Abiraterone single succinic acid ester and preparation method thereof

A technology of abiraterone and succinate, which is applied in the field of drug synthesis, can solve problems such as safety discount of abiraterone acetate, and achieve the effect of simple post-processing and mild reaction conditions

Inactive Publication Date: 2015-02-18
SHANGHAI YANAN PHARMA HUBEI CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the clinical use of abiraterone acetate, patients often have some adverse reactions (≥5%), such as joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flushes, diarrhea, urinary tract infection, cough, high Blood pressure, arrhythmia, frequent urination, nocturia, indigestion and upper respiratory tract infection, etc., greatly reduce the safety of abiraterone acetate

Method used

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  • Abiraterone single succinic acid ester and preparation method thereof
  • Abiraterone single succinic acid ester and preparation method thereof
  • Abiraterone single succinic acid ester and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Abiraterone (3.50g, 10mmol), succinic anhydride (1.20g, 12mmol) were sequentially added in tetrahydrofuran (25mL), and then pyridine (3.95g, 50mmol); the reaction mixture was stirred at 65-75°C for 20 hours, TLC (thin-layer chromatography plate) shows that abiraterone has reacted completely (developing agent is sherwood oil: the volume ratio of ethyl acetate=1: 3), and reaction mixture is added sherwood oil, after filtering, filter cake is washed with methanol and Abiraterone monosuccinate (3.03 g, yield 67.3%, white powder) was obtained by drying.

[0024] Proton NMR spectrum (500MHz, DMSO) δH12.16-12.18(s, 1H), 8.56(d, 1H), 8.40-8.41(d-d, 1H), 7.72-7.74(t-t, 1H), 7.29-7.32(m , 1H), 6.09(m, 1H), 5.36(d, 1H), 4.40-4.50(m, 1H), 2.44(s, 4H), 2.25-2.27(d, 2H), 2.16-2.21(m, 1H ), 1.99-2.05(m, 3H), 1.45-1.83(m, 8H), 1.36-1.44(m, 1H), 0.96-1.02(d, 8H);

[0025] Carbon NMR spectrum (500MHz, DMSO) δC19.4, 22.2, 22.5, 28.4, 29.1, 29.5, 31.7, 32.5, 33.8, 37.4, 37.5, 37.6, 38.5,...

Embodiment 2

[0029] Abiraterone (3.50g, 10mmol), succinic anhydride (1.20g, 12mmol) were successively added in ethyl acetate (200mL), then triethylamine (2.0g, 20mmol) was added; the reaction mixture was stirred at 65-70°C After 48 hours, TLC (thin layer chromatography plate) showed that abiraterone had reacted completely (developing solvent is sherwood oil: ethyl acetate=1: 3), and the reaction mixture was added sherwood oil, after filtering, the filter cake was washed with methanol And dried to obtain abiraterone monosuccinate (3.38g, yield 75.1%, white powder). The product was subjected to H NMR spectroscopy ( 1 H-NMR), carbon nuclear magnetic resonance spectrum ( 13 C-NMR) and liquid chromatography-mass spectrometry (LCMS) confirmed the structure as the target compound abiraterone monosuccinate.

Embodiment 3

[0031] Abiraterone (3.50g, 10mmol), succinic anhydride (1.20g, 12mmol) were added successively in toluene (50mL), and then 4-(N,N-dimethylamino)pyridine (0.61g, 5mmol) was added for reaction mixing The solution was stirred at 115-120°C for 8 hours, TLC (thin-layer chromatography plate) showed that the abiraterone had completely reacted (the polarity of the developer was petroleum ether: ethyl acetate=1:3), and petroleum ether was added to the reaction mixture. , after filtration, the filter cake was washed with methanol and dried to obtain abiraterone monosuccinate (3.82g, yield 85.1%, white powder). The product was subjected to H NMR spectroscopy ( 1 H-NMR), carbon nuclear magnetic resonance spectrum ( 13 C-NMR) and liquid chromatography-mass spectrometry (LCMS) confirmed the structure as the target compound abiraterone monosuccinate.

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Abstract

The invention discloses a derivative abiraterone, namely abiraterone single succinic acid ester, and a preparation method thereof. The structural formula of abiraterone single succinic acid ester is as shown in Formula I: (as shown in the Specification). The preparation method comprises the following step: carrying out an esterification reaction on succinic anhydride and abiraterone as shown in Formula III to obtain abiraterone single succinic acid ester. According to the preparation method, an appropriate synthesis method is adopted to efficiently and rapidly synthesize abiraterone single succinic acid ester; the preparation method is moderate in reaction conditions, simple in follow-up processing and suitable for industrial preparation, and provides a chemical entity source for follow-up medicinal chemical and clinical researches.

Description

technical field [0001] The invention relates to abiraterone monosuccinate and a preparation method thereof, belonging to the technical field of drug synthesis. Background technique [0002] Abiraterone acetate (II) is an oral irreversible inhibitor of CYP17 enzyme developed by Ceotocor Ortho Company. It was approved by the US FDA on April 28, 2011. It is used in combination with prednisone to treat previous chemotherapy containing docetaxel. Metastatic castration-resistant prostate cancer, compared with the current conventional treatment, has better efficacy and lower side effects. Its active molecule in vivo is abiraterone (III). In the clinical use of abiraterone acetate, patients often have some adverse reactions (≥5%), such as joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flushes, diarrhea, urinary tract infection, cough, high Blood pressure, arrhythmia, frequent urination, nocturia, indigestion and upper respiratory tract infection, etc., gr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00
CPCC07J43/003
Inventor 廖文胜田勇唐飞宇王学亮
Owner SHANGHAI YANAN PHARMA HUBEI CO LTD
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