Technical Note pubs.acs.org/OPRD
Improved Procedure for Preparation of Abiraterone Acetate Mukesh Kumar Madhra,* Hari Mohan Sriram, Murad Inamdar, Mukesh Kumar Sharma, Mohan Prasad, and Sony Joseph Chemical Research Division, Ranbaxy Research Laboratory, Gurgaon, Haryana 122001, India S Supporting Information *
ABSTRACT: An improved procedure for the preparation of abiraterone acetate is described. The present process highlights reduced reaction time, isolation with acid−base treatment without involving column chromatography, multiple crystallization and is amenable to large-scale synthesis.
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inorganic salts. Recently, an approach was reported8 of using 3silyl protected DHEA with 3-bromopyridine in the presence of butyllithium. The drawbacks of this method are the use of protection−deprotection and the use of column chromatography for purification. In order to overcome the drawbacks of the reported methods, our aim was to develop a commercially viable, simple, cost-effective, and efficient process for preparation of abiraterone acetate (1).
INTRODUCTION Abiraterone acetate (1) is a prodrug of abiraterone (2) (Figure 1) used for the treatment of metastatic castration-resistant prostate cancer. It is marketed as Zytiga in the United States and is an orally administrated CYP17 inhibitor.1,2
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RESULTS AND DISCUSSION The present method involves Suzuki coupling using (3β)-17bromoandrosta-5,16-dien-3-ol (DHEA-Br,10) instead of DHEA-I, 5 (Scheme 4). The rationale for choosing DHEA-Br over DHEA-I was due to the reduction in the reaction time from days to hours and also the cost advantage of NBS over iodine in the synthesis of 10.3a Further with the use of DHEABr, the bis-steroidal impurity 6 was not formed due to reduced reaction time which inhibits the Heck-type coupling reaction of 2 with palladium derivative of 10. The reported synthesis9 of DHEA-Br (10) involves the bromination of (3β,17E)-17-hydrazinylidene androst-5-en-3-ol (9) using NBS and pyridine as base. The product was isolated using column chromatography in moderate yield. Utilizing a previously described procedure10 9 could be prepared in quantitative yield from (3β)-3-hydroxyandrost-5-en-17-one (DHEA). In the present method the bromination was carried out using NBS with 1,1,3,3-tetramethyl guanidine (TMG) resulting in 10 in 60−62% isolated yield without column chromatography, which was further converted to 2 using Suzuki coupling. During our development work, for the preparation of 2 using Suzuki coupling of 10 with 4, our emphasis was on selection of solvent, base, and catalyst. Solvents. Different solvents were screened for the coupling reaction as depicted in Table 1. The reported3a solvent for the reaction is THF. From the above table, Me-THF and t-BuOH are found to be the solvents of choice. In both solvents the reaction completed
Figure 1.
The initial approach3 for the synthesis of 1 involves the Suzuki coupling of the intermediate 3β-acetyloxyandrosta-5,1617-yl-trifluoromethanesulphonate (DHEA-OTf, 3) with diethyl (3-pyridyl) borane (4), in the presence of a palladium catalyst (Scheme 1). This method is not commercially viable due to the usage of expensive and noxious triflic anhydride and the purification by column chromatography. An improvement in this method was reported4 by changing base during the triflate formation and controlling the impurities in abiraterone acetate by crystallization of its methane sulphonic acid salt. However, recovery of 1 from the corresponding methane sulphonate salt leads to partial hydrolysis of the acetyl group. This results in lower yields and requires subsequent acetylation of 3β-OH of 2 formed as byproduct. Suzuki coupling based on steroidal vinyl halide, 17-iodoandrosta-5,16-diene-3β-ol (DHEA-I, 5), with 4, is also reported5 (Scheme 2). This coupling requires 4 days for reaction completion, and this prolonged reaction time leads to the formation of the bis-steroidal impurity 6 (Figure 2), which could be eliminated only by reverse phase chromatography.5 In another reported method6 boronic acid of dehydroepiandrosterone (DHEA) 7 is coupled with 3-bromopyridine and results in 8 (Scheme 3), and the yields reported are poor. For the synthesis of 2, Negashi coupling has also been reported7 using 5 with 3-bromopyridine. This process requires cryogenic conditions and laborious workup to remove the © 2014 American Chemical Society
