CN118324837A

CN118324837A - Preparation method of 16 beta-methyl-17 alpha-hydroxy glucocorticoid and analogue

Info

Publication number: CN118324837A
Application number: CN202311809796.0A
Authority: CN
Inventors: 陈芬儿; 韦建海; 张娅娇; 何杭利
Original assignee: Fudan University
Current assignee: Fudan University
Priority date: 2023-12-26
Filing date: 2023-12-26
Publication date: 2024-07-12

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of 16 beta-methyl-17 alpha-hydroxy glucocorticoid and analogues thereof. The invention synthesizes a target product 16 beta-methyl-17 alpha-hydroxyl glucocorticoid and analogues thereof by a raw material compound of 16-methyl-16-alkene-20-ketone in one step: in the presence of oxygen or air, 16-methyl-16-alkene-20-ketone takes a manganese catalyst, an iron catalyst or a cobalt catalyst as a catalyst, takes silicon hydrogen as a hydrogenation reagent, and carries out hydration reaction in an organic solvent; and then reducing by using triethyl phosphite or trimethyl phosphite as a reducing agent to obtain the 16 beta-methyl-17 alpha-hydroxy glucocorticoid and analogues thereof. The invention shortens the original three or four steps of reaction to one step; the reaction yield and the selectivity are high, and beta methyl can be constructed with extremely high dr value; the reaction is carried out at room temperature, the conditions are mild, the operation is simple and convenient, the equipment requirement is low, and the method is suitable for industrial production.

Description

Preparation method of 16 beta-methyl-17 alpha-hydroxy glucocorticoid and analogue

Technical Field

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of 16 beta-methyl-17 alpha-hydroxy glucocorticoid and analogues thereof.

Background

16 Beta-methyl-17 alpha-hydroxy glucocorticoid and analogues thereof are important components of glucocorticoid medicaments and can be used for synthesizing 16 beta-methyl glucocorticoid medicaments. The structural formula is shown in the following figure (I).

Wherein R ₁ is fluorine or hydrogen, R ₂ is fluorine, chlorine or hydrogen, R ₃ is carbonyl, hydroxyl, hydrogen or C9,10 is epoxy, R ₄ is hydrogen, hydroxyl, acetoxy, propionyloxy, halogen, R ₅ is oxo, hydroxyl, acetoxy, etc., the C1,2 positions are single or double bonds, and the C3,4 positions are single or double bonds.

U.S. Pat. No. 3, 3485854 and J.am.chem.Soc.1960,82,15,4012-4026 disclose the use of pregna-16-methyl-3β -acetoxy-16-ene-11, 20-dione by palladium hydrocarbon condensation followed by acetic anhydride, the formation of vinyl acetate from p-toluene sulfonic acid in the presence of benzene as solvent, oxidation by m-chloroperoxybenzoic acid, hydrolysis under alkaline conditions to yield pregna-16β -methyl-3β,17α -dihydroxy-11, 20-dione.

However, the method has longer steps, acetyl protection is needed to be carried out on the 3-position, and expensive palladium-carbon is needed in the reduction reaction, so that the cost is greatly increased, and the inconvenience is brought to industrial production.

Another method for preparing pregna-16β -methyl-3β,17α -dihydroxy 9 (11) -en-20-one by oxidation of hydrogen peroxide, protection of the 20 th carbonyl group by ethylene glycol, methylation ring opening by Grignard reagent, hydrolysis under alkaline conditions, and acidolysis is reported in U.S. Pat. No. 3, 3067195 and Synthetic Commun.2006, 36:865-874.

The method needs to carry out acetylation protection on the 3-position, glycol protection on the 20-position carbonyl, hydrolysis, acidolysis and the like under alkaline conditions, has long steps, and brings inconvenience to industrial production.

The literature J Chem Res (2017), 41 (5), 266-270 reports that another pregna-16-methyl-21-acetoxy-4, 9 (11), 16-triene-3, 20-dione is used as a raw material, the double bond at the 16,17 position is firstly oxidized by m-chloroperoxybenzoic acid, then hydrogen bromide is used for ring opening, debromination is carried out under alkaline condition, and triphenylphosphine rhodium chloride is used for hydrogenation to obtain pregna-16 beta-methyl-17 alpha-hydroxy-21-acetoxy-1, 4,9 (11) -triene-3, 20-dione.

The method needs to oxidize m-chloroperoxybenzoic acid firstly, and oxidizes the 9 (11) position simultaneously when oxidizing, needs to use pyridine, dioxane and other solvents with larger toxicity, needs to use triphenylphosphine rhodium chloride noble metal catalyst, has higher cost and longer steps, and is not easy to industrialize.

The three routes all have the problems of longer steps, higher cost and the like.

Disclosure of Invention

The invention aims to solve the defects of the prior art, and provides a high-efficiency preparation method of 16 beta-methyl-17 alpha-hydroxyl glucocorticoid and analogues thereof, which can synthesize the raw materials into a target product in one step without considering whether 3-hydroxyl needs to be protected, has high selectivity and low cost, and is suitable for industrial production.

The invention provides a preparation method of 16 beta-methyl-17 alpha-hydroxyl glucocorticoid and analogues thereof, which is characterized in that a target product 16 beta-methyl-17 alpha-hydroxyl glucocorticoid and analogues thereof (I) are synthesized by a raw material compound 16-methyl-16-alkene-20-ketone (II) in one step, and the synthetic route is shown as the following formula:

The preparation method comprises the following specific steps:

(1) Taking 16-methyl-16-alkene-20-ketone (II) as a raw material, and carrying out hydration reaction in an organic solvent in the presence of oxygen or air by taking a manganese catalyst, an iron catalyst or a cobalt catalyst as a catalyst and taking silicon hydrogen as a hydrogenation reagent;

(2) And then reducing by using triethyl phosphite or trimethyl phosphite as a reducing agent to obtain 16 beta-methyl-17 alpha-hydroxy glucocorticoid and analogues thereof (I).

Further:

The starting compounds (II) described can be prepared by reference J.Am.chem.Soc.1960,82,15,4012-4026 and J Chem Res (2017), 41 (5), 266-270.

The manganese catalyst, the iron catalyst and the cobalt catalyst are complexes of manganese, iron, cobalt, 2, 6-tetramethyl-3, 5-heptenoic acid, acetylacetone, acetic acid and the like. The method specifically comprises the following steps: manganese tris (2, 6-tetramethyl-3, 5-heptenoate), manganese bis (2, 6-tetramethyl-3, 5-heptenoate), manganese triacetylacetonate, manganese diacetylacetonate, manganese acetate, iron tris (2, 6-tetramethyl-3, 5-heptenoic acid), iron bis (2, 6-tetramethyl-3, 5-heptenoic acid), iron triacetylacetonate, iron diacetylacetonate, iron acetate, cobalt tris (2, 6-tetramethyl-3, 5-heptenoate), cobalt bis (2, 6-tetramethyl-3, 5-heptenoate), cobalt triacetylacetonate, cobalt diacetylacetonate, cobalt acetate.

