CN114656385A - Preparation method of maxacalcitol - Google Patents

Abstract

The invention relates to a synthesis method of a medicine, in particular to a preparation method of maxacalcitol. The maxacalcitol is prepared by taking dehydroepiandrosterone as an initial raw material through acylation, Grignard reaction, oxidation, saponification, hydroxyl protection, epoxidation, reduction, elimination, NBS bromination/dehydrobromination, deprotection group and illumination ring opening, and is simple to operate, high in yield and suitable for large-scale industrial production.

Description

Preparation method of maxacalcitol

Technical Field

The invention relates to a synthesis method of a medicine, and particularly relates to a preparation method of maxacalcitol.

Background

Maxacalcitol is a vitamin D3 derivative with antiproliferative activity, with a weak hyperemic effect. It is a third-generation active vitamin D3 medicine developed by Chinese and foreign pharmaceutical companies, and is deeply developed in Japan. Maxacalcitol has a certain affinity for VDRs located in human epidermal keratinocytes, lower than that of calciferol H, but maxacalcitol can penetrate into the interior of the nucleus to exert physiological effects. The maxacalcitol has excellent effects of inducing epidermal keratinocyte differentiation and inhibiting epidermal keratinocyte proliferation, has an inducing effect on expression of an epidermal cell differentiation standard loricrin of a psoriasis patient, and can induce expression of an echinocyte endoprotein and improve epidermal hypertrophy. After the affected part is smeared with the maxacalcitol ointment, the DNA synthesis and nuclear division speed in keratinocytes can be delayed, the expression of mRNA (messenger ribonucleic acid) which is a keratinocyte differentiation standard substance is promoted, and the proliferation of epidermal keratinocytes is obviously inhibited.

Psoriasis is a disease which is difficult to cure and easy to relapse, dry dermatosis including psoriasis has great influence on human health and life quality, normal life of patients is seriously interfered, meanwhile, the psoriasis patients are numerous, and active vitamin D3 medicines have become powerful weapons for resisting skin diseases such as psoriasis in the world. Therefore, the maxacalcitol ointment has a wide market in China, can effectively relieve the symptoms of patients with psoriasis, improve the skin injury of the patients, improve the life quality of the patients, and meet the requirements of the patients with psoriasis and other skin diseases.

In the Maxacalcitol synthesis discussion (Guozai, university of Shandong, Master's academic thesis), 1 alpha-hydroxy epiandrosterone is used as a raw material, two secondary hydroxyl groups are protected by TBS, NBS is used for bromination, and dehydrobromination is carried out under alkaline conditions to prepare conjugated diene; introducing double bonds through a Wittig reaction, performing a hydroboration-oxidation reaction, and stereoselectively introducing hydroxyl at the 20 th position; by Willi amson

An ether forming reaction, a Wacker oxidation reaction and addition with a Grignard reagent are carried out to prepare tertiary alcohol 9; and (3) performing ring opening by photochemical reaction and thermal rearrangement reaction, and removing the TBS protecting group by tetrabutylammonium fluoride to obtain the maxacalcitol. In "research on preparation Process of 1 α -hydroxydehydroepiandrosterone" (Stmingbo, university of Calius, Master's academic paper), a synthetic method of 1 α -hydroxydehydroepiandrosterone is disclosed, which is divided into a chemical method and a microbiological method, and when 1, 4-androstenedione is used as a starting material for preparation, diborane with low yield and high toxicity is used, which is not suitable for industrial production; when dehydroepiandrosterone is used as an initial raw material, the chemical method is used for preparation, so that the production process has high requirements, the reaction conditions are harsh, and the industrial production is difficult; when the synthesis is carried out by a microbiological method, the production period is long, the production cost is high, the yield is low, and the synthesis application is limited.

The Chinese patent with the application number of 201310475989.7 discloses a synthetic intermediate of maxacalcitol and a preparation method and application thereof, wherein vitamin D2 is used as a starting material to obtain a compound shown as a formula II, and the compound is creatively synthesized through the steps of oxidation, chiral reduction, side chain connection, introduction of a hydroxyl at the C-1 position, photochemical turnover and the like.

Chinese patent application No. 201610059835.3 discloses a method for synthesizing a maxacalcitol intermediate, wherein a compound of formula (II) is subjected to deprotection in a protic solvent of a deprotection agent to obtain a compound of formula (I). The deprotection agent is CH₃OH & HCl, and the protic solvent is methanol. The preparation method has the advantages of simple operation, short reaction time, high yield, no side reaction and suitability for large-scale industrial production.

Although the method avoids the use of 1 alpha-hydroxy epiandrosterone raw material, the preparation of the intermediate of the ring A needs complicated chemical synthesis steps, and the yield is extremely low; the preparation of the C/D ring intermediate needs to adopt steroid raw materials such as vitamin D2 and the like with higher price to prepare in modes such as oxidative cracking and the like, and has the disadvantages of long chemical reaction steps, low yield, high cost and non-conformity with the green chemical principle.

Disclosure of Invention

In order to solve the problems, the preparation method of maxacalcitol provided by the invention does not need to use 1 alpha-hydroxy epiandrosterone, innovatively uses dehydroepiandrosterone which is easily available in the market and relatively low in price as a raw material, efficiently completes the total synthesis of maxacalcitol, is simple to operate, has high yield, and is suitable for large-scale industrial production.

The technical scheme adopted by the invention for realizing the purpose is as follows:

a preparation method of maxacalcitol comprises the following technical processes:

s1, dissolving 20g of dehydroepiandrosterone in 200-400 mL of tetrahydrofuran, adding 5.63-28.13 g of imidazole and butyl dimethyl silicon chloride for reflux reaction, and evaporating to remove the solvent after reduced pressure distillation, ethyl acetate extraction, saturated sodium chloride water washing and dehydration to obtain a white solid, namely the compound 18;

s2, adding 28.05g of compound 18, 30.88-128.65 g of ethyl triphenyl phosphonium bromide and 9.33-46.66 g of potassium tert-butoxide into 28-560 ml of tetrahydrofuran solvent for reflux reaction, extracting with petroleum ether, washing with saturated sodium chloride water, drying with anhydrous sodium sulfate, concentrating in vacuum to obtain yellowish solid, and recrystallizing and purifying to obtain 14.44-27.44 g of compound 19;

s3, adding 25.6g of compound 19 and 14.99-149.90 g of 9-boron bicyclo (3,3,1) -nonane into 25-510 mL of tetrahydrofuran solvent, carrying out ice bath reaction, oxidizing with hydrogen peroxide, extracting with ethyl acetate, sodium sulfite solution, saturated saline, washing with water, drying with anhydrous sodium sulfate, concentrating in vacuum, and purifying with column chromatography (the chromatography condition is that petroleum ether and ethyl acetate are 30:1) to obtain 11.93-24.40 g of compound 20;

s4, reacting 21.95g of the compound 20 with 20-440 mL of methanol and 0.12-11.81 g of camphorsulfonic acid in 20-440 mL of tetrahydrofuran solvent, purifying with ethyl acetate, washing with water, drying with anhydrous sodium sulfate, and recrystallizing with methanol to obtain 9.78-15.97 g of the compound 21;

s5, adding 15.1g of compound 21 and 32.08-85.55 g of 2, 3-dichloro-5, 6-dicyan p-benzoquinone into 30-1500 mL of dioxane serving as a solvent, reacting, filtering, extracting with dichloromethane, washing with saturated sodium chloride water, drying with anhydrous sodium sulfate, concentrating to obtain an oily viscous substance, and separating by column chromatography (the chromatography condition is that petroleum ether and ethyl acetate are 10:1) to obtain 2.94-10.30 g of compound 22;

s6, adding 8.0g of compound 22, 4.31-21.54 g of 3, 4-dihydropyran and 0.005-0.02 g of p-toluenesulfonic acid into 40-800 mL of dichloromethane solvent, extracting with ethyl acetate, washing with saturated sodium chloride water, drying with anhydrous sodium sulfate, vacuum concentrating and crystallizing with methanol after reaction to obtain 5.58-9.95 g of compound 23;