Received: February 6, 2014 Published: March 24, 2014 555
dx.doi.org/10.1021/op500044p | Org. Process Res. Dev. 2014, 18, 555−558
Organic Process Research & Development
Technical Note
Scheme 1
involving multiple crystallization resulted in loss of product, which impacted the yield. To avoid recrystallization, an acid− base purification involving multiple isolations is reported.11 Herein we report an improved acid−base treatment method, without isolation of the acid salt of 2, to remove the residual impurities. The crude wet solid was suspended in a mixture of methanol/water and acidified with conc. HCl followed by hexane extraction. The organic layer containing 4 and other impurities was discarded. The aqueous layer was then basified to obtain pure 2 with a chromatographic purity >99.5%. The isolation using acid−base treatment avoided multiple crystallization and column chromatography to get pure product in high yield. Subsequently, abiraterone acetate3a (1) was synthesized from 2 with an improved condition of using acetic anhydride in the presence of a catalytic amount of DMAP. In a typical experiment DHEA-Br (10) was prepared by bromination of 9 using NBS (2.5 equiv) in the presence of TMG (8.45 equiv). DHEA-Br (10) was then coupled with 4 (1.15 equiv) in the presence of Na2CO3 (3.0 equiv) and Pd(PPh)4 (0.01 mol equiv) in a mixture of t-BuOH/H2O (7/4 v/v) at reflux temperature. The reaction was completed in 3 h with 85−90% product formation measured by HPLC. The crude product was filtered and purified by acid−base treatment in a methanol/H2O mixture resulting in 70−73% isolated yield of 2 with purity above 99.5% by HPLC against the reported3a yield of 56% from 5. The acetylation of 2 with acetic anhydride (1.5 equiv) in the presence of catalytic DMAP provided 1 in 81% yield. This modified process combined with acid−base purification of 2 resulted in 1 in good yield and high purity.
Scheme 2
Figure 2. Bis-steroidal impurity.
in 3−6 h, and the formation of bis-steroidal impurity was not detected. This eliminated the multiple recrystallizations as reported in the prior article.3a In ethanol also the reaction did proceed to approximately 75−80%, but due to 4 sticking on the wall of the reaction vessel, the condition is not favorable from a scale-up point of view and also impacts the product quality. tBuOH was selected for this conversion as it resulted in a better yield of 70−73%, compared to 60−65% in methyl THF. Bases. Bases screened for this coupling were Na2CO3, K2CO3, NaOH, KOH, and t-BuOK. Use of sodium carbonate (3.0 or more equiv) produced the optimum conversion. Catalysts. Homogeneous catalysts such as bis(triphenylphosphine)Pd(II) chloride, Pd(PCy3)2Cl2, tetrakis(triphenylphosphine)palladium(0), and heterogeneous palladium on carbon were attempted for C−C coupling. The results are summarized in Table 2. The reaction with Pd/C did not go to completion even on higher loading. Pd(Pcy3)2 Cl2 resulted in lower conversion with higher reaction time. With Pd(PPh3)2Cl2 and Pd(PPh3)2Cl2 catalyst, better conversion and lower reaction time was achieved. However, Pd(PPh3)4 was a preferred catalyst for the reaction due to reduced reaction time and economical and commercial availability. Improved Workup and Isolation. After the reaction was completed, the crude product was isolated by filtration which contained the residual 4 as an impurity. Attempts to remove 4
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CONCLUSION In conclusion, a cost-effective and commercially viable process for the preparation of abiraterone acetate (1) with improved yield and shorter reaction time is reported. This process does not involve column chromatography or multiple crystallizations for isolation.
