Steroid 17-side chain protection method and application

Abstract

The application provides a steroid 17-position side chain protection method and application, and relates to the technical field of chemical synthesis. The steroid 17-position side chain protection method comprises a bromination reaction, a reduction reaction and a 17-position side chain protection reaction, and in the reaction, 11-hydroxyl is directly converted into 11-methyl formate; in the subsequent side chain protection reaction, the 11-methyl formate does not participate in the reaction, the problem of byproduct generation caused by the reaction of 11-hydroxyl in the prior art is solved, the 17-position side chain protection product does not need to be post-treated by using a column chromatography method and the like, and the product can be obtained by using a conventional method, has high yield and high purity, and the production applicability is improved.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and in particular to a method and application for protecting the 17-position side chain of steroidal compounds. Background Technology

[0002] Steroid hormone drugs are hormones whose molecular structure contains a steroidal structure. They are widely used clinically and mainly include two categories: adrenocortical hormones and sex hormones. Adrenocortical hormones, in particular, possess a variety of pharmacological effects, including anti-inflammatory, anti-allergic, immunosuppressive, stress-enhancing, anti-endotoxin, and anti-shock effects. Clinically, they are used to treat many diseases and are an indispensable class of drugs. Pharmacological studies have shown that the efficacy of steroid hormone drugs is closely related to the C17 side chain; protection of the C17 side chain is essential when the steroid needs to react with a strong base.

[0003] Currently, the publicly disclosed methods for protecting the 17-position side chain of steroidal compounds all involve reacting steroid molecules with a hydroxyl group at position 11 with formaldehyde solution or paraformaldehyde in the presence of concentrated hydrochloric acid. The reaction equations are as follows:

[0004]

[0005] However, in practice and in related literature, it has been found that the product obtained by protecting the 17-position side chain is not unique, with the ratio of main product to byproduct being approximately 5:1. The actual reaction is as follows:

[0006]

[0007] To address the issue of the aforementioned byproducts, the literature reports the following methods:

[0008] (1) Column chromatography: When the amount of feed is small, column chromatography can be used to collect only the main product, but this method is not suitable for industrial production.

[0009] (2) US 8163724 B2 reports that by increasing the amount of concentrated hydrochloric acid and formaldehyde (the molar ratio of substrate hydrocortisone, formaldehyde, and hydrochloric acid = 1:77.2:70.6), all the substrates are converted into double-protected products, and both protections can be removed simultaneously in the subsequent deprotection reaction. The disadvantage of this method is that the amount of concentrated hydrochloric acid and formaldehyde used is relatively large.

[0010] Currently available methods for obtaining compounds with 17-position side chain protection are not ideal.

[0011] In view of this, the present invention is hereby proposed. Summary of the Invention

[0012] The main objective of this invention is to provide a method for protecting the 17-position side chain of a steroid compound and its application in the preparation of a cortivastatin intermediate, in order to at least partially solve at least one of the above-mentioned technical problems.

[0013] As a first aspect of the present invention, the present invention provides a method for protecting the 17-position side chain of a steroid compound, comprising the following steps:

[0014]

[0015] (b) Bromination reaction: Compound II reacts with a brominizing agent and a formylating agent under the action of an acidic catalyst to give compound III;

[0016] (c) Reduction reaction: Compound III reacts with a hydrogen donor, an azo radical initiator and an optional base reagent to give compound IV;

[0017] (d) 17-position side chain protection reaction: Compound IV reacts with formaldehyde or paraformaldehyde to give compound V;

[0018] Among them, R1 and R2 shown in the structural formulas of compounds II, III, IV, and V are chosen independently of each other, and:

[0019] R1 = H, α-halogen, α-CH3 or CH2;

[0020] R2 = H or CH3;

[0021] It can be a single bond or a double bond.