s7, taking 16-410 mL of methanol as a solvent, reacting 8.2g of the compound 23 with 11.7-117 mL of hydrogen peroxide under an alkaline condition, extracting with ethyl acetate, washing with a sodium bicarbonate aqueous solution, drying with anhydrous sodium sulfate, concentrating in vacuum, and crystallizing with methanol to obtain 1.71-7.34 g of the compound 24;

s8, taking 25-500 mL of tetrahydrofuran as a solvent, reacting 2.5g of compound 24 with lithium amide at a low temperature of-20 to-80 ℃, carrying out water washing for delamination, extracting with ethyl acetate, washing, drying with anhydrous sodium sulfate, concentrating, and carrying out column chromatography on the concentrate (chromatography conditions: petroleum ether: ethyl acetate: 4:1) to obtain 0.63-2.08 g of compound 25;

s9, taking 16-400 mL of dichloromethane as a solvent, reacting 0.8g of compound 25, 0.82-4.10 g of lutidine and 1.11-5.05 g of tert-butyl dimethyl silyl ether trifluoromethanesulfonate, evaporating the solvent, precipitating with anhydrous methanol, and filtering to obtain 0.87-1.22 g of compound 26;

s10, reacting 1.0g of compound 26 with 1.0-10.0 mL of methanol in 5-100 mL of dichloromethane solvent, extracting with dichloromethane, washing with saturated sodium bicarbonate water, drying with anhydrous sodium sulfate, concentrating, and recrystallizing with methanol to obtain 0.57-0.84 g of compound 12;

s11, dissolving 3.85g of compound 12 in 8-190 mL of tetrahydrofuran solvent, adding 0.33-3.28 g of NaH and 1.73-11.56 g of 3-bromomethyl-2, 2-dimethyl-ethylene oxide for reaction, and adding saturated NH₄Extracting a Cl aqueous solution with ethyl acetate, washing, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography (the chromatography condition is that petroleum ether and ethyl acetate account for 20:1) to obtain 2.88-4.20 g of crude epoxide, namely compound 17;

dissolving the obtained 3.85g of crude epoxide in 20-400 mL of tetrahydrofuran, and mixing with 0.27-1.13 g of LiAlH₄Reacting, adding 10-50 mL of NaOH solution and 3-27 mL of hydrogen peroxide solution for reaction, and reacting with 2-20 g of Na₂S₂O₃And extracting with 20-400 ml of ethyl acetate, washing, and drying with anhydrous sodium sulfate. Performing rotary evaporation and concentration, and performing column chromatography (the chromatography conditions are that petroleum ether and ethyl acetate account for 10:1) to obtain 1.54-3.40 g of a compound 15;

s12, dissolving 9.0g of compound 15 in 45-900 mL of n-hexane solution, adding 2.5-4.9 g of NBS and 0.2-2.0 g of AlBN, filtering after reaction, evaporating the solvent, dissolving with 10-100 mL of toluene, adding 5-15 g of 2,4, 6-trimethylpyridine, carrying out reflux reaction, extracting with ethyl acetate, washing, drying with anhydrous sodium sulfate, carrying out rotary evaporation and concentration, and carrying out column chromatography (the chromatography condition is that petroleum ether: ethyl acetate is 10:1) to obtain 3.1-7.0 g of compound 9;

s13, dissolving 5g of compound 9 in 10-500 mL of tetrahydrofuran solvent, adding 20-200 mL of tetrahydrofuran solution in which 4.0-40.4 g of tetrabutylammonium fluoride is dissolved, performing reflux reaction, extracting with ethyl acetate, washing, drying with anhydrous sodium sulfate, performing rotary evaporation concentration, and performing column chromatography to obtain 1.9-3.0 g of compound 16;

s14, dissolving 6g of the obtained compound 16 in 250-5000 mL of tetrahydrofuran solution, performing light reaction (the light reaction condition is that in an XPA light reaction instrument, the light reaction lasts for 10-60min), and concentrating; and carrying out photochemical reaction and thermal rearrangement to obtain a product (0.6-1.8 g) crude maxacalcitol, recovering a raw material compound 16, and carrying out preparative chromatography to obtain a fine product.

Further, the chemical equation involved is:

the invention has the following beneficial effects:

the existing literature reports that most of steroid parent nucleus 1 alpha-hydroxy epiandrosterone is used as a raw material, and a semi-chemical synthesis method is adopted to prepare maxacalcitol, however, the chemical synthesis method of 1 alpha-hydroxy epiandrosterone is not mature, the preparation is required to be carried out through microbial fermentation, the technical yield is low, and the technology is monopolized by foreign companies. Then, people develop a full synthesis mode, firstly adopt a chemical synthesis method to prepare an A ring intermediate and a C/D ring intermediate, and then prepare a target compound in a Witting-horner condensation reaction mode. Although the method avoids the use of 1 alpha-hydroxy epiandrosterone raw material, the preparation of the intermediate of the ring A needs complicated chemical synthesis steps, and the yield is very low; the preparation of the C/D ring intermediate needs to adopt steroid raw materials such as vitamin D2 and the like with higher price to prepare in modes such as oxidative cracking and the like, and has the disadvantages of long chemical reaction steps, low yield, high cost and non-conformity with the green chemical principle.

According to the invention, 1 alpha-hydroxy epiandrosterone is not needed, dehydroepiandrosterone which is easily available in the market and relatively low in price is innovatively used as a raw material, a steroid mother nucleus is modified, 20-bit hydroxy is introduced stereoselectively through reactions such as hydroxy protection, Wittig reaction, oxidation and the like, then conjugated ketene is synthesized, 1 alpha-hydroxy is introduced into the 1-bit of the A ring to obtain a maxacalcitol parent structure, finally a side chain is introduced, photochemical ring opening is carried out, and maxacalcitol is obtained with high yield.

Drawings

Fig. 1 is a flow diagram of a maxacalcitol preparation method according to the present invention.

Detailed Description

The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the embodiments of the present application, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.

Example 1

The preparation method of the maxacalcitol comprises the following specific process flows as shown in figure 1:

preparation of S1, (3R) -tert-butyldimethylsiloxy-androst-5-en-17-one (acylation I): dissolving 20g of dehydroepiandrosterone in 200mL of tetrahydrofuran, adding 9.5g of imidazole and 15.8g of tert-butyl dimethyl silicon chloride at 37 ℃ for reflux reaction, carrying out reduced pressure distillation, ethyl acetate extraction, saturated sodium chloride solution washing, dehydration and solvent evaporation after reaction for 3h to obtain 28.05g of white solid, namely (3R) -tert-butyl dimethyl silica-androst-5 ene-17 ketone, which is marked as a compound 18, wherein the reaction process is as follows:

C₁₉H₂₈O₂+C₆H₁₅ClSi+C₃H₄N₂→C₂₅H₄₂O₂Si+C₃H₅N₂Cl；

preparation of S2, (17Z,3R) -tert-butyldimethylsiloxy-androsta-5, 17-diene (Grignard reaction I): keeping the temperature at 55 ℃, slowly adding 18.05g of compound 18, 51.65g of ethyl triphenyl phosphonium bromide and 19.60g of potassium tert-butoxide into 300mL of tetrahydrofuran solvent for reflux reaction for 5h, extracting by petroleum ether, washing by saturated sodium chloride solution, drying by anhydrous sodium sulfate, concentrating in vacuum to obtain yellowish solid, recrystallizing and purifying to obtain 25.60g of (17Z,3R) -tert-butyl dimethyl silica-androstane-5, 17-diene, which is marked as compound 19, wherein the reaction process is as follows:

