Preparation method of abiraterone acetate impurity

Abstract

The invention relates to a novel synthesis method of abiraterone acetate impurities. According to the method, starting materials are easy to obtain, synthesis steps are few, and operation is safe and simple. The required materials are easy to store and have no harm, the obtained product is easy to purify, the yield and the purity are relatively high, and the preparation requirements of the impurity can be met.

Description

Technical Field

[0001] The invention relates to the field of chemical pharmacy, and in particular to a method for preparing abiraterone acetate impurities. Background Art

[0002] Abiraterone acetate is an orally effective, highly selective, irreversible CYP17 enzyme inhibitor developed by CentocorOrtho, a subsidiary of Johnson & Johnson. The drug was first launched in the United States in April 2011 and in China in May 2015. This product is a selective oral inhibitor of 17α-hydroxylase-C17,20-lyase (human cytochrome P45017 enzyme), a key enzyme in testosterone synthesis. It can reduce the level of tumor marker prostate specific antigen (PSA) and can be used for prostate cancer patients whose tumors continue to grow after drug treatment or surgical resection. At present, abiraterone acetate is the first-line drug for the treatment of metastatic castration-resistant prostate cancer (mCRPC) and high-risk metastatic endocrine-sensitive prostate cancer (mHSPC).

[0003] If the content of certain impurities in drugs exceeds a certain standard, it may cause side effects, affect the safety of clinical medication, and even threaten the patient's life. Therefore, the content of impurities in raw materials must be strictly controlled during production. 1-((8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-2,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl)ethan-1-one (hereinafter referred to as abiraterone acetate impurity, the structure is as follows: ) is a process impurity in the production process of abiraterone acetate. This impurity is included in the abiraterone acetate system suitability standards published in the USP United States Pharmacopoeia.

[0004] Patent CN113292624A provides a method for preparing impurities of abiraterone acetate as follows:

[0005]

[0006] This method has a long route and uses flammable and dangerous reagents such as methyl lithium. Summary of the invention

[0007] In order to solve the problems existing in the prior art, the present invention provides a new method for preparing abiraterone acetate impurities, which only undergoes three steps of reaction, improves the synthesis efficiency of the impurities, and has a high yield, which is of great significance to the quality control and impurity research of abiraterone acetate.

[0008] The present invention provides a method for preparing an abiraterone acetate impurity represented by formula I, the preparation method comprising the following steps:

[0009] S1: Compound A (i.e., abiraterone) reacts with ketone to obtain compound B;

[0010] S2: Compound B reacts with a halogenating agent to obtain compound C;

[0011] S3: Compound C and Reaction to obtain a compound shown in formula I;

[0012]

[0013] Wherein, X represents a halogen, such as fluorine, chlorine, bromine, iodine;

[0014] Y is selected from hydrogen, a trialkylsilyl protecting group, a trialkyltin protecting group;

[0015] Z is selected from C1-10 alkyl or C3-10 cycloalkyl, preferably C1-6 alkyl or C3-6 cycloalkyl, such as methyl, ethyl, n-butyl, isobutyl, tert-butyl, cyclohexyl and the like.

[0016] According to an embodiment of the present invention, Y is selected from hydrogen, tributyltin, trimethylsilyl, and Z is selected from ethyl, n-butyl.

[0017] According to an embodiment of the present invention, It is vinyl ethyl ether, vinyl n-butyl ether, tributyl (1-ethoxyethylene) tin, and (1-ethoxyvinyl)-trimethylsilane.

[0018] According to an embodiment of the present invention, in step S1, the reaction is carried out in the presence of a base.

[0019] Preferably, the base is selected from one, two or more of aluminum isopropoxide, aluminum tert-butoxide, trimethylaluminum and aluminum phenolate, exemplified by aluminum isopropoxide.

[0020] According to an embodiment of the present invention, in step S1, the ketone is selected from alkyl ketones and cycloalkyl ketones; for example, one, two or more of acetone, methyl ethyl ketone and cyclohexanone, exemplified by cyclohexanone.