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EXPERIMENTAL SECTION General. Reagents were used as such without purification. 1 H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded using a Bruker spectrometer. The chemical shift data
Scheme 3
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dx.doi.org/10.1021/op500044p | Org. Process Res. Dev. 2014, 18, 555−558
Organic Process Research & Development
Technical Note
Scheme 4
Table 1. Effect of solvent for Suzuki couplinga solvent
reaction temp. (°C)
product formation (% HPLC)
reaction time (h)
yield (%)
80−82 70−75 90−93 80−82 90−92 90−92
80−85 80−85 65−70 75−80 55−60 60−65
3 6 6 8 6 6
70−73 60−65 not isolated 84b not isolated not isolated
t-BuOH Me-THF DMF ethanol dioxane isopropyl acetate
DHEA-Br (10). To a suspension of NBS (6.32 kg, 0.0355 kmol) in dichloromethane (21.5 L) at 0−5 °C, was added a solution of 9 (4.3 kg, 0.0142 kmol) in TMG (13.84 kg, 0.12 kmol) in 60 min, keeping the temperature 0−5 °C. The stirring was continued for 30 min at 0−5 °C and the reaction monitored by HPLC. The reaction mixture was warmed to room temperature and then diluted with dichloromethane (21.5 L) and water (43 L). The organic layer was separated and diluted with methanol (4.3 L). To this solution was added 2.5 N HCl (43 L) in 30 min, keeping the temperature 20−30 °C. After stirring for 30 min, the organic layer was separated and washed with a mixture of methanol (4.3 L) and water (21.5 L). The organic layer was concentrated to give a thick slurry. To this slurry was added IPA (30 L) and heated to 65−70 °C to recover ∼6.5 L solvent. The temperature was raised to reflux to get a clear solution, and then water (21.5 L) was added over a period of 60 min at 80−60 °C. After water addition, the reaction mixture was cooled to room temperature, stirred for 15 min, and filtered. The solid was washed with a solution of IPA/ water (8.6 L, 1: 1 v/v), dried at 60−65 °C under vacuum for 15 h, and afforded 9 in 60% yield (3.01 kg). HPLC Purity: 97.70%, IR (KBr) (cm−1): 3275, 2930, 1591, 1452, 1057, 833. 1H NMR (400 MHz, CDCI3): δ 5.84−5.83 (dd, 1 H), 5.37−5.35 (dd, 1 H), 3.56−3.49 (m, 1 H), 2.31−2.11 (m, 3H), 1.99−1.94 (m, 1H), 1.92−1.83 (m, 3H), 1.77−1.45 (m, 9H), 1.31−1.02 (m, 5H), 0.85 (s, 3H) Abiraterone (2). The reactor was evacuated and released under nitrogen. All the operations were carried out under nitrogen. Na2CO3 (3.62 kg, 0.034 kmol) was dissolved in water (16.8 L). t-BuOH (28 L) was added, followed by 10 (4 kg, 0.011 kmol), 4 (1.928 kg, 0.013 kmol), and Pd(PPh3)4 (0.132 kg, 0.112 mol) at room temperature. The resulting mixture was heated to reflux and stirred for 3 h. The reaction was monitored by HPLC. After the reaction completion, the reaction mixture was cooled to 30−35 °C and filtered. The wet cake was washed with a 1:1 mixture of t-BuOH/water (8 L). The wet solid was suspended in a mixture of water (32 L), methanol (32 L), and conc HCl (2 L) and heated 40−45 °C to obtain a clear solution. n-Hexane (20 L) was added and stirred for 10−15 min at 40−45 °C. The aqueous layer was separated and re-
a
Standard conditions: t-BuOH (7 vols), water (4 vols), Na2CO3 (4.0 equiv), 4 (1.15 equiv), Pd(PPh3)4 (0.01 equiv). bPurity of isolated 2 was only 74%
Table 2. Effect of Catalysta catalyst
quantity (equiv)
Pd(PPh3)2Cl2 Pd(PPh3)4 Pd(Pcy3)2 Cl2
0.01 0.01 0.01
Pd/C (10% w/ w)
0.5 (w/w)
product formation (%) 80−85 80−85 incomplete reaction incomplete reaction
time (h) 8 3 24 14
yield (%) 69 72 not isolated not isolated
a Standard conditions: t-BuOH (7 vols), water (4 vols), Na2CO3 (3 equiv), 4 (1.15 equiv), Pd(PPh3)4 (0.01 equiv).
