Method for synthesizing abiraterone at low cost

Abstract

The invention discloses a low-cost abiraterone synthesis method, and relates to the technical field of medicine preparation, and the method comprises the following steps: (1) preparing an organic zinc reagent: adding an inorganic catalyst, an initiator, zinc powder or zinc chloride into an aprotic polar solvent, and dropwise adding 3-bromopyridine to obtain the organic zinc reagent; (2) synthesizing an intermediate: adding the intermediate III, a metal catalyst and a ligand into an aprotic polar solvent, dropwise adding an organic zinc reagent, and carrying out a coupling reaction at a certain temperature to obtain an intermediate II; (3) mixing and stirring the intermediate II and a hydrochloric acid aqueous solution for deprotection, filtering and purifying to obtain abiraterone; the method has the advantages of low preparation cost, high yield, high purity and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, and particularly relates to a method for synthesizing abiraterone at low cost. BACKGROUND

[0002] Prostate cancer is the second leading cause of cancer death.

[0003] Previous drugs for treating prostate cancer mainly include Lupron of Abbott and Casoex of AstraZeneca, etc., but the drug efficacy disappears with the extension of the use time of these drugs.

[0004] Abiraterone acetate is used for treating metastatic castration-resistant prostate cancer and newly diagnosed high-risk metastatic endocrine therapy-sensitive prostate cancer. After entering the human body by oral administration, it is decomposed into the effective component abiraterone. Abiraterone blocks the synthesis of androgens in prostate cancer cells by inhibiting the activity of the key enzyme CYP17 in androgen synthesis, thereby inhibiting the growth of prostate cancer cells.

[0005] At present, the synthesis routes of abiraterone acetate mainly include the following: The patent US5604213 provides a synthesis route as follows:

[0006] In this route, triflic acid, diethylpyridine borane and palladium catalyst are used, which have high cost, and there are many by-products and low yield.

[0007] The patent CN117683073A provides a synthesis route as follows:

[0008] In this route, an expensive iodide intermediate and a palladium catalyst are used, and it is difficult to completely form the hydrochloride of abiraterone, even if 36% hydrochloric acid is used, a certain amount of abiraterone is not formed into a salt.

[0009] The patent CN119143832A provides a synthesis route as follows:

[0010] In this route, the acetylation at position 3 is advanced, and the deacetylation phenomenon occurs in the subsequent phosphonate esterification and coupling reaction process, and the borate is expensive, and the advantage is not obvious.

[0011] The patent WO95 / 09178 provides a synthesis route as follows:

[0012] In this route, the material cost is also high, the iodination reaction yield is low, the coupling reaction time is long, and the use of hydrazine hydrate has certain risks.

[0013] Patent CN103864878A provides two synthetic routes as follows:

[0014] In the above synthetic routes, the first route uses triflate, which is not only genotoxic but also expensive, and elimination reaction occurs during the use of triflate, small molecule acetic acid is removed, and the generated impurities cannot be removed by recrystallization in subsequent steps, which is difficult to purify; the second route of metal reagent will react with 3-hydroxyl, which will significantly affect the yield, and the coupling product will further react with the raw material at 16-position to generate impurities, which cannot be removed by recrystallization. SUMMARY

[0015] The present application aims at the defects of high cost of raw and auxiliary materials, genotoxic risk, many by-products and difficult to remove, and low yield of the prior art, and provides a low-cost synthesis method of abiraterone.

[0016] A low-cost synthesis method of abiraterone, comprising the following steps: (1) Preparation of organic zinc reagent: An inorganic catalyst, an initiator, zinc powder or zinc chloride is added in an aprotic polar solvent, and then 3-bromopyridine is added dropwise to obtain an organic zinc reagent; The structure of the prepared organic zinc reagent is as follows:

[0017] In the preparation process of the organic zinc reagent, the molar ratio of zinc powder or zinc chloride:inorganic catalyst: initiator:3-bromopyridine is 1-1.5:1-1.5:0-0.1:1.

