Preparation method and application of 16,17-dihydroxy steroid compounds

Abstract

The present invention provides a preparation method and application of a 16,17-dihydroxy steroid compound, relating to the technical field of chemical synthesis. It includes the following steps: (a) reacting a compound of formula I, a Lewis acid and an azole compound to obtain a compound of formula II; (b) reacting the compound of formula II with a cyclic acyl peroxide and water, and then hydrolyzing under alkaline conditions to obtain a compound of formula III. In the present invention, the Lewis acid and the azole compound are used in the dehydration reaction of the compound of formula I, with simple operation, mild reaction conditions, low energy cost and high safety factor. In the present invention, the cyclic acyl peroxide is used in the oxidation reaction of the compound of formula II, with good atom economy, few side reactions, no excessive impurities introduced into the product, easy to implement and repeat, no heavy metals involved, environmentally friendly, safer, and with good application prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a preparation method and application of a 16,17-dihydroxy steroid compound. Background Art

[0002] Steroid hormone drugs refer to hormone drugs with a steroid structure in the molecular structure. They are widely used clinically and mainly include two categories: adrenal cortical hormones and sex hormones. Among them, adrenal cortical hormones have various pharmacological effects such as anti-inflammatory, anti-allergic, immunosuppressive, enhancing stress response, anti-endotoxin, and anti-shock. Clinically, they can be used to treat many diseases and are an important class of drugs indispensable in clinical practice, such as fluocinonide and nide corticosteroid drugs. Sex hormones include progestogens, estrogens, and androgens. For example, megestrol acetate is a highly effective progestogen and is mainly used for short-term and long-term contraception clinically.

[0003] Steroid compounds with a 16,17-dihydroxy structure are an important intermediate and can be used to prepare fluocinonide acetate, fluocinonide, nide drugs, and megestrol acetate, etc. Currently reported methods for preparing such compounds mainly involve dehydration and oxidation reactions of substrates containing a 17-hydroxy group. In the prior art, generally, a substrate containing a 17-hydroxy group is dehydrated under the action of acetate, phosphorus oxychloride, acidic ionic liquid, or gemini surfactant to obtain a dehydrated product with a 16,17-double bond. The dehydrated product is oxidized with potassium permanganate, hydrogen peroxide, or osmium-based catalyst to introduce double hydroxyl groups, obtaining a 16,17-dihydroxy steroid compound. In the existing dehydration reactions, acetate, acidic ionic liquid, or gemini surfactant all need to react at a relatively high temperature (above 100 °C), which is relatively high in energy cost for industrial production; while phosphorus oxychloride may cause poisoning if not operated properly. In the oxidation reaction, while potassium permanganate oxidizes the 16,17-double bond, it will also cause the 11-hydroxy group in the molecule to be oxidized, resulting in many impurities and difficult purification; hydrogen peroxide oxidation is not easy to achieve and repeat; and osmium-based catalysts use heavy metals, with poor application prospects.

[0004] In view of this, the present invention is specifically proposed. Summary of the Invention

[0005] The main object of the present invention is to provide a preparation method and application of a 16,17-dihydroxy steroid compound, in order to at least partially solve at least one of the above technical problems.

[0006] As the first aspect of the present invention, the present invention provides a preparation method of a 16,17-dihydroxy steroid compound, including the following steps:

[0007] (b) The compound of formula II reacts with cyclic acyl peroxide and water, and then undergoes hydrolysis under alkaline conditions to obtain the compound of formula III; the reaction formula is as follows:

[0008]

[0009] Among them, R1, R2, R3 and R4 shown in the structural formulas of the compound of formula II and the compound of formula III are independently selected from each other, and:

[0010] R1 = H, methyl or halogen, and halogen = F, Cl, Br or I;

[0011] R2 = H or halogen, and halogen = F, Cl, Br or I;

[0012] R3 = H or hydroxyl;

[0013] R4 = H, OH or OCOR5, and R5 is an alkyl group with six or fewer carbon atoms;

[0014] The dotted line is a single bond or a double bond.

[0015] For the preparation method of the 16,17-dihydroxy steroid compound provided by the present invention, the compound of formula II reacts with cyclic acyl peroxide and water, and then undergoes hydrolysis under alkaline conditions to obtain the compound of formula III. The present invention uses cyclic acyl peroxide in the oxidation reaction of the compound of formula II. Compared with potassium permanganate, hydrogen peroxide or osmium-based catalysts in the prior art, it has good atom economy, fewer side reactions, will not introduce too many impurities into the product, is easy to implement and repeat, does not involve heavy metals, is green and environmentally friendly, safer, and has good application prospects.

[0016] Furthermore, R1, R2, R3 and R4 shown in the structural formulas of the compound of formula II and the compound of formula III are independently selected from each other, and:

[0017] R1 = H or F;

[0018] R2 = H or F;

[0019] R3 = H or hydroxyl;

[0020] R4 = H, OH or OCOCH3;

[0021] The dotted line is a single bond or a double bond.

[0022] Furthermore, it includes the following steps:

[0023] (b) Add the compound of formula II, cyclic acyl peroxide, water and a phase transfer catalyst to a second organic solvent for reaction, and then undergo hydrolysis under alkaline conditions to obtain the compound of formula III.

[0024] Furthermore, it includes the following steps:

[0025] (b) Add the compound of formula II, cyclic acyl peroxide, water and a phase transfer catalyst to a second organic solvent, react at 0 - 30 °C, and then hydrolyze under alkaline conditions at 0 - 60 °C to obtain the compound of formula III.

[0026] In the present invention, in the step (b), the typical but non-limiting reaction temperatures can be, for example, 0 °C, 1 °C, 2 °C, 3 °C, 4 °C, 5 °C, 6 °C, 7 °C, 8 °C, 9 °C, 10 °C, 11 °C, 12 °C, 13 °C, 14 °C, 15 °C, 16 °C, 17 °C, 18 °C, 19 °C, 20 °C, 21 °C, 22 °C, 23 °C, 24 °C, 25 °C, 26 °C, 27 °C, 28 °C, 29 °C or 30 °C.

[0027] In the present invention, in the step (b), the typical but non-limiting hydrolysis temperatures can be, for example, 0 °C, 2 °C, 4 °C, 6 °C, 8 °C, 10 °C, 12 °C, 14 °C, 16 °C, 18 °C, 20 °C, 22 °C, 24 °C, 26 °C, 28 °C, 30 °C, 32 °C, 34 °C, 36 °C, 38 °C, 40 °C, 42 °C, 44 °C, 46 °C, 48 °C, 50 °C, 52 °C, 54 °C, 56 °C, 58 °C or 60 °C.