The hydrogenation reagent is selected from phenylsilane, diphenylsilane, triphenylsilane, triethylsilane and diethylsilane.

The organic solvent is alcohol such as methanol, ethanol or isopropanol, or is a mixed solvent of monohalogenated and polyhaloalkane (such as dichloromethane, chloroform, dichloroethane, etc.) and the alcohol.

The molar ratio of the raw material compound (II), the catalyst, the hydrogenation reagent and the reducing agent is 1 (0.03-0.1), 1-2, 0.5-1, the reaction temperature is 0-25 ℃, and the reaction time is 6-12 hours.

The optimal conditions in the invention are as follows:

In the preparation of compound (I) from compound (II), the solvent is ethanol.

In the preparation of compound (I) from compound (II), the gas is oxygen.

In the preparation of compound (I) from compound (II), the catalyst is manganese tris (2, 6-tetramethyl-3, 5-heptenoate).

In the preparation of compound (I) from compound (II), the hydrogenation reagent is phenylsilane.

In the preparation of the compound (I) from the compound (II), the reducing agent is triethyl phosphite.

The mol ratio of the compound (II), the catalyst, the hydrogenation reagent and the reducing agent is 1 (0.03-0.1): 1-2): 0.5-1, the reaction temperature is 0-25 ℃, and the reaction time is 6-12 hours.

Compared with the traditional synthesis method, the preparation method of the 16 beta-methyl-17 alpha-hydroxyl glucocorticoid and the analogues thereof provided by the invention has the following advantages:

(1) The reaction step is effectively shortened, and the original three or four steps of reaction is shortened to one step;

(2) The reaction yield and the selectivity are high, and beta methyl can be constructed by the dr value of 82:18-99:1;

(3) The reaction condition is mild, the operation is simple and convenient, and the equipment requirement is low.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.

Example 1

PhSiH ₃ (1.0 g,9.26 mmol) was dissolved in ethanol (3 mL) and the resulting solution was added dropwise to a solution of the compound pregna-16-methyl-3α -hydroxy-16-ene-11, 20-dione (1.6 g,4.63 mmol) and manganese tris (2, 6-tetramethyl-3, 5-heptenoate) (81.5 mg,0.14 mmol) in ethanol (20 mL) at 0deg.C under O ₂. After the completion of the dropwise addition, the mixture was stirred at room temperature under O ₂ for 6 hours. After the reaction was completed, triethyl phosphite (0.77 g,4.63 mmol) was added and stirring at room temperature was continued for 20 minutes. Then 30mL of water was added, the organic phases were extracted with ethyl acetate (3X 50 mL), and the combined organic phases were washed with 50mL of saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the white solid pregna-16β -methyl-3α,17α -dihydroxy-11, 20-dione was isolated by column chromatography (gradient: 0→50% EA in PE). (1.44 g,3.98mmol,86% yield), dr value is 99:1.m.p:181.5-183.5℃.[α]_D ²⁰＝45.0(c＝0.5,CHCl₃).¹H NMR(400MHz,CDCl₃)δ3.71(p,J＝5.8Hz,1H),2.61–2.50(m,2H),2.44(d,J＝10Hz,1H),2.23(ddd,J＝14.6,9.6,7.4Hz,2H),2.16–1.99(m,5H),1.94–1.84(m,2H),1.78(dd,J＝5.8,3.0Hz,1H),1.69–1.58(m,4H),1.56–1.46(m,2H),1.44–1.38(m,1H),1.35(d,J＝4.7Hz,1H),1.31–1.20(m,3H),1.01(s,6H),0.90(d,J＝5.3Hz,3H).¹³C NMR(100MHz,CDCl₃)δ211.5,211.5,89.6,70.3,62.6,53.2,49.7,46.9,41.0,39.4,39.0,38.0,35.5,34.7,33.4,31.4,29.4,28.2,27.8,17.2,16.8,15.9.HRMS(ESI)m/z calcd for C₂₂H₃₅O₄,[M+H]⁺＝363.2451,found:363.2457.

Example 2

PhSiH ₃ (1.0 g,9.26 mmol) was dissolved in ethanol (3 mL) and the resulting solution was added dropwise to a solution of the compound pregna-16-methyl-3-hydroxy-9 (11), 16-dien-20-one (1.52 g,4.63 mmol) and manganese tris (2, 6-tetramethyl-3, 5-heptenoate) (81.5 mg,0.14 mmol) in ethanol (20 mL) at 5℃under O ₂. After the completion of the dropwise addition, the mixture was stirred at room temperature under O ₂ for 8 hours. After the reaction was completed, triethyl phosphite (0.77 g,4.63 mmol) was added and stirring at room temperature was continued for 20 minutes. Then 30mL of water was added, the organic phases were extracted with ethyl acetate (3X 50 mL), and the combined organic phases were washed with 50mL of saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the white solid pregna-16β -methyl-3, 17α -dihydroxy 9 (11) -en-20-one was isolated by column chromatography (gradient: 0→50% EA in PE). (1.33 g,3.84mmol,83% yield), dr value 99:1.m.p:194.7-196.9℃.[α]_D ²⁰＝39.0(c＝0.5,1,4-dioxane).¹H NMR(400MHz,CDCl₃)δ5.19(td,J＝5.0,0.5Hz,1H),3.77(p,J＝6.0Hz,1H),2.62(dd,J＝9.9,4.9Hz,1H),2.25–2.11(m,2H),2.10(s,3H),1.95(qd,J＝6.2,0.7Hz,1H),1.75–1.61(m,3H),1.61–1.55(m,1H),1.54–1.48(m,3H),1.46–1.35(m,2H),1.34–1.19(m,5H),1.14(dt,J＝7.4,3.7Hz,1H),1.01(s,3H),0.96–0.92(m,4H),0.90(d,J＝5.3Hz,3H).¹³C NMR(100MHz,CDCl₃)δ211.5,144.0,116.2,88.7,70.3,51.8,46.6,44.2,39.0,38.6,37.7,37.6,37.4,36.8,34.4,32.0,31.7,27.8,27.1,24.7,16.8,15.3.HRMS(ESI)m/z calcd for C₂₂H₃₅O₃,[M+H]⁺＝347.2506,found:347.2508.