[0018] In the preparation process of the organic zinc reagent, the aprotic polar solvent is mainly an ether selected from one or more of methyl tert-butyl ether, tetrahydrofuran, dioxane, isopropyl ether, and preferably tetrahydrofuran or dioxane.

[0019] In the preparation process of the organic zinc reagent, the inorganic catalyst is selected from one of LiF, LiCl, LiBr, Lil, LiOTf, and preferably LiCl or LiBr.

[0020] In the preparation process of the organic zinc reagent, the initiator is selected from one or more of iodine, 1,2-dibromoethane, and trimethylchlorosilane, and preferably a mixture of 1,2-dibromoethane and trimethylchlorosilane.

[0021] (2) Synthesis of intermediate: In a non-protic polar solvent, intermediate III, metal catalyst, ligand, and organic zinc reagent are added, and a coupling reaction occurs at a certain temperature to obtain intermediate II. II.

[0022] The intermediate III has the following structure: III.

[0023] In the formula, R 1 is methoxymethyl (MOM), methoxyethoxymethyl (MEM), trimethylsilyl (TMS), trimethylsilyl ethoxymethyl (SEM), or 2-tetrahydropyranyl (THP), preferably methoxyethoxymethyl (MEM), trimethylsilyl (TMS), or 2-tetrahydropyranyl (THP).

[0024] In the coupling reaction, the metal catalyst is any one of CuCl2, Cu(acac), Cu(OAc)2, Cu(OTf)2.

[0025] In the coupling reaction, the ligand is any one of PPh3, TMEDA, P(o-ToI)3, DPPF, Xantphos, , , preferably TMEDA, , .

[0026] In the formula, G ’ is selected from methyl, methoxy, ethoxy, hydroxy, PPh3, chloro, bromo, iodo, acetyl, trifluoromethyl, cyclohexyl, nitrile, or C1-C6 alkyl thiol.

[0027] In the coupling reaction, the molar ratio of the materials is intermediate III: organic zinc reagent: metal catalyst: ligand = 1:1.5-2.5:0.005-0.02:0.1-0.5.

[0028] The reaction temperature of step (2) is 40-60°C, and the reaction time is 3-12 hours.

[0029] (3) Intermediate II and aqueous hydrochloric acid are mixed and stirred to remove the protection, filtered and purified to obtain abiraterone.

[0030] Preferably, the reaction solution of intermediate II prepared in step (2) is directly mixed with aqueous hydrochloric acid to remove the protection to obtain crude abiraterone.

[0031] Preferably, in the deprotection reaction, the mass concentration of the aqueous hydrochloric acid is 5-36%, preferably 5-15%.

[0032] The reaction equation of the present application is as follows:

[0033] The principle and benefits of the present application are as follows: (1) The present application provides a brand new synthesis process of abiraterone. The process adopts coupling / hydrolysis combined process. First, the bromide protected at C-3 position (intermediate III) is used as the substrate to couple with organic zinc reagent under the action of copper catalyst and ligand to obtain intermediate II. Then, a certain concentration of hydrochloric acid solution is added to hydrolyze at room temperature to obtain abiraterone. After simple post-treatment, abiraterone crude product with almost no pigment and low impurity content can be obtained. Abiraterone finished product with single impurity below 0.1% can be obtained by beating and purifying the abiraterone crude product with a small volume of single solvent or mixed solvent.

[0034] (2) Compared with the prior art, the present application has low preparation cost, high yield and high purity.

[0035] The present application uses low-cost intermediate III and copper catalyst. In the preparation process, intermediate II is not taken out in step (2), but is mixed with hydrochloric acid aqueous solution to deprotect to obtain abiraterone crude product, thereby further reducing the cost.

[0036] The present application adopts copper catalyst catalyzed negishi coupling reaction, optimizes the process conditions, and adopts coupling / deprotection combined process to avoid the material loss caused by taking out intermediate II first. Only a small amount of material is lost when purifying the abiraterone crude product, so the yield is better.

