CN117486960A - Preparation method of cholesterol and intermediate thereof - Google Patents

Preparation method of cholesterol and intermediate thereof Download PDF

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Publication number
CN117486960A
CN117486960A CN202210880883.4A CN202210880883A CN117486960A CN 117486960 A CN117486960 A CN 117486960A CN 202210880883 A CN202210880883 A CN 202210880883A CN 117486960 A CN117486960 A CN 117486960A
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compound
reaction
molar ratio
reagent
formatting
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耿美玲
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Suzhou Bao'erpu Biomedical Technology Co ltd
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Suzhou Bao'erpu Biomedical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

The invention provides cholesterol and a preparation method of the cholesterol intermediate, wherein the cholesterol is obtained by taking 21-hydroxy-20-methyl pregna-4-ene-3-one (4-BA) as a raw material through sulfonylation reaction, etherification reaction, formatting reaction, acetylation reaction and reduction reaction. The method provided by the invention has the advantages of short synthetic route and high reaction yield, does not use drastic drugs and other reagents with serious pollution to the environment in the reaction route, and is suitable for industrial production and application.

Description

Preparation method of cholesterol and intermediate thereof
Technical Field
The application belongs to the technical field of medicines, and particularly relates to a preparation method of a steroid compound, in particular to a preparation method of cholesterol and an intermediate thereof.
Background
Cholesterol, also known as cholesterol (5-cholesten-3 beta-ol), is a derivative of cyclopentane polyhydrophenanthrene and is also a steroid compound found earliest, and the structural formula of the cholesterol is shown as the following formula I:
cholesterol is widely present in blood, fat, brain marrow and nervous tissue of humans and animals. It is an indispensable important substance for animal tissue cells, and not only participates in the formation of cell membranes, but also is a raw material for synthesizing bile acid, vitamin D and steroid hormone. Cholesterol is a raw material of steroid hormone (such as estrone, androsterone, testosterone, cortisone, etc.), vitamin D3, artificial bezoar, can be used as liquid crystal, biological agent and prawn feed additive, and can be used as a multifunctional auxiliary agent with biological activity for cosmetics. At present, cholesterol mainly comprises serial products such as bilirubin, hyodeoxycholic acid, taurocholate, hyodeoxycholic acid and the like, and has been widely applied to medical raw material intermediates, synthetic raw materials, veterinary raw materials, intermediates and the like.
At present, cholesterol is mainly obtained by saponifying brain and spinal tendon of pig, cattle and sheep and extracting with organic solvent. Since many of the diseases now found are transmitted by animals to humans, especially mad cow disease in the last europe of the last century, and streptococcus suis infection in the beginning of the century, people doubt about the safety of cholesterol produced by conventional methods, and people need a cholesterol with a high safety factor.
Thus, research has been undertaken to produce cholesterol using synthetic or semi-synthetic methods. Because of the complex molecular structure of cholesterol, cholesterol was found as early as 1815, but the synthesis of steroids has not been broken through until the last 50 th century. In 1951, woodwald (R.B Woodward) completed the total synthesis of cholesterol, however, the method adopted only requires 36 steps of chemical reaction steps, and the separation requires more steps, the yield is low, and the mixture of various optical isomers is finally obtained, which is not suitable for industrial production.
Patent CN113651866a discloses a method for synthesizing cholesterol by using 21-hydroxy-20-methyl pregna-4-en-3-one (4-BA) as a raw material through etherification reaction, oxidation reaction, addition reaction, sulfonylation reaction, reduction reaction, acetylation reaction and re-reduction reaction, wherein the synthetic route is as follows:
the synthesis route has seven steps of reaction, the total yield is about 58.9%, the reaction steps are longer, the yield is lower, the operation is complex, the oxidation reaction is required, and the use of highly toxic methanesulfonyl chloride has serious pollution and great potential safety hazard, and is not suitable for industrialized application.
