Preparation method and production system of 16α-hydroxyprednisone intermediate

Abstract

The present invention belongs to the field of pharmaceutical synthesis technology, and specifically relates to a preparation method and production system for a 16α-hydroxyprednisone intermediate. This patent uses 21-hydroxypregnane-1,4,9(11),16-tetraene-3,20-dione-21-acetate as a raw material, and prepares a compound of formula II through a bromohydroxylation reaction; the compound of formula II is then subjected to a debromination reaction to prepare 11β,21-dihydroxypregnane-1,4,16-triene-3,20-dione-21-acetate. The present invention improves the traditional steroid compound 11β hydroxyl preparation method, controls the generation of impurities, improves the reaction conversion rate, and uses a new generation of steroid front-end compounds as raw materials, shortens the preparation steps, and improves the preparation efficiency. The method of the present invention has low requirements for the reaction apparatus, short production time, simple operation, is suitable for industrial production, and has good market prospects.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method and a production system for a 16α-hydroxyprednisone intermediate. Background Art

[0002] Non-halogenated corticosteroids are widely used to treat intractable asthma and inflammation. Among them, budesonide and ciclesonide have become the first choice drugs for the clinical treatment of severe asthma and allergic rhinitis due to their advantages such as small dosage, strong local anti-inflammatory effect and small systemic side effects. In recent years, they have been widely used to treat inflammation caused by upper respiratory tract infections in children.

[0003] 16α-Hydroxyprednisolone is an important intermediate in the synthesis of budesonide and ciclesonide. The literature "Progress in the Synthesis of 16α-Hydroxyprednisolone" provides a detailed analysis of its synthesis methods. Based on the starting materials, the synthesis methods can be divided into two categories: prednisolone and prednisone. The routes using prednisone as the raw material have a common disadvantage: the reaction selectivity is poor when the 11-ketone is reduced to an alcohol, and it is easy to produce multiple reductions and 11-position chiral isomer impurities, which affect product quality and yield. The route using prednisolone as the raw material has become the mainstream route for the synthesis of 16α-hydroxyprednisolone due to its simple reaction, high selectivity, and high yield. Among them, the compound of formula I is an important intermediate in the synthesis of 16α-hydroxyprednisolone.

[0004]

[0005] There are two publicly known routes for synthesizing 16α-hydroxyprednisolone using prednisolone as a raw material. Route 1: Patent Publication No. CN101863952B discloses a method for obtaining 16α-hydroxyprednisolone via esterification, elimination, oxidation, and hydrolysis. This route is shorter and operates under mild reaction conditions, but the yield of the final hydrolysis step is only approximately 70%, suggesting that this route may suffer from low purity of the preceding intermediates or difficulty in hydrolyzing the 11-acetyl group. Route 2: Patent Publication No. CN103724396A discloses a six-step method for obtaining 16α-hydroxyprednisolone via a cyclic ester reaction, hydrolysis, esterification, elimination, oxidation, and hydrolysis. Although this route involves more steps, it is a classic method for preparing steroidal compounds and, therefore, has greater industrial production value than the method disclosed in Patent Publication No. CN101863952B. However, the method of patent CN103724396A also has obvious shortcomings. When the double bond at positions 16 and 17 is prepared by eliminating the acetoxy group, that is, when preparing compound formula I, a large number of side reaction impurities are generated, which affects the yield and product quality of the overall route.

[0006] Therefore, it is necessary to improve the preparation method of the compound of formula I to shorten its synthetic route and improve the preparation yield and quality of the compound of formula I. Summary of the Invention

[0007] In view of this, one of the objects of the present invention is to provide a method for preparing a compound of formula II. The present invention controls the concentration of bromide ions by adding a brominating agent in batches, thereby reducing side reactions and improving the quality and yield of the corresponding intermediates.

[0008] To achieve the above object, the present invention adopts the following technical solutions:

[0009] The preparation method of the compound of formula II is to prepare the compound of formula II by bromohydroxylation reaction using the compound of formula III as a raw material, comprising the following steps: dissolving the compound of formula III in a mixed solvent of organic solvent A and water, adding a catalyst and controlling the temperature; adding a brominating agent in portions and stirring; after the reaction is complete, adding a reducing agent, controlling the temperature and dripping water for crystallization, and filtering to obtain the compound of formula II;

[0010]

[0011] Furthermore, the organic solvent A is any one or more of tetrahydrofuran, acetone, and methyl isobutyl ketone.

[0012] Furthermore, the organic solvent A is preferably tetrahydrofuran.

[0013] Furthermore, the ratio of the organic solvent A to the compound of formula III is 3 ml / g to 20 ml / g, preferably 5 ml / g.

[0014] Furthermore, the volume ratio of the organic solvent A to water is 20:1 to 5:1, preferably 5:1.