[0037] The present application adopts copper catalyst catalyzed negishi coupling reaction, optimizes the process conditions, and adopts coupling / deprotection combined process to avoid the material loss caused by taking out intermediate II first. Only a small amount of material is lost when purifying the abiraterone crude product, so the yield is better. DETAILED DESCRIPTION

[0038] The present application will be further illustrated by the following examples, but the present application is not limited to these examples. The reagents and raw materials used in the present application are known technology or commercially available products, unless otherwise specified.

[0039] Example 1

[0040] (1) Synthesis of organic zinc reagent: Lithium chloride (2.27 g, 53.48 mmol) and zinc powder (3.58 g, 54.71 mmol) were added to a 100 ml three-necked flask. After nitrogen purging, the flask was heated with a hot air gun and evacuated for 15 min. After nitrogen purging, the flask was cooled to room temperature. 50 ml of tetrahydrofuran was added and stirred thoroughly. Trimethylchlorosilane (0.13 g, 1.23 mmol) was added dropwise. After the addition was complete, the flask was stirred for 30 min. Then, 1,2-dibromoethane (0.29 g, 1.52 mmol) was added dropwise. After the addition was complete, the flask was stirred for 30 min. Finally, a tetrahydrofuran solution (10 ml) of 3-bromopyridine (6.5 g, 41.14 mmol) was slowly added dropwise at room temperature. After the addition was complete, the flask was kept warm and stirred for 2 h to obtain the organozinc reagent.

[0041] (2) Synthesis of abiraterone: Add 20 ml of THF, 3β-trimethylsiloxyandrost-5,16-diene-17-bromo (8.78 g, 20.73 mmol), copper chloride (0.03 g, 0.24 mmol), and (4-methoxyphenylethyl)diphenylphosphine (1.34 g, 4.19 mmol) to a 250 ml three-necked flask. After complete nitrogen purging, heat to 50 °C and add organozinc reagent (41.14 mmol) dropwise. After the addition is complete, maintain the temperature for 6 h, cool, and add 15 ml of 3.76% saline solution to quench the reaction. Separate the liquid and aqueous phases. Back-extract the product from the aqueous phase with 10 ml of MTBE. Combine the oil phases and add 15 ml of 10% hydrochloric acid solution to the oil phase. Stir at room temperature for 3 h, filter, and dry to obtain crude abiraterone. Slurry the crude product in acetone to obtain abiraterone with less than 0.1% impurities (7.19 g, 94.88%).

[0042] Product confirmation: 1 H NMR (400MHz, CDCl3): 0.96 (s, 3H), 0.97 (s, 3H), 3.40-3.63 (m, 1H), 5.32 (d, 1H, J =4.8Hz), 5.91 (s, 1H), 7.11-7.17 (m, 1H), 7.58 (d, 1H, J=8.1Hz), 8.37 (d, 1H, J=4.5Hz), 8.55 (s, 1H).

[0043] Replacement example To investigate the effects of catalysts and ligands on the synthesis of abiraterone, the preparation method shown in Example 1 was used, with the difference being that the selection of catalysts and ligands in step (2) of Example 1 was adjusted, and their effects on the yield of abiraterone were tested, as shown in Table 1.

[0044] Table 1 .

[0045] As shown in Table 1: (1) The influence of different catalysts on the reaction: the catalytic effect of copper chloride and copper acetylacetonate is better than that of copper triflate.

[0046] (2) The influence of ligand on the catalyst: the addition of ligand can significantly improve the catalytic effect of the catalyst. Under the same conditions without adding ligand, the catalytic effect of copper acetylacetonate is obviously better than that of copper chloride and copper triflate, and the yield reaches 80.63%, but under the addition of ligand, the catalytic performance of copper chloride is significantly improved.

[0047] (3) The selectivity of ligand to catalyst: it can be seen that different ligands have obvious differences in auxiliary catalytic effect, which shows that the selection of ligand is important. Among them, the combination of copper acetylacetonate and N,N'-dimethylcyclohexane-1,2-diamine has the best effect, and the yield reaches 95.18%, while the combination of copper chloride and (4-methoxyphenethyl) diphenylphosphine has a similar effect, and the yield reaches 94.88%.