Patent number CN104961788A adopts a method for synthesizing cholesterol by taking pregnenolone as a raw material, and the synthetic route is as follows:
the synthetic route needs to use an expensive rhodium metal catalyst for selective hydrogenation in the hydrogenation reaction, has high cost, higher requirements on equipment, is not easy to operate, can introduce less part of perhydrogenation impurities in the reaction process, is difficult to purify, has higher production cost, and is not suitable for industrialized application.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention aims to provide a preparation method of cholesterol and an intermediate thereof, which has the advantages of short reaction route and high yield and is suitable for industrial production and application.
First, the present invention provides a process for preparing intermediate compound BA02 for preparing cholesterol, comprising the steps of: the compound BA03 is subjected to a formatting reaction with a formatting reagent G01, and converted into a compound BA02:
wherein X in the structure of the format reagent G01 is selected from Cl, br or I, preferably Br.
In a preferred embodiment, the formative reagent is selected from the group consisting of isopentylmagnesium bromide.
In a preferred embodiment, the formatting of the compound BA03 with the formatting reagent G01 is carried out in lithium tetrachlorocuprate (Cl 4 CuLi 2 ) Is carried out under catalysis of (2).
In a preferred embodiment, the molar ratio of said compound BA03 to the lithium tetrachlorocuprate catalyst is between 1:0.1 and 0.5, for example 1:0.1 to 0.4,1:0.1 to 0.3, or 1:0.1 to 0.2, etc.
In a preferred embodiment, the molar ratio of compound BA03 to formative reagent G01 (e.g., isopentylmagnesium bromide or isopentylmagnesium chloride) is from 1:2 to 8, such as 1:3,1:4,1:5,1:6,1:7, and any value therebetween.
In a preferred embodiment, the solvent for the formatting reaction of compound BA03 with the formatting reagent G01 is selected from tetrahydrofuran solution or 2-methyltetrahydrofuran.
The isopentyl magnesium bromide can be commercial grade, can also be obtained by self-making, can be prepared by any method known in the art, for example, can be obtained by reacting magnesium and bromoisopentane under the catalysis of iodine, specifically, the molar ratio of magnesium to bromoisopentane is 1:0.8-1.2, preferably 1:0.8-1, the reaction solution is preferably THF, and the iodine content is of catalyst grade.
The lithium tetrachlorocuprate according to the present invention may be commercially available, or may be obtained by self-making, which may be performed by any method known in the art, for example, by reacting copper chloride with lithium chloride in tetrahydrofuran solution, wherein the molar ratio of the reactants of copper chloride and lithium chloride is 1:1-3, such as 1:2 to 3, or 1:2.5, etc.
In a preferred embodiment, the formatting reaction of the above compound BA03 with the formatting reagent G01 comprises cooling the THF solution of isopentylmagnesium bromide to not higher than-10 ℃, such as-20 ℃, then adding THF of lithium tetrachlorocuprate thereto, and finally adding the THF solution of the compound BA03 to carry out the reaction.
The preparation method of the compound BA02 optionally further comprises a post-treatment process, wherein the post-treatment process comprises one or more steps of quenching, regulating the pH value, extracting, filtering, adsorbing, crystallizing, recrystallizing, concentrating and the like after the reaction is finished, and the steps of quenching, regulating the pH value, extracting, filtering, adsorbing, crystallizing, recrystallizing, concentrating and the like can be sequentially or alternately carried out, or a purification method such as crystallizing or recrystallizing can be carried out for a plurality of times. In a preferred embodiment of the present invention, the post-treatment process comprises adding saturated ammonium chloride to the reaction mixture to quench, separating the mixture, and concentrating the mixture to isolate the target compound BA02 after the reaction.
In a second aspect, the present invention provides a process for the preparation of compound BA03, comprising: etherification reaction is carried out on the compound BA04 and triethyl orthoformate, and the compound BA04 is converted into a compound BA03:
in a preferred embodiment, the etherification reaction is carried out under the catalysis of phosphotungstic acid or p-toluenesulfonic acid, more preferably the reaction is carried out under the catalysis of p-toluenesulfonic acid.
In a preferred embodiment, the molar ratio of said compound BA04 to triethyl orthoformate is from 1:1 to 5, for example from 1:4 to 5, from 1:3 to 5, or from 1:3 to 4, etc.