are reported as δ (ppm) using tetramethylsilane as internal standard. Mass spectra were recorded using an API 2000 (MPS SCIEX) instrument. Infrared spectra were recorded using Perkin-Elmer FTIR (Spectrum One) instrument. HPLC analysis was performed on a Waters instrument with a UV detector (210 nm) using a Zorbax Eclipse XDB C18 (150 mm × 4.6 mm, 5 μm) column. Mobile phase A [prepared by mixture of buffer* and acetonitirile in the ratio (95:5 v/v)]: mobile phase B [acetonitrile], flow 1.5 mL/min, gradient 85:15 (0−40 min), 15:85 (40−50 min), 2:98 (50−80 min), 85:15 (80−90 min), (buffer was prepared by accurately transferring about 2 mL of orthophosphoric acid into 2000 mL of water) 557
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Technical Note
extracted with n-hexane (20 L).The pH of the aqueous layer was adjusted to 7.5−8.0, using aqueous NaOH solution (10% w/v). After stirring for 15−20 min and filtration, the solid was washed with a mixture of 1:1 methanol/water (8 L) with drying under vacuum at 60−65 °C for 15 h to give 2 (2.88 kg, 72%) as a white solid. HPLC Purity: 99.87%. MS: m/z = 350.3 [M + H]+. IR (KBr) (cm−1): 3236, 3062, 3031, 2931,1596, 1065, 803. 1H NMR (400 MHz, CDCI3): δ 8.61 (s, 1 H), 8.44−8.46 (d, 1 H), 7.63−7.65 (d, 1 H), 7.20−7.23 (dd, 1 H), 5.993− 5.996 (d, 1 H), 5.38−5.99 (d, 1 H), 3.48−3.54 (m, 1 H), 2.24− 2.32 (m, 3H), 1.97−2.10 (m, 3H), 1.47−1.86 (m, 10H), 1.04− 1.10 (s, 8H). 13C NMR (CDCl3): δ 16.58, 19.34, 20.88, 30.45, 31.52, 31.63, 31.81, 35.27, 36.71, 37.20, 42.32, 47.34, 50.37, 57.56, 71.62, 121.28, 123.03, 129.24, 132.99, 133.70, 141.21, 147.79, 147.88, 151.68 Abiraterone Acetate (1). To a stirred solution of 2 (2 kg, 0.0057 kmol) and DMAP (60 g) in dichloromethane (12 L) was added acetic anhydride (0.876 kg, 0.086 kmol) at 25−30 °C over a period of 15 min. The stirring was continued for 60 min at 25−30 °C and the reaction monitored by HPLC. After completion of reaction, water (8 L) was added and stirred for 10 min. The organic layer was separated, water (8 L) was added, and the pH was adjusted to 6−7 with aqueous NaOH (10% w/v). The organic layer was separated, washed with water (4 L), and then concentrated. To the residue was added IPA (4 L) and was concentrated at 70−75 °C. IPA (16 L) was added to the residue at 55−50 °C; the mixture was heated to reflux and treated with activated carbon (0.1 kg). The solution was filtered hot, and the bed was washed with IPA (4 L). The filtrate was heated to reflux and added water (12 L) at reflux temperature in 1 h. The resulting mixture was then cooled to 15−20 °C and stirred for 2 h at this temperature. The resulting solid was filtered and washed with IPA/water (4 L, 1:1) and dried under vacuum at 60−65 °C for 12 h to give 1 in 81% yield (1.8 kg). HPLC Purity: 99.72%, Assay: 98.8% (HPLC, w/ w). MS: m/z = 392.7 [M + H]+. IR (KBr) (cm−1): 3047, 2936, 1735, 1244, 1035, 801, 714. 1H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 1 H), 8.43−8.42 (d, 1 H), 7.76−7.74 (d, 1 H), 7.34− 7.31 (dd, 1 H), 6.11 (s, 1 H), 5.38 (s, 1 H), 4.44 (m, 1H), 2.19−2.50 (m, 3H), 1.98−2.08 (m, 6H), 1.39−1.85 (m, 9H), 1.03−1.11 (m, 8H). 13C NMR (CDCl3): δ 170.4, 151.6, 147.9, 147.8, 140.0, 133.6, 132.9, 129.1, 122.9, 122.2, 73.8, 57.4, 50.2, 47.3, 38.1, 36.9, 36.7, 35.1, 31.7, 31.4, 30.3, 27.7, 21.4, 20.8, 19.2, 16.5.
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Analytical Division of Ranbaxy Research Laboratories for their analytical and spectral support.
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ASSOCIATED CONTENT
S Supporting Information *
1 H, 13C, IR spectral data, and HPLC chromatogram of compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Tel: (91-124) 4011832. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to Dr. Hashim Nizar, Associate Director, and Dr. Neera Tewari, Director Chemical Research and Development, for their valuable discussion and guidance. We also thank 558
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