[0022] Further steps include the following:

[0023]

[0024] (a) Hydrolysis reaction: Compound I reacts under alkaline conditions to give compound II;

[0025] (b) Bromination reaction: Compound II reacts with a brominizing agent and a formylating agent under the action of an acidic catalyst to give compound III;

[0026] (c) Reduction reaction: Compound III reacts with a hydrogen donor, an azo radical initiator and an optional base reagent to give compound IV;

[0027] (d) 17-position side chain protection reaction: Compound IV reacts with formaldehyde or paraformaldehyde to give compound V;

[0028] In this context, R1, R2, and R3, as shown in the structural formulas of compounds I, II, III, IV, and V, are chosen independently of each other, and:

[0029] R1 = H, α-halogen, α-CH3 or CH2;

[0030] R2 = H or CH3;

[0031] R3 = C1-C6 alkyl group;

[0032] It can be a single bond or a double bond.

[0033] Furthermore, in compounds I, II, III, IV, and V, R1, R2, and R3 are chosen independently of each other, and:

[0034] R1 = H;

[0035] R2 = CH3;

[0036] R3 = α-CH3;

[0037] It is a single key.

[0038] Furthermore, in step (b), the brominating agent is selected from one or a combination of several of dibromohydantoin, dibromocyanoacetamide, dibromocyanopropionamide, N-bromoacetamide, N-bromophthalamide, or N-bromosuccinimide; the acidic catalyst is selected from perchloric acid; and the formylated agent is selected from N,N-dimethylformamide.

[0039] In step (c), the azo radical initiator is selected from one or a combination of several of azobisisobutyrazoline hydrochloride (AIBI), azobisisobutyramidine hydrochloride (AIBA), azobisisoheptanenitrile (ABVN), and azobisisobutyronitrile (AIBN); the hydrogen donor is selected from hypophosphorous acid; and the base reagent is selected from organic bases and / or inorganic bases.

[0040] Furthermore, in step (b), the brominating agent is selected from dibromohydantoin or N-bromosuccinimide; the acidic catalyst is selected from perchloric acid; and the formylated agent is selected from N,N-dimethylformamide.

[0041] In step (c), the azo radical initiator is selected from one or a combination of several of azobisisobutyrazoline hydrochloride, azobisisobutyramidine dihydrochloride, or azobisisoheptanenitrile; the hydrogen donor is selected from hypophosphorous acid; and the base reagent is selected from inorganic bases.

[0042] Furthermore, in step (a), the temperature of the reaction is selected from 50-65°C.

[0043] In step (b), the temperature of the reaction is selected from -10 to 20°C;

[0044] In step (c), the reaction temperature is selected from 50-65°C;

[0045] In step (d), the temperature of the reaction is selected from 0-40°C.

[0046] Furthermore, in step (a), the reaction temperature is selected as 60-65℃.

[0047] In step (b), the reaction temperature is selected from -5 to 0°C;

[0048] In step (c), the reaction temperature is selected from 60-65°C;

[0049] In step (d), the reaction temperature is selected from 20-25°C.

[0050] Furthermore,

[0051] In step (a), the solvent for the reaction is selected from chloroform and / or methanol;

[0052] In step (b), the solvent for the reaction is selected from N,N-dimethylformamide;

[0053] In step (c), the solvent for the reaction is selected from methanol and / or ethanol;

[0054] In step (d), the solvent for the reaction is selected from chloroform and / or dichloromethane.

[0055] Furthermore, in step (a), hydrolysis is performed using an alkaline reagent selected from one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, or sodium hydroxide.

[0056] As a second aspect of the present invention, a steroidal intermediate is provided:

[0057]

[0058] As a third aspect of the present invention, a steroidal intermediate is provided:

[0059]

[0060] As a fourth aspect of the present invention, the present invention provides a method for protecting the 17-position side chain of the above-mentioned steroidal compound and the application of the above-mentioned two steroidal intermediates in the preparation of quaternazole and its intermediates.