In a preferred embodiment, the molar ratio of compound BA04 to catalyst p-toluene sulfonic acid is from 1:0.01 to 0.2, for example 1:0.01 to 0.1,1:0.01 to 0.02,1:0.01 to 0.05, etc.
In a preferred embodiment, the molar ratio of compound BA04 to catalyst phosphotungstic acid is from 1:20 to 50, for example 1: 30-50 or 1:35 to 40, etc.
In a preferred embodiment, the etherification reaction of the compound BA04 with triethyl orthoformate is carried out at a temperature of from 10 to 70℃and preferably from 20 to 50 ℃.
In a preferred embodiment, the solvent for the etherification of the compound BA04 with triethyl orthoformate is selected from the group consisting of C1-3 haloalkane solvents, ether solvents and C1-3 alcohol solvents;
preferably, the C1-3 haloalkane solvent is selected from the group consisting of halomethane solvents selected from the group consisting of dichloromethane and tetrachloromethane, preferably dichloromethane;
the ether solvent is selected from tetrahydrofuran, methyl tertiary butyl ether, dioxane, tertiary butyl ether, n-butyl ether and tetrahydropyran, preferably tetrahydrofuran or dioxane;
the C1-5 alcohol solvent is selected from methanol, ethanol, propanol and isopropanol, preferably methanol or ethanol;
further preferably, the reaction solvent is selected from any one of tetrahydrofuran, ethanol, methanol, 1, 4-dioxane, and dichloromethane.
In a preferred embodiment, the above process optionally further comprises a step of isolation and purification after the reaction is completed, for example, after the reaction is completed, the reaction is terminated with sodium hydrogen carbonate, suction filtration and washing with water to obtain the objective compound BA03.
In a third aspect of the present invention, there is provided a process for the preparation of compound BA04, which comprises subjecting compound 4-BA to a sulfonylation reaction with p-toluenesulfonyl chloride under basic conditions to convert to compound BA04:
in a preferred embodiment, the sulfonylation is carried out in the presence of pyridine or a pyridine derivative, preferably selected from C 1～6 Alkyl-substituted pyridines, or C 1～6 Alkyl-substituted aminopyridine, more preferably 4-dimethylaminopyridine.
In a preferred embodiment, the molar ratio of the compound 4-BA to pyridine or pyridine derivative is from 1:0.05 to 0.5, such as from 1:0.1 to 0.2, from 1:0.1 to 0.3, or from 1:0.1 to 0.4, etc.
In a preferred embodiment, the molar ratio of the compound 4-BA to p-toluenesulfonyl chloride is 1:1-2.
In a preferred embodiment, the molar ratio of the compound 4-BA to the base is 1:2 to 3.
In a preferred embodiment, the base is selected from C 3-10 Tertiary amine compound of (C) 3-10 The tertiary amine compound of (2) is selected from trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-dimethylethylamine, tetramethyl ethylenediamine or tetramethyl propylenediamine, preferably triethylamine, tetramethyl ethylenediamine or diisopropylethylamine; more preferably triethylamine.
In a preferred embodiment, the temperature at which the sulfonylation of the compound 4-BA with p-toluenesulfonyl chloride is carried out under basic conditions is from 10 to 70℃and preferably from 20 to 50 ℃.
In a preferred embodiment, the above method optionally further comprises a step of separating and purifying the reaction product after the sulfonylation reaction is completed, wherein the purification step comprises one or more steps of adding methanol and water to the reaction system after the reaction is completed, quenching reaction, extraction, concentration, crystallization, recrystallization and the like, and the steps can be sequentially or alternatively performed.