[0048] Example 2

[0049] (1) Synthesis of organic zinc reagent: Into a 100ml three-necked flask, lithium chloride (2.27g, 53.48mmol), zinc chloride (7.91g, 58.00mmol), magnesium (1.39g, 58.00mmol) were added, and after nitrogen replacement, the hot air gun was heated while vacuuming for 15min, then nitrogen was replaced, and the temperature was lowered to room temperature. 50ml of tetrahydrofuran was added, then 1,2-dibromoethane (0.26, 1.40mmol) was added dropwise, and after stirring for 30min, a solution of 3-bromopyridine (6.5g, 41.14mmol) in tetrahydrofuran (10ml) was slowly added dropwise at room temperature, and after stirring for 2h, the organic zinc reagent was obtained.

[0050] (2) Synthesis of abiraterone Into a 250ml three-necked flask, 20ml THF, 3β-methoxyethoxymethoxyl androst-5, 16-diene-17-bromo (9.11g, 20.73mmol), copper acetylacetonate (0.06g, 0.24mmol), N, N'-dimethylcyclohexane-1, 2-diamine (0.3g, 2.13mmol), after nitrogen replacement, temperature was raised to 50℃, and then the organic zinc reagent (31.10mmol) was added dropwise. After the addition was completed, the reaction was incubated for 6h. Then 10ml 4.5% hydrochloric acid aqueous solution was added to quench the reaction. The liquid was separated, and the aqueous phase was back-extracted with 10ml MTBE. The oil phase was combined, 15ml 15% hydrochloric acid aqueous solution was added at 50℃, and stirred for 3-4h. Then the pH of the aqueous phase was adjusted to 7 by adding 30ml sodium carbonate aqueous solution. The filter cake was dried under vacuum to obtain abiraterone 1. The aqueous phase was discarded after separation, and the oil phase was concentrated. The filter cake was dried under vacuum with 30ml acetonitrile to obtain abiraterone 2. The two parts of abiraterone were combined, and the final product (6.60g, 91.05%) was obtained by acetic acid ethyl ester.

[0051] Example 3

[0052] (1) Synthesis of organic zinc reagent: Into a 100ml three-necked flask, lithium chloride (2.52g, 59.45mmol), zinc powder (3.76g, 57.59mmol) were added. After nitrogen replacement, the hot air gun was heated while vacuuming for 15min. Then the nitrogen was replaced, and the temperature was lowered to room temperature. Then 50ml tetrahydrofuran was added, and stirred thoroughly. Then trimethylchlorosilane (0.13g, 1.23mmol) was added dropwise. After the addition was completed, the mixture was stirred for 30min. Then 1, 2-dibromoethane (0.29, 1.52mmol) was added dropwise. After the addition was completed, the mixture was stirred for 30min. Then 3-bromopyridine (6.5g, 41.14mmol) in tetrahydrofuran (10ml) was added dropwise at room temperature. After the addition was completed, the mixture was incubated and stirred for 2h to obtain the organic zinc reagent.

[0053] (2) Synthesis of abiraterone Into a 250ml three-necked flask, 20ml THF, 3β-tetrahydropyranyl androst-5, 16-diene-17-bromide (9.03g, 20.73mmol), copper trifluoromethanesulfonate (0.09g, 0.24mmol), (4-acetylphenethyl) diphenylphosphine (0.74g, 2.13mmol), after nitrogen replacement, temperature was raised to 60℃, zinc reagent (31.10mmol) was added dropwise, after dropwise addition, the reaction was kept for 6h, 30ml 2.5% aqueous solution of brine was added to quench the reaction, after separation, 20ml MTBE was added to extract the aqueous phase, the oil phase was combined, 15ml 15% aqueous solution of hydrochloric acid was added to stir for 2h, 30ml aqueous solution of sodium carbonate was added to adjust pH to 8, concentrated to obtain a water / solid mixture, filtered and washed to obtain abiraterone wet product, which was washed with 50ml and 30ml acetonitrile respectively and then dried to obtain the finished product (6.76g, 93.33%).