[0015] Furthermore, the catalyst is any one or more of perchloric acid and fluoroboric acid.

[0016] Furthermore, the catalyst is preferably perchloric acid.

[0017] Furthermore, the molar ratio of the catalyst to the compound of formula III is 0.1 to 0.5:1, preferably 0.4:1.

[0018] Furthermore, after adding the catalyst, the temperature is controlled to be -20 to 10°C; after adding the reducing agent, the temperature is controlled to be 20 to 40°C.

[0019] Furthermore, the brominating agent is any one or more of NBS and dibromohydantoin.

[0020] Furthermore, the brominating agent is preferably dibromohydantoin.

[0021] Furthermore, the reducing agent is any one or more of sodium metabisulfite and an aqueous solution of sodium sulfite.

[0022] Furthermore, the reducing agent is preferably a sulfurous acid solution.

[0023] Furthermore, the volume ratio of crystal water to tetrahydrofuran is 1:1 to 1:5, preferably 5:1.

[0024] The preparation route of the compound of formula II is as follows:

[0025]

[0026] The second object of the present invention is to provide a method for preparing the compound of formula I using the method described in the first object, which solves the problems of excessive preparation routes for the compound of formula I, numerous impurities that are difficult to remove, high cost, and low yield.

[0027] To achieve the above object, the present invention adopts the following technical solutions:

[0028] The method for preparing the compound of formula I using the method described in the first object comprises the following steps:

[0029] (1) Bromohydroxylation reaction: prepare the compound of formula II by the method according to claim 1;

[0030] (2) Debromination reaction: add chromium chloride and N times equivalent zinc powder to organic solvent B, stir, and add thioglycolic acid dropwise under temperature control, and stir after the addition is complete; add the mixed solution of the compound of formula II obtained in step (1) and organic solvent C dropwise under temperature control to react; add M times equivalent zinc powder in batches to react; filter, drip water, crystallize, and filter to obtain the compound of formula I.

[0031]

[0032] Furthermore, in step (2), the total amount of zinc powder is 1.0 to 1.5 times the molar amount of the compound of formula II, wherein the N-fold equivalent is 0.3 to 0.7 times the molar amount of the compound of formula II, and the M-fold equivalent is the total amount of zinc powder minus the N-fold equivalent of zinc powder, that is, the M-fold equivalent is [(1.0 to 1.5) - N] times the molar amount of the compound of formula II.

[0033] Furthermore, in step (2), the organic solvent B is any one or more of acetone, dimethylformamide, dimethylacetamide, and N-methylpyrrolidone.

[0034] Furthermore, the organic solvent B is preferably dimethylformamide.

[0035] Furthermore, in step (2), the organic solvent C is any one or more of dimethylformamide, dimethylacetamide, and N-methylpyrrolidone.

[0036] Furthermore, the organic solvent C is preferably dimethylformamide.

[0037] Furthermore, the step (2) is carried out under nitrogen protection.

[0038] Furthermore, in step (2), the temperature is controlled twice at -15 to -5°C.

[0039] The preparation route of the compound of formula I is as follows:

[0040]

[0041] The general route for preparing the compound of formula I is as follows:

[0042]

[0043] The compound of formula I is 11β,21-dihydroxypregnane-1,4,16-triene-3,20-dione-21-acetate; the compound of formula III is 21-hydroxypregnane-1,4,9(11),16-tetraene-3,20-dione-21-acetate, referred to as tetraene acetate or 3TR; the compound of formula II is 9α-bromo-11β,21-dihydroxypregnane-1,4,16-triene-3,20-dione-21-acetate

[0044] The third object of the present invention is to provide a production system for preparing the compound of formula I described in the second object.

[0045] To achieve the above object, the present invention adopts the following technical solutions:

[0046] A production system for preparing a compound of formula I comprises a production unit 1, a temperature control unit, a filtration unit 1, a drying unit 1, a production unit 2, a filtration unit 2, and a drying unit 3; the production unit 1 is sequentially connected to the filtration unit 1, the drying unit 1, the production unit 2, the filtration unit 2, and the drying unit 3; the temperature control unit is respectively connected to the production unit 1 and the production unit 2; the compound of formula III undergoes a bromohydroxylation reaction in the production unit 1 under the action of a catalyst, a brominating agent, and a reducing agent in sequence, and the temperature is controlled by the temperature control unit, and the compound is filtered and dried through the filtration unit 1 and the drying unit 1 to obtain the compound of formula II; the compound of formula II undergoes a debromination reaction in the production unit 2 under the conditions of chromium chloride, thioglycolic acid, and the addition of zinc powder in batches, and the temperature is controlled by the temperature control unit, and the compound is filtered and dried through the filtration unit 2 and the drying unit 2 to obtain the compound of formula I.