In a fourth aspect, the present invention provides a process for the preparation of cholesterol (I), the process comprising:
(c) Carrying out formatting reaction on a compound BA03 and a formatting reagent G01 under the catalysis of lithium tetrachlorocuprate, and converting the compound BA03 into a compound BA02, wherein X in the structure of the formatting reagent G01 is selected from Cl, br or I, preferably Br;
(d) The compound BA02 and isopropenyl acetate are subjected to acetylation reaction under the catalysis of concentrated sulfuric acid or p-toluenesulfonic acid, and are converted into a compound BA01;
(e) Subjecting compound BA01 to a reduction reaction with sodium borohydride to convert to cholesterol (I):
further preferably, the present invention provides a process for the preparation of cholesterol (I) starting from compound 4-BA, said process comprising the steps of: (a) Carrying out sulfonylation reaction on the compound 4-BA and p-toluenesulfonyl chloride under alkaline conditions to convert the compound into a compound BA04;
(b) Etherification reaction is carried out on the compound BA04 and triethyl orthoformate, and the compound BA04 is converted into a compound BA03;
(c) Subjecting compound BA03 to a formatting reaction with a formatting reagent G01, to convert it into compound BA02, wherein X in the structure of the formatting reagent G01 is selected from Cl, br or I, preferably Br;
(d) Hydrolyzing the compound BA02 under an acidic condition, and then carrying out an acetylation reaction with isopropenyl acetate under the catalysis of p-toluenesulfonic acid to convert the compound BA02 into a compound BA01;
(e) Compound BA01 is converted to compound BA01 by a reduction reaction.
Wherein the process of step (a) for preparing compound BA04 from compound 4-BA, step (b) for preparing compound BA03 from compound BA04, and step (c) for preparing compound BA02 from compound BA03 is as described herein before.
In a preferred embodiment, the acid of step (d) is preferably sulfuric acid, hydrochloric acid or nitric acid, the hydrolysis reaction temperature is preferably 30 to 60 ℃, and further the reaction temperature with isopropenyl acetate is 70 to 120 ℃, preferably 80 to 100 ℃;
further preferably, the molar ratio of the compound BA02 to the p-toluenesulfonic acid is 1:0.1-0.5, such as 1:0.1-0.2, 1:0.1-0.3 or 1:0.1-0.4, etc.;
further preferably, step (d) isopropenyl acetate is both the reaction solvent and the acylating agent;
it is further preferred that the process of step (d) further comprises a further purification step, e.g. after completion of the reaction, concentration of the reaction solution and further purification of the target compound by crystallization from methanol.
In a preferred embodiment, the reaction of step (e) is carried out with a reducing agent selected from the group consisting of sodium borohydride, potassium borohydride, pb/C and H 2 Preferably, the reducing agent is sodium borohydride;
further preferably, the reduction reaction is carried out by adopting sodium borohydride or potassium borohydride to reduce in ethanol, methanol or tetrahydrofuran solvent, and anhydrous calcium chloride and pyridine are added as catalysts;
further preferably, the molar ratio of the compound BA01 to the reducing agent is 1:2-3;
further preferably, the molar ratio of the compound BA01 to pyridine is 1:2-3;
further preferably, the molar ratio of the compound BA01 to the calcium chloride is 1:0.1 to 0.5, such as 1:0.1 to 0.3,1:0.2 to 0.4, etc.
In a preferred embodiment, the reaction of step (d), optionally further comprising a work-up procedure, e.g. after completion of the reaction, the reaction is poured into ice water, followed by quenching the reaction with an acid (preferably hydrochloric or acetic acid) solution, filtration and crystallization (preferably the crystallization solvent is methanol or ethanol) to give purified cholesterol.
The steps (d) and (e) of the present invention may also employ methods already disclosed in the prior art, for example, the preparation of compound BA01 from compound BA02 and the preparation of cholesterol from compound BA01 are disclosed in CN113651866a, the disclosure of which is incorporated herein by reference.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is a conflict, the present application provides definitions. All patents, published patent applications, and publications cited herein are incorporated by reference.
The invention is described as "C 1-6 Alkyl "defines straight and branched chain saturated hydrocarbon groups having 1 to 6 carbon atoms, such as: methyl, ethyl, propyl, butyl, pentyl, 1-methylbutyl, 2-dimethylpropyl, 2-dimethylethyl, and the like.