[0028] Furthermore, it includes the following steps:

[0029] (b) Add the compound of formula II, cyclic acyl peroxide, water and a phase transfer catalyst to a second organic solvent, react at 0 - 10 °C, and then hydrolyze under alkaline conditions at 40 - 60 °C to obtain the compound of formula III.

[0030] Furthermore, in the step (b), the cyclic acyl peroxide is selected from one or a combination of several of 5,6 - dioxaspiro[2.4]heptane - 4,7 - dione, 6,7 - dioxaspiro[3.4]octane - 5,8 - dione, 2,3 - dioxaspiro[4.4]nonane - 1,4 - dione or (1S,4R)-spiro[bicyclo[2.2.1]heptane - 2,4'-[1,2]dioxolane]-3',5'-dione.

[0031] Furthermore, in the step (b), the cyclic acyl peroxide is selected from 5,6 - dioxaspiro[2.4]heptane - 4,7 - dione and / or 6,7 - dioxaspiro[3.4]octane - 5,8 - dione.

[0032] Furthermore, in the step (b), the phase transfer catalyst is selected from one or a combination of several of tetramethylammonium bromide, tetrapropylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, triethylbenzylammonium bromide or triethylhexylammonium bromide.

[0033] Both the compound of formula II and the cyclic acyl peroxide in the present invention can be dissolved in the second organic solvent, while water is insoluble in the second organic solvent. The phase transfer catalyst is used in the present invention to promote the full contact of water with the compound of formula II and the cyclic acyl peroxide in the second organic solvent, thereby increasing the reaction rate.

[0034] Further, in the step (b), the hydrolysis is carried out using a base reagent, and the base reagent is selected from one or a combination of several of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate.

[0035] Further, in the step (b), the molar ratio of the cyclic acyl peroxide, water and the compound of formula II is (1.1 - 1.5):(1.1 - 1.5):1.

[0036] In the present invention, in the step (b), typical but non-limiting molar ratios of the cyclic acyl peroxide, water and the compound of formula II can be, for example, 1.1:1.1:1, 1.1:1.2:1, 1.1:1.3:1, 1.1:1.4:1, 1.1:1.5:1, 1.2:1.1:1, 1.2:1.2:1, 1.2:1.3:1, 1.2:1.4:1, 1.2:1.5:1, 1.3:1.1:1, 1.3:1.2:1, 1.3:1.3:1, 1.3:1.4:1, 1.3:1.5:1, 1.4:1.1:1, 1.4:1.2:1, 1.4:1.3:1, 1.4:1.4:1, 1.4:1.5:1, 1.5:1.1:1, 1.5:1.2:1, 1.5:1.3:1, 1.5:1.4:1 or 1.5:1.5:1.

[0037] Further, in the step (b), the second organic solvent is selected from one or a combination of several of chloroform, toluene, 2-methyltetrahydrofuran or dichloromethane.

[0038] Further, the following steps are also included:

[0039] (a) Reacting a compound of formula I, a Lewis acid and a nitrogenazole compound to obtain a compound of formula II;

[0040]

[0041] Wherein, R1, R2, R3 and R4 shown in the structural formulas of the compound of formula I and the compound of formula II are independently selected from each other, and:

[0042] R1 = H, methyl or halogen, halogen = F, Cl, Br or I;

[0043] R2 = H or halogen, halogen = F, Cl, Br or I;

[0044] R3 = H or hydroxyl group;

[0045] R4 = H, OH or OCOR5, where R5 is an alkyl group with six or fewer carbon atoms;

[0046] The dotted line represents a single bond or a double bond.

[0047] Furthermore, R1, R2, R3, and R4 shown in the structural formulas of the compound of formula I and the compound of formula II are independently selected from each other, and:

[0048] R1 = H or F;

[0049] R2 = H or F;

[0050] R3 = H or hydroxyl group;

[0051] R4 = H, OH or OCOCH3;

[0052] The dotted line represents a single bond or a double bond.

[0053] The present invention uses the compound of formula I as the starting material and reacts it under the action of a Lewis acid and an azole compound to obtain the compound of formula II. The present invention uses the Lewis acid and the azole compound in the dehydration reaction of the compound of formula I. Compared with the acetate or phosphorus oxychloride or acidic ionic liquid or gemini surfactant in the prior art, the operation is simple, the reaction conditions are mild, the energy cost is low, and the safety factor is high.

[0054] Furthermore, it includes the following steps:

[0055] (a) Add the compound of formula I, the Lewis acid, and the azole compound to a first organic solvent and react at 0 - 80 °C to obtain the compound of formula II.

[0056] In the present invention, in step (a), the typical but non-limiting temperatures of the reaction can be, for example, 0 °C, 2 °C, 4 °C, 6 °C, 8 °C, 10 °C, 12 °C, 14 °C, 16 °C, 18 °C, 20 °C, 22 °C, 24 °C, 26 °C, 28 °C, 30 °C, 32 °C, 34 °C, 36 °C, 38 °C, 40 °C, 42 °C, 44 °C, 46 °C, 48 °C, 50 °C, 52 °C, 54 °C, 56 °C, 58 °C, 60 °C, 62 °C, 64 °C, 66 °C, 68 °C, 70 °C, 72 °C, 74 °C, 76 °C, 78 °C or 80 °C.

[0057] Furthermore, it includes the following steps:

[0058] (a) Add the compound of formula I, the Lewis acid, and the azole compound to a first organic solvent and react at 30 - 60 °C to obtain the compound of formula II.

[0059] Further, in the step (a), the azole compound is selected from one or a combination of several of 1-(pyridin-2-yl)-1H-benzo[d][1,2,3]triazole, 1,2,3-benzotriazole, 1,2,4-triazole, 1,2,3-triazole, 1-methylbenzotriazole, 1-(1H-benzo[d][1,2,3]triazol-1-yl)-N,N-dimethylmethanamine, 2-(1H-tetrazol-1-yl)pyridine, 1-(4-aminobenzyl)imidazole, 4-azabenzimidazole, (5-amino-1H-[1,2,4]triazol-3-yl)-methanol, or 2-(1H-benzo[d][1,2,3]triazol-1-yl)ethanol.

[0060] Further, in the step (a), the azole compound is selected from one or a combination of several of 1-(pyridin-2-yl)-1H-benzo[d][1,2,3]triazole, 1,2,3-benzotriazole, 1-methylbenzotriazole, 1-(1H-benzo[d][1,2,3]triazol-1-yl)-N,N-dimethylmethanamine, 2-(1H-tetrazol-1-yl)pyridine, 1-(4-aminobenzyl)imidazole.