[0061] Furthermore, the preparation of the quaternary intermediate includes the following steps:

[0062]

[0063] (e) Compound V undergoes a methyleneization reaction to yield reactant VI;

[0064] (f) Reactant VI undergoes a hydrolysis reaction to obtain reactant VII;

[0065] (g) Reactant VII undergoes a transposition reaction to give the cortivazol intermediate.

[0066] In the preparation of the cortivazole intermediate, the methyleneization, hydrolysis and transposition reactions were all carried out using conventional technical conditions.

[0067] Compared with the prior art, the present invention has the following beneficial effects:

[0068] (1) The method for protecting the 17-position side chain of steroidal compounds provided by the present invention directly converts the 11-position hydroxyl group into 11-carboxylate in the reaction. In the subsequent side chain protection reaction, the 11-carboxylate does not participate in the reaction, which solves the problem of byproduct generation caused by the reaction of the 11-position hydroxyl group in the prior art. The 17-position side chain protected product does not need to be post-processed by column chromatography or other methods. It can be processed by conventional methods. The product has high yield and high purity, which improves the applicability to production.

[0069] (2) The present invention uses the method of protecting the 17-position side chain of steroidal compounds to prepare key intermediates of quaternazole, which is highly operable, has a high safety factor, and improves the applicability to production. Detailed Implementation

[0070] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions were applied in the examples. Reagents or instruments used, unless otherwise specified, are all commercially available products.

[0071] Example 1 Hydrolysis reaction

[0072] Example 1-1

[0073]

[0074] Example 1-1-1

[0075] Compound I-1 (50 g), potassium bicarbonate (50 g), chloroform (150 mL), and methanol (250 mL) were added to a reaction flask. The mixture was heated to 60 °C and refluxed. TLC monitoring showed no remnants of compound I-1, indicating the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the pH was adjusted to 6.5. The solution was concentrated under reduced pressure, flushed with methanol, concentrated again, cooled to 0 °C, filtered, and dried to obtain compound II-1 (44 g), with a yield of 88%.

[0076] Example 1-1-2

[0077] In a reaction flask, 50 g of compound I-1, 10 g of potassium hydroxide, 200 mL of chloroform, and 250 mL of methanol were added. The mixture was heated to 50 °C, and TLC monitoring showed no remnants of compound I-1, indicating the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the pH was adjusted to 6.8. The solution was concentrated under reduced pressure, flushed with methanol, concentrated again, cooled to -5 °C, filtered under vacuum, and dried to obtain 143.7 g of compound II-1, with a yield of 87.4%.

[0078] Examples 1-2

[0079]

[0080] Compound I-2 (50 g), sodium carbonate (15 g), chloroform (180 mL), and ethanol (300 mL) were added to a reaction flask. The mixture was heated to 65 °C and refluxed. TLC monitoring showed no remnants of compound I-2, indicating the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the pH was adjusted to 6.0. The solution was concentrated under reduced pressure, flushed twice with methanol, concentrated again, cooled to -2 °C, filtered under vacuum, and dried to obtain compound II-2 (43 g), with a yield of 86%.

[0081] Example 2: Bromination reaction and reduction reaction

[0082] Example 2-1

[0083]

[0084] Example 2-1-1

[0085] Bromination reaction: 8 mL of perchloric acid and 40 g of compound II-1 were added to 200 mL of DMF (N,N-dimethylformamide). 30 g of DBH (dibromohydantoin) was added in portions. The temperature was maintained at -10 °C. TLC monitoring was performed until no compound II-1 was detected, indicating the reaction was complete. Then, 400 mL of 10% sodium sulfite solution was slowly added dropwise. After the addition was complete, the pH of the reaction solution was adjusted to 6.5 with acetic acid. The reaction solution was diluted 20 times with ice water, stirred, and allowed to stand. The solution was filtered and dried to obtain compound III-1.

