple to prepare, can be prepared from a plant source raw material 21-hydroxy-20-methyl pregn-4-ene-3 ketone, is cheap and easy to obtain, and can effectively avoid product application limitation caused by animal source raw materials; the feeding reagent is generally catalytic amount, generates less waste, particularly avoids a large amount of triphenyl oxyphosphorus oxide solid waste generated in the existing Wittig synthesis process, is environment-friendly, and has good industrial application prospect.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited. The results obtained under the optimized experimental conditions are shown in the following examples, and have potential application values.
The preparation process of the cholesterol is shown as the following formula:
EXAMPLE 1 preparation of Cholesterol
Under the protection of nitrogen, 10.5g of potassium iodide, 5g of bipyridine, 700mL of DMAI, 8g of anhydrous nickel iodide, 2g of pyridine and 27.8g of manganese powder are sequentially added into a reaction bottle. Placing a reaction bottle in an ice bath, adding 100g of compound 1 (prepared by BA and obtained by reference patent document CN 112608361A) and 57g of bromo-isopentane under stirring, then slowly dropwise adding 6.5g of TMSCl, controlling the internal temperature to be not more than 10 ℃, raising the temperature to room temperature after the dropwise adding, stirring for 10 minutes, and raising the temperature to 70 ℃ for reacting for 3-6 hours. And detecting the reaction end point by TLC. The reaction mixture was cooled to room temperature and filtered through celite, the filter cake was washed with DMA (100 mL × 3), the filtrate was poured into 2L of water with stirring, the solid precipitated, stirred for 30 minutes, filtered, washed with water (200 mL × 4) to give crude cholesterol, which was further crystallized with ethanol and dried to give pure cholesterol 88.5g with a molar yield of 90.5%.
EXAMPLE 2 preparation of Cholesterol
The solvent is changed into DMSO (700 mL), zinc powder is used as a reducing agent (32.3 g), and the other operations are the same as those in the embodiment 1 of the invention, so that 80.5g of pure cholesterol is obtained, and the molar yield is 82.3%.
EXAMPLE 3 preparation of Cholesterol
The catalyst was changed to 10g of nickel iodide tetrahydrate, and the same operations as in example 1 of the present invention were carried out to obtain 86.5g of pure cholesterol product with a molar yield of 88.5%.
EXAMPLE 4 preparation of Cholesterol
Under the protection of nitrogen, 500mg of bipyridine, 70 mL of DMAC, 800mg of anhydrous nickel iodide and 2.8g of manganese powder are sequentially added into a reaction bottle. 10g of Compound 1 and 5.7g of bromoisopentane were added thereto with stirring at room temperature, and the mixture was heated to 60 ℃ to react for 18 hours. And detecting the reaction end point by TLC. The reaction mixture was cooled to room temperature, filtered through celite, the filter cake was washed with DMA (10 mL × 3), the filtrate was poured into 150mL of water with stirring, extracted with ethyl acetate (200 mL × 3), the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried to give the crude product. Purification by column chromatography gave 6.7g of pure cholesterol in 68% yield.
EXAMPLE 5 preparation of Cholesterol
Under the protection of nitrogen, additives (inorganic salts 0.25eq, organic base 0.1 eq), bipyridine 250mg (0.12 eq), DMA40 mL, anhydrous nickel iodide 400mg (0.1 eq), and manganese powder 1.4g (2 eq) were added to a reaction flask in this order. 5g of Compound 1, 2.9g (1.5 eq) of bromoisopentane, and an activator (0.25 eq, e.g. trimethylchlorosilane, cooled to below 10 ℃ and then added slowly) were added with stirring at room temperature. The temperature is raised to 70 ℃ for reaction for 18 hours. And detecting the reaction end point by TLC. The reaction mixture was cooled to room temperature, filtered through celite, the filter cake was washed with DMA (10 mL × 3), the filtrate was poured into 100mL of water with stirring, extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried to give the crude product. Purifying by column chromatography to obtain pure cholesterol, and calculating the yield. The results are shown in Table 1.