[0061] Further, in the step (a), the azole compound is selected from 1,2,3-benzotriazole.

[0062] Further, in the step (a), the Lewis acid is selected from one or a combination of several of aluminum chloride, iron(III) chloride, iron(III) bromide, iron(III) acetylacetonate, iron(II) chloride, cobalt(II) chloride, nickel(II) chloride, iron(III) acetate, zinc chloride, or copper(II) chloride.

[0063] Further, in the step (a), the Lewis acid is selected from aluminum chloride.

[0064] Further, in the step (a), the molar ratio of the azole compound, the Lewis acid, and the compound of formula I is (0.3 - 0.8):(0.1 - 0.5):1.

[0065] In the present invention, in the step (a), typical but non-limiting molar ratios of the azole compound, the Lewis acid, and the compound of formula I may be, for example, 0.3:0.1:1, 0.3:0.2:1, 0.3:0.3:1, 0.3:0.4:1, 0.4:0.5:1, 0.4:0.1:1, 0.4:0.2:1, 0.4:0.3:1, 0.4:0.4:1, 0.4:0.5:1, 0.5:0.1:1, 0.5:0.2:1, 0.5:0.3:1, 0.5:0.4:1, 0.5:0.5:1, 0.6:0.1:1, 0.6:0.2:1, 0.6:0.3:1, 0.6:0.4:1, 0.6:0.5:1, 0.7:0.1:1, 0.7:0.2:1, 0.7:0.3:1, 0.7:0.4:1, 0.7:0.5:1, 0.8:0.1:1, 0.8:0.2:1, 0.8:0.3:1, 0.8:0.4:1, or 0.8:0.5:1.

[0066] Further, in the step (a), the first organic solvent is selected from one or a combination of alcohol solvents having 1 to 4 carbon atoms, dichloromethane, acetone, tetrahydrofuran, toluene, chloroform, or acetonitrile.

[0067] Further, in the step (a), the alcohol solvent having 1 to 4 carbon atoms is selected from methanol, ethanol, isopropanol, or n-butanol.

[0068] As a second aspect of the present invention, the present invention also provides an application of the above preparation method in the preparation of corticosteroid drugs.

[0069] Further, the corticosteroid drugs are selected from triamcinolone acetonide, budesonide, ciclesonide, fluocinolone acetonide, fluocinonide acetate, or progesterone benzoate.

[0070] The corticosteroid drugs that can be used for preparation in the present invention include but are not limited to the above drugs.

[0071] Compared with the prior art, the present invention has the following beneficial effects:

[0072] (1) The preparation method of the 16,17-dihydroxy steroid compound provided by the present invention uses the compound of formula I as the starting material, reacts under the action of a Lewis acid and an azole compound to obtain the compound of formula II; the compound of formula II reacts with a cyclic acyl peroxide and water, and then undergoes hydrolysis under alkaline conditions to obtain the compound of formula III. The present invention uses a Lewis acid and an azole compound in the dehydration reaction of the compound of formula I. Compared with the acetate or phosphorus oxychloride or acidic ionic liquid or gemini surfactant in the prior art, the operation is simple, the reaction conditions are mild, the energy cost is low, and the safety factor is high. The present invention uses a cyclic acyl peroxide in the oxidation reaction of the compound of formula II. Compared with potassium permanganate, hydrogen peroxide or osmium-based catalysts in the prior art, the atom economy is good, the side reactions are few, too many impurities will not be introduced into the product, it is easy to implement and repeat, there is no heavy metal participation, it is green and environmentally friendly, safer, and has good application prospects.

[0073] (2) The present invention applies the above preparation method to the preparation of corticosteroid drugs, which can greatly shorten the reaction steps, save production costs, and is conducive to industrial production. Detailed implementation mode

[0074] The following will describe the implementation scheme of the present invention in detail with reference to the examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. Those not specified in the examples are carried out under conventional conditions. Those reagents or instruments not specified by the manufacturer can be obtained as conventional products through commercial purchase.

[0075] To help a clearer understanding of the present invention, the technical solutions of the present invention will be further described below with reference to the examples.

[0076] Preparation of the compound of formula II

[0077] Example 1

[0078]

[0079] Example 1-1

[0080] At room temperature, 1.1 g of aluminum chloride, 1.7 g of 1,2,3-benzotriazole, 10 g of the compound of formula I-1 and 200 mL of dichloromethane were successively added to a reaction flask, and the reaction was carried out at 40 °C with heat preservation. When TLC showed no compound of formula I-1, the insoluble matter was filtered off, the organic solvent was concentrated under reduced pressure, and refined with acetone to obtain 8.3 g of the compound of formula II-1, with a yield of 86.6% and an HPLC purity of 97.8%.

[0081] Example 1-2

[0082] At room temperature, 2.0 g of iron(III) acetylacetonate, 2.2 g of 1-(pyridin-2-yl)-1H-benzo[d][1,2,3]triazole, 10 g of the compound of formula I-1 and 300 mL of acetone were successively added to a reaction flask. The mixture was kept at 30 °C for reaction. When TLC showed no compound of formula I-1, the insoluble substances were filtered off. The organic solvent was concentrated under reduced pressure and purified with acetone to obtain 8.2 g of the compound of formula II-1, with a yield of 85.5% and an HPLC purity of 97.5%.

[0083] Example 1-3

[0084] At room temperature, 1.8 g of iron(III) chloride, 2.2 g of 1-methylbenzotriazole, 10 g of the compound of formula I-1 and 100 mL of ethanol were successively added to a reaction flask. The mixture was kept at 60 °C for reaction. When TLC showed no compound of formula I-1, the insoluble substances were filtered off. The organic solvent was concentrated under reduced pressure and purified with acetone to obtain 8.1 g of the compound of formula II-1, with a yield of 84.5% and an HPLC purity of 97.5%.

[0085] Example 1-4

[0086] At room temperature, 0.4 g of zinc chloride, 1.5 g of 1-(1H-benzo[d][1,2,3]triazol-1-yl)-N,N-dimethylmethanamine, 10 g of the compound of formula I-1 and 150 mL of tetrahydrofuran were successively added to a reaction flask. The mixture was kept at 0 °C for reaction. When TLC showed no compound of formula I-1, the insoluble substances were filtered off. The organic solvent was concentrated under reduced pressure and purified with acetone to obtain 7.5 g of the compound of formula II-1, with a yield of 78.2% and an HPLC purity of 97.1%.