[0047] The beneficial effects of the present invention are:

[0048] 1. The raw materials selected in the present invention are earlier intermediates than prednisolone, which are cheaper and easier to obtain;

[0049] 2. The reaction conditions of the present invention are mild, the overall conversion rate is higher than 85%, and the product purity is higher than 99.0%;

[0050] 3. In step 1, compared with the traditional method of adding the brominating agent, the present invention controls the concentration of bromide ions by adding the brominating agent in batches, thereby reducing side reactions and improving the quality and yield of the corresponding intermediate;

[0051] 4. The combination of chromium chloride, thioglycolic acid, and zinc powder is a classic method for removing the bromine atom at the 9th position of steroid compounds. Compared with the traditional method of adding zinc powder all at once, the present invention effectively controls the occurrence of side reactions by adding zinc powder at different stages and controlling the amount added, thereby improving the quality and yield of the intermediate.

[0052] 5. The present invention is simple to operate, does not require special reaction conditions and operations, can be well industrialized, and has good market prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the compound of formula II;

[0054] Figure 2 is the hydrogen nuclear magnetic resonance spectrum of the compound of formula I. DETAILED DESCRIPTION

[0055] The technical solutions of the present invention will be further described in detail below with reference to specific embodiments. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Therefore, all other embodiments derived by those skilled in the art based on the embodiments of the present invention without inventive effort are intended to fall within the scope of protection of the present invention.

[0056] Example 1. Preparation of compound of formula II

[0057] 100g of the compound of formula III (0.27mol), 100mL of purified water, and 1000mL of tetrahydrofuran were added to a reaction flask, stirred, and cooled to -15°C to -10°C. 5.0g of fluoroboric acid was added; the temperature was maintained at -15°C to -5°C, and 73g of N-bromosuccinimide (NBS) (0.41mol) was added (in five portions, 10 minutes apart, with 14.6g added each time). After the addition, the reaction was allowed to proceed at -15°C to -5°C for 1.0 hour, and the starting material spot disappeared by TLC. After the reaction was complete, 10% sodium metabisulfite was added dropwise at -15°C to -5°C until the starch KI test did not turn blue. After the addition was complete, 3000ml of purified water was added dropwise at 20-30°C. After the addition was complete, the mixture was stirred, filtered, and dried to obtain 125g of the compound of formula II, with a moisture content of 11.1%, an HPLC purity of 97.5%, and a yield of 88%.

[0058] The H NMR spectrum of the compound of formula II prepared in this example is as follows: Figure 1 As shown, the H NMR spectrum data are as follows:

[0059] 1 H NMR(400MHz,DMSO)δ7.35(d,1H),6.99(m,1H),6.23(dd,1H),5.99(t,1H),5.68(d,1H),5.10(d,1H),4.94(d,1H) ,4.56(dd,1H),2.68(td,1H),2.40-2.21(m,6H),2.09-2.01(m,5H),1.69(s,3H),1.63-1.54(m,1H),1.17(s,3H).

[0060] Example 2. Preparation of compound of formula II

[0061] Add 100g of Formula III compound (0.27mol), 100mL of purified water, and 1000mL of tetrahydrofuran to a reaction flask, stir, and cool to -15°C to -10°C. Add 9.8g of perchloric acid; then, at -15°C to -5°C, add 75g of dibromohydantoin (0.26mol) in five 10-minute increments. After addition, allow to react at -15°C to -5°C for 1.0 hour, as determined by TLC, until the starting material spot disappears. After the reaction is complete, add 5% sodium sulfite dropwise at -15°C to -5°C until the starch KI test does not turn blue. Add 5000ml of purified water dropwise at 20°C to 30°C, stir, filter, and dry to obtain 131g of Formula II compound, with a moisture content of 12.1%, an HPLC purity of 98.5%, and a yield of 91%.

[0062] Example 3. Preparation of compound of formula II

[0063] 100 g of compound III (0.27 mol), 100 mL of purified water, and 1000 mL of tetrahydrofuran were added to a reaction flask, stirred, and cooled to -15°C to -10°C. 9.8 g of perchloric acid was added; the temperature was controlled at -15°C to -5°C, and 75 g of dibromohydantoin (0.26 mol) was added (in one go). After the addition was complete, the temperature was controlled at -15°C to -5°C, and the reaction was allowed to proceed for 1.0 hour, as indicated by TLC, until the starting material point disappeared. After the reaction was complete, 10% sodium metabisulfite was added dropwise at -15°C to -5°C until the starch KI test did not turn blue. After the addition was complete, 4000 ml of purified water was added dropwise at 20°C to 30°C. After the addition was complete, the mixture was stirred, filtered, and dried to obtain 128 g of compound II, with a moisture content of 12.8%, an HPLC purity of 95.2%, and a yield of 89%.