[0021] According to an embodiment of the present invention, in step S1, the reaction is carried out in solvent I.

[0022] Preferably, the solvent I is selected from one, two or more of 1,4-dioxane, ethylene glycol dimethyl ether, toluene and xylene, exemplified by toluene.

[0023] According to an embodiment of the present invention, in step S1, the mass volume ratio of the compound A to the solvent I is 1:5-1:15 (g:mL), exemplarily 1:10 (g:mL).

[0024] According to an embodiment of the present invention, in step S1, the mass volume ratio of the compound A to the ketone is 1:1-1:5 (g:mL), exemplarily 1:3 (g:mL).

[0025] According to an embodiment of the present invention, in step S1, the molar ratio of compound A to base is 1:(1-3), for example 1:2.

[0026] According to an embodiment of the present invention, in step S1, the reaction temperature is 60-110°C, for example 80°C;

[0027] And / or, the reaction time is 1-10 h, such as 2 h.

[0028] According to an embodiment of the present invention, step S1 includes the following steps: adding 1 times the amount of compound A (in moles) and ketone to solvent I, heating to 60-110°C, adding 1-3 times the amount of base (in moles), reacting at 60-110°C, and then separating and purifying to obtain compound B.

[0029] According to an embodiment of the present invention, in step S2, the halogenating agent is selected from one, two or more of phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, iodine, and trimethylsilicon iodide, exemplified by phosphorus oxychloride and phosphorus trichloride.

[0030] According to an embodiment of the present invention, in step S2, the molar ratio of compound B to the halogenating agent is 1:(1-5), for example, 1:3.

[0031] According to an embodiment of the present invention, in step S2, the reaction is carried out in solvent II;

[0032] Preferably, solvent II is selected from acetic acid, methanesulfonic acid, trifluoroacetic acid and the like.

[0033] According to an embodiment of the present invention, the mass volume ratio of compound B to solvent II is 1:3-1:30 (g:mL), exemplarily 1:10 (g:mL).

[0034] According to an embodiment of the present invention, in step S2, the reaction temperature is 0-30°C, preferably 0-25°C, for example 0-10°C;

[0035] And / or, the reaction time is 5-48 h, preferably 5-40 h, such as 18 h.

[0036] According to an embodiment of the present invention, step S2 includes the following steps: adding 1 times the amount of compound B (in moles) to solvent II, adding dropwise 1-5 times the amount of halogenating reagent (in moles), reacting at 0-30°C, and finally obtaining compound C by separation and purification.

[0037] According to an embodiment of the present invention, in step S3, compound C and The molar ratio of can be 1:(1-10), exemplified by 1:5.

[0038] According to an embodiment of the present invention, the reaction temperature of step S3 is 70-120°C, for example 100°C.

[0039] According to an embodiment of the present invention, in step S3, the reaction is carried out in the presence of a catalyst;

[0040] Preferably, the catalyst is selected from one, two or more of Pd(dppf)Cl2, Pd(pph3)4 and Pd(OAc)2, for example Pd(pph3)4.

[0041] According to an embodiment of the present invention, in step S3, the reaction is carried out in solvent III;

[0042] Preferably, the solvent III is selected from one, two or more of tetrahydrofuran, 1,4-dioxane, toluene and ethylene glycol dimethyl ether (DME), such as toluene.

[0043] According to an embodiment of the present invention, in step S3, the mass volume ratio of the compound C to the solvent III is 1:3-1:30 (g:mL), exemplarily 1:10 (g:mL).

[0044] According to an embodiment of the present invention, in step S3, the reaction is carried out under the protection of an inert atmosphere, such as under the protection of argon.

[0045] According to an embodiment of the present invention, step S3 comprises: adding 1 times the amount of compound C (in moles), 1-10 times the amount of The catalyst is added into solvent III, protected by argon, and the temperature is raised to 70-120° C. for reaction, and finally separated and purified to obtain the compound of formula I.