[0087] Example 1-5

[0088] At room temperature, 1.9 g of copper(II) chloride, 1.6 g of 2-(1H-tetrazol-1-yl)pyridine, 1.9 g of 1-(4-aminobenzyl)imidazole, 10 g of the compound of formula I-1 and 250 mL of toluene were successively added to a reaction flask. The mixture was kept at 80 °C for reaction. When TLC showed no compound of formula I-1, the insoluble substances were filtered off. The organic solvent was concentrated under reduced pressure and purified with acetone to obtain 7.8 g of the compound of formula II-1, with a yield of 81.4% and an HPLC purity of 97.3%.

[0089] Example 1-6

[0090] The difference between this example and Example 1-1 is that 1.1 g of aluminum chloride was replaced by 1.1 g of zinc chloride, and the other conditions were the same. After post-treatment, 8.1 g of the II-1 compound was obtained, with a yield of 84.5% and an HPLC purity of 97.7%.

[0091] Example 1-7

[0092] The difference between this example and Example 1-1 is that 1.1 g of aluminum chloride is replaced by 4.5 g of ferric chloride, and the other conditions are the same. After post-treatment, 7.9 g of Compound II-1 is obtained, with a yield of 82.4% and an HPLC purity of 96.9%.

[0093] Example 1-8

[0094] The difference between this example and Example 1-1 is that 1.1 g of aluminum chloride is replaced by 1.1 g of ferrous chloride, and the other conditions are the same. After post-treatment, 7.8 g of Compound II-1 is obtained, with a yield of 81.4% and an HPLC purity of 96.8%.

[0095] Example 1-9

[0096] The difference between this example and Example 1-1 is that 1.1 g of aluminum chloride is replaced by 0.1 g of cobalt chloride and 0.4 g of nickel chloride and 0.7 g of nickel chloride, and the other conditions are the same. After post-treatment, 7.9 g of Compound II-1 is obtained, with a yield of 82.4% and an HPLC purity of 97.0%.

[0097] Example 1-10

[0098] The difference between this example and Example 1-1 is that the reaction temperature of 40 °C is replaced by 0 °C, and the other conditions are the same. After post-treatment, 7.6 g of Compound II-1 is obtained, with a yield of 79.3% and an HPLC purity of 97.3%.

[0099] Example 1-11

[0100] The difference between this example and Example 1-1 is that the reaction temperature of 40 °C is replaced by 80 °C, and the other conditions are the same. After post-treatment, 7.8 g of Compound II-1 is obtained, with a yield of 81.4% and an HPLC purity of 97.0%.

[0101] Example 1-12

[0102] The difference between this example and Example 1-1 is that the reaction temperature of 40 °C is replaced by 30 °C, and the other conditions are the same. After post-treatment, 8.2 g of Compound II-1 is obtained, with a yield of 85.5% and an HPLC purity of 97.7%.

[0103] Example 1-13

[0104] The difference between this example and Example 1-1 is that the reaction temperature of 40 °C is replaced by 60 °C, and the other conditions are the same. After post-treatment, 8.3 g of Compound II-1 is obtained, with a yield of 86.6% and an HPLC purity of 97.6%.

[0105] Example 2

[0106]

[0107] Example 2-1

[0108] At room temperature, 1.4 g of iron acetate, 1.5 g of 1,2,3-benzotriazole, 10 g of the compound of formula I-2 and 200 mL of chloroform were successively added to a reaction flask, and the reaction was carried out at 40 °C with heat preservation. TLC was used until there was no compound of formula I-2. The insoluble substances were removed by filtration, the organic solvent was concentrated under reduced pressure, and purified with acetone to obtain 8.2 g of the compound of formula II-2, with a yield of 85.3% and an HPLC purity of 97.9%.

[0109] Example 2-2

[0110] At room temperature, 0.6 g of ferrous chloride, 1.2 g of 4-azabenzimidazole, 10 g of the compound of formula I-2 and 300 mL of methanol were successively added to a reaction flask, and the reaction was carried out at 30 °C with heat preservation. TLC was used until there was no compound of formula I-2. The insoluble substances were removed by filtration, the organic solvent was concentrated under reduced pressure, and purified with acetone to obtain 7.9 g of the compound of formula II-2, with a yield of 82.2% and an HPLC purity of 97.7%.

[0111] Example 2-3

[0112] At room temperature, 1.3 g of cobalt chloride, 1.7 g of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol, 10 g of the compound of formula I-2 and 100 mL of isopropanol were successively added to a reaction flask, and the reaction was carried out at 60 °C with heat preservation. TLC was used until there was no compound of formula I-2. The insoluble substances were removed by filtration, the organic solvent was concentrated under reduced pressure, and purified with acetone to obtain 7.9 g of the compound of formula II-2, with a yield of 82.2% and an HPLC purity of 97.7%.

[0113] Example 2-4

[0114] At room temperature, 0.3 g of nickel chloride, 1.2 g of 2-(1H-benzo[d][1,2,3]triazol-1-yl)ethan-1-ol, 10 g of the compound of formula I-2 and 150 mL of acetonitrile were successively added to a reaction flask, and the reaction was carried out at 0 °C with heat preservation. TLC was used until there was no compound of formula I-2. The insoluble substances were removed by filtration, the organic solvent was concentrated under reduced pressure, and purified with acetone to obtain 7.6 g of the compound of formula II-2, with a yield of 79.1% and an HPLC purity of 97.1%.

[0115] Example 2-5

[0116] At room temperature, 2.7 g of iron bromide, 3.5 g of 1-(4-aminobenzyl)imidazole, 10 g of the compound of formula I-2 and 250 mL of n-butanol were successively added to a reaction flask, and the mixture was kept at 80 °C for reaction. When TLC showed that there was no compound of formula I-2, the insoluble matter was filtered off, the organic solvent was concentrated under reduced pressure, and the residue was purified with acetone to obtain 7.7 g of the compound of formula II-2, with a yield of 80.1% and an HPLC purity of 97.5%.

[0117] Example 2-6

[0118] The difference between this example and Example 2-1 is that 2.5 g of 1-(pyridin-2-yl)-1H-benzo[d][1,2,3]triazole was used instead of 1.5 g of 1,2,3-benzotriazole, and the other conditions were the same. After post-treatment, 8.0 g of the compound II-2 was obtained, with a yield of 83.2% and an HPLC purity of 98.0%.

[0119] Example 2-7

[0120] The difference between this example and Example 2-1 is that 1.7 g of 1-methylbenzotriazole was used instead of 1.5 g of 1,2,3-benzotriazole, and the other conditions were the same. After post-treatment, 8.1 g of the compound II-2 was obtained, with a yield of 84.3% and an HPLC purity of 97.9%.