Example 3

PhSiH ₃ (0.22 g,2 mmol) was dissolved in ethanol (0.4 mL) and the resulting solution was added dropwise to a solution of the compound pregna-16-methyl-21-acetoxy-4, 9 (11), 16-triene-3, 20-dione (0.38 g,1 mmol) and manganese tris (2, 6-tetramethyl-3, 5-heptenoic acid) (18.2 mg,0.03 mmol) in ethanol (5 mL) at 0deg.C under O ₂. After the completion of the dropwise addition, the mixture was stirred at room temperature under O ₂ for 6 hours. After the reaction was completed, triethyl phosphite (0.17 g,1 mmol) was added thereto, and stirring at room temperature was continued for 20 minutes. Then 30mL of water was added, the organic phases were extracted with ethyl acetate (3X 50 mL), and the combined organic phases were washed with 50mL of saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the white solid pregna-16β -methyl-17α -hydroxy-21-acetoxy-1, 4,9 (11) -triene-3, 20-dione was isolated by column chromatography (gradient: 0→50% EA in PE). (0.33 g,0.83mmol,83% yield), dr value is 99:1.[α]_D ²⁰＝123.5(c＝0.2,CH₂Cl₂).C16-α[α]_D ²⁰＝67.0(c＝0.2,CH₂Cl₂).¹H NMR(400MHz,CDCl₃)δ＝5.67(s,1H),5.47(d,J＝5.6,1H),4.89(q,J＝17.8,2H),2.67–2.23(m,6H),2.23–2.13(m,2H),2.11(s,3H),2.09–1.91(m,4H),1.74(dd,J＝17.1,5.0,1H),1.67–1.56(m,1H),1.26(s,3H),1.22–1.11(m,1H),1.09(d,J＝7.0,3H),1.07–0.99(m,1H),0.70(s,3H).¹³C NMR(101MHz,CDCl₃)δ205.1,199.8,170.7,170.2,143.6,123.9,119.0,89.4,69.4,49.4,48.4,46.6,41.0,37.2,36.0,34.3,33.8,32.9,32.4,26.1,20.7,19.7,14.4.HRMS(ESI)m/z calcd for C₂₄H₃₃O₅,[M+H]⁺＝401.2323,found:401.2320.

Example 4

PhSiH ₃ (1.0 g,9.26 mmol) was dissolved in ethanol (3 mL) and the resulting solution was added dropwise to a solution of the compound pregna-16-methyl-4, 9 (11), 16-triene-3, 20-dione (1.5 g,4.63 mmol) and ferric triacetylacetonate (49.2 mg,0.14 mmol) in ethanol (20 mL) at 10deg.C under O ₂. After the completion of the dropwise addition, the mixture was stirred at room temperature under O ₂ for 10 hours. After the reaction was completed, triethyl phosphite (0.77 g,4.63 mmol) was added and stirring at room temperature was continued for 20 minutes. Then 30mL of water was added, the organic phases were extracted with ethyl acetate (3X 50 mL), and the combined organic phases were washed with 50mL of saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the white solid pregna-16β -methyl-17α -hydroxy-4, 9 (11) -diene-3, 20-dione was isolated by column chromatography (gradient: 0→50% EA in PE). (1.27 g,3.70mmol,80% yield), dr value is 98:2m.p:167.2-168.3℃.[α]_D ²⁰＝82.0(c＝0.5,CHCl₃).¹H NMR(400MHz,CDCl₃)δ5.74(1H,d,J＝1.2),5.50(1H,dd,J＝16.3,4.9),2.97(1H,s),2.68-2.42(4H,m),2.39-2.31(1H,m),2.26(3H,s),2.25-1.99(6H,m),1.83-1.70(1H,m),1.65(1H,ddd,J＝17.0,5.8,1.5),1.34(3H,s),1.19(3H,d,J＝7.2),1.17-1.08(2H,m),0.87(3H,s).¹³C NMR(100MHz,CDCl₃)δ211.0,199.5,170.0,143.8,123.9,118.9,90.0,47.5,47.2,46.9,41.0,37.1,36.0,34.3,33.8,33.3,32.9,32.3,30.0,26.1,20.1,15.3.HRMS(ESI)m/z calcd for C₂₂H₃₁O₃,[M+H]⁺＝343.2268,found:343.2274.

Example 5

Betamethasone was synthesized in the same manner as in example 1 using pregna-16-methyl-21-hydroxy-9α -fluoro-11β -hydroxy-1, 4, 16-triene-3, 20-dione (112.2 mg,0.3 mmol) as a starting material. White solid (97.6 mg,0.249mmol,83% yield), dr value 95:5.m.p:236.4-237.7℃.[α]_D ²⁵＝105.3(c＝0.5,acetone).[lit.⁵⁸:[α]^acetone _D＝108.]¹H NMR(400MHz,DMSO-d₆)δ7.29(1H,d,J＝10.1),6.22(1H,d,J＝10.1),6.02(1H,s),5.23(1H,s),5.12(1H,s),4.55-4.29(2H,m),4.21-3.93(2H,m),2.64(1H,td,J＝13.4,5.6),2.47-2.27(2H,m),2.19-2.03(2H,m),2.01-1.76(3H,m),1.50(3H,s),1.44-1.36(1H,m),1.32(1H,d,J＝13.6),1.11-0.99(4H,m),0.97(3H,s).¹³C NMR(100MHz,DMSO-d₆)δ212.2,185.3,167.0,152.8,129.0,124.1,101.2(d,J＝175.2),87.7,70.7(d,J＝36.5),67.7,47.9(d,J＝22.7),47.9,46.8,42.9,36.2,34.6,33.2(d,J＝19.4),30.30,27.57,22.9(d,J＝5.7),19.8,17.0.IR(cm^-1):3445,3364,2977,2936,2907,1708,1659,1615,1602,1053;HRMS(ESI)m/z calcd for C₂₂H₂₉FNaO₅,[M+Na]⁺＝415.1891,found:415.1894.