[0046] The present invention also provides a compound shown in the following formula C:

[0047]

[0048] Wherein, X is a halogen.

[0049] The present invention provides the use of a compound represented by formula C in preparing an abiraterone acetate impurity represented by formula I;

[0050]

[0051] Wherein, X is a halogen.

[0052] Beneficial effects of the present invention:

[0053] The present invention relates to a novel synthesis method of abiraterone acetate impurity, wherein the method has easy-to-obtain starting materials, few synthesis steps, and safe and simple operation. The materials required by the present invention are easy to store and harmless, and the obtained product is easy to purify, and the yield and purity are high, and the preparation requirements of the impurity can be met, and the research on the impurity of abiraterone acetate is of great significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 is the compound B prepared in step S1 1 H-NMR spectrum, the solvent is deuterated CDCl3;

[0055] Figure 2 The compound of formula I prepared in step S3 1 H-NMR spectrum, the solvent is deuterated CDCl3;

[0056] Figure 3 is the liquid chromatography-mass spectrometer of the compound of formula I prepared in step S3;

[0057] Figure 4 The HPLC liquid phase spectrum of the compound of formula I prepared in step S3. DETAILED DESCRIPTION

[0058] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0059] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0060] Example 1

[0061] S1: Synthesis of Compound B:

[0062]

[0063] Compound A (20g, 1eq, 0.0572mol), cyclohexanone (60ml, 3V), toluene (200mL, 10V) were added to a 500mL three-necked flask, heated to 80°C, and aluminum isopropoxide (23.4g, 2eq, 0.1144mol) was added, and the reaction was refluxed for 2h. After the reaction of the raw materials was completed, the reaction solution was extracted with water and ethyl acetate twice, the organic phases were combined and washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and spin-dried to obtain a crude yellow oil. Column chromatography purification: wet loading, eluted with petroleum ether to remove cyclohexanone, and eluted with petroleum ether: ethyl acetate = 3 / 1 to obtain the product compound B, 17.30g, with a yield of 87%.

[0064] TLC single point, Rf=0.35 (developing solvent: n-hexane / ethyl acetate=1 / 1).

[0065] 1 H-NMR (400MHz, CDCl3): δ1.04-1.09 (4H, m), δ1.16-1.21 (1H, m), δ1.26 (3H, s), δ1.50-1.76 (5H, m), δ1.84-1.96 (2H, m), δ2. 04-2.17 (3H, m), δ2.31-2.49 (5H, m), δ5.77 (1H, s), δ6.08 (1H, s), δ7.36 (1H, dd), δ7.79 (1H, d), δ8.50 (1H, d), δ8.65 (1H, s).

[0066] Compound B 1 H-NMR spectrum Figure 1 described.

[0067] S2: Synthesis of Compound C:

[0068]

[0069] Compound B (10 g, 1 eq, 0.0288 mol) obtained in step S1 was added to acetic acid (100 mL, 10 V), cooled to 0-10° C., phosphorus oxychloride (13.24 g, 3 eq, 0.0863 mol) was added dropwise, and the mixture was reacted at room temperature for 18 h to gradually precipitate a solid.

[0070] After the reaction of the raw materials is completed, the following treatments are performed: filtering, dissolving the filter cake in dichloromethane, washing with saturated brine, drying the organic phase over anhydrous sodium sulfate, filtering, concentrating the filtrate and spinning it to dryness to obtain 8.1 g of a yellow solid, with a yield of 77%.

[0071] S3: Synthesis of compounds of formula I

[0072]

[0073] Add compound C (5 g, 1 eq, 0.0137 mol) prepared in step S2, ethyl vinyl ether (4.93 g, 5 eq, 0.0683 mol), Pd(PPh3)4 (1.58 g, 0.1 eq, 0.0014 mol), and toluene (50 mL, 10 v) into a 250 ml three-necked flask, protect with argon, and heat to 100 °C for 4 h.