TABLE 1 Effect of different additives on the reaction
a. The reaction temperature is 80 ℃; b. the reaction time was 4 hours
As can be seen from table 1 above, the addition of inorganic iodide salt can effectively improve the reaction yield; the yield is not obviously improved by adding the organic base, but the reaction is relatively more thorough and rapid, and the improvement effect is not seen by adding the triethylamine; after trimethylchlorosilane is added for activation, the reaction time is greatly shortened to 4 hours; the increase in temperature does not increase the reaction rate much and decreases the yield.
EXAMPLE 6 preparation of Cholesterol
Under the protection of nitrogen, 340mg of 4, 4-dimethoxy bipyridine, DMA40 mL of DMA40, 400mg of anhydrous nickel iodide and 1.4g of manganese powder are sequentially added into a reaction bottle, 5g of compound 1 and 2.9g of bromo-isopentane are added under stirring, the reaction temperature is reduced to below 10 ℃, and 350mg of trimethylchlorosilane is slowly added dropwise. After the dropwise addition, the temperature was raised to 70 ℃ to react for 4 hours. And detecting the reaction end point by TLC. The reaction mixture was cooled to room temperature, filtered through celite, the filter cake was washed with DMA (10 mL × 3), the filtrate was poured into 100mL of water with stirring, extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried to give the crude product. Purification by column chromatography gave 4.25g of pure cholesterol in 87% yield.
EXAMPLE 7 preparation of Cholesterol
The ligand was changed to 285mg (0.1 eq) of 1,10-phenanthroline, and the other operations were the same as in example 6 of the present invention, to give 4.3g of pure cholesterol in 88% yield.
EXAMPLE 8 preparation of Cholesterol
Under the protection of nitrogen, 250mg of bipyridyl, DMA40 mL of nickel iodide anhydrous and 1.4g of manganese powder are sequentially added into a reaction bottle, 5g of compound 1 and bromoisopentane (1-2 eq) are added under stirring, the reaction temperature is reduced to below 10 ℃, and 350mg of trimethylchlorosilane is slowly added dropwise. After the dropwise addition, the temperature was raised to 70 ℃ to react for 4 hours. And detecting the reaction end point by TLC. The reaction mixture was cooled to room temperature, filtered through celite, the filter cake was washed with DMA (10 mL × 3), the filtrate was poured into 100mL of water with stirring, extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried to give the crude product. Purifying by column chromatography to obtain pure cholesterol, and calculating the yield. The results are shown in Table 2.
TABLE 2 Effect of Isopentane Bromide amount on reaction
| Numbering | Amount (eq) of bromoisopentane | Yield (%) |
| 1 | 1 | 56 |
| 2 | 1.3 | 84 |
| 3 | 2 | 91 |
When the equivalent of the bromoisopentane in the reaction is reduced to 1 equivalent, part of raw materials are remained, so that the yield is greatly reduced; when the yield is increased to 1.3 equivalents, the yield is still slightly reduced; when the amount is increased to 2 equivalents, the yield is not greatly affected. The optimal dosage of the bromoisopentane is 1.5 equivalents by comprehensively considering the yield and the cost.
EXAMPLE 9 preparation of Cholesterol
The operation was carried out in the same manner as in example 8 of the present invention except that 3.8g (1.5 eq) of isopentane iodide was used instead of isopentane bromide to obtain 4.0g of a pure product of cholesterol in a yield of 82%.
The protection content of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.
Claims (9)
1. A cholesterol synthesis method for constructing a cholesterol side chain is characterized in that a reaction process of the method is shown as a reaction formula (I), 21-halo-20-methylpregna-5-en-3-ol is used as a raw material, and is subjected to coupling reaction with halogenated isopentane in an organic solvent under the action of a catalyst, a ligand and a reducing agent to construct the cholesterol side chain, so that a reaction product, namely cholesterol:
wherein X1、X2Respectively is any one of I, br and Cl.