Example 6

Betamethasone-21-acetate was synthesized as in example 1 starting from pregna-16-methyl-21-acetoxy-9α -fluoro-11β -hydroxy-1, 4, 16-triene-3, 20-dione (41.6 mg,0.1 mmol). (35.1 mg,0.081mmol,81% yield), dr value was 94:6.m.p:214.4-215.8℃.[α]_D ²⁰＝103(c＝0.2,EtOH).¹H NMR(400MHz,DMSO)δ7.29(d,J＝10.1,1H),6.22(d,J＝9.9,1H),6.01(s,1H),5.36(s,1H),5.31(d,J＝3.2,1H),4.89(dd,J＝73.1,17.7,2H),4.14(s,1H),2.63(dd,J＝12.7,7.8,1H),2.47–2.26(m,2H),2.10(s,2H),2.09(s,3H),2.03–1.78(m,3H),1.50(s,3H),1.47–1.31(m,2H),1.13–1.03(m,1H),1.01(d,J＝7.1,3H),0.92(s,3H).¹³C NMR(101MHz,DMSO)δ206.0,185.8,170.2,167.5,153.3,129.4,124.6,101.7(d,J＝175.5Hz),88.4,71.06(d,J＝36.4Hz),69.7,48.9,48.4(d,J＝22.9Hz),47.4,43.3,36.5,35.0,33.7(d,J＝19.4Hz),30.8,28.1,23.4(d,J＝5.6Hz),20.9,20.2,17.1.IR(cm^-1):3586,3430,2950,1738,1717,1661,1603,1268,1247,1067;HRMS(ESI)m/z calcd for C₂₄H₃₂FO₆,[M+H]⁺＝435.2177,found:435.2175.

Example 7

Betamethasone-21-propionate was synthesized as in example 1 starting from pregna-16-methyl-21-propionyloxy-9α -fluoro-11β -hydroxy-1, 4, 16-triene-3, 20-dione (43.0 mg,0.1 mmol). White solid (37.6 mg,0.084mmol,84% yield), dr value 82:18.m.p:216.0-219.7℃.[α]_D ²⁰＝105(c＝0.2,EtOH).¹H NMR(400MHz,DMSO)δ7.29(d,J＝10.1,1H),6.22(d,J＝10.0,1H),6.01(s,1H),5.35(s,1H),5.31(d,J＝2.5,1H),4.90(dd,J＝63.5,17.7,2H),4.14(s,1H),2.76–2.55(m,1H),2.38(dt,J＝22.3,9.4,4H),2.08(t,J＝18.9,2H),2.03–1.76(m,3H),1.50(s,3H),1.39(dd,J＝24.7,15.5,2H),1.16–0.96(m,7H),0.92(s,3H).¹³C NMR(101MHz,DMSO)δ206.0,185.7,173.5,167.5,153.3,129.4,124.6,101.7(d,J＝175.4Hz),88.4,71.1(d,J＝36.3Hz),69.6,48.8,48.4(d,J＝22.7Hz),47.4,43.3,36.5,35.0,33.7(d,J＝19.4Hz),30.8,28.1,27.1,23.5(d,J＝5.6Hz),20.2,17.1,9.5.IR(cm^-1):3544,3360,2979,2948,1740,1720,1662,1623,1615,1407,1203;HRMS(ESI)m/z calcd for C₂₅H₃₄FO₆,[M+H]⁺＝449.2334,found:449.2337.

Example 8

Clobetasol was synthesized in the same manner as in example 4, starting from pregna-16-methyl-21-chloro-9α -fluoro-11β -hydroxy-1, 4, 16-triene-3, 20-dione (37.2 mg,0.1 mmol). White solid (34.7 mg,0.89mmol,89% yield), dr value 97:3,m.p:194.2-196.8℃.¹H NMR(400MHz,DMSO)δ7.33(d,J＝10.2,1H),6.19(d,J＝10.2,1H),6.12(s,1H),5.62(s,1H),4.58(s,1H),4.27(ddd,J＝23.7,19.4,4.9,2H),3.34(s,1H),3.18(dd,J＝11.0,6.7,1H),2.64(t,J＝10.9,1H),2.48–2.35(m,2H),2.23(t,J＝22.8,1H),2.11–1.76(m,3H),1.50(s,1H),1.50(s,3H),1.22–1.03(m,1H),1.00(d,J＝6.8,3H),0.79(s,3H).¹³C NMR(101MHz,DMSO)δ＝206.58,206.31,205.66,185.35,170.38,164.75,152.04,129.65,126.05,100.93,99.12,87.39,69.70,52.38,47.94,47.51,46.56,46.33,42.60,37.86,37.66,34.13,30.95,27.35,21.70,21.64,20.87,19.76,15.38.HRMS(ESI)m/z calcd for C₂₂H₂₈ FO₅,[M+H]⁺＝391.1915,found:391.1928.

Example 9

Pregna-9α -fluoro-17α -hydroxy-16β -methyl-21-hydroxy-1, 4-diene-3, 11, 20-trione was synthesized as in example 1 starting from pregna-16-methyl-21-hydroxy-9α -fluoro-11β -hydroxy-1, 4, 16-triene-3, 20-dione (111.6 mg,0.3 mmol). White solid (94.8 mg, 0.255 mmol,81% yield) with dr value 98:2.m.p:201.2-202.7℃.[α]_D ²⁰＝128(c＝0.2,EtOH).¹H NMR(400MHz,DMSO)δ＝7.29(d,J＝10.1,1H),6.22(d,J＝9.9,1H),6.01(s,1H),5.36(s,1H),5.31(d,J＝3.2,1H),4.89(dd,J＝73.1,17.7,2H),4.14(s,1H),2.63(dd,J＝12.7,7.8,1H),2.47–2.26(m,2H),2.10(s,2H),2.09(s,3H),2.03–1.78(m,3H),1.50(s,3H),1.47–1.31(m,2H),1.13–1.03(m,1H),1.01(d,J＝7.1,3H),0.92(s,3H).¹³C NMR(101MHz,DMSO)δ212.1,206.6(d,J＝27.4Hz),185.4,164.8,152.0,129.6,126.0,100.1(d,J＝182.4Hz),87.2,68.0,52.1,48.3,47.1,46.4(d,J＝23.1Hz),42.6,37.7(d,J＝20.5Hz),34.1,30.9,27.3,21.7(d,J＝5.8Hz),19.9,15.8.IR(cm^-1):3274,2959,2938,1723,1708,1662,1613,1601,901;HRMS(ESI)m/z calcd for C₂₂H₂₅FO₅,[M+H]⁺＝391.1915,found:391.1928.