[0086] Reduction reaction: 26.4 mL of hypophosphoric acid was slowly added dropwise to 16.8 g of potassium carbonate and 320 mL of methanol. After the addition was complete, the reaction solution was heated to 50 °C. Then, compound III-1 from the previous step and 19.2 g of AIBI (azobisisobutyrazoline hydrochloride) were added, and the mixture was heated to 60 °C. The system was refluxed, and during the reaction, 30 mL of a pre-prepared 25% potassium carbonate solution was slowly added dropwise, maintaining the pH of the system at 6. The reaction was monitored by HPLC until complete. Heating was stopped, and the reaction solution was cooled to room temperature, concentrated under reduced pressure, rinsed twice with water, and concentrated until no solvent evaporated. The solution was diluted 20 times with water, stirred, filtered, and dried to obtain 43.6 g of compound IV-1. The yield of the two-step reaction was 109%.

[0087] Example 2-1-2

[0088] Bromination reaction: 9 mL of perchloric acid and 40 g of compound II-1 were added to 230 mL of DMF (N,N-dimethylformamide). 28 g of DBH (dibromohydantoin) was added in portions. The temperature was maintained at -5 °C. TLC monitoring was performed until no compound II-1 was detected, indicating the reaction was complete. Then, 450 mL of 10% sodium sulfite solution was slowly added dropwise. After the addition was complete, the pH of the reaction solution was adjusted to 6.5 with acetic acid. The reaction solution was diluted 20 times with ice water, stirred, and allowed to stand. The solution was filtered and dried to obtain compound III-1.

[0089] Reduction reaction: 27 mL of hypophosphite was slowly added dropwise to 17 g of potassium bicarbonate and 280 mL of methanol. After the addition was complete, the reaction solution was heated to 55 °C. Then, compound III-1 from the previous step and 20 g of AIBA (azobisisobutylamidine dihydrochloride) were added, and the mixture was heated to 65 °C. The system was refluxed, and during the reaction, 30 mL of a pre-prepared 25% potassium carbonate solution was slowly added dropwise, maintaining the pH of the system at 6. The reaction was monitored by HPLC until complete. Heating was stopped, and the reaction solution was cooled to room temperature, concentrated under reduced pressure, rinsed twice with water, and concentrated until no solvent evaporated. The solution was diluted 20 times with water, stirred, filtered, and dried to obtain 43.1 g of compound IV-1. The yield of the two-step reaction was 108%.

[0090] Example 2-2

[0091]

[0092] Bromination reaction: 10 mL of perchloric acid and 40 g of compound II-3 were added to 250 mL of DMF (N,N-dimethylformamide). 40 g of NBS (N-bromosuccinimide) was added in portions. The temperature was controlled at 20 °C. TLC monitoring was performed until no compound II-2 was detected, indicating the reaction was complete. Then, 500 mL of 10% sodium sulfite solution was slowly added dropwise. After the addition was complete, the pH of the reaction solution was adjusted to 6.5 with acetic acid. The reaction solution was diluted 15 times with ice water, stirred, and allowed to stand. The solution was filtered and dried to obtain compound III-2.

[0093] Reduction reaction: 28 mL of hypophosphoric acid was slowly added dropwise to 15 g of sodium bicarbonate and 300 mL of ethanol. After the addition was complete, the reaction solution was heated to 52 °C. Then, compound III-2 from the previous step and 25 g of ABVN (azobisisoheptanenitrile) were added, and the temperature was further increased to 60 °C. During the reaction, 30 mL of a pre-prepared 25% potassium carbonate solution was slowly added dropwise, maintaining the pH of the system at 6. The reaction was monitored by HPLC until complete. Heating was stopped, and the reaction solution was cooled to room temperature. The solution was concentrated under reduced pressure, rinsed twice with water, and concentrated until no solvent evaporated. It was then diluted 20 times with water and stirred. The solution was filtered and dried to obtain 42.5 g of compound IV-2. The yield of the two-step reaction was 106%.