[0121] Example 2-8

[0122] The difference between this example and Example 2-1 is that 2.2 g of 1-(1H-benzo[d][1,2,3]triazol-1-yl)-N,N-dimethylmethanamine was used instead of 1.5 g of 1,2,3-benzotriazole, and the other conditions were the same. After post-treatment, 8.0 g of the compound II-2 was obtained, with a yield of 83.2% and an HPLC purity of 97.6%.

[0123] Example 2-9

[0124] The difference between this example and Example 2-1 is that 1.3 g of 2-(1H-tetrazol-1-yl)pyridine and 0.7 g of 1-(4-aminobenzyl)imidazole were used instead of 1.5 g of 1,2,3-benzotriazole, and the other conditions were the same. After post-treatment, 8.0 g of the compound II-2 was obtained, with a yield of 83.2% and an HPLC purity of 97.8%.

[0125] Example 2-10

[0126] The difference between this example and Example 2-1 is that 1.5 g of 1,2,3-benzotriazole is replaced with 0.6 g of 4-azabenzimidazole and 0.9 g of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol, and the other conditions are the same. After post-treatment, 7.7 g of Compound II-2 is obtained, with a yield of 80.1% and an HPLC purity of 96.3%.

[0127] Example 2-11

[0128] The difference between this example and Example 2-1 is that 1.5 g of 1,2,3-benzotriazole is replaced with 2.0 g of 2-(1H-benzotriazol-1-yl)ethanol, and the other conditions are the same. After post-treatment, 7.6 g of Compound II-2 is obtained, with a yield of 79.7% and an HPLC purity of 96.1%.

[0129] Example 2-12

[0130] The difference between this example and Example 2-1 is that 1.5 g of 1,2,3-benzotriazole is replaced with 0.7 g of 1,2,4-triazole and 1.0 g of 1,2,3-triazole, and the other conditions are the same. After post-treatment, 7.6 g of Compound II-2 is obtained, with a yield of 79.7% and an HPLC purity of 96.3%.

[0131] Example 3

[0132]

[0133] Example 3-1

[0134] At room temperature, 1.2 g of aluminum chloride, 1.8 g of 1,2,3-benzotriazole, 10 g of Compound I-3, and 200 mL of dichloromethane were successively added to a reaction flask, and the reaction was carried out at 40 °C with heat preservation. When TLC showed that there was no Compound I-3, the insoluble substances were filtered off, the organic solvent was concentrated under reduced pressure, and the product was purified with acetone to obtain 8.1 g of Compound II-3, with a yield of 86.4% and an HPLC purity of 97.8%.

[0135] Example 3-2

[0136] At room temperature, 1.1 g of iron(III) acetylacetonate, 0.6 g of 1,2,4-triazole, 10 g of Compound I-3, and 300 mL of acetone were successively added to a reaction flask, and the reaction was carried out at 0 °C with heat preservation. When TLC showed that there was no Compound I-3, the insoluble substances were filtered off, the organic solvent was concentrated under reduced pressure, and the product was purified with acetone to obtain 7.2 g of Compound II-3, with a yield of 76.8% and an HPLC purity of 97.3%.

[0137] Example 3-3

[0138] At room temperature, 2.4 g of ferric chloride, 1.7 g of 1,2,3-triazole, 10 g of Compound I-3 and 100 mL of toluene were successively added to a reaction flask, and the mixture was kept at 80 °C for reaction. When there was no Compound I-3 detected by TLC, the insoluble substances were filtered off, the organic solvent was concentrated under reduced pressure, and the residue was purified with acetone to obtain 7.4 g of Compound II-3, with a yield of 78.9% and an HPLC purity of 97.2%.

[0139] Example 4

[0140]

[0141] Example 4-1

[0142] At room temperature, 1.0 g of aluminum chloride, 1.4 g of 1,2,3-benzotriazole, 10 g of Compound I-4 and 200 mL of chloroform were successively added to a reaction flask, and the mixture was kept at 40 °C for reaction. When there was no Compound I-4 detected by TLC, the insoluble substances were filtered off, the organic solvent was concentrated under reduced pressure, and the residue was purified with acetone to obtain 8.1 g of Compound II-4, with a yield of 84.4% and an HPLC purity of 97.6%.

[0143] Example 4-2

[0144] At room temperature, 0.3 g of zinc chloride, 0.5 g of 1,2,4-triazole, 10 g of Compound I-4 and 300 mL of acetonitrile were successively added to a reaction flask, and the mixture was kept at 0 °C for reaction. When there was no Compound I-4 detected by TLC, the insoluble substances were filtered off, the organic solvent was concentrated under reduced pressure, and the residue was purified with acetone to obtain 7.1 g of Compound II-4, with a yield of 74.0% and an HPLC purity of 97.3%.

[0145] Example 4-3

[0146] At room temperature, 1.5 g of copper chloride, 1.3 g of 1,2,3-triazole, 10 g of Compound I-4 and 100 mL of toluene were successively added to a reaction flask, and the mixture was kept at 80 °C for reaction. When there was no Compound I-4 detected by TLC, the insoluble substances were filtered off, the organic solvent was concentrated under reduced pressure, and the residue was purified with acetone to obtain 7.2 g of Compound II-4, with a yield of 75.1% and an HPLC purity of 97.2%.

[0147] Preparation of Compound III

[0148] Example 5

[0149]

[0150] Example 5-1

[0151] At room temperature, 1.9 g of tetrabutylammonium bromide, 0.68 g of water, 5.4 g of 6,7-dioxaspiro[3.4]octane-5,8-dione, 10 g of the compound of formula II-1 and 100 mL of dichloromethane were successively added to a reaction flask. The reaction was carried out at 0 °C with heat preservation. When TLC showed no compound of formula II-1, the reaction solution was added to 1000 mL of 5% aqueous sodium thiosulfate solution and stirred for 0.5 h, then extracted with ethyl acetate. After liquid separation, the organic phase was concentrated under reduced pressure. The residue was added to a mixture of 850 mL of 1 mol / L sodium carbonate solution and 850 mL of methanol and stirred at 55 °C for 14 h. After completion, the pH was adjusted to neutral, and most of the organic solvents were removed by concentration under reduced pressure. Then, it was filtered, washed with water, and dried to obtain 10.1 g of the compound of formula III-1, with a yield of 92.5% and an HPLC purity of 98.4%.