The invention is described as "C 1～6 Alkyl-substituted pyridine "means pyridine substituted with methyl, ethyl, propyl, isopropyl, tert-butyl, n-butyl, pentyl, 2-methylbutyl, neopentyl, cyclohexyl, n-hexyl, preferably 2-methylpyridine, 2, 6-dimethylpyridine;
the invention is described as "C 1～6 Alkyl substituted aminopyridines "include, but are not limited to, pyridines such as those substituted with dimethylamino, methylamino, ethylamino, methylethylamino, propylamino, isopropylamino, methylpropylamino, and the like, where the substitution may be at the 2-, 3-, 4-position of the pyridine; preferably, the C 1～6 The alkyl-substituted aminopyridine is 4-dimethylaminopyridine, 4-methylaminopyridine, 2-dimethylaminopyridine, or 2-methylaminopyridine.
DMAP refers to 4-dimethylaminopyridine.
The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps. Those skilled in the art will appreciate that such terms as "comprising" encompass the meaning of "consisting of …".
The terms "selected from …", "preferably …" and "more preferably …" refer to one or more elements of the group listed thereafter, independently selected, and may include combinations of two or more elements, with one element of the group listed thereafter being preferred in the present invention.
The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The terms "substituted" and "substituted" refer to the replacement of one or more (e.g., one, two, three, or four) hydrogens on the designated atom with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The beneficial effects of the invention are as follows:
firstly, the invention provides a brand new preparation method of cholesterol and intermediate compounds BA02, BA03 and BA04 thereof, which takes 4-BA as a starting material, and obtains the cholesterol through sulfonylation reaction, etherification reaction, isopentyl magnesium bromide formatting reaction, acetylation reaction and reduction reaction. Is obviously higher than the prior art (the yield is improved by more than about 20 percent compared with the prior art by taking 4-BA as a starting material). In addition, the method provided by the invention has less side reaction in each step, the related impurities introduced by the intermediate preparation are easy to remove, and the finally prepared cholesterol has high purity and can meet the medicinal standard.
Secondly, the invention takes 4-BA as a starting material, and carries out the sulfonylation reaction and then the formatting reaction after the etherification reaction, so that the side reaction caused by the formatting can be obviously reduced, the proportion of bromoisopentane and copper salt in the formatting reaction process is reduced, and the utilization efficiency of the reactant is improved.
In addition, the toxicity of the reagent used in the preparation method provided by the invention is lower (the toxicity of the p-toluenesulfonyl chloride is obviously lower than that of the methanesulfonyl chloride), the labor protection requirement is low, an expensive noble metal catalyst is not needed, and the production cost and the production risk are obviously reduced; in addition, compared with the prior art, the method provided by the invention omits an oxidation step, has strong operability, and is more suitable for industrial production. The acetylation reaction step adopts an acetylation reagent as a solvent directly, and the method can be recovered, has low cost and is environment-friendly.
Detailed Description
The invention is further described below in conjunction with the specific embodiments. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Example 1: preparation of 21-p-toluenesulfonyloxy-20-methylpregna-4-en-3-one (BA 04)
Into a 2L three-necked flask, 200g (0.60 mol) of Compound 4-BA was charged, 10g (0.08 mol) of DMAP was introduced at room temperature, and Et 3 N153 g (1.51 mol) was dissolved in 1L of methylene chloride, replaced with argon, and stirred until the solution was clear, and refluxed at elevated temperature. 500ml of methylene chloride solution dissolved in 150g (0.79 mol) of p-toluenesulfonyl chloride was slowly added to the system, reflux was continued after completion of the dropwise addition, after completion of TLC monitoring, the system was cooled to 10℃and quenched with 100ml of methanol/water (volume ratio: 1:1), followed by adding water to the aqueous solution, washing the organic layer with water, removing most of the solvent under reduced pressure, concentrating to a viscous state, and then pouring the liquid into methanol, stirring, suction filtration, and washing with iced methanol to give 287g of pure compound BA04 in a molar yield of 98%.