Example 10

Pregna-9α -fluoro-17α -hydroxy-16β -methyl-21-acetoxy-1, 4-diene-3, 11, 20-trione was synthesized as in example 1 starting from pregna-16-methyl-21-acetoxy-9α -fluoro-1, 4, 16-triene-3, 11, 20-dione (41.4 mg,0.1 mmol). White solid (32.8 mg,0.076mmol,76% yield)), dr value was 98:2.m.p:214.9-215.6℃.[α]_D ²⁰＝116(c＝0.2,EtOH).¹H NMR(400MHz,DMSO)δ7.34(d,J＝10.2,1H),6.20(d,J＝10.2,1H),6.12(s,1H),5.87(s,1H),5.05–4.76(m,2H),3.22(dd,J＝10.8,6.8,1H),2.63(dd,J＝18.0,8.3,1H),2.50–2.36(m,3H),2.30(d,J＝7.2,1H),2.14(d,J＝10.6,1H),2.09(s,3H),1.99(s,1H),1.89(dd,J＝24.3,8.8,1H),1.51(s,1H),1.50(s,3H),1.06(d,J＝9.3,1H),1.00(d,J＝6.3,3H),0.69(s,3H).¹³C NMR(101MHz,DMSO)δ206.4(d,J＝27.4Hz),205.7,185.3,170.4,164.8,152.0,129.6,126.0,100.0(d,J＝182.4Hz),87.4,69.7,52.4,47.9,47.5,46.4(d,J＝23.1Hz),42.6,37.8(d,J＝20.5Hz),34.1,31.0,27.4,21.7(d,J＝5.8Hz),20.9,19.8,15.4.IR(cm^-1):3256,2923,2852,1747,1732,1716,1660,1614;HRMS(ESI)m/z calcd for C₂₄H₃₀FO₆,[M+H]⁺＝433.2021,found:433.2016.

Example 11

Pregna-9α -fluoro-17α -hydroxy-16β -methyl-21-propionyloxy-1, 4-diene-3, 11, 20-trione was synthesized as in example 1 starting from pregna-16-methyl-21-propionyloxy-9α -fluoro-1, 4, 16-triene-3, 11, 20-dione (42.8 mg,0.1 mmol). White solid (37.2 mg,0.083mmol,83% yield), dr value 97:3.m.p:208.4-210.9℃.[α]_D ²⁰＝131(c＝0.2,EtOH).¹H NMR(400MHz,DMSO)δ7.35(d,J＝10.2,1H),6.20(d,J＝10.2,1H),6.12(s,1H),5.87(s,1H),5.04–4.79(m,2H),3.22(dd,J＝10.8,6.9,1H),2.64(t,J＝10.8,1H),2.48–1.76(m,9H),1.51(s,1H),1.50(s,3H),1.06(t,J＝6.7,4H),1.00(d,J＝6.4,3H),0.69(s,3H).¹³C NMR(101MHz,DMSO)δ206.5(d,J＝27.4Hz),205.7,185.3,173.7,164.7,152.0,129.6,126.1,100.0(d,J＝182.4Hz),87.4,69.6,52.4,47.9,47.5,46.5(d,J＝23.1Hz),42.6,37.8(d,J＝20.7Hz),34.1,31.0,27.4,27.0,21.7(d,J＝5.8Hz),19.8,15.4,9.4.IR(cm^-1):3252,2927,1749,1732,1716,1660,1614;HRMS(ESI)m/z calcd for C₂₅H₃₂FO₆,[M+H]⁺＝447.2177,found:447.2173.

Example 12

PhSiH ₃ (21.6 mg,0.2 mmol) was dissolved in ethanol (0.5 mL) and the resulting solution was added dropwise to a solution of the compound pregna-16-methyl-21-chloro-9α -fluoro-1, 4, 16-triene-3, 11, 20-dione (39.0 mg,0.1 mmol) and cobalt triacetylacetonate (1.1 mg, 0.003mmol) in ethanol (0.5 mL) at 0deg.C under O ₂. After the completion of the dropwise addition, the mixture was stirred at room temperature under O ₂ for 12 hours. After the reaction was completed, triethyl phosphite (16.6 mg,0.1 mmol) was added thereto, and stirring at room temperature was continued for 20 minutes. Then 30mL of water was added, the organic phases were extracted with ethyl acetate (3X 30 mL), and the combined organic phases were washed with 30mL of saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and column chromatography (gradient: 0.fwdarw.50% EA in PE) was used to isolate the product clobetasol (37.1 mg,0.091mmol,91% yield) as a white solid. dr is 98:2.m.p:207.3-208.9℃.[α]_D ²⁰＝169(c＝0.2,EtOH).¹H NMR(400MHz,DMSO)δ7.33(d,J＝10.2,1H),6.19(d,J＝10.1,1H),6.12(s,1H),5.92(s,1H),4.68(dd,J＝51.3,17.3,2H),3.16(dd,J＝11.1,6.8,1H),2.70–2.56(m,1H),2.49–2.23(m,4H),2.03(t,J＝13.7,2H),1.94–1.77(m,1H),1.51(s,1H),1.50(s,3H),1.07(dd,J＝20.0,10.9,1H),0.98(d,J＝6.7,3H),0.79(s,3H).¹³C NMR(101MHz,DMSO)δ206.5(d,J＝27.5Hz),203.4,185.3,164.7,152.0,129.7,126.0,100.0(d,J＝182.5Hz),88.2,52.2,51.4,48.3,47.0,46.4(d,J＝23.1Hz),42.7,37.7(d,J＝20.6Hz),34.0,30.9,27.3,21.7(d,J＝5.8Hz),19.8,15.8.IR(cm^-1):3273,2956,1724,1662,1615,1602;HRMS(ESI)m/z calcd for C₂₂H₂₇ClFO₄,[M+H]⁺＝409.1576,found:409.1571.

Example 13

Synthesis of pregna-16 beta-methyl-17 alpha-hydroxy-21-acetoxy-9 beta, 11 beta-epoxy-1, 4-diene-3, 20-dione from pregna-16-methyl-21-acetoxy-9 beta, 11 beta-epoxy-1, 4, 16-triene-3, 20-dione (39.8 mg,0.1 mmol) was synthesized as in example 1. White solid (36.0 mg,0.087mmol,87% yield), dr value was 99:1.m.p:224.4-225.9℃.[α]_D ²⁵＝86.0(c＝0.5,1,4-dioxane).¹H NMR(400MHz,CDCl₃)δ6.65(1H,d,J＝10.1),6.19(1H,d,J＝10.1),6.14(1H,s),4.92(2H,dd,J＝81.9,17.7),3.21(1H,s),2.77-2.59(1H,m),2.58-2.39(2H,m),2.37-2.21(4H,m),2.17(3H,s),2.16-2.02(2H,m),1.84(1H,d,J＝14.7),1.66(1H,td,J＝11.8,5.4),1.49(1H,s),1.45(3H,s),1.12(3H,d,J＝6.4),0.95(3H,s).¹³C NMR(100MHz,CDCl₃)δ204.9,186.5,170.9,166.1,153.1,127.7,124.7,88.5,69.5,65.8,62.8,50.6,48.2,47.4,44.3,35.9,33.8,30.9,30.6,29.5,23.6,20.7,20.0,17.5.IR(cm^-1):3295,2937,1749,1728,1659,1615,1401,1259,1228,1049,887;HRMS(ESI)m/z calcd for C₂₄H₃₀NaO₆,[M+Na]⁺＝437.1935,found:437.1938.