[0152] Example 5-2

[0153] At room temperature, 0.4 g of tetramethylammonium bromide, 0.78 g of water, 4.1 g of 5,6-dioxaspiro[2.4]heptane-4,7-dione, 10 g of the compound of formula II-1 and 50 mL of chloroform were successively added to a reaction flask. The reaction was carried out at 10 °C with heat preservation. When TLC showed no compound of formula II-1, the reaction solution was added to 1000 mL of 5% aqueous sodium thiosulfate solution and stirred for 0.5 h, then extracted with ethyl acetate. After liquid separation, the organic phase was concentrated under reduced pressure. The residue was added to a mixture of 850 mL of 1 mol / L sodium bicarbonate solution and 850 mL of ethanol and stirred at 60 °C for 14 h. After completion, the pH was adjusted to neutral, and most of the organic solvents were removed by concentration under reduced pressure. Then, it was filtered, washed with water, and dried to obtain 9.9 g of the compound of formula III-1, with a yield of 90.7% and an HPLC purity of 97.5%.

[0154] Example 5-3

[0155] At room temperature, 3.2 g of tetrapropylammonium chloride, 0.57 g of water, 6.8 g of 2,3-dioxaspiro[4.4]nonane-1,4-dione, 10 g of the compound of formula II-1 and 150 mL of 2-methyltetrahydrofuran were successively added to a reaction flask. The reaction was carried out at 15 °C with heat preservation. When TLC showed no compound of formula II-1, the reaction solution was added to 1000 mL of 5% aqueous sodium thiosulfate solution and stirred for 0.5 h, then extracted with ethyl acetate. After liquid separation, the organic phase was concentrated under reduced pressure. The residue was added to a mixture of 850 mL of 1 mol / L potassium carbonate solution and 850 mL of chloroform and stirred at 40 °C for 14 h. After completion, the pH was adjusted to neutral, and most of the organic solvents were removed by concentration under reduced pressure. Then, it was filtered, washed with water, and dried to obtain 9.7 g of the compound of formula III-1, with a yield of 88.9% and an HPLC purity of 97.2%.

[0156] Example 5-4

[0157] At room temperature, 2.4 g of triethylbenzylammonium bromide, 0.73 g of water, 7.4 g of (1S,4R)-spiro[bicyclo[2.2.1]heptane-2,4'-[1,2]dioxolane]-3',5'-dione, 10 g of the compound of Formula II-1 and 80 mL of toluene were successively added to a reaction flask, and the mixture was kept at 30 °C for reaction. When there was no more compound of Formula II-1 by TLC, the reaction solution was added to 1000 mL of 5% aqueous sodium thiosulfate solution and stirred for 0.5 h, then extracted with ethyl acetate, separated, and the organic phase was concentrated under reduced pressure. The residue was added to a mixture of 850 mL of 1 mol / L potassium bicarbonate solution and 850 mL of dichloromethane and stirred at 45 °C for 14 h. After completion, the pH was adjusted to neutral, concentrated under reduced pressure to remove most of the organic solvents, filtered, washed with water, and dried to obtain 9.6 g of the compound of Formula III-1, with a yield of 87.9% and an HPLC purity of 97.1%.

[0158] Example 5-5

[0159] The difference between this example and Example 3-1 is that 5.4 g of 6,7-dioxaspiro[3.4]octane-5,8-dione was replaced with 4.8 g of 5,6-dioxaspiro[2.4]heptane-4,7-dione, and the other conditions were the same. After post-treatment, 10.0 g of Compound III-1 was obtained, with a yield of 91.6% and an HPLC purity of 98.2%.

[0160] Example 5-6

[0161] The difference between this example and Example 3-1 is that 5.4 g of 6,7-dioxaspiro[3.4]octane-5,8-dione was replaced with 5.9 g of 2,3-dioxaspiro[4.4]nonane-1,4-dione, and the other conditions were the same. After post-treatment, 9.6 g of Compound III-1 was obtained, with a yield of 87.9% and an HPLC purity of 97.5%.

[0162] Example 5-7

[0163] The difference between this example and Example 3-1 is that 5.4 g of 6,7-dioxaspiro[3.4]octane-5,8-dione was replaced with 6.9 g of (1S,4R)-spiro[bicyclo[2.2.1]heptane-2,4'-[1,2]dioxolane]-3',5'-dione, and the other conditions were the same. After post-treatment, 9.7 g of Compound III-1 was obtained, with a yield of 88.9% and an HPLC purity of 97.2%.

[0164] Example 5-8

[0165] The difference between this example and Example 3-1 is that 5.4 g of 6,7-dioxaspiro[3.4]octane-5,8-dione is replaced by 2.5 g of 6,7-dioxaspiro[3.4]octane-5,8-dione and 2.6 g of 5,6-dioxaspiro[2.4]heptane-4,7-dione, and the other conditions are the same. After post-treatment, 10.0 g of Compound III-1 is obtained, with a yield of 91.6% and an HPLC purity of 98.1%.

[0166] Example 6

[0167]

[0168] Example 6-1

[0169] At room temperature, 1.9 g of tetrabutylammonium iodide, 0.61 g of water, 4.8 g of 6,7-dioxaspiro[3.4]octane-5,8-dione, 10 g of Compound II-2, and 100 mL of dichloromethane were successively added to a reaction flask, and the reaction was carried out at 0 °C with heat preservation. When TLC showed no Compound II-2, the reaction solution was added to 1000 mL of 5% sodium thiosulfate aqueous solution and stirred for 0.5 h, then extracted with ethyl acetate, separated, and the organic phase was concentrated under reduced pressure. The residue was added to a mixture of 850 mL of 1 mol / L sodium carbonate solution and 850 mL of methanol and stirred at 45 °C for 14 h. After completion, the pH was adjusted to neutral, concentrated under reduced pressure to remove most of the organic solvents, filtered, washed with water, and dried to obtain 8.7 g of Compound III-2, with a yield of 88.9% and an HPLC purity of 97.6%.

[0170] Example 6-2

[0171] At room temperature, 0.7 g of triethylhexylammonium bromide, 0.51 g of water, 3.7 g of 5,6-dioxaspiro[2.4]heptane-4,7-dione, 10 g of Compound II-2, and 50 mL of chloroform were successively added to a reaction flask, and the reaction was carried out at 10 °C with heat preservation. When TLC showed no Compound II-2, the reaction solution was added to 1000 mL of 5% sodium thiosulfate aqueous solution and stirred for 0.5 h, then extracted with ethyl acetate, separated, and the organic phase was concentrated under reduced pressure. The residue was added to a mixture of 850 mL of 1 mol / L sodium bicarbonate solution and 850 mL of ethanol and stirred at 40 °C for 14 h. After completion, the pH was adjusted to neutral, concentrated under reduced pressure to remove most of the organic solvents, filtered, washed with water, and dried to obtain 8.5 g of Compound III-2, with a yield of 86.8% and an HPLC purity of 97.2%.