[0074] After the reaction of the raw materials is completed, water is added and stirred, and ethyl acetate is extracted twice. The organic phases are combined and washed once with saturated sodium chloride. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and spun dry to obtain a brown oil. Column chromatography purification: dry loading, elution with petroleum ether: ethyl acetate = 3 / 1 to obtain the product. Then acetonitrile is used to beat the white solid to obtain 2.8g, with a yield of 55%. HPLC purity 99.48%

[0075] 1 H-NMR (400MHz, CDCl3): δ0.96 (3H, s), δ1.08 (3H, s), δ1.11-1.18 (2H, m), δ1.51-2.21 (10H, m), δ2.27-2.60 (6H, m), δ5 .90-5.92 (1H, m), δ6.01 (1H, dd), δ6.93 (1H, d), δ7.21-7.25 (1H, m), δ7.65-7.67 (1H, m), δ8.47 (1H, dd), δ8.63 (1H, d).

[0076] LC-MS: m / z 374.0 [M+H] +

[0077] Compounds of formula I 1 H-NMR spectrum, liquid chromatography-mass spectrometry and HPLC liquid chromatography spectrometry are shown in Figure 1. Figure 2-4 shown.

[0078] Example 2

[0079] S1: Synthesis of Compound B:

[0080] Compound A (20 g, 1 eq, 0.0572 mol), acetone (60 ml, 3 V), and toluene (200 mL, 10 V) were added into a 500 mL three-necked flask, the temperature was raised to 60° C., aluminum isopropoxide (23.4 g, 2 eq, 0.1144 mol) was added, and the mixture was refluxed for 2 h.

[0081] After the reaction of the raw materials was completed, the reaction solution was extracted twice with water and ethyl acetate, the organic phases were combined and washed once with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and spin-dried to obtain a crude yellow oil. Column chromatography purification: wet loading, eluted with petroleum ether: ethyl acetate = 3 / 1 to obtain the product compound B, 15.30 g, with a yield of 77%.

[0082] TLC single point, Rf = 0.35 (developing solvent: n-hexane / ethyl acetate = 1 / 1)

[0083] S2: Synthesis of Compound C:

[0084] Compound B (10 g, 1 eq, 0.0288 mol) obtained in step S1 was added to acetic acid (100 mL, 10 V), cooled to 0-10° C., phosphorus trichloride (11.85 g, 3 eq, 0.0863 mol) was added dropwise, and the mixture was reacted at room temperature for 18 h to gradually precipitate a solid.

[0085] After the reaction of the raw materials is completed, the following treatments are performed: filtering, dissolving the filter cake in dichloromethane, washing with saturated brine, drying the organic phase over anhydrous sodium sulfate, filtering, concentrating the filtrate and spinning it to dryness to obtain 7.2 g of a yellow solid, with a yield of 68%.

[0086] S3: Synthesis of compounds of formula I

[0087] Add compound C (5 g, 1 eq, 0.0137 mol) prepared in step S2, vinyl n-butyl ether (6.84 g, 5 eq, 0.0683 mol), Pd(PPh3)4 (1.58 g, 0.1 eq, 0.0014 mol), and toluene (50 mL, 10 v) into a 250 ml three-necked flask, protect with argon, and heat to 100 °C for 4 h.

[0088] After the reaction of the raw materials is completed, water is added and stirred, and ethyl acetate is extracted twice. The organic phases are combined and washed once with saturated sodium chloride. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and spin-dried to obtain a brown oil. Column chromatography purification: dry loading, elution with petroleum ether: ethyl acetate = 3 / 1 to obtain the product. Then acetonitrile is used to beat the white solid to obtain 2.6g, and the yield is 51%.