C₂₅H₄₂O₂Si+C₂₀H₂₀BrP+C₄H₉OK→C₂₇H₄₆OSi+C₁₈H₁₅OP+KBr+C₄H₁₀O；

preparation of S3, (3R,20S) -3-tert-butyldimethylsiloxy-20-hydroxy-androst-5-ene (oxide I): 25.60g of compound 19 and 48.20g of 9-borabicyclo (3,3,1) -nonane are added into 395mL of tetrahydrofuran solvent, the mixture reacts in an ice bath for 4h, and is oxidized with 85mL of hydrogen peroxide for 5h at room temperature, the mixture is extracted by ethyl acetate, washed by aqueous sodium sulfite solution, dried by anhydrous sodium sulfate and concentrated in vacuum, and then purified by column chromatography (chromatographic conditions: petroleum ether: ethyl acetate: 30:1) to obtain 21.95g of (3R,20S) -3-tert-butyldimethylsiloxy-20-hydroxy-androst-5 ene, which is marked as compound 20, and the reaction process is as follows:

C₂₇H₄₆OSi+C₈H₁₅B+H₂O₂→C₂₇H₄₈O₂Si+H₂O+C₈H₁₃B；

¹H NMR(600MHz，CDCl3)δ:5.32(d，J＝4.8Hz，1H)，3.70-3.72(m,1H)，3.46-3.50(m，1H)，2.24-2.30(m，1H)，2.15-2.20(m，lH)，1.96-2.05(m,2H)，1.87-1.93(m，2H)，1.79-1.82(m，1H)，1.64-1.73(m，2H)，1.43-1.58(m，5H)，1.31-1.36(m，1H)，1.01-1.20(m，4H)，1.23(d，J＝6.6Hz，3H)，1.00(S，3H)，0.9l-0.96(m，1H)，0.89(s，9H)，O.68(s，3H)，0.06(m，6H)。

preparation of S4, (3R,20S) -3, 20-dihydroxy-androst-5-ene (saponification): in 220mL tetrahydrofuran solvent, raising the temperature to 37 ℃, reacting 21.95g of compound 20 with 220mL methanol and 1.1g camphorsulfonic acid for 3h, purifying by ethyl acetate, washing by saturated sodium chloride water, drying by anhydrous sodium sulfate, and recrystallizing by methanol to obtain 15.1g of (3R,20S) -3, 20-dihydroxy-androst-5-ene, which is marked as compound 21, wherein the reaction process is as follows:

C₂₇H₄₈O₂Si+CH₃OH→C₂₁H₃₅O₂+C₇H₁₆OSi；

preparation of S5, (20S) -hydroxy-androst-1, 4, 6-trien-3-one (oxide II): using 650mL dioxane as solvent, adding 15.1g compound 21 and 45.0g2, 3-dichloro-5, 6-dicyan p-benzoquinone at 45 ℃, filtering after reaction, extracting with dichloromethane, washing with saturated sodium chloride water, drying with anhydrous sodium sulfate, concentrating to obtain oily viscous substance, separating by column chromatography (chromatography condition: petroleum ether: ethyl acetate 10:1) to obtain 8.33g (20S) -hydroxy-androstane-1, 4, 6-trien-3-one, which is marked as compound 22, wherein the reaction process is as follows:

C₂₁H₃₅O₂+3C₈C_l2N₂O→C₂₁H₂₉O₂+3C₈H₂Cl₂N₂O；

¹H NMR(600MHz，CDCl3)δ:7.07(d，J＝10.2Hz，IH)，6.23-6.26(m，2H)，6.O4-6.06(d，J＝9.6Hz，1H)，6.01(S，1H)，3.75(S，1H)，2.28(t，J＝10.2Hz，1H)，1.97-1.98(m，2H)，1.77-1.87(m，2H)，1.61-1.67(m，2H)，1.33-1.51(m，4H)，I.24-1.30(m，4H)，1.20(s,3H)，0.79(s,3H)。

preparation of S6, (20S) -tetrahydrofuryloxy-androst-1, 4, 6-trien-3-one (hydroxy protection): adding 8.0g of compound 22, 12.5mL of 3, 4-dihydropyran and 0.01g of p-toluenesulfonic acid into 400mL of dichloromethane solvent, reacting for 4 hours at room temperature, extracting with ethyl acetate after reaction, washing with saturated sodium chloride water, drying with anhydrous sodium sulfate, concentrating in vacuum, and crystallizing with methanol to obtain 8.3g of (20S) -tetrahydrofuryloxy-androstane-1, 4, 6-trien-3-one, which is marked as compound 23, wherein the reaction process is as follows:

C₂₁H₂₉O₂+C₅H₈O→C₂₆H₃₇O₃；

in the step, dichloromethane is used as a solvent, p-toluenesulfonic acid is used as a catalyst, so that 3, 4-dihydropyran reacts with (20S) -hydroxy-androstane-1, 4, 6-triene-3-ketone to replace hydroxy hydrogen on the (20S) -hydroxy-androstane-1, 4, 6-triene-3-ketone, and hydroxy is protected.

Preparation of S7, (1S,2S) -epoxy- (20S) -tetrahydrofuroxy-androsta-4, 6-dien-3-one (epoxidation): using 180mL of methanol as a solvent, reacting 8.2g of the compound 23 with hydrogen peroxide at 20 ℃ for 3h under an alkaline condition, extracting with ethyl acetate, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating in vacuum, and crystallizing with methanol to obtain 4.5g of (1S,2S) -epoxy- (20S) -tetrahydrofuryl-androstane-4, 6-diene-3-ketone, which is marked as a compound 24, wherein the reaction process is as follows:

C₂₆H₃₇O₃+H₂O₂→C₂₆H₃₇O₄+H₂O；

¹H NMR(600Mnz，CDCl3)δ:6.06-6.111l(m，2H)，5.87(s,1H)，4.63and 4.71(each s,1H)，3.91-3.96(m,1H)，3.56-3.75(m,2H),3.47-3.51(m，lH)，3.44-3.45(m，1H)，2.24(m,1H)，1.95-2.13(m,3H)，1.89-1.9l(m,lH)，1.79-1.84(m，2H)，1.42-1.70(m，9H)，1.30and 1.33(each s,3H)，1.18(s，3H)，0.82-0.89(m，2H)，0.77and 0.79(each s，3H)。

in the step, NaOH solution and hydrogen peroxide are added, the oxidability of the hydrogen peroxide is enhanced under an alkaline condition to form HOO-conjugate base, and simultaneously, methanol is used as a solvent and is used as a protic solvent to further promote the heterolysis of hydrogen peroxide molecules, form active oxygen species and reduce the reaction energy barrier.

S8, preparation of (1S,3R) -dihydroxy- (20S) -tetrahydrofurfuryl oxy-androst-5-ene (reduction reaction I): reaction of 2.5g of compound 24 with 12.4g of lithium amide in 250mL of tetrahydrofuran as solvent at-40 ℃, washing with saturated sodium chloride, separation by chromatography, extraction with ethyl acetate, washing, drying over anhydrous sodium sulfate, concentration and column chromatography of the concentrate (chromatography conditions: petroleum ether: ethyl acetate 4:1) gives 1.2g of (1S,3R) -dihydroxy- (20S) -tetrahydrofuroxy-androst-5-ene, identified as compound 25, the procedure is as follows:

C₂₆H₃₇O₄+6Li+6H2O→C₂₆H₄₃O₄+6LiOH；

¹H NMR(600MHz,CDCl3)δ:6.26(s，lH)，4.62and 4.71(each s，lH)，4.29-4.3l(m,1H)，4.08(s，1H)，3.91-3.96(m，lH)，3.54-3.72(m,1H)，3.49-3.50(m，1H)，2.76-2.78(m，1H)，2.58-2.60(m,1H)，2.15-2.17(m，1H)，2.06-2.07(m，1H)，1.79-1.96(m，3H)，1.29-1.79(m,14H)，1.26(s，3H)，1.18(s，3H),1.18(s,3H),0.84-0.89(m,3H),0.73(s，3H),0.70(s,3H)。

in the synthesis step, under a low-temperature environment, (1S,2S) -epoxy- (20S) -tetrahydrofuryloxy-androstane-4, 6-diene-3-ketone reacts with lithium amide, and the epoxy is selectively opened to obtain (1S,3R) -dihydroxy- (20S) -tetrahydrofuryloxy-androstane-5-ene.