[0064] Example 4. Preparation of compound of formula I

[0065] Under nitrogen protection, 250 mL of dimethylformamide and 14.4 g (0.054 mol) of chromium trichloride hexahydrate were cooled to -15 to -5°C, 4.2 g (0.064 mol) of zinc powder was added, and the temperature was controlled at -15 to -5°C. 19.8 g (0.21 mol) of thioglycolic acid, 50 g (0.11 mol) of the compound of formula II obtained in Example 1 and 250 mL of dimethylformamide were added dropwise in sequence. After the addition was completed, the temperature was controlled at -15 to -5°C and the reaction was continued for 30 minutes. Then 4.2 g (0.064 mol) of zinc powder was added (in three portions, 10 minutes apart, and 1.4 g was added each time). After the addition was completed, TLC was performed until the raw material point disappeared. 2000 ml of drinking water was added dropwise, the mixture was filtered, washed with drinking water, and dried. The filter cake was dissolved in 500 ml of dichloromethane and 500 ml of methanol, filtered, and the filtrate was concentrated to a residual amount of about 200 ml. The temperature was lowered, crystallized, and filtered to obtain 39 g of the compound of formula I with an HPLC purity of 99.2% and a yield of 95.1%.

[0066] The H NMR spectrum of the compound of formula I prepared in this example is as follows: Figure 2 As shown, the H NMR spectrum data are as follows:

[0067] 1 H NMR(400MHz,DMSO-d6)δ7.35(d,1H),6.95(t,1H),6.17-6.14(dd,1H),5.91(s,1H),5.10-4.83(ddd,3H),4.20-4.16(m,1H),2.60-2.52(m, 1H),2.39-2.29(m,3H),2.21-2.01(m,6H),1.43-1.39(m,3H),1.37-1 .36(d,1H),1.30-1.24(m,1H),1.15-1.01(m,3H),0.99-0.98(s,2H).

[0068] Example 5. Preparation of compound of formula I

[0069] Under nitrogen, 250 mL of dimethylformamide and 14.4 g (0.054 mol) of chromium trichloride hexahydrate were cooled to -15--5°C. 8.4 g (0.12 mol) of zinc powder was added, and a solution prepared by adding 19.8 g (0.21 mol) of mercaptoacetic acid and 50 g (0.11 mol) of the compound of Formula II in 250 mL of dimethylformamide was added dropwise sequentially at a temperature of -15--5°C. After completion of the addition, the temperature was controlled at -15--5°C to react for 1 hour. When the starting material point disappeared by TLC, 2000 mL of drinking water was added dropwise, the mixture was filtered, washed with drinking water, and drained. The filter cake was dissolved in 500 mL of dichloromethane and 500 mL of methanol, filtered, and the filtrate was concentrated to a residual volume of approximately 200 mL. The mixture was cooled, crystallized, and filtered to obtain 32 g of the compound of Formula I with an HPLC purity of 95.2% and a yield of 78%.

Claims

1. A method for preparing a compound of formula I, characterized in that: The steps include: (1) Bromohydroxylation reaction: dissolve the compound of formula III in a mixed solvent of organic solvent A and water, add a catalyst and control the temperature; add the brominating agent in portions and stir; after the reaction is complete, add the reducing agent, control the temperature and add water to crystallize, and filter to obtain the compound of formula II; (2) Debromination reaction: add chromium chloride and N times equivalent zinc powder to organic solvent B, stir, and add thioglycolic acid dropwise at a controlled temperature, and stir after the addition is complete; add the mixed solution of the compound of formula II obtained in step (1) and organic solvent C dropwise at a controlled temperature to react; add M times equivalent zinc powder in batches to react; filter, drip water, crystallize, and filter to obtain the compound of formula I; the total amount of zinc powder is 1.0 to 1.5 times the molar amount of the compound of formula II, wherein the N times equivalent is 0.3 to 0.7 times the molar amount of the compound of formula II, and the M times equivalent is the total amount of zinc powder minus N times equivalent zinc powder; 2. The method according to claim 1, characterized in that In step (1), the organic solvent A is any one or more of tetrahydrofuran, acetone, and methyl isobutyl ketone; and the ratio of the organic solvent A to the compound of formula III is 3 ml / g to 20 ml / g.

3. The method according to claim 1, characterized in that In step (1), the catalyst is any one or more of perchloric acid and fluoroboric acid.

4. The method according to claim 1, wherein In step (1), the brominating agent is any one or more of NBS and dibromohydantoin.

5. The method according to claim 1, wherein In step (1), the reducing agent is any one or more of sodium metabisulfite and an aqueous solution of sodium sulfite.

6. The method according to claim 1, characterized in that In step (2), the organic solvent B is any one or more of acetone, dimethylformamide, dimethylacetamide, and N-methylpyrrolidone.

7. The method according to claim 1, characterized in that In step (2), the organic solvent C is any one or more of dimethylformamide, dimethylacetamide, and N-methylpyrrolidone.

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