[0094] Example 317 Side Chain Protection Reaction

[0095] Example 3-1

[0096]

[0097] Example 3-1-1

[0098] 50 g of paraformaldehyde was dissolved in 60 mL of concentrated hydrochloric acid. Paraformaldehyde hydrochloric acid solution, 40 g of compound IV-1, and 120 mL of chloroform were added to a reaction flask. The reaction was carried out at 20 °C. TLC monitoring showed no further reaction of compound IV-1, indicating completion of the reaction. The organic phase was separated from the reaction solution, and the aqueous phase was extracted twice with chloroform. The combined organic phases were washed with 5% sodium carbonate solution. The solution was concentrated under reduced pressure, flushed twice with methanol, concentrated to a small volume, cooled to 0 °C, filtered, and dried to give 142.4 g of compound V-1, with a yield of 106%.

[0099] Example 3-1-2

[0100] 200 mL of 40% formaldehyde solution, 40 g of compound IV-1, and 100 mL of chloroform were added to a reaction flask. The reaction was carried out at 40 °C. TLC monitoring showed no change in compound IV-1, indicating the reaction was complete. The organic phase was separated from the reaction solution, and the aqueous phase was extracted twice with chloroform. The organic phases were combined and washed with 5% sodium carbonate solution. The solution was concentrated under reduced pressure, flushed twice with methanol, concentrated to a small volume, cooled to 0 °C, filtered, and dried to give 141.8 g of compound V-1, with a yield of 105%.

[0101] Example 3-2

[0102]

[0103] 60 g of paraformaldehyde was dissolved in 100 mL of 30% sulfuric acid solution. Paraformaldehyde-sulfuric acid solution, 40 g of compound IV-2, and 100 mL of dichloromethane were added to a reaction flask. The reaction was carried out at 0 °C. TLC monitoring showed no further reaction of compound IV-2. After the reaction was complete, the organic phase was separated from the reaction solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with 5% sodium carbonate solution. The solution was concentrated under reduced pressure, flushed twice with methanol, concentrated to a small volume, cooled to -5 °C, filtered, and dried to give compound V-2 41.0 g, with a yield of 103%.

[0104] Example 4: Preparation of Cortivastatin Intermediate

[0105]

[0106] Example 4-1

[0107] Preparation of Schiff base: 40 g of compound V, 240 mL of ethanol, 20 mL of triethyl orthoformate, and 0.68 g of p-toluenesulfonic acid monohydrate were added to a reaction flask. The reaction solution was heated to 40 °C, and TLC monitoring showed no remnants of compound V. 10 mL of N-methylaniline and 8 mL of 35% formaldehyde aqueous solution were added to the system, and the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and 20 mL of 5% sodium bicarbonate solution was added and stirred. The reaction solution was diluted 25 times with ice water, stirred, allowed to stand overnight, filtered, and discharged.

[0108] Methylene reaction: Add the above Schiff base and 100 mL of tetrahydrofuran to the reaction flask, lower the system temperature to -5°C, slowly add 60 mL of concentrated hydrochloric acid to the system, and continue the reaction after the addition is complete. Monitor the reaction by TLC until the reaction is complete, dilute the reaction solution in 25 times ice water, stir, filter, and dry to obtain compound VI 36 g, with a mass yield of 90%.

[0109] Hydrolysis reaction: 30 g of compound VI, 90 mL of methanol, and 90 mL of dichloromethane were added to a reaction flask and reacted at room temperature (20 °C). 45 mL of a 10% potassium hydroxide methanol solution was added dropwise to the system. The reaction was monitored by TLC until completion. The pH of the reaction solution was adjusted to 6.5 with acetic acid. The solution was concentrated under reduced pressure, flushed twice with methanol, concentrated to a small volume, cooled to -5 to 0 °C, filtered, and dried to obtain 27 g of compound VII (yield: 90%).