Example 14

Synthesis of beclomethasone was performed as in reference example 4, starting from pregna-16-methyl-21-hydroxy-9α -chloro-11β -hydroxy-1, 4, 16-triene-3, 20-dione (39.4 mg,0.1 mmol). White solid (34.2 mg,0.084mmol,84% yield), dr value 85:15.m.p:184.2-185.6℃.[α]_D ²⁵＝131.7(c＝0.2,1,4-dioxane).¹H NMR(400MHz,DMSO-d₆)δ7.29(1H,d,J＝10.1),6.22(1H,d,J＝9.8),5.98(1H,s),5.41(1H,t,J＝10.1),5.16(1H,s),4.55-4.02(4H,m),2.81-2.55(2H,m),2.39(2H,dd,J＝33.5,12.2),2.28-2.01(2H,m),2.01-1.72(2H,m),1.61(3H,s),1.57-1.44(1H,m),1.27(1H,d,J＝13.4),1.18-1.07(1H,m),1.04(3H,d,J＝7.2),0.98(3H,s).¹³C NMR(100MHz,DMSO-d₆)δ212.8,185.7,167.2,153.3,129.1,124.5,88.2,86.0,74.7,68.2,50.2,48.9,47.2,43.3,36.1,34.6,34.4,30.4,28.1,24.9,20.4,18.1.IR(cm^-1):3430,2931,2908,1707,1659,1614,1615,1039;HRMS(ESI)m/z calcd for C₂₂H₃₀ClO₅,[M+H]⁺＝409.1776,found:409.1785.

Example 15

Diflorasone was synthesized in the same manner as in example 1 using pregna-16-methyl-6α,9α -difluoro-11β, 21-dihydroxy-1, 4, 16-triene-3, 20-dione (39.2 mg,0.1 mmol) as a starting material. White solid (35.7 mg,0.087mmol,87% yield), dr value 94:6.m.p:231.8-233.6℃.[α]_D ²⁰＝100(c＝0.2,EtOH).¹H NMR(400MHz,DMSO)δ7.26(d,J＝10.0,1H),6.25(dd,J＝24.0,8.9,1H),6.11(s,1H),5.64(d,J＝46.5,1H),5.33(s,1H),5.25–5.07(m,1H),4.50(d,J＝4.4,1H),4.38(dd,J＝19.4,4.5,1H),4.14(d,J＝13.1,2H),2.75–2.52(m,1H),2.28(s,1H),2.02(dd,J＝43.8,19.3,4H),1.52(d,J＝6.8,1H),1.50(s,3H),1.33(d,J＝13.6,1H),1.09(d,J＝16.9,1H),1.04(d,J＝6.5,3H),0.96(s,3H).¹³C NMR(101MHz,DMSO)δ212.7,184.9,163.5(d,J＝13.4Hz),152.5,129.5,119.9(d,J＝12.8Hz),100.6(d,J＝176.7Hz),87.4(d,J＝180.2Hz),88.1,71.0(d,J＝36.0Hz),68.2,48.7(d,J＝3.6Hz),48.4,47.2,43.1,36.5,34.7,34.6(d,J＝18.7Hz),32.3(dd,J＝18.9,11.2Hz),23.3(d,J＝5.2Hz),20.3,17.4.IR(cm^-1):3501,3418,2988,2965,2951,2932,2911,1711,1666,1622,1061,904;HRMS(ESI)m/z calcd for C₂₂H₂₉F₂O₆,[M+H]⁺＝411.1978,found:411.1971.

Example 16

Diflularsone-21-acetate was synthesized in the same manner as in example 1 using pregna-16-methyl-21-acetoxy-6α,9α -difluoro-11β -hydroxy-1, 4, 16-triene-3, 20-dione (130.2 mg,0.3 mmol) as a starting material. White solid (116.6 mg,0.258mmol,86% yield), dr value 95:5.m.p:141.5-143.9℃.[α]_D ²⁰＝108(c＝0.2,EtOH).¹H NMR(400MHz,DMSO)δ7.26(d,J＝10.0,1H),6.29(d,J＝10.0,1H),6.10(s,1H),5.64(d,J＝46.1,1H),5.37(d,J＝34.2,2H),4.89(dd,J＝67.8,17.7,2H),4.14(s,1H),2.55(d,J＝23.6,1H),2.28(s,1H),2.18–1.86(m,7H),1.51(s,1H),1.46(d,J＝22.8,4H),1.06(d,J＝11.6,1H),1.01(d,J＝6.6,3H),0.91(s,3H).¹³C NMR(101MHz,DMSO)δ205.6,184.9,170.2,163.5(d,J＝14.3Hz),152.5,129.5,119.8(d,J＝12.8Hz),100.6(d,J＝176.6Hz),88.3,87.4(d,J＝177.2Hz),70.8(d,J＝35.7Hz),69.7,48.9,48.5(dd,J＝22.2,3.7Hz),47.3,43.1,36.3,34.8,34.6(d,J＝18.3Hz),32.3(dd,J＝18.7,11.3Hz),23.3(d,J＝5.2Hz),20.9,20.2,17.0.IR(cm^-1):3446,2958,1717,1667,1623,1235,1065;HRMS(ESI)m/z calcd for C₂₄H₃₁ F₂O₆,[M+H]⁺＝453.2083,found:453.2078.

Example 17

Diflularsone-21-propionate was synthesized in the same manner as in example 1, starting from pregna-16-methyl-21-propionyloxy-6α,9α -difluoro-11β -hydroxy-1, 4, 16-triene-3, 20-dione (44.8 mg,0.1 mmol). White solid (40.1 mg,0.086mmol,86% yield), dr value was 93:7.m.p:174.2-177.3℃.[α]_D ²⁰＝104(c＝0.2,EtOH).¹H NMR(400MHz,DMSO)δ7.26(d,J＝10.1,1H),6.29(d,J＝9.9,1H),6.11(s,1H),5.81-5.47(m,1H),5.46–5.21(m,2H),4.90(dd,J＝58.0,17.7,2H),4.15(s,1H),2.76–2.53(m,1H),2.40(dd,J＝14.5,7.1,2H),2.28(s,1H),2.22–1.85(m,4H),1.52(d,J＝7.9,1H),1.49(s,3H),1.45(s,1H),1.17–0.97(m,7H),0.92(s,3H).¹³C NMR(101MHz,DMSO)δ205.6,184.9,173.5,163.5(d,J＝13.8Hz),152.4,129.5,119.8(d,J＝12.9Hz),100.6(d,J＝176.9Hz),88.3,87.4(d,J＝180.5Hz),70.8(d,J＝35.6Hz),69.6,48.9,48.6(dd,J＝22.3,3.8Hz),47.3,43.1,36.3,34.8,34.6(d,J＝18.2Hz),32.3(dd,J＝18.4,11.6Hz),27.1,23.3(d,J＝5.3Hz),20.2,17.0,9.5.IR(cm^-1):3339,2988,2965,2942,1751,1727,1664,1616,1603,1171,1071;HRMS(ESI)m/z calcd for C₂₅H₃₃F₂O₆,[M+H]⁺＝467.2240,found:467.2243.