Preparation of S9, (1S,3R) -di (tert-butyldimethylsilyloxy) - (20S) -tetrahydrofuryloxy-androst-5-ene (acylation II): using 80mL of dichloromethane as a solvent, 0.8g of compound 25, 2.06mL of lutidine and 2.6mL of tert-butyldimethylsilyl ether trifluoromethanesulfonate were reacted, after evaporation of the solvent, precipitated with anhydrous methanol and filtered to give 1.10g of (1S,3R) -bis (tert-butyldimethylsilyloxy) - (20S) -tetrahydrofuryloxy-androst-5-ene, which was designated as compound 26, by the following reaction sequence:

C₂₆H₄₃O₄+2C₇H₁₅F₃O₃SSi+2C₇H₉N→C₃₈H₇₁O₄Si₂+2C₈H₁₀F₃O₃N；

¹H NMR(600MHz，CDCl3)δ：5.45(s，IH)，4.61and 4.71(each s，lH)，3.9l-4.Ol(m,2H)，3.79-3.85(m，lH)，3.76(s，1H)，3.52-3.69(m，lH)，3.47-3.49(m，1H)，2.27-2.31(m，lH)，2.18-2.22(m，lH)，2.00-2.04(m，1H)，1.79-1.93(m，5H)，1.63-1.7 1(m，3H)，1.26-1.53(m，12H)，1.14(d,J＝6Hz,3H),0.95(s，3H)，0.85(s，18H)，0.66and 0.69(each s，3H)，0.07(s，3H)，0.05(s，3H)，0.04(s，3H)，0.02(s，3H)。

in order to protect hydroxyl, the (1S,3R) -dihydroxy- (20S) -tetrahydrofuran oxy-androst-5-ene reacts with tert-butyl dimethyl silicon ether triflate in the presence of dimethyl pyridine, and the protection of the hydroxyl is realized without influencing other groups.

Preparation of S10, (1S,3R) -di (tert-butyldimethylsilyloxy) - (20S) -hydroxy-androst-5-ene (elimination reaction): reacting 1.0g of compound 26 with 2.5mL of methanol in 50mL of dichloromethane solvent at 35 ℃, extracting with dichloromethane, washing with aqueous sodium bicarbonate solution, drying over anhydrous sodium sulfate, concentrating, recrystallizing with methanol to obtain 0.8g of (1S,3R) -bis (tert-butyldimethylsiloxy) - (20S) -hydroxy-androst-5-ene, which is designated as compound 12, and repeating the above test a plurality of times; the reaction process is as follows:

C₃₈H₇₁O₄Si₂+CH₄O→C₃₃H₆₂O₃Si₂+C₆H₁₃O₂；

¹H NMR(600MHz,CDCl3)δ:5.45(d,J＝5.4Hz，1H)，3.96-4.01(m，1H)，3.77(s，1H)，3.68-3.73(m，1H)，2.27-2.29(m，1H)，2.19-2.22(m,1H)，1.83-1.93(m，3H)，1.67-1.71(m，2H)，1.50-1.56(m，3H)，1.31-1.42(m，4H)，1.02-1.20(m，4H)，1.22(d，J＝6Hz，3H)，0.96(s，3H)，0.88(s，1.8H)，0.68(s，3H)，0.07(s，3H)，0.05(s，3H)，0.04(s，3H)，0.03(s，3H)。

preparation of S11, (1S,3R,20S) -1, 3-bis (tert-butyldimethylsiloxy) -20- (3-hydroxy-3-methylbutoxy) -androst-5-ene: at room temperature, 3.85g of Compound 12 is dissolved in 14.5mL of tetrahydrofuran solvent, and 1.09g of NaH and 4.5g of 3-bromomethyl-2, 2-dimethyl-oxirane are added to react, saturated NH is added₄After extraction with ethyl acetate, washing, drying over anhydrous sodium sulfate, concentration and separation by column chromatography (chromatographic conditions: petroleum ether: ethyl acetate 20:1), aqueous Cl solution was used to obtain 3.85g of crude epoxide, i.e., (1S,3R,20S) -1, 3-bis (tert-butyldimethylsiloxy) -20- (3-hydroxy-3-methylbutoxy) -androst-5-ene, which was denoted as compound 17, in the following reaction sequence (grignard reaction II):

C₃₃H₆₂O₃Si₂+C₅H₉BrO+NaH→C₃₈H₇₀O₄Si₂+NaBr+H₂；

¹H NMR(600MHz，CDCl3)δ:5.46(s，1H)，3.95-4.Ol(m，1H)，3.82-3.85(m，lH)，3.79(s，lH)，3.76(m,lH)，3.46-3.49(m,1H)，3.23-3.27(m，lH)，2.26-2.30(m，1H)，2.19-2.22(m，1H)，1.88-1.92(m，2H)，1.83-1.86(m，2H)，1.60-1.73(m，5H)，1.47-1.53(m，2H)，1.35-1.42(m，4H)，1.22-1.23(m，6H)，0.98-1.16(m，3H)，1.18(d，J＝6Hz，3H)，0.95(s，3H)，0.88(s，l8H)，0.66(s，3H)，0.07(s，3H)，0.05(s，3H)，0.04(s，3H)，0.02(s，3H)。

the crude epoxide (3.85 g) was dissolved in tetrahydrofuran (40 mL) and reacted with LiAlH (0.46 g) under ice-bath conditions₄Reacting, adding 20mL of 10% NaOH solution and 9mL of hydrogen peroxide solution, reacting with 20mL of saturated Na₂S₂O₃60mL of ethyl acetate, washed, and dried over anhydrous sodium sulfate. After rotary evaporation and concentration, 2.4g of (1S,3R,20S) -1, 3-bis (tert-butyldimethylsiloxy) -20- (3-hydroxy-3-methylbutoxy) -androst-5-ene, which is marked as compound 15, is obtained by column chromatography (chromatography conditions: petroleum ether: ethyl acetate: 10:1), and the procedure is repeated for a plurality of times as follows (reduction reaction II):

4C₃₈H₇₀O₄Si₂+BH₄Na+2H₂O→4C₃₈H₇₂O₄Si₂+BNaO₂；

s12, (preparation of 1S,3R,20S) -1, 3-bis (tert-butyldimethylsiloxy) -20- (3-hydroxy-3-methylbutoxy-androst-5.7-diene (NBS bromination/dehydrobromination) 9.0g of Compound 15 was dissolved in 100mL of n-hexane solution at room temperature, 3.2g of NBS and 0.67g of AlBN were added, the reaction was filtered, the solvent was evaporated and then dissolved in 100mL of toluene, 7.2g of 2,4, 6-trimethylpyridine was added, the reflux reaction was carried out, extraction was carried out with ethyl acetate, washing and drying was carried out with anhydrous sodium sulfate, the reflux reaction was carried out, column chromatography was carried out (conditions: petroleum ether: ethyl acetate 10:1) was carried out to obtain 5.5g of (1S,3R,20S) -1, 3-bis (tert-butyldimethylsiloxy) -20- (3-hydroxy-3-methylbutoxy-androst-5.7-diene, the specific reaction process is shown as compound 9 as follows:

bromination reaction:

C₃₈H₇₂O₄Si₂+C₄H₄BrNO₂→C₃₈H₇₁BrO₄Si₂+C₄H₅NO₂；

dehydrobromination reaction:

C₃₈H₇₁BrO₄Si₂+C₈H₁₁N→C₃₈H₇₀O₄Si₂+C₈H₁₂NBr。

¹H NMR(600MHz，CDCl3)δ:5.58(s，1H)，5.33(s，1H)，4.03-4.05(m,1H)，3.83-3.86(m-1H)，3.79(s，1H)，3.70(m,1H)，3.48-3.51(m,1H)，3.25-3.27(m,1H)，2.78(m,1H)，2.33-2.36(m,2H)，1.98-2.02(m,1H)，1.86-1.96(m,3H),1.70-1.74(m，4H)，1.52-1.62(m,4H)，1.42-1.46(m，2H)，1.23-1.25(m，6H)，1.20(d,J＝6Hz,3H)，0.90(s，3H)，0.88(s，1 8H)，0.61(s，3H)，0.10(s，3H)，0.07(s，3H)，0.06(s，3H)，0.05(s，3H)。

s13, (1S,3R,20S) -20- (3-hydroxy-3-methylbutoxy-androsta-5, 7-diene-1, 3-diol preparation (deprotection) 5.0g of Compound 9 was dissolved in 100mL of tetrahydrofuran solvent at room temperature, and 46.5mL of tetrahydrofuran solution in which 12.2g of tetrabutylammonium fluoride was dissolved was added, followed by reflux reaction, extraction with ethyl acetate, washing, drying over anhydrous sodium sulfate, rotary evaporation and concentration, and column chromatography (chromatography conditions: petroleum ether: ethyl acetate: 4:1) was performed to obtain 2.8g of (1S,3R,20S) -20- (3-hydroxy-3-methylbutoxy-androsta-5, 7-diene-1, 3-diol as Compound 16, which was repeated a plurality of times, the specific reaction process is as follows:

C₃₈H₇₀O₄Si₂+2C₁₆H₃₆FN+2H₂O→2C₁₆H₃₇O+2C₆H₁₅FSi+C₂₆H₄₂O₄；¹H NMR(600MHz，CDCl3)6：5.71-5.72(m，1H)，5.38-5.39(m，IH)，4.04-4.08(m，IH)，3.84-3.87(m，1H)，3.88(s，lH)，3.76(m，1H)，3.48-3.51(m，IH)，3.24-3.29(m，1H)，2.65-2.70(m,1H)，2.52-2.60(m,1H)，2.32-2.36(m，1H)，2.12-2.1 5(m，IH)，1.92-2.01(m，4H)，1.62-1.79(m，5H)，1.43-1.60(m，4H)，1.23-1.25(m，6H)，1.20(d，J＝6Hz，3H)，0.93(s,3H)，0.61(s，3H)。

preparation of S14, (+) - (5Z,7E) - (1S,3R,20S) -20- (3-hydroxy-3-methylbutoxy) -9, 10-secoandrosta-5, 7, 10(19) -triene-1, 3-diol (photoring opening): dissolving the obtained 6.0g of compound 16 in 2000mL of tetrahydrofuran solution, performing light reaction (the light condition is that the light is irradiated for 50min in an XPA photochemical apparatus), and concentrating; 1.0g of maxacalcitol obtained after photochemical reaction and thermal rearrangement is subjected to preparative chromatography to obtain 0.12g of refined product, the total yield is 12%, and the reaction process is as follows:

C₂₆H₄₂O₄→C₂₆H₄₂O₄；

¹H NMR(600MHz，CDCl3)6：6.36(d，J＝10.8Hz,l H)，6.02(d，J＝10.8Hz，lH)，5.33(s，lH)，4.99(s，lH)，4.43(m,lH)，4.22(m,lH)，3.83(m，lH)，3.80(s，lH)，3.49(m，lH)，3.26(m，lH)，2.82-2.84(m，lH)，2.58-2.60(m,lH)，2.29-2.33(m,lH)，1.86-1.99(m，3H)，1.67-1.73(m,5H)，1.5 1-1.58(m，4H)，1.18-1.29(m,12H)，0.53(s，3H).EI-MS：m/z：419(M+H).IR(KBr,cm-)：3417，2964，2926，2873，2852，1644，1448，1404，1376，1346，1262，1220，1151，1091，1057，956，909，895，800，743。

¹³C NMR(CDCl3)δ:147.6，142.3，133.3，124.8，117.5，111.9，78.8，70.8，70，66.8，65.6，57.0，56.0，45.2，44.8，42.8，41.4，39.5，29.2，29.1，28.9，25.6，23.2，22.2，18.8，l2.6.UV(EtOH)：λmax 263nm。

in the prior art, most of steroid parent nucleus 1 alpha-hydroxy epiandrosterone is used as a raw material, and maxacalcitol is prepared by adopting a semi-chemical synthesis method, however, the chemical synthesis method of 1 alpha-hydroxy epiandrosterone is not mature, people develop a full synthesis mode, firstly adopt a chemical synthesis method to prepare an A ring intermediate and a C/D ring intermediate, and then prepare a target compound by a Witting-horner condensation reaction mode. Although the method avoids the use of 1 alpha-hydroxy epiandrosterone raw material, the preparation of the intermediate of the ring A needs complicated chemical synthesis steps, and the yield is very low; the preparation of the C/D ring intermediate needs to adopt steroid raw materials such as vitamin D2 and the like with higher price to prepare in modes such as oxidative cracking and the like, and has the disadvantages of long chemical reaction steps, low yield, high cost and non-conformity with the green chemical principle.

According to the invention, 1 alpha-hydroxy epiandrosterone is not needed, dehydroepiandrosterone which is easily available in the market and relatively low in price is innovatively used as a raw material, a steroid mother nucleus is modified, 20-bit hydroxy is introduced stereoselectively through reactions such as hydroxy protection, Wittig reaction, oxidation and the like, then conjugated ketene is synthesized, 1 alpha-hydroxy is introduced into the 1-bit of the A ring to obtain a maxacalcitol parent structure, finally a side chain is introduced, photochemical ring opening is carried out, and maxacalcitol is obtained with high yield.

Example 2

A preparation method of maxacalcitol comprises the following specific technological processes:

preparation of S1, (3R) -tert-butyldimethylsiloxy-androst-5-en-17-one: 20g of dehydroepiandrosterone is dissolved in 200mL of tetrahydrofuran, 15.0g of imidazole and 21.9g of tert-butyl dimethyl silicon chloride are added for reflux reaction, and the mixture is subjected to reduced pressure distillation, ethyl acetate extraction, saturated sodium chloride water washing and dehydration, and then the solvent is evaporated to obtain 28.0g of white solid, namely (3R) -tert-butyl dimethyl silicon oxygen-androst-5 ene-17 ketone, which is marked as a compound 18.

Preparation of S2, (17Z,3R) -tert-butyldimethylsiloxy-androsta-5, 17-diene: 28.0g of compound 18, 77.19g of ethyltriphenylphosphonium bromide and 98.0g of potassium tert-butoxide are added into 200mL of tetrahydrofuran solvent for reflux reaction, and the mixture is extracted with petroleum ether, washed with saturated sodium chloride water, dried with anhydrous sodium sulfate and concentrated in vacuum to obtain a yellowish solid, and the yellowish solid is recrystallized and purified to obtain 26.30g of (17Z,3R) -tert-butyldimethylsiloxy-androsta-5, 17-diene, which is marked as compound 19.

Preparation of S3, (3R,20S) -3-tert-butyldimethylsilyloxy-20-hydroxy-androst-5-ene: to 614mL of tetrahydrofuran solvent were added 25.6g of compound 19 and 74.95g of 9-borabicyclo (3,3,1) -nonane, reacted in an ice bath, oxidized with 100mL of hydrogen peroxide, extracted with ethyl acetate, washed with saturated aqueous sodium sulfite solution, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography (chromatography conditions: petroleum ether: ethyl acetate: 30:1) to give 23.4g of (3R,20S) -3-tert-butyldimethylsiloxy-20-hydroxy-androst-5-ene, which was designated as compound 20.

Preparation of S4, (3R,20S) -3, 20-dihydroxy-androst-5-ene: in 150mL tetrahydrofuran solvent, 21.95g compound 20 was reacted with 150mL methanol, 2.0g camphorsulfonic acid, purified with ethyl acetate, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, and recrystallized from methanol to give 15.4g (3R,20S) -3, 20-dihydroxy-androst-5-ene as compound 21.