[0054] Cost accounting: According to the production of 1000g of abiraterone, the cost accounting of the present application and prior art was carried out, and the statistics are shown in Table 2: Table 2 .

[0055] As shown in Table 2: compared with the prior art, the technical scheme of the present application uses low-cost intermediate III and copper catalyst, and in step (2) of the preparation process, intermediate II is not removed, but the reaction solution of intermediate II is mixed with aqueous hydrochloric acid to deprotect to obtain abiraterone crude product, which further reduces the cost. The present application has the advantages of low preparation cost, high yield and high purity.

Claims

1. A low-cost method for synthesizing abiraterone, characterized in that, Includes the following steps: (1) Preparation of organozinc reagent: An organozinc reagent is obtained by adding an inorganic catalyst, initiator, zinc powder or zinc chloride to an aprotic polar solvent, followed by the dropwise addition of 3-bromopyridine. The structure of the organozinc reagent is as follows: ； (2) Synthetic intermediates: Intermediate III, a metal catalyst, and a ligand are added to an aprotic polar solvent, followed by the addition of an organozinc reagent. A coupling reaction occurs at a certain temperature to obtain intermediate II. II; The intermediate III has the following structural formula: III; In the formula: R 1 It can be methoxymethyl, methoxyethoxymethyl, trimethylsilyl, trimethsilylethoxymethyl, or 2-tetrahydropyranyl; (3) Mix intermediate II with hydrochloric acid aqueous solution, stir to remove protection, filter and purify to obtain abiraterone.

2. The method for low-cost synthesis of abiraterone according to claim 1, characterized in that: In step (1), the molar ratio of materials is zinc powder or zinc chloride: inorganic catalyst: initiator: 3-bromopyridine = 1~1.5: 1~1.5: 0~0.1:

1.

3. The method for low-cost synthesis of abiraterone according to claim 1, characterized in that: In step (1), the aprotic polar solvent is selected from one or more of methyl tert-butyl ether, tetrahydrofuran, dioxane, and isopropyl ether.

4. The method for low-cost synthesis of abiraterone according to claim 1, characterized in that: In step (1), the inorganic catalyst is selected from one of LiF, LiCl, LiBr, LiI, and LiOTf.

5. The method for low-cost synthesis of abiraterone according to claim 1, characterized in that: In step (1), the initiator is selected from one or more of iodine, 1,2-dibromoethane, and trimethylchlorosilane.

6. The method for low-cost synthesis of abiraterone according to claim 1, characterized in that: In step (2), the metal catalyst is any one of CuCl2, Cu(acac), Cu(OAc)2, and Cu(OTf)2.

7. The method for low-cost synthesis of abiraterone according to claim 1, characterized in that: In step (2), the ligand is PPh3, TMEDA, P(o-ToI)3, DPPF, Xantphos, , Any one of them; Wherein: G ’ It is selected from methyl, methoxy, ethoxy, hydroxy, PPh3, chlorine, bromine, iodine, acetyl, trifluoromethyl, cyclohexyl, nitrile or C1-C6 alkyl mercapto.

8. The method for low-cost synthesis of abiraterone according to claim 1, characterized in that: In step (2), the molar ratio of the materials is intermediate III: organozinc reagent: metal catalyst: ligand = 1:1.5~2.5:0.005~0.02:0.1~0.

5.

9. The method for low-cost synthesis of abiraterone according to claim 1, characterized in that: In step (2), the reaction temperature is 40-60℃ and the reaction time is 3-12 hours.

10. The method for low-cost synthesis of abiraterone according to claim 1, characterized in that: The intermediate II reaction solution prepared in step (2) is directly mixed with hydrochloric acid aqueous solution for deprotection reaction to obtain abiraterone.

Images