Example 18

Synthesis of pregna-16 beta-methyl-17 alpha-hydroxy-21-acetoxy-1, 4,9 (11) -triene-3, 20-dione Using pregna-16-methyl-21-acetoxy-4, 9 (11), 16-triene-3, 20-dione (38.2 mg,0.1 mmol) as a raw material was performed in the same manner as in reference example 1. White solid (33.2 mg,0.083mmol,83% yield), dr value 99:1m.p:207.7-209.0℃.[α]_D ²⁰＝123.5(c＝0.2,CH₂Cl₂).¹H NMR(400MHz,CDCl₃)δ＝5.67(s,1H),5.47(d,J＝5.6,1H),4.89(q,J＝17.8,2H),2.67–2.23(m,6H),2.23–2.13(m,2H),2.11(s,3H),2.09–1.91(m,4H),1.74(dd,J＝17.1,5.0,1H),1.67–1.56(m,1H),1.26(s,3H),1.22–1.11(m,1H),1.09(d,J＝7.0,3H),1.07–0.99(m,1H),0.70(s,3H).¹³C NMR(101MHz,CDCl₃)δ205.1,199.8,170.7,170.2,143.6,123.9,119.0,89.4,69.4,49.4,48.4,46.6,41.0,37.2,36.0,34.3,33.8,32.9,32.4,26.1,20.7,19.7,14.4.IR(cm^-1):3501,3234,2988,2959,2936,2923,2862,1755,1723,1635,1614,1371,1258,1236,1082,1054;HRMS(ESI)m/z calcd for C₂₄H₃₃O₅,[M+H]⁺＝401.2323,found:401.2320.

Example 19

The synthesis of pregna-16 beta-methyl-17 alpha-hydroxy-21-hydroxy-1, 4,9 (11) -triene-3, 20-dione was synthesized by the method of reference example 1, mainly using pregna-16-methyl-21-hydroxy-4, 9 (11), 16-triene-3, 20-dione (34.0 mg,0.1 mmol) as a raw material. White solid (18.6 mg,0.052mmol,52% yield), dr value 97:3m.p:163.0-165.2℃.[α]_D ²⁰＝87.0(c＝0.2,CH₂Cl₂).¹H NMR(400MHz,CDCl₃)δ＝5.76(s,1H),5.54(d,J＝5.6,1H),4.64–4.29(m,2H),3.26(t,J＝4.8,1H),2.68–2.54(m,2H),2.51–2.47(m,1H),2.38(d,J＝14.4,1H),2.27(ddd,J＝11.0,10.1,6.3,2H),2.20–2.10(m,4H),2.06–1.98(m,1H),1.80–1.73(m,1H),1.64(dd,J＝16.8,5.8,1H),1.36(s,3H),1.34–1.31(m,1H),1.16(d,J＝7.2,3H),1.03–0.86(m,1H),0.83(s,3H).¹³C NMR(101MHz,CDCl₃)δ212.1,199.5,169.8,143.8,124.0,118.7,89.2,68.6,49.5,48.6,46.9,41.0,37.2,35.9,34.3,33.8,33.1,32.9,32.4,26.1,19.7,14.8.IR(cm^-1):3480,3256,2988,2961,2938,2923,2906,2863,1652;HRMS(ESI)m/z calcd for C₂₂H₂₉O₄,[M+H]⁺＝359.2217,found:359.2220.

Example 20

The synthesis of pregna-16 beta-methyl-17 alpha-hydroxy-21-propionyloxy-1, 4,9 (11) -triene-3, 20-dione was synthesized by the method of reference example 1, mainly using pregna-16-methyl-21-propionyloxy-4, 9 (11), 16-triene-3, 20-dione (39.6 mg,0.1 mmol) as a raw material. White solid (35.2 mg,0.085mmol,85% yield), dr value was 98:2m.p:176.1-178.2℃.[α]_D ²⁰＝122.0(c＝0.2,CH₂Cl₂).¹H NMR(400MHz,CDCl₃)δ5.67(s,1H),5.47(d,J＝5.6,1H),5.03–4.74(m,2H),2.69–2.22(m,8H),2.22–1.85(m,7H),1.84–1.73(m,1H),1.67–1.53(m,1H),1.26(s,3H),1.15–1.07(m,6H),1.06–0.99(m,1H),0.70(s,3H).¹³C NMR(101MHz,CDCl₃)δ205.2,199.8,174.2,170.2,143.6,123.9,119.1,89.4,69.3,49.4,48.3,46.6,41.0,37.3,36.0,34.3,33.8,32.9,32.9,32.4,27.2,26.1,19.7,14.4,9.0.IR(cm^-1):3502,3445,2958,2935,1724,1670,1653,1646;HRMS(ESI)m/z calcd for C₂₅H₃₅O₅,[M+H]⁺＝415.2479,found:415.2482.

Example 21

The synthesis of pregna-16 beta-methyl-17 alpha-hydroxy-9 beta, 11 beta-epoxy-21-hydroxy-1, 4-diene-3, 20-dione was synthesized by the method of reference example 1, mainly using pregna-16-methyl-21-hydroxy-9 beta, 11 beta-epoxy-4, 16-diene-3, 20-dione (35.6 mg,0.1 mmol) as a raw material. White solid (17.2 mg,0.046mmol,46% yield), dr value 98:2m.p:184.9-186.9℃.[α]_D ²⁰＝28.0(c＝0.2,CH₂Cl₂).¹H NMR(400MHz,CDCl₃)δ5.71(s,1H),4.34(dd,J＝88.5,20.0,2H),3.36(s,1H),2.75(s,1H),2.51–2.36(m,3H),2.35–2.21(m,3H),2.19–2.07(m,2H),2.07–1.97(m,1H),1.93–1.81(m,1H),1.75–1.46(m,4H),1.37(s,3H),1.30–1.11(m,1H),1.06(d,J＝7.2,3H),1.04–0.98(m,1H),0.92(s,3H).¹³C NMR(101MHz,CDCl₃)δ211.7,199.3,170.8,124.1,88.7,68.6,65.3,60.2,48.6,48.3,44.8,39.5,35.8,34.6,33.9,31.3,30.9,29.4,26.0,23.7,20.0,17.5.IR(cm^-1):3355,2944,1716,1652,1646,1617;HRMS(ESI)m/z calcd for C₂₂H₃₁O₅,[M+H]⁺＝375.2166,found:375.2172.