[0089] 1H-NMR (400MHz, CDCl3): δ0.96 (3H, s), δ1.08 (3H, s), δ1.11-1.18 (2H, m), δ1.51-2.21 (10H, m), δ2.27-2.60 (6H, m), δ5 .90-5.92 (1H, m), δ6.01 (1H, dd), δ6.93 (1H, d), δ7.21-7.25 (1H, m), δ7.65-7.67 (1H, m), δ8.47 (1H, dd), δ8.63 (1H, d).

[0090] Example 3

[0091] S1: The synthesis of compound B is the same as in Example 1;

[0092] S2: The synthesis of compound C is the same as in Example 1;

[0093] S3: Synthesis of compounds of formula I

[0094] Add compound C (5 g, 1 eq, 0.0137 mol) prepared in step S2, tributyl(1-ethoxyethylene)tin (26.58 g, 5 eq, 0.0683 mol), Pd(PPh3)4 (1.58 g, 0.1 eq, 0.0014 mol), and toluene (50 mL, 10 v) into a 250 ml three-necked flask, protect with argon, and heat to 100 °C for reaction for 5 h.

[0095] After the reaction of the raw materials is completed, water is added and stirred, and ethyl acetate is extracted twice. The organic phases are combined and washed once with saturated sodium chloride. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and spin-dried to obtain a brown oil. Column chromatography purification: dry loading, elution with petroleum ether: ethyl acetate = 3 / 1 to obtain the product. Then acetonitrile is used to beat the white solid to obtain 2.2g, and the yield is 43%.

[0096] 1 H-NMR (400MHz, CDCl3): δ0.96 (3H, s), δ1.08 (3H, s), δ1.11-1.18 (2H, m), δ1.51-2.21 (10H, m), δ2.27-2.60 (6H, m), δ5 .90-5.92 (1H, m), δ6.01 (1H, dd), δ6.93 (1H, d), δ7.21-7.25 (1H, m), δ7.65-7.67 (1H, m), δ8.47 (1H, dd), δ8.63 (1H, d).

[0097] Example 4

[0098] S1: The synthesis of compound B is the same as in Example 1;

[0099] S2: The synthesis of compound C is the same as in Example 1;

[0100] S3: Synthesis of compounds of formula I

[0101] Add compound C (5 g, 1 eq, 0.0137 mol) prepared in step S2, (1-ethoxyvinyl)-trimethylsilane (9.86 g, 5 eq, 0.0683 mol), Pd(PPh3)4 (1.58 g, 0.1 eq, 0.0014 mol), and toluene (50 mL, 10 v) into a 250 ml three-necked flask, protect with argon, and heat to 100 °C for reaction for 5 h.

[0102] After the reaction of the raw materials is completed, water is added and stirred, and ethyl acetate is extracted twice. The organic phases are combined and washed once with saturated sodium chloride. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and spin-dried to obtain a brown oil. Column chromatography purification: dry loading, elution with petroleum ether: ethyl acetate = 3 / 1 to obtain the product. Then acetonitrile is used to beat the white solid to obtain 2.0g, and the yield is 39%.

[0103] 1 H-NMR (400MHz, CDCl3): δ0.96 (3H, s), δ1.08 (3H, s), δ1.11-1.18 (2H, m), δ1.51-2.21 (10H, m), δ2.27-2.60 (6H, m), δ5 .90-5.92 (1H, m), δ6.01 (1H, dd), δ6.93 (1H, d), δ7.21-7.25 (1H, m), δ7.65-7.67 (1H, m), δ8.47 (1H, dd), δ8.63 (1H, d).

[0104] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing the abiraterone acetate impurity of formula I, the preparation method comprising the following steps: S1: Compound A (i.e., abiraterone) reacts with ketone to obtain compound B; S2: Compound B reacts with a halogenating agent to obtain compound C; S3: Compound C and Reaction to obtain a compound shown in formula I; in, X represents halogen, such as fluorine, chlorine, bromine, iodine; Y is selected from hydrogen, a trialkylsilyl protecting group, a trialkyltin protecting group; Z is selected from C1-10 alkyl or C3-10 cycloalkyl, preferably C1-6 alkyl or C3-6 cycloalkyl, such as methyl, ethyl, n-butyl, isobutyl, tert-butyl, cyclohexyl and the like.