[0172] Example 6-3

[0173] At room temperature, 2.3 g of tetrapropylammonium chloride, 0.70 g of water, 6.1 g of 2,3-dioxaspiro[4.4]nonane-1,4-dione, 10 g of the compound of Formula II-2 and 150 mL of 2-methyltetrahydrofuran were successively added to a reaction flask, and the reaction was carried out at 15 °C with heat preservation. When there was no compound of Formula II-2 detected by TLC, the reaction solution was added to 1000 mL of 5% aqueous sodium thiosulfate solution and stirred for 0.5 h, then extracted with ethyl acetate, and the layers were separated. The organic phase was concentrated under reduced pressure. The residue was added to a mixture of 850 mL of 1 mol / L potassium carbonate solution and 850 mL of chloroform, stirred at 60 °C for 14 h. After completion, the pH was adjusted to neutral, concentrated under reduced pressure to remove most of the organic solvents, filtered, washed with water, and dried to obtain 8.5 g of the compound of Formula III-2, with a yield of 86.8% and an HPLC purity of 97.1%.

[0174] Example 6-4

[0175] At room temperature, 2.0 g of tetramethylammonium bromide, 0.56 g of water, 5.7 g of (1S,4R)-spiro[bicyclo[2.2.1]heptane-2,4'-[1,2]dioxolane]-3',5'-dione, 10 g of the compound of Formula II-2 and 80 mL of toluene were successively added to a reaction flask, and the reaction was carried out at 30 °C with heat preservation. When there was no compound of Formula II-2 detected by TLC, the reaction solution was added to 1000 mL of 5% aqueous sodium thiosulfate solution and stirred for 0.5 h, then extracted with ethyl acetate, and the layers were separated. The organic phase was concentrated under reduced pressure. The residue was added to a mixture of 850 mL of 1 mol / L potassium bicarbonate solution and 850 mL of dichloromethane, stirred at 55 °C for 14 h. After completion, the pH was adjusted to neutral, concentrated under reduced pressure to remove most of the organic solvents, filtered, washed with water, and dried to obtain 8.4 g of the compound of Formula III-2, with a yield of 85.8% and an HPLC purity of 97.3%.

[0176] Example 6-5

[0177] The difference between this example and Example 4-1 is that the reaction temperature of 0 °C was replaced with 10 °C, and the other conditions were the same. After post-treatment, 8.7 g of Compound III-1 was obtained, with a yield of 88.9% and an HPLC purity of 97.8%.

[0178] Example 6-6

[0179] The difference between this example and Example 4-1 is that the reaction temperature of 0 °C was replaced with 15 °C, and the other conditions were the same. After post-treatment, 8.5 g of Compound III-1 was obtained, with a yield of 86.8% and an HPLC purity of 97.1%.

[0180] Example 6-7

[0181] The difference between this example and Example 4-1 is that the reaction temperature of 0 °C is replaced by 30 °C, and the other conditions are the same. After post-treatment, 8.4 g of Compound III-1 is obtained, with a yield of 85.8% and an HPLC purity of 97.1%.

[0182] Example 7

[0183]

[0184] Example 7-1

[0185] At room temperature, 2.1 g of tetrabutylammonium bromide, 0.75 g of water, 6.0 g of 6,7-dioxaspiro[3.4]octane-5,8-dione, 10 g of Compound II-3, and 120 mL of dichloromethane were successively added to a reaction flask, and the reaction was carried out at 0 °C with heat preservation. TLC was used until there was no Compound II-3. The reaction solution was added to 1000 mL of 5% aqueous sodium thiosulfate solution and stirred for 0.5 h, then extracted with ethyl acetate, separated, and the organic phase was concentrated under reduced pressure. The residue was added to a mixture of 850 mL of 1 mol / L sodium carbonate solution and 850 mL of methanol and stirred at 55 °C for 14 h. After completion, the pH was adjusted to neutral, concentrated under reduced pressure to remove most of the organic solvents, filtered, washed with water, and dried to obtain 9.9 g of Compound III-3, with a yield of 89.2% and an HPLC purity of 97.8%.

[0186] Example 7-2

[0187] At room temperature, 0.5 g of tetramethylammonium bromide, 0.86 g of water, 4.5 g of 5,6-dioxaspiro[2.4]heptane-4,7-dione, 10 g of Compound II-3, and 50 mL of chloroform were successively added to a reaction flask, and the reaction was carried out at 20 °C with heat preservation. TLC was used until there was no Compound II-3. The reaction solution was added to 1000 mL of 5% aqueous sodium thiosulfate solution and stirred for 0.5 h, then extracted with ethyl acetate, separated, and the organic phase was concentrated under reduced pressure. The residue was added to a mixture of 850 mL of 1 mol / L sodium bicarbonate solution and 850 mL of ethanol and stirred at 45 °C for 14 h. After completion, the pH was adjusted to neutral, concentrated under reduced pressure to remove most of the organic solvents, filtered, washed with water, and dried to obtain 9.7 g of Compound III-3, with a yield of 87.5% and an HPLC purity of 97.6%.

[0188] Example 7-3

[0189] At room temperature, 3.5 g of tetrapropylammonium chloride, 0.63 g of water, 7.5 g of 2,3-dioxaspiro[4.4]nonane-1,4-dione, 10 g of the compound of formula II-3 and 150 mL of 2-methyltetrahydrofuran were successively added to a reaction flask, and the reaction was carried out at 30 °C with heat preservation. When TLC showed no compound of formula II-3, the reaction solution was added to 1000 mL of 5% aqueous sodium thiosulfate solution and stirred for 0.5 h, then extracted with ethyl acetate, separated, and the organic phase was concentrated under reduced pressure. The residue was added to a mixture of 850 mL of 1 mol / L sodium hydroxide solution and 850 mL of dichloromethane and stirred at 10 °C for 14 h. After completion, the pH was adjusted to neutral, concentrated under reduced pressure to remove most of the organic solvents, filtered, washed with water, and dried to obtain 9.5 g of the compound of formula III-3, with a yield of 85.7% and an HPLC purity of 97.5%.

[0190] Example 8

[0191]

[0192] Example 8-1

[0193] At room temperature, 1.9 g of tetrabutylammonium bromide, 0.56 g of water, 4.4 g of 6,7-dioxaspiro[3.4]octane-5,8-dione, 10 g of the compound of formula II-4 and 100 mL of dichloromethane were successively added to a reaction flask, and the reaction was carried out at 0 °C with heat preservation. When TLC showed no compound of formula II-4, the reaction solution was added to 1000 mL of 5% aqueous sodium thiosulfate solution and stirred for 0.5 h, then extracted with ethyl acetate, separated, and the organic phase was concentrated under reduced pressure. The residue was added to a mixture of 850 mL of 1 mol / L potassium carbonate solution and 850 mL of methanol and stirred at 60 °C for 14 h. After completion, the pH was adjusted to neutral, concentrated under reduced pressure to remove most of the organic solvents, filtered, washed with water, and dried to obtain 8.7 g of the compound of formula III-4, with a yield of 88.6% and an HPLC purity of 97.7%.