Preparation of S5, (20S) -hydroxy-androst-1, 4, 6-trien-3-one: with 400mL of dioxane as a solvent, 15.1g of compound 21 and 37.43g of 2, 3-dichloro-5, 6-dicyan p-benzoquinone are added into the solvent, after reaction, the mixture is filtered, extracted by dichloromethane, washed by saturated sodium chloride water, dried by anhydrous sodium sulfate and concentrated to obtain oily sticky matter, and then the oily sticky matter is separated by column chromatography (the chromatography condition is that petroleum ether and ethyl acetate are 10:1) to obtain 9.7g of (20S) -hydroxy-androstane-1, 4, 6-triene-3-ketone, wherein the yield is 65.9%.

Preparation of S6, (20S) -tetrahydrofuroxy-androst-1, 4, 6-trien-3-one: 8.0g of compound 22, 21.54g of 3, 4-dihydropyran and 0.01g of p-toluenesulfonic acid are added to 200mL of dichloromethane solvent, and after reaction, extraction with ethyl acetate, washing with saturated sodium chloride water, drying over anhydrous sodium sulfate, vacuum concentration and methanol crystallization, 9.3g of (20S) -tetrahydrofuroxy-androst-1, 4, 6-trien-3-one is obtained and is marked as compound 23.

Preparation of S7, (1S,2S) -epoxy- (20S) -tetrahydrofuranyloxy-androsta-4, 6-dien-3-one: using 240mL of methanol as a solvent, reacting 8.2g of the compound 23 with hydrogen peroxide under an alkaline condition, extracting with ethyl acetate, washing with saturated sodium chloride water, drying with anhydrous sodium sulfate, concentrating in vacuum, and crystallizing with methanol to obtain 5.1g of (1S,2S) -epoxy- (20S) -tetrahydrofuryloxy-androstane-4, 6-diene-3-one, which is marked as a compound 24.

Preparation of S8, (1S,3R) -dihydroxy- (20S) -tetrahydrofuranylox-androst-5-ene: 2.5g of compound 24 were reacted with 15.0g of lithium amide at-60 ℃ in 300mL of tetrahydrofuran as solvent, the mixture was washed with saturated sodium chloride, separated, extracted with ethyl acetate, washed, dried over anhydrous sodium sulfate, concentrated and the concentrate was subjected to column chromatography (chromatography conditions: petroleum ether: ethyl acetate 4:1) to give 1.9g of (1S,3R) -dihydroxy- (20S) -tetrahydrofuryloxy-androst-5-ene, which was designated as compound 25.

Preparation of S9, (1S,3R) -bis (tert-butyldimethylsilyloxy) - (20S) -tetrahydrofuroxy-androst-5-ene: 0.8g of Compound 25, 3.07g of lutidine and 4.04g of tert-butyldimethylsilyl ether trifluoromethanesulfonate were reacted with 100mL of methylene chloride as a solvent, and the solvent was distilled off, followed by precipitation with anhydrous methanol and filtration to obtain 1.15g of (1S,3R) -bis (tert-butyldimethylsilyloxy) - (20S) -tetrahydrofuroxy-androst-5-ene, which was designated as Compound 26.

Preparation of S10, (1S,3R) -bis (tert-butyldimethylsiloxy) - (20S) -hydroxy-androst-5-ene: 1.0g of Compound 26 was reacted with 5mL of methanol in 50mL of dichloromethane solvent, extracted with dichloromethane, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, concentrated and recrystallized from methanol to give 0.83g of (1S,3R) -bis (tert-butyldimethylsilyloxy) - (20S) -hydroxy-androst-5-ene as Compound 12.

Preparation of S11, (1S,3R,20S) -1, 3-bis (tert-butyldimethylsiloxy) -20- (3-hydroxy-3-methylbutoxy) -androst-5-ene: 3.85g of Compound 12 are dissolved in 30mL of tetrahydrofuran solvent, and 1.64g of NaH and 5.75g of 3-bromomethyl-2, 2-dimethyl-oxirane are added to react, saturated NH is added₄After the extraction of the aqueous solution of Cl with ethyl acetate, washing, drying over anhydrous sodium sulfate, concentrating and separating by column chromatography (chromatographic conditions: petroleum ether: ethyl acetate: 20:1), 4.03g of crude epoxide was obtained as (1S,3R,20S) -1, 3-bis (tert-butyldimethylsiloxy) -20- (3-hydroxy-3-methylbutoxy) -androst-5-ene, which was recorded as compound 17.

4.0g of the crude epoxide obtained are dissolved in 120mL of tetrahydrofuran and admixed with 0.68g of LiAlH₄Reacting, adding 30mL of 10% NaOH solution and 12mL of hydrogen peroxide solution, reacting with 20mL of saturated Na₂S₂O₃Then, the mixture was extracted with 100mL of ethyl acetate, washed, and dried over anhydrous sodium sulfate. After rotary evaporation and concentration, column chromatography (chromatographic conditions: petroleum ether: ethyl acetate: 10:1) was performed to obtain 3.3g of (1S,3R,20S) -1, 3-bis (tert-butyldimethylsiloxy) -20- (3-hydroxy-3-methylbutoxy) -androst-5-ene, which was denoted as compound 15.

S12, (1S,3R,20S) -1, 3-bis (tert-butyldimethylsiloxy) -20- (3-hydroxy-3-methylbutoxy-androst-5.7-diene) was prepared by dissolving 9.0g of Compound 15 in 120mL of n-hexane solution, adding 3.7g of NBS and 0.91g of AlBN, filtering after the reaction, evaporating the solvent, dissolving with 120mL of toluene, adding 7.2g of 2,4, 6-trimethylpyridine, refluxing, extracting with ethyl acetate, washing, drying over anhydrous sodium sulfate, rotary-evaporating and concentrating, subjecting to column chromatography (conditions for chromatography: petroleum ether: ethyl acetate ═ 10:1) to give 6.8g of (1S,3R,20S) -1, 3-bis (tert-butyldimethylsiloxy) -20- (3-hydroxy-3-methylbutoxy-androst-5.7-diene), denoted as compound 9.

S13, (1S,3R,20S) -20- (3-hydroxy-3-methylbutoxy-androst-5, 7-diene-1, 3-diol was prepared by dissolving 2.0g of Compound 9 in 50mL of tetrahydrofuran solvent, adding 30.9mL of tetrahydrofuran solution in which 8.08g of tetrabutylammonium fluoride was dissolved, refluxing, extracting with ethyl acetate, washing, drying over anhydrous sodium sulfate, concentrating by rotary evaporation, and subjecting to column chromatography (chromatography conditions: petroleum ether: ethyl acetate 4:1) to give 1.21g of (1S,3R,20S) -20- (3-hydroxy-3-methylbutoxy-androst-5, 7-diene-1, 3-diol as Compound 16.

Preparation of S14, (+) - (5Z,7E) - (1S,3R,20S) -20- (3-hydroxy-3-methylbutoxy) -9, 10-secoandrosta-5, 7, 10(19) -triene-1, 3-diol: dissolving the obtained 6.0g of compound 16 in 2000mL of tetrahydrofuran solution, performing light reaction (light condition: XPA illuminator, light irradiation for 30min), and concentrating; 0.8g of crude maxacalcitol after photochemical reaction and thermal rearrangement is subjected to preparative chromatography to obtain 0.11g of refined product, and the total yield is 13.8%.

The rest of the reaction conditions and the operation steps are referred to example 1.

Example 3

A preparation method of maxacalcitol comprises the following specific technological processes:

preparation of S1, (3R) -tert-butyldimethylsiloxy-androst-5-en-17-one: 20.0g of dehydroepiandrosterone is dissolved in 400mL of tetrahydrofuran, 7.03g of imidazole and 11.42g of tert-butyl dimethyl silicon chloride are added for reflux reaction, and 26.2g of white solid, namely (3R) -tert-butyl dimethyl silicon oxygen-androst-5 ene-17 ketone, is obtained by distilling under reduced pressure, extracting by ethyl acetate, washing by saturated sodium chloride with water, dehydrating and then evaporating off the solvent, and is marked as a compound 18.