1 H NMR(400MHz,Chloroform-d)δ7.83–7.77(m,2H),7.36(d,J＝8.1Hz,2H),5.77–5.69(m,1H),3.98(dd,J＝9.2,3.1Hz,1H),3.80(dd,J＝9.3,6.4Hz,1H),2.47(s,3H),2.39(dddd,J＝17.0,15.0,7.1,5.2Hz,3H),2.27(ddd,J＝14.6,4.4,2.4Hz,1H),2.07–1.92(m,2H),1.83(ddt,J＝12.8,5.7,2.7Hz,1H),1.73–1.35(m,8H),1.25–0.91(m,14H),0.69(s,3H)。
Example 2: preparation of 21-p-toluenesulfonyloxy-20-methylpregna-3-ethoxy-3, 5-diene (BA 03)
Method 1: to a 2L three-necked flask, 100g (0.21 mol) of 21-p-toluenesulfonyloxy-20-methyl pregna-4-en-3-one and 1.2L of p-toluenesulfonic acid (1.42 g,8.25 mmol) were added, the mixture was dissolved in 1.2L of ethanol, the reaction mixture was heated to 40℃and then 146g (0.99 mol) of triethyl orthoformate was added dropwise over 1 hour, the reaction was continued for 0.5 to 2 hours, then a saturated aqueous sodium hydrogencarbonate solution was added to terminate the reaction, water was added for dilution, suction filtration and drying to give 102g of 21-p-toluenesulfonyloxy-20-methyl pregna-3-ethoxy-3, 5-diene (BA 03) with a molar yield of 96.4%.
1 H NMR(300MHz,Chloroform-d)δ7.83–7.74(m,2H),7.35(d,J＝8.0Hz,2H),5.22–5.15(m,1H),5.11(d,J＝1.9Hz,1H),3.98(dd,J＝9.2,3.1Hz,1H),3.84–3.68(m,3H),2.45(s,3H),2.29(td,J＝14.5,11.5,4.6Hz,1H),2.21–2.03(m,2H),1.94(dt,J＝12.4,3.4Hz,1H),1.86–1.76(m,1H),1.75–1.49(m,6H),1.40(dd,J＝12.7,3.6Hz,1H),1.24(dt,J＝32.3,6.0Hz,8H),1.08–0.92(m,8H),0.66(s,3H)。
Method 2: to a 2L three-necked flask, 100g (0.21 mol) of 21-p-toluenesulfonyloxy-20-methyl pregna-4-en-3-one was added, phosphotungstic acid (2.72 g,8.25 mmol) was dissolved in 1.2L ethanol, the reaction mixture was heated to 40℃and then 146g (0.99 mol) of triethyl orthoformate was added dropwise over 1 hour, the reaction was continued for 0.5 to 2 hours, then a saturated aqueous sodium hydrogencarbonate solution was added to terminate the reaction, water was added for dilution, suction filtration and drying to give 100g of 21-p-toluenesulfonyloxy-20-methyl pregna-3-ethoxy-3, 5-diene (BA 03) with a molar yield of 94.52%.
Example 3: preparation of 3-ethoxy-3, 5-diene-22-diene cholestane (BA 02)
Method 1:
to a 100mL dry reaction flask was added 157mg (1.17 mmol) of copper chloride, 99mg (2.3 mmol) of lithium chloride, 10mL of THF, and argon gas were substituted three times at room temperature, and the reaction was continued at room temperature for 1-2 hours until the solution was clear, to obtain a lithium tetrachlorocuprate solution 1.
To a 500mL dry reaction flask was added 853mg (35.10 mmol) of freshly prepared magnesium turnings, 5.30g (35.10 mmol) of bromoisopentane, a trace of iodine (about 100mg-200 mg), 100mL THF, and argon for three substitutions at room temperature. After the initiation of the grignard reagent, the grignard reagent is reacted at 40 ℃ for about 4 hours to obtain a grignard reagent reaction liquid 2.
Cooling the reaction solution 2 to-20 ℃, dropwise adding a lithium tetrachlorocuprate solution 1, after the dropwise adding, dropwise adding a solution of 21-p-toluenesulfonyloxy-20-methyl pregna-3-ethoxy-3, 5-diene (11.7 mmol) in THF (50 mL), after the dropwise adding is finished, slowly heating to room temperature for reaction, controlling the temperature to 10 ℃, adding 50mL of 0.5mol/L sulfuric acid aqueous solution for quenching after TLC monitoring, stirring for 10-30 minutes, concentrating under reduced pressure until no fraction exists basically, extracting by suction filtration, washing by water, washing by brine, drying and concentrating, and washing by methanol to obtain 4.6g of 3-ethoxy-3, 5-diene-22-diene cholestane (BA 02) with the molar yield of 95%.