[0110] Transposition reaction: 25 g of compound VII, 7.5 g of wet palladium / carbon, and 250 mL of ethanol were added to a reaction flask. The reaction mixture was heated to 80 °C and refluxed. Benzyl alcohol ethanol solution was slowly added dropwise. The reaction was monitored by TLC until completion. The reaction mixture was then cooled to 50 °C to remove the palladium / carbon from the system. The mixture was concentrated under reduced pressure, flushed twice with methanol, concentrated to a small volume, cooled to -5 °C, filtered, and dried to obtain 24 g of the diclofenac intermediate, with a yield of 96%.

[0111] Example 4-2

[0112] Preparation of Schiff base: 40 g of compound V, 300 mL of methanol, 30 mL of triethyl orthopropionate, and 4 g of pyridine hydrobromide were added to a reaction flask. The reaction solution was heated to 65 °C, and TLC monitoring showed no remnants of compound V. 10 mL of dimethylamine and 10 mL of 35% formaldehyde aqueous solution were added to the system, and TLC monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, and 20 mL of 5% sodium bicarbonate solution was added and stirred. The reaction solution was diluted in 25 times its volume of ice water, stirred, allowed to stand overnight, filtered, and discharged.

[0113] Methylene reaction: Add the above Schiff base and 50 mL of acetone to the reaction flask, lower the system temperature to 0 °C, slowly add 60 mL of 30% concentrated sulfuric acid to the system, and continue the reaction after the addition is complete. Monitor the reaction by TLC until the reaction is complete, dilute the reaction solution in 25 times ice water, stir, filter, and dry to obtain compound VI 35 g, with a mass yield of 88%.

[0114] Hydrolysis reaction: 30 g of compound VI, 90 mL of methanol, and 100 mL of chloroform were added to a reaction flask and reacted at room temperature (20 °C). 50 mL of a 10% potassium hydroxide methanol solution was added dropwise to the system. The reaction was monitored by TLC until completion. The pH of the reaction solution was adjusted to 6.5 with acetic acid. The solution was concentrated under reduced pressure, flushed twice with methanol, concentrated to a small volume, cooled to -5 to 0 °C, filtered, and dried to obtain 28 g of compound VII (yield: 93%).

[0115] Transposition reaction: 25 g of compound VII, 7.5 g of wet palladium / carbon, and 300 mL of methanol were added to a reaction flask. The reaction solution was heated to 65 °C and refluxed. Benzyl alcohol methanol solution was slowly added dropwise to the system. The reaction was monitored by TLC until completion. The reaction solution was then cooled to 50 °C to remove the palladium / carbon from the system. The mixture was concentrated under reduced pressure, flushed with methanol, concentrated to a small volume, cooled to 0 °C, filtered, and dried to obtain 23 g of the divalvazole intermediate, with a yield of 92%.

[0116] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for protecting the 17-position side chain of a steroid compound, characterized in that, Includes the following steps: (b) Bromination reaction: Compound II reacts with a brominizing agent and a formylating agent under the action of an acidic catalyst to give compound III; (c) Reduction reaction: Compound III reacts with a hydrogen donor, an azo radical initiator and an optional base reagent to give compound IV; (d) 17-position side chain protection reaction: Compound IV reacts with formaldehyde or paraformaldehyde to give compound V; In step (b), the brominating agent is selected from one or a combination of several of dibromohydantoin, dibromocyanoacetamide, dibromocyanopropionamide, N-bromoacetamide, N-bromophthalamide, or N-bromosuccinimide; the acidic catalyst is selected from perchloric acid; and the formylated agent is selected from N,N-dimethylformamide. In step (c), the azo radical initiator is selected from one or a combination of several of azobisisobutyrazoline hydrochloride, azobisisobutyramidine dihydrochloride, azobisisoheptanenitrile, and azobisisobutyronitrile; the hydrogen donor is selected from hypophosphite; and the base reagent is selected from organic bases and / or inorganic bases. Among them, 11-carboxylate does not participate in the side chain protection reaction in step (d), and no column chromatography purification is required after the reaction. High-purity compound V can be obtained by conventional methods. R1 and R2 shown in the structural formulas of compounds II, III, IV, and V are chosen independently of each other, and: R1 = H, α-halogen, α-CH3 or CH2; R2 = H or CH3; and It can be a single bond or a double bond.