2. The method of claim 1, wherein in the reacting,
the organic solvent is selected from one or more of N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and toluene; and/or the presence of a gas in the gas,
the catalyst is selected from one or more of anhydrous nickel iodide, hydrated nickel iodide, anhydrous nickel chloride, hexahydrate nickel chloride and anhydrous nickel bromide; and/or the presence of a gas in the atmosphere,
the ligand is selected from one or more of bipyridyl, 4-dimethoxy bipyridyl, 4-di-tert-butyl bipyridyl and 1, 10-phenanthroline; and/or the presence of a gas in the atmosphere,
the reducing agent is selected from one or more of zinc powder and manganese powder.
3. The method of claim 1, wherein in the coupling reaction, the mass ratio of the 21-halo-20-methylpregn-5-en-3-ol, the halogenated isopentane, the catalyst, the ligand, and the reducing agent is 1: (0.4-1.1): (0.02-0.15): (0.01-0.08): (0.14-0.4).
4. The method according to claim 1, wherein a halogenated inorganic salt, an organic base, and an activator may be further added to the reaction.
5. The method of claim 4,
the halogenated inorganic salt is selected from one or more of sodium iodide, potassium iodide, sodium bromide and potassium bromide; and/or the presence of a gas in the atmosphere,
the organic base is selected from one or more of pyridine, trimethyl pyridine and triethylamine; and/or the presence of a gas in the gas,
the activating agent is selected from one or more of trimethylchlorosilane and trimethylsilyl trifluoromethanesulfonate.
6. The method of claim 4, wherein in the coupling reaction, the mass ratio of the 21-halo-20-methylpregn-5-en-3-ol, the halogenated isopentane, the catalyst, the ligand, the reducing agent, the halogenated inorganic salt, the organic base, and the activating agent is 1: (0.4-1.1): (0.02-0.15): (0.01-0.08): (0.14-0.4): (0.04-0.2): (0.01-0.04): (0.02-0.15).
7. The method of claim 1, wherein the temperature of the coupling reaction is between 10 ℃ and 80 ℃; and/or the reaction time of the coupling reaction is 2 to 18 hours.
8. The method of claim 5, wherein the reaction yield is 68 to 90.5%.
9. A cholesterol side chain constructed according to any of the methods of claims 1-8, the resulting cholesterol being characterized,
the structure of the constructed cholesterol side chain is as follows
The synthesized cholesterol has the structure
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5182393A (en) * | 1991-08-09 | 1993-01-26 | Hoffmann-La Roche Inc. | Process for precursors to calcitriol and related compounds |
| CN112608361A (en) * | 2019-12-19 | 2021-04-06 | 湖南科瑞生物制药股份有限公司 | Process for preparing cholesterol, derivatives and analogues thereof |
| CN113336786A (en) * | 2021-05-31 | 2021-09-03 | 南京工业大学 | Diastereoselective polysubstituted naphthenic compound and preparation method thereof |
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- 2022-07-07 CN CN202210793255.2A patent/CN115260266A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5182393A (en) * | 1991-08-09 | 1993-01-26 | Hoffmann-La Roche Inc. | Process for precursors to calcitriol and related compounds |
| CN112608361A (en) * | 2019-12-19 | 2021-04-06 | 湖南科瑞生物制药股份有限公司 | Process for preparing cholesterol, derivatives and analogues thereof |
| CN113336786A (en) * | 2021-05-31 | 2021-09-03 | 南京工业大学 | Diastereoselective polysubstituted naphthenic compound and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 徐海亮 等: "镍催化卤代烷烃交叉偶联反应的配体优化", 上海大学学报（自然科学版）, vol. 20, pages 221 - 227 * |
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