1 H NMR(400MHz,Chloroform-d)δ5.25–5.18(m,1H),5.12(d,J＝1.9Hz,1H),3.84–3.68(m,2H),2.30(ddd,J＝17.8,12.2,5.6Hz,1H),2.19–1.97(m,3H),1.89–1.77(m,2H),1.72–1.45(m,6H),1.46–0.96(m,20H),0.95–0.82(m,9H),0.70(s,3H)。
Method 2:
to a 100mL dry reaction flask at room temperature was added 157.3mg (1.17 mmol) of copper chloride, 99.2mg (2.3 mmol) of lithium chloride, 10mL of THF, and argon gas were replaced three times, and the reaction was continued at room temperature for 1 to 2 hours until the solution was clear, to obtain a lithium tetrachlorocuprate solution 1.
To a 500mL dry reaction flask was added 2.28g (93.61 mmol) of freshly prepared magnesium turnings, 14.14g (93.61 mmol) of bromoisopentane, a trace of iodine (about 100mg-200 mg), 100mL THF, and argon replaced three times at room temperature. After the initiation of the grignard reagent, the grignard reagent is reacted at 40 ℃ for about 4 hours to obtain a grignard reagent reaction liquid 2.
Cooling the reaction solution 2 to-20 ℃, dropwise adding a lithium tetrachlorocuprate solution 1, after the dropwise adding, dropwise adding a solution of 21-p-toluenesulfonyloxy-20-methyl pregna-3-ethoxy-3, 5-diene (11.7 mmol) in THF (50 mL), after the dropwise adding is finished, slowly heating to room temperature for reaction, controlling the temperature to 10 ℃, adding 50mL of 0.5mol/L sulfuric acid aqueous solution for quenching after TLC monitoring, stirring for 10-30 minutes, concentrating under reduced pressure until no fraction exists basically, extracting by suction filtration, washing by water, washing by brine, drying and concentrating, and recrystallizing methyl tertiary butyl ether and methanol to obtain 4.5g of 3-ethoxy-3, 5-diene-22-diene cholestane (BA 02) with the molar yield of 93.16%.
Example 4: preparation of 3-acetoxy-3, 5-diene-22-diene cholestane (BA 01)
A500 ml round bottom flask was charged with 10g (24 mmol) of 3-ethoxy-3, 5-diene-22-diene cholestane, dissolved in 250ml of acetone, followed by 25ml of 2% aqueous sulfuric acid, reaction at 40℃for about 4 hours, recovery of acetone, washing with water, suction filtration, addition of the solid to 20ml (182.8 mmol) of isopropenyl acetate, further addition of 1g (5.8 mmol) of p-toluene sulfonic acid, reaction at 90℃for about 2 hours, precipitation of the cooled solid, suction filtration, methanol washing to give 9g of 3-acetoxy-3, 5-diene-22-diene cholestane, molar yield 87%. 1 H NMR(300MHz,Chloroform-d)δ5.68(d,J＝2.3Hz,1H),5.39(d,J＝5.0Hz,1H),2.45(ddd,J＝18.1,12.4,5.6Hz,1H),2.25–1.97(m,6H),1.83(td,J＝13.0,7.1Hz,2H),1.69–1.44(m,5H),1.43–0.83(m,27H),0.70(s,3H)。
Example 5: preparation of cholesterol (I)
5. Reduction reaction: to a 250mL dry round bottom flask was added 430mg (3.87 mmol) of anhydrous calcium chloride, 2.5mL (31 mmol) of pyridine was dissolved in a mixed solution of 50mL of methanol and 50mL of THF, then cooled to-10℃and 1g (26.4 mmol) of sodium borohydride was added in 4 portions, the reaction temperature was maintained below 0℃during the addition, then 5g (11.7 mmol) of 3-acetoxy-3, 5-diene-22-diene cholestane was added, then allowed to react at room temperature overnight, monitored by TLC, no starting material remained, the reaction solution was slowly poured into 300mL of ice water with stirring until the solid was precipitated, stirring was completed, 1.5mL of glacial acetic acid was slowly added dropwise to the system with suction filtration, water washing, and recrystallized from ethanol to give 4.4g of cholesterol with a molar yield of 97%.