Example 22

The synthesis of pregna-16 beta-methyl-17 alpha-hydroxy-9 beta, 11 beta-epoxy-21-acetoxy-1, 4-diene-3, 20-dione was synthesized by the method of reference example 1 mainly using pregna-16-methyl-21-acetoxy-9 beta, 11 beta-epoxy-4, 16-diene-3, 20-dione (39.8 mg,0.1 mmol) as raw material. White solid (34.5 mg,0.083mmol,83% yield), dr value 99:1m.p:182.8-183.4℃.[α]_D ²⁰＝60.0(c＝0.2,CH₂Cl₂).¹H NMR(400MHz,CDCl₃)δ5.79(s,1H),4.93(dd,J＝81.2,17.7,2H),3.45(s,1H),2.69(s,1H),2.58–2.44(m,3H),2.42–2.28(m,3H),2.28–2.20(m,1H),2.19(s,3H),2.17–2.03(m,2H),1.95–1.86(m,2H),1.82–1.71(m,1H),1.70–1.54(m,2H),1.44(s,3H),1.15(d,J＝7.2,3H),1.11–1.03(m,1H),0.97(s,3H).¹³C NMR(101MHz,CDCl₃)δ205.5,199.2,170.7,170.7,124.2,89.0,69.3,65.1,60.3,48.7,48.1,44.6,39.5,35.8,34.6,33.9,31.4,30.8,29.4,26.0,23.7,20.7,20.0,17.2.IR(cm^-1):3487,2981,2957,2899,2868,1705,1698,1669,1653,1270,1239;HRMS(ESI)m/z calcd for C₂₄H₃₃O₆,[M+H]⁺＝417.2272,found:417.2277.

Example 23

The synthesis of pregna-16 beta-methyl-17 alpha-hydroxy-9 beta, 11 beta-epoxy-21-propionyloxy-1, 4-diene-3, 20-dione was synthesized by the method of reference example 1, mainly using pregna-16-methyl-21-propionyloxy-9 beta, 11 beta-epoxy-4, 16-diene-3, 20-dione (41.6 mg,0.1 mmol) as raw material. White solid (35.3 mg,0.082mmol,82% yield), dr value 99:1m.p:170.4-172.5℃.[α]_D ²⁰＝41.0(c＝0.2,CH₂Cl₂).¹H NMR(400MHz,CDCl₃)δ5.80(s,1H),4.94(dd,J＝69.2,17.4,2H),3.45(s,1H),2.67(s,1H),2.61–2.43(m,5H),2.43–2.29(m,3H),2.14(d,J＝37.2,3H),1.92(d,J＝14.2,2H),1.82–1.71(m,1H),1.70–1.55(m,2H),1.45(s,3H),1.26–1.11(m,6H),1.09(d,J＝9.2,1H),0.99(s,3H).¹³C NMR(101MHz,CDCl₃)δ204.5,199.2,174.2,170.6,124.2,89.0,69.1,65.1,60.3,48.7,48.1,44.6,39.5,35.8,34.6,33.9,31.4,30.8,29.4,27.2,26.0,23.7,20.0,17.2,9.0.IR(cm^-1):3502,2980,2958,2925,1754,1724,1652,1646,1635,1177;HRMS(ESI)m/z calcd for C₂₅H₃₅O₆,[M+H]⁺＝431.2428,found:431.2427.

Claims

1. The preparation method of the 16 beta-methyl-17 alpha-hydroxyglucocorticoid and the analogue (I) thereof is characterized in that a target product 16 beta-methyl-17 alpha-hydroxyglucocorticoid and the analogue (I) thereof are synthesized by one step from a raw material compound 16-methyl-16-en-20-one (II), and the synthetic route is shown as the following formula:

Wherein R ₁ is fluorine or hydrogen, R ₂ is fluorine, chlorine or hydrogen, R ₃ is carbonyl, hydroxyl, hydrogen or C9,10 is epoxy, R ₄ is hydrogen, hydroxyl, acetoxy, propionyloxy, halogen, R ₅ is oxo, hydroxyl, acetoxy, etc., the C1, 2-position is a single bond or a double bond, and the C3, 4-positions are single bonds or double bonds;

the preparation method comprises the following specific steps:

(1) In the presence of oxygen or air, 16-methyl-16-alkene-20-ketone (II) takes a manganese catalyst, an iron catalyst or a cobalt catalyst as a catalyst, takes silicon hydrogen as a hydrogenation reagent, and carries out hydration reaction in an organic solvent;

2. The method of preparation according to claim 1, wherein the catalyst is selected from the group consisting of: manganese tris (2, 6-tetramethyl-3, 5-heptenoate), manganese bis (2, 6-tetramethyl-3, 5-heptenoate), manganese triacetylacetonate, manganese diacetylacetonate, manganese acetate, iron tris (2, 6-tetramethyl-3, 5-heptenoic acid), iron bis (2, 6-tetramethyl-3, 5-heptenoic acid), iron triacetylacetonate, iron diacetylacetonate, iron acetate, cobalt tris (2, 6-tetramethyl-3, 5-heptenoate), cobalt bis (2, 6-tetramethyl-3, 5-heptenoate), cobalt triacetylacetonate, cobalt diacetylacetonate, cobalt acetate.

3. The method according to claim 1, wherein the hydrogenation reagent is selected from the group consisting of phenylsilane, diphenylsilane, triphenylsilane, triethylsilane, diethylsilane.

4. The method according to claim 1, wherein the organic solvent is an alcohol or a mixed solvent of a monohalogenated or polyhalogenated alkane and the alcohol.

5. The method according to claim 4, wherein the alcohol is methanol, ethanol or isopropanol; the polyhalogenated alkane is dichloromethane, chloroform or dichloroethane.

6. The process for preparing the catalyst according to claim 1 to 5zhiyi, wherein the molar ratio of the starting compound (II), the catalyst, the hydrogenation reagent and the reducing agent is 1 (0.03 to 0.1): 1 to 2): 0.5 to 1, the reaction temperature is 0 to 25℃and the reaction time is 6 to 12 hours.