2. The preparation method according to claim 1, characterized in that: Y is selected from hydrogen, tributyltin, trimethylsilyl, And / or, Z is selected from ethyl and n-butyl.

3. The preparation method according to claim 1 or 2, characterized in that: It is vinyl ethyl ether, vinyl n-butyl ether, tributyl (1-ethoxyethylene) tin, and (1-ethoxyvinyl)-trimethylsilane.

4. The preparation method according to any one of claims 1 to 3, characterized in that In step S1, the reaction is carried out in the presence of a base; preferably, the base is selected from one, two or more of aluminum isopropoxide, aluminum tert-butoxide, trimethylaluminum and aluminum phenolate, exemplified by aluminum isopropoxide; And / or, in step S1, the ketone is selected from alkyl ketones and cycloalkyl ketones; for example, one, two or more of acetone, methyl ethyl ketone and cyclohexanone, exemplified by cyclohexanone; And / or, in step S1, the reaction is carried out in a solvent I; preferably, the solvent I is selected from one, two or more of 1,4-dioxane, ethylene glycol dimethyl ether, toluene and xylene, exemplified by toluene.

5. The preparation method according to any one of claims 1 to 4, characterized in that: In step S1, the mass volume ratio of the compound A to the solvent I is 1:5-1:15 (g:mL), exemplarily 1:10 (g:mL); And / or, in step S1, the mass volume ratio of the compound A to the ketone is 1:1-1:5 (g:mL), exemplarily 1:3 (g:mL); And / or, in step S1, the molar ratio of compound A to base is 1:(1-3), for example 1:2; And / or, in step S1, the reaction temperature is 60-110°C, for example 80°C; And / or, in step S1, the reaction time is 1-10 hours, for example 2 hours.

6. The preparation method according to any one of claims 1 to 5, characterized in that: In step S2, the halogenating agent is selected from one, two or more of phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, iodine, and trimethylsilicon iodide, exemplified by phosphorus oxychloride, phosphorus trichloride, and phosphorus trichloride; And / or, in step S2, the molar ratio of compound B to halogenating agent is 1:(1-5), for example 1:3; And / or, in step S2, the reaction is carried out in a solvent II; preferably, the solvent II is selected from acetic acid, methanesulfonic acid, trifluoroacetic acid, etc.; And / or, in step S2, the reaction temperature is 0-30°C, preferably 0-25°C, for example 0-10°C; And / or, in step S2, the reaction time is 5-48 h, preferably 5-40 h, for example 18 h.

7. The preparation method according to claim 6, characterized in that: In step S2, the mass volume ratio of compound B to solvent II is 1:3-1:30 (g:mL), exemplarily 1:10 (g:mL).

8. The preparation method according to any one of claims 1 to 7, characterized in that: In step S3, compound C and The molar ratio of may be 1:(1-10), exemplarily 1:5; and / or, the reaction temperature in step S3 is 70-120° C., for example, 100° C.; And / or, in step S3, the reaction is carried out in the presence of a catalyst; preferably, the catalyst is selected from one, two or more of Pd(dppf)Cl2, Pd(pph3)4 and Pd(OAc)2, for example, Pd(pph3)4; And / or, in step S3, the reaction is carried out in a solvent III; preferably, the solvent III is selected from one, two or more of tetrahydrofuran, 1,4-dioxane, toluene and ethylene glycol dimethyl ether (DME), such as toluene; And / or, in step S3, the reaction is carried out under the protection of an inert atmosphere, such as argon; And / or, in step S3, the mass volume ratio of the compound C to the solvent III is 1:3-1:30 (g:mL), exemplarily 1:10 (g:mL).

9. The compound represented by formula C: in, X is halogen.

10. Use of the compound represented by formula C in the preparation of the abiraterone acetate impurity represented by formula I; in, X is halogen.

Images