Preparation of S2, (17Z,3R) -tert-butyldimethylsiloxy-androsta-5, 17-diene: 26.0g of compound 18, 35.78g of ethyltriphenylphosphonium bromide and 10.81g of potassium tert-butoxide are added into 260mL of tetrahydrofuran solvent for reflux reaction, and after petroleum ether extraction, saturated sodium chloride water washing, anhydrous sodium sulfate drying and vacuum concentration, yellowish solid is obtained, and the yellowish solid is recrystallized and purified to obtain 22.1g of (17Z,3R) -tert-butyldimethylsiloxy-androstane-5, 17-diene, which is marked as a compound 19.

S3, preparation of (3R,20S) -3-tert-butyldimethylsiloxy-20-hydroxy-androst-5-ene: 22.0g of compound 19 and 32.21g of 9-borabicyclo (3,3,1) -nonane are added into 264mL of tetrahydrofuran solvent, the mixture is reacted in an ice bath, oxidized with 80mL of hydrogen peroxide, extracted with ethyl acetate, washed with sodium sulfite solution, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by column chromatography (chromatographic conditions: petroleum ether: ethyl acetate: 30:1) to obtain 17.09g of (3R,20S) -3-tert-butyldimethylsilyloxy-20-hydroxy-androst-5-ene, which is recorded as compound 20.

Preparation of S4, (3R,20S) -3, 20-dihydroxy-androst-5-ene: in 170mL tetrahydrofuran solvent, compound 20 was reacted with 170mL methanol, 1.0g camphorsulfonic acid, purified with ethyl acetate, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, and recrystallized from methanol to give 11.61g (3R,20S) -3, 20-dihydroxy-androst-5-ene as compound 21.

Preparation of S5, (20S) -hydroxy-androst-1, 4, 6-trien-3-one: 230mL of dioxane is used as a solvent, 11.6mL of compound 21 and 41.08g of 2, 3-dichloro-5, 6-dicyan p-benzoquinone are added into the dioxane, after reaction, the mixture is filtered, extracted by dichloromethane, washed by saturated sodium chloride water, dried by anhydrous sodium sulfate and concentrated to obtain oily sticky substances, and then the oily sticky substances are separated by column chromatography (the chromatographic conditions are that petroleum ether and ethyl acetate are 10:1) to obtain 5.88g of (20S) -hydroxy-androstane-1, 4, 6-triene-3-ketone, which is marked as compound 22.

Preparation of S6, (20S) -tetrahydrofuryloxy-androst-1, 4, 6-trien-3-one: 5.0g of Compound 22, 13.46g of 3, 4-dihydropyran and 0.01g of p-toluenesulfonic acid are added to 150mL of dichloromethane solvent, and after reaction, extraction with ethyl acetate, washing with saturated sodium chloride water, drying over anhydrous sodium sulfate, vacuum concentration and methanol crystallization, 6.09g of (20S) -tetrahydrofuroxy-androst-1, 4, 6-trien-3-one is obtained, which is marked as Compound 23.

Preparation of S7, (1S,2S) -epoxy- (20S) -tetrahydrofuranyloxy-androsta-4, 6-dien-3-one: using 200mL of methanol as a solvent, reacting 8.2g of the compound 23 with hydrogen peroxide under an alkaline condition, extracting with ethyl acetate, washing with saturated sodium chloride water, drying with anhydrous sodium sulfate, concentrating in vacuum, and crystallizing with methanol to obtain 4.95g of (1S,2S) -epoxy- (20S) -tetrahydrofuryloxy-androstane-4, 6-diene-3-one, which is marked as a compound 24.

Preparation of S8, (1S,3R) -dihydroxy- (20S) -tetrahydrofuranylox-androst-5-ene: 2.5g of compound 24 were reacted with 2.78g of lithium amide at-60 ℃ in 100mL of tetrahydrofuran as solvent, the mixture was washed with saturated sodium chloride and the layers were separated, extracted with ethyl acetate, washed, dried over anhydrous sodium sulfate, concentrated and the concentrate was subjected to column chromatography (chromatography conditions: petroleum ether: ethyl acetate 4:1) to give 1.1g of (1S,3R) -dihydroxy- (20S) -tetrahydrofuryloxy-androst-5-ene, which was designated as compound 25.

Preparation of S9, (1S,3R) -di (tert-butyldimethylsilyloxy) - (20S) -tetrahydrofuryloxy-androst-5-ene: 0.8g of Compound 25, 0.82g of lutidine and 1.01g of tert-butyldimethylsilyl ether trifluoromethanesulfonate were reacted with 160mL of methylene chloride as a solvent, and the solvent was distilled off, followed by precipitation with anhydrous methanol and filtration to obtain 0.94g of (1S,3R) -bis (tert-butyldimethylsilyloxy) - (20S) -tetrahydrofuroxy-androst-5-ene, which was designated as Compound 26.

Preparation of S10, (1S,3R) -bis (tert-butyldimethylsilyloxy) - (20S) -hydroxy-androst-5-ene: 1.0g of Compound 26 was reacted with 1.5mL of methanol in 50mL of dichloromethane solvent, extracted with dichloromethane, washed with sodium bicarbonate water, dried over anhydrous sodium sulfate, concentrated and recrystallized from methanol to give 0.73g of (1S,3R) -bis (tert-butyldimethylsilyloxy) - (20S) -hydroxy-androst-5-ene as Compound 12.

Preparation of S11, (1S,3R,20S) -1, 3-bis (tert-butyldimethylsiloxy) -20- (3-hydroxy-3-methylbutoxy) -androst-5-ene: 3.85g of Compound 12 are dissolved in 100mL of tetrahydrofuran solvent, and 0.66g of NaH and 2.31g of 3-bromomethyl-2, 2-dimethyl-oxirane are added to react, saturated NH is added₄Extracting with ethyl acetate, washing, drying with anhydrous sodium sulfate, concentrating, and separating with column chromatography (under the chromatography conditions: petroleum ether: ethyl acetate: 20:1) to obtainTo 3.17g of crude epoxide, i.e. (1S,3R,20S) -1, 3-bis (tert-butyldimethylsiloxy) -20- (3-hydroxy-3-methylbutoxy) -androst-5-ene, was identified as compound 17.

The crude epoxide (3.17 g) was dissolved in 120mL tetrahydrofuran and mixed with LiAlH (0.28 g)₄Reacting, adding 20mL of 10% NaOH solution and 9mL of hydrogen peroxide solution, reacting with 20mL of Na₂S₂O₃The saturated solution was extracted with 100mL of ethyl acetate, washed, and dried over anhydrous sodium sulfate. After rotary evaporation and concentration, column chromatography (chromatographic conditions: petroleum ether: ethyl acetate: 10:1) was performed to obtain 1.93g of (1S,3R,20S) -1, 3-bis (tert-butyldimethylsiloxy) -20- (3-hydroxy-3-methylbutoxy) -androst-5-ene, which was denoted as compound 15.

S12, (1S,3R,20S) -1, 3-bis (tert-butyldimethylsiloxy) -20- (3-hydroxy-3-methylbutoxy-androst-5.7-diene) was prepared by dissolving 9.0g of Compound 15 in 90mL of n-hexane solution, adding 4.94g of NBS and 0.91g of AlBN, filtering after the reaction, evaporating the solvent, dissolving with 90mL of toluene, adding 7.2g of 2,4, 6-trimethylpyridine, refluxing, extracting with ethyl acetate, washing, drying over anhydrous sodium sulfate, rotary-evaporating and concentrating, subjecting to column chromatography (conditions for chromatography: petroleum ether: ethyl acetate ═ 10:1) to give 7.08g of (1S,3R,20S) -1, 3-bis (tert-butyldimethylsiloxy) -20- (3-hydroxy-3-methylbutoxy-androst-5.7-diene), denoted as compound 9.