1 H NMR(300MHz,Chloroform-d)δ5.46–5.23(m,1H),3.52(dq,J＝15.2,5.5,4.8Hz,1H),2.38–2.16(m,2H),2.10–1.70(m,5H),1.66–0.97(m,25H),0.93–0.83(m,9H),0.68(s,3H)。

Claims (10)

1. A process for the preparation of compound BA02, comprising the steps of: the compound BA03 is subjected to a formatting reaction with a formatting reagent G01, and converted into a compound BA02:
wherein X in the structure of the format reagent G01 is selected from Cl, br or I, preferably Br.
2. The process according to claim 1, further comprising subjecting compound BA04 to an etherification reaction with triethyl orthoformate to convert to compound BA03:
3. the process according to claim 1, further comprising sulfonylating the compound 4-BA with p-toluenesulfonyl chloride under basic conditions to convert to compound BA04:
4. the method according to claim 1, wherein the grignard reaction of the compound BA03 with the grignard reagent G01 is performed under the catalysis of lithium tetrachlorocuprate;
preferably, the molar ratio of compound BA03 to formative reagent G01 is: 1:2-8;
preferably, the molar ratio of the compound BA03 to the catalyst lithium tetrachlorocuprate is 1:0.1-0.5.
5. The process according to claim 2, wherein the etherification reaction is carried out under the catalysis of phosphotungstic acid or p-toluene sulfonic acid;
preferably, the molar ratio of the compound BA04 to the triethyl orthoformate is 1:1-5;
preferably, the molar ratio of the compound BA04 to the catalyst p-toluenesulfonic acid is 1:0.01-0.2.
6. The process according to claim 3, wherein the sulfonylation is carried out in the presence of pyridine or a pyridine derivative selected from C 1～6 Alkyl-substituted pyridines, or C 1～6 Alkyl substituted aminopyridine; preferably 4-dimethylaminopyridine;
further preferably, the molar ratio of the compound 4-BA to pyridine or a pyridine derivative is 1:0.05-0.5;
further preferably, the base is selected from C 3-10 Preferably the base is selected from triethylamine;
further preferably, the molar ratio of the compound 4-BA to the p-toluenesulfonyl chloride is 1:1-2;
further preferably, the molar ratio of the compound 4-BA to the base is 1:2-3.
7. A method for preparing cholesterol, comprising the steps of:
(c) Carrying out formatting reaction on a compound BA03 and a formatting reagent G01 under the catalysis of lithium tetrachlorocuprate, and converting the compound BA03 into a compound BA02, wherein X in the structure of the formatting reagent G01 is selected from Cl, br or I, preferably Br;
(d) The compound BA02 and isopropenyl acetate are subjected to acetylation reaction under the catalysis of concentrated sulfuric acid or p-toluenesulfonic acid, and are converted into a compound BA01;
(e) Subjecting compound BA01 to a reduction reaction with sodium borohydride to convert to cholesterol (I):
8. the process according to claim 7, characterized in that it further comprises the step of subjecting compound BA04 to etherification with triethyl orthoformate according to any one of claims 2 or 5 to convert to compound BA03:
optionally, the process further comprises the step of sulfonylating the compound 4-BA with p-toluenesulfonyl chloride according to any one of claims 3 or 6 under basic conditions to convert to compound BA04:
9. the method according to any one of claims 7 to 8, wherein the formatting reaction of the compound BA03 with the formatting reagent G01 is performed under the catalysis of lithium tetrachlorocuprate;
preferably, the molar ratio of compound BA03 to formative reagent G01 is: 1:2-8;
preferably, the molar ratio of the compound BA03 to the catalyst lithium tetrachlorocuprate is 1:0.1-0.5.
10. An intermediate for the preparation of cholesterol, characterized by the following structure:
CN202210880883.4A 2022-07-26 2022-07-26 Preparation method of cholesterol and intermediate thereof Pending CN117486960A (en)

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