2. The method for protecting the 17-position side chain of a steroid compound according to claim 1, characterized in that, Includes the following steps: (a) Hydrolysis reaction: Compound I reacts under alkaline conditions to give compound II; (b) Bromination reaction: Compound II reacts with a brominizing agent and a formylating agent under the action of an acidic catalyst to give compound III; (c) Reduction reaction: Compound III reacts with a hydrogen donor, an azo radical initiator and an optional base reagent to give compound IV; (d) 17-position side chain protection reaction: Compound IV reacts with formaldehyde or paraformaldehyde to give compound V; In step (b), the brominating agent is selected from one or a combination of several of dibromohydantoin, dibromocyanoacetamide, dibromocyanopropionamide, N-bromoacetamide, N-bromophthalamide, or N-bromosuccinimide; the acidic catalyst is selected from perchloric acid; and the formylated agent is selected from N,N-dimethylformamide. In step (c), the azo radical initiator is selected from one or a combination of several of azobisisobutyrazoline hydrochloride, azobisisobutyramidine dihydrochloride, azobisisoheptanenitrile, and azobisisobutyronitrile; the hydrogen donor is selected from hypophosphite; and the base reagent is selected from organic bases and / or inorganic bases. Among them, 11-carboxylate does not participate in the side chain protection reaction in step (d), and no column chromatography purification is required after the reaction. High-purity compound V can be obtained by conventional methods. R1, R2, and R3 shown in the structural formulas of compounds I, II, III, IV, and V are chosen independently of each other, and: R1 = H, α-halogen, α-CH3 or CH2; R2 = H or CH3; R3 = C1-C6 alkyl group; and It can be a single bond or a double bond.

3. The method for protecting the 17-position side chain of a steroid compound according to claim 2, characterized in that: wherein, R1, R2, and R3 shown in the structural formulas of compounds I, II, III, IV, and V are chosen independently of each other, and: R1=H; R2=α-CH3; R3=CH3; and It can be a single bond or a double bond.

4. The method for protecting the 17-position side chain of a steroid compound according to any one of claims 1-3, characterized in that: In step (b), the brominating agent is selected from dibromohydantoin or N-bromosuccinimide; the acidic catalyst is selected from perchloric acid; and the formylating agent is selected from N,N-dimethylformamide. In step (c), the azo radical initiator is selected from one or a combination of several of azobisisobutyrazoline hydrochloride, azobisisobutyramidine dihydrochloride, or azobisisoheptanenitrile; the hydrogen donor is selected from hypophosphorous acid; and the base reagent is selected from inorganic bases.

5. The method for protecting the 17-position side chain of a steroid compound according to claim 2 or 3, characterized in that: In step (a), the reaction temperature is selected from 50-65°C; In step (b), the temperature of the reaction is selected from -10 to 20°C; In step (c), the reaction temperature is selected from 50-65°C; In step (d), the temperature of the reaction is selected from 0-40°C.

6. The method for protecting the 17-position side chain of a steroid compound according to claim 5, characterized in that: In step (a), the reaction temperature is selected as 60-65℃; In step (b), the reaction temperature is selected from -5 to 0°C; In step (c), the reaction temperature is selected from 60-65°C; In step (d), the reaction temperature is selected from 20-25°C.

7. The method for protecting the 17-position side chain of a steroid compound according to claim 1, and its application in the preparation of cortivastatin and its intermediates.

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