S13, (1S,3R,20S) -20- (3-hydroxy-3-methylbutoxy-androst-5, 7-diene-1, 3-diol was prepared by dissolving 2.0g of Compound 9 in 50mL of tetrahydrofuran solvent, adding 12.36mL of tetrahydrofuran solution in which 1.03g of tetrabutylammonium fluoride was dissolved, refluxing, extracting with ethyl acetate, washing, drying over anhydrous sodium sulfate, concentrating by rotary evaporation, and subjecting to column chromatography (chromatography conditions: petroleum ether: ethyl acetate: 4:1) to give 1.03g of (1S,3R,20S) -20- (3-hydroxy-3-methylbutoxy-androst-5, 7-diene-1, 3-diol as Compound 16.

Preparation of S14, (+) - (5Z,7E) - (1S,3R,20S) -20- (3-hydroxy-3-methylbutoxy) -9, 10-secoandrosta-5, 7, 10(19) -triene-1, 3-diol: dissolving the obtained 6.0g of compound 16 in 2000mL of tetrahydrofuran solution, performing light reaction (light condition: XPA illuminator, light irradiation for 40min), and concentrating; and then the photochemical reaction and the thermal rearrangement are carried out on the product, namely 0.85g of crude maxacalcitol, and 0.13g of refined product is obtained through preparative chromatography, wherein the yield is 15.3%.

¹H NMR(600MHz，CDCl3)6：6.36(d，J＝10.8Hz,l H)，6.02(d，J＝10.8Hz，lH)，5.33(s，lH)，4.99(s，lH)，4.43(m,lH)，4.22(m,lH)，3.83(m，lH)，3.80(s，lH)，3.49(m，lH)，3.26(m，lH)，2.82-2.84(m，lH)，2.58-2.60(m,lH)，2.29-2.33(m,lH)，1.86-1.99(m，3H)，1.67-1.73(m,5H)，1.5 1-1.58(m，4H)，1.18-1.29(m,12H)，0.53(s，3H).EI-MS：m/z：419(M+H).IR(KBr,cm-)：3417，2964，2926，2873，2852，1644，1448，1404，1376，1346，1262，1220，1151，1091，1057，956，909，895，800，743。

¹³C NMR(CDCl3)δ:147.6，142.3，133.3，124.8，117.5，111.9，78.8，70.8，70.，66.8，65.6，57.0，56.0，45.2，44.8，42.8，41.4，39.5，29.2，29.1，28.9，25.6，23.2，22.2，1 8.8，l2.6.UV(EtOH)：λmax 263nm。

The remaining reaction conditions and operation were as in example 1.

It should be noted that, in this document, relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.

Although embodiments of the present application have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the application, the scope of which is defined in the appended claims and their equivalents.

Claims (6)

1. The preparation method of the maxacalcitol is characterized by comprising the following technical processes:

s1, dissolving dehydroepiandrosterone in tetrahydrofuran, adding imidazole and tert-butyl dimethyl silicon chloride for reflux reaction, and evaporating to remove the solvent after reduced pressure distillation, ethyl acetate extraction, water washing and dehydration to obtain a white solid, namely the compound 18;

s2, adding the compound 18, ethyl triphenyl phosphonium bromide and potassium tert-butoxide into a tetrahydrofuran solvent for reflux reaction, extracting by petroleum ether, washing by water, drying, concentrating in vacuum to obtain a yellowish solid, and recrystallizing for purification to obtain a compound 19;

s3, adding the compound 19 and 9-boron bicyclo (3,3,1) -nonane into a tetrahydrofuran solvent, carrying out ice-bath reaction, oxidizing with hydrogen peroxide, extracting with ethyl acetate, washing with water, drying, concentrating in vacuum, and purifying by column chromatography to obtain a compound 20;

s4, reacting the compound 20 with methanol and camphorsulfonic acid in a tetrahydrofuran solvent, purifying with ethyl acetate, washing with water, drying, and recrystallizing with methanol to obtain a compound 21;

s5, adding the compound 21 and 2, 3-dichloro-5, 6-dicyan p-benzoquinone into dioxane serving as a solvent, reacting, filtering, extracting with dichloromethane, washing with water, drying, concentrating to obtain an oily sticky substance, and performing column chromatography separation to obtain a compound 22;

s6, adding the compound 22, 3, 4-dihydropyran and p-toluenesulfonic acid into a dichloromethane solvent, reacting, extracting with ethyl acetate, washing with water, drying, vacuum concentrating and crystallizing with methanol to obtain a compound 23;

s7, taking methanol as a solvent, reacting the compound 23 with hydrogen peroxide under an alkaline condition, and obtaining a compound 24 after ethyl acetate extraction, water washing, drying, vacuum concentration and methanol crystallization;

s8, reacting the compound 24 with lithium amide at low temperature by taking tetrahydrofuran as a solvent, carrying out water washing for layering, extracting with ethyl acetate, washing, drying and concentrating, and carrying out column chromatography on the concentrate to obtain a compound 25;

s9, using dichloromethane as a solvent, reacting the compound 25, dimethyl pyridine and tert-butyl dimethyl silyl ether triflate, evaporating to remove the solvent, precipitating with anhydrous methanol, and filtering to obtain a compound 26;

s10, reacting the compound 26 with methanol in a dichloromethane solvent, extracting with dichloromethane, washing with water, drying, concentrating, and recrystallizing with methanol to obtain a compound 12;

s11, dissolving compound 12 in tetrahydrofuran solvent, adding NaH and 3-bromomethyl-2, 2-dimethyl-oxirane for reaction, and adding saturated NH₄Extracting the Cl aqueous solution with ethyl acetate, washing, drying, concentrating, and separating by column chromatography to obtain an epoxide crude product, namely a compound 17;

dissolving the obtained crude epoxide in tetrahydrofuran, and reacting with LiAlH₄Reacting, adding NaOH solution and hydrogen peroxide solution for reaction, and reacting with Na₂S₂O₃Extracting with ethyl acetate, washing, drying, rotary steaming, concentrating, and performing column chromatography to obtain compound 15;

s12, dissolving the compound 15 in n-hexane solution, adding NBS and AlBN, filtering after reaction, evaporating to remove the solvent, dissolving with toluene, adding 2,4, 6-trimethylpyridine, refluxing for reaction, extracting with ethyl acetate, washing, drying, carrying out rotary evaporation and concentration, and carrying out column chromatography to obtain a compound 9;

s13, dissolving the compound 9 in a tetrahydrofuran solvent, adding a tetrahydrofuran solution in which tetrabutylammonium fluoride is dissolved, carrying out reflux reaction, extracting with ethyl acetate, washing, drying, carrying out rotary evaporation concentration, and carrying out column chromatography to obtain a compound 16;

s14, dissolving the obtained compound 16 in tetrahydrofuran solution, performing light reaction, and concentrating; then carrying out photochemical reaction and thermal rearrangement to obtain a product maxacalcitol, and then carrying out preparative chromatography to obtain a refined product.

2. The method for preparing maxacalcitol according to claim 1, characterized in that the chemical equation involved is:

3. the method for preparing maxacalcitol according to claim 1, characterized in that the conditions of column chromatography are as follows: petroleum ether: and ethyl acetate is 4-30: 1.

4. The method for preparing maxacalcitol according to claim 1, wherein in step S14, the lighting conditions are as follows: in an XPA light reaction instrument, the light reaction is carried out for 30-50 min.

5. The method for preparing the maxacalcitol according to claim 1, wherein the tetrahydrofuran is anhydrous tetrahydrofuran, and the treatment method comprises the following steps: adding sufficient lithium aluminum hydride into commercial tetrahydrofuran, heating and refluxing, distilling out the fraction at 66 ℃, collecting the fraction into a distiller, adding sodium filament and benzophenone, introducing nitrogen for protection, sealing and storing, and heating and distilling when in use.

6. The method for preparing the maxacalcitol according to claim 1, wherein the dichloromethane used is anhydrous dichloromethane, and the processing method comprises the following steps: adding sufficient calcium hydride into commercially available dichloromethane, heating and refluxing, distilling to collect 40 deg.C fraction, adding molecular sieve, and sealing for storage.

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