[0194] Example 8-2

[0195] At room temperature, 0.4 g of tetramethylammonium bromide, 0.65 g of water, 3.4 g of 5,6-dioxaspiro[2.4]heptane-4,7-dione, 10 g of the compound of formula II-4 and 50 mL of chloroform were successively added to a reaction flask, and the reaction was carried out at 15 °C with heat preservation. When TLC showed no compound of formula II-4, the reaction solution was added to 1000 mL of 5% aqueous sodium thiosulfate solution and stirred for 0.5 h, then extracted with ethyl acetate, separated, and the organic phase was concentrated under reduced pressure. The residue was added to a mixture of 850 mL of 1 mol / L potassium bicarbonate solution and 850 mL of ethanol and stirred at 40 °C for 14 h. After completion, the pH was adjusted to neutral, concentrated under reduced pressure to remove most of the organic solvents, filtered, washed with water, and dried to obtain 8.5 g of the compound of formula III-4, with a yield of 86.6% and an HPLC purity of 97.6%.

[0196] Example 8-3

[0197] At room temperature, 3.2 g of tetrapropylammonium chloride, 0.48 g of water, 5.6 g of 2,3-dioxaspiro[4.4]nonane-1,4-dione, 10 g of the compound of Formula II-4 and 150 mL of 2-methyltetrahydrofuran were successively added to a reaction flask, and the reaction was carried out at 30 °C with heat preservation. When TLC showed no compound of Formula II-4, the reaction solution was added to 1000 mL of 5% aqueous sodium thiosulfate solution and stirred for 0.5 h, then extracted with ethyl acetate, separated, and the organic phase was concentrated under reduced pressure. The residue was added to a mixture of 850 mL of 1 mol / L potassium hydroxide solution and 850 mL of chloroform, stirred at 0 °C for 14 h, then the pH was adjusted to neutral, concentrated under reduced pressure to remove most of the organic solvents, filtered, washed with water, and dried to obtain 8.3 g of the compound of Formula III-4, with a yield of 84.6% and an HPLC purity of 97.6%.

[0198] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention, not to limit them; although the present invention has been described in detail with reference to the foregoing examples, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing examples, or perform equivalent substitutions on some or all of the technical features; and these modifications or substitutions do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a 16,17-dihydroxy steroid compound, characterized in that, It includes the following steps: (b) A compound of formula II, a cyclic acyl peroxide, water and a phase transfer catalyst, and then hydrolyze under alkaline conditions to obtain a compound of formula III; the reaction formula is as follows: Among them, R1, R2, R3 and R4 shown in the structural formulas of the compound of formula II and the compound of formula III are independently selected from each other, and: R1 = H, methyl or halogen, and halogen = F, Cl, Br or I; R2 = H or halogen, and halogen = F, Cl, Br or I; R3 = H or hydroxyl; R4 = H, OH or OCOR5, and R5 is an alkyl group with no more than six carbons; The dotted line is a single bond or a double bond; The cyclic acyl peroxide is selected from one or a combination of several of 5,6-dioxaspiro[2.4]heptane-4,7-dione, 6,7-dioxaspiro[3.4]octane-5,8-dione, 2,3-dioxaspiro[4.4]nonane-1,4-dione or (1S,4R)-spiro[bicyclo[2.2.1]heptane-2,4'-[1,2]dioxolane]-3',5'-dione; The phase transfer catalyst is selected from one or a combination of several of tetramethylammonium bromide, tetrapropylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, triethylbenzylammonium bromide or triethylhexylammonium bromide; The hydrolysis uses an alkali reagent, and the alkali reagent is selected from one or a combination of several of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate.

2. The method for preparing a 16,17-dihydroxy steroid compound according to claim 1, characterized in that, It includes the following steps: (b) Add the compound of formula II, the cyclic acyl peroxide, water and the phase transfer catalyst to a second organic solvent, react at 0 - 30 °C, and then hydrolyze under alkaline conditions at 0 - 60 °C to obtain a compound of formula III.

3. The method for preparing a 16,17-dihydroxy steroid compound according to any one of claims 1-2, characterized in that, In the step (b), the molar ratio of the cyclic acyl peroxide, water and the compound of formula II is (1.1 - 1.5):(1.1 - 1.5):

1.

4. The method for preparing a 16,17-dihydroxy steroid compound according to claim 1, characterized in that, It further includes the following steps: (a) Add the compound of formula I, a Lewis acid and an azole compound to a first organic solvent, and react at 0 - 80 °C to obtain a compound of formula II; Among them, R1, R2, R3 and R4 shown in the structural formulas of the compound of formula I and the compound of formula II are independently selected from each other, and: R1 = H, methyl or halogen, and halogen = F, Cl, Br or I; R2 = H or halogen, and halogen = F, Cl, Br or I; R3 = H or hydroxyl; R4 = H, OH or OCOR5, and R5 is an alkyl group with no more than six carbons; The dotted line is a single bond or a double bond; In the step (a), the azole compound is selected from one or a combination of several of 1-(pyridin-2-yl)-1H-benzo[d][1,2,3]triazole, 1,2,3-benzotriazole, 1,2,4-triazole, 1,2,3-triazole, 1-methylbenzotriazole, 1-(1H-benzo[d][1,2,3]triazol-1-yl)-N,N-dimethylmethanamine, 2-(1H-tetrazol-1-yl)pyridine, 1-(4-aminobenzyl)imidazole, 4-azabenzimidazole, (5-amino-1H-[1,2,4]triazol-3-yl)-methanol or 2-(1H-benzo[d][1,2,3]triazol-1-yl)ethan-1-ol; The Lewis acid is selected from one or a combination of several of aluminum chloride, iron(III) chloride, iron(III) bromide, iron(III) acetylacetonate, iron(II) chloride, cobalt(II) chloride, nickel(II) chloride, iron(III) acetate, zinc chloride or copper(II) chloride.

5. The method for preparing a 16,17-dihydroxy steroid compound according to claim 4, characterized in that, In the step (a), the molar ratio of the azole compound, the Lewis acid and the compound of formula I is (0.3 - 0.8):(0.1 - 0.5):1.

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