154229-19-3

Usage

Uses

Used in Pharmaceutical Industry:
Abiraterone is used as a steroidal cytochrome P 450 17α-hydroxylase-17,20-lyase inhibitor (CYP17) for the treatment of androgen-dependent prostate cancer. It is currently undergoing phase II clinical trials as a potential drug for this application.
Used in Oncology:
Abiraterone is used as an antiandrogen agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel. On April 28, 2011, the U.S. Food and Drug Administration approved abiraterone acetate (Zytiga Tablets, Centocor Ortho Biotech, Inc.) for use in combination with prednisone for this purpose.
Used in Clinical Trials:
Abiraterone is being investigated in clinical trials for its potential use in earlier stages of prostate cancer and advanced breast cancer, as well as for its ability to help control symptoms and improve the quality of life for patients.

Therapeutic agent for prostate cancer

Currently, for patients of advanced prostate cancer, androgen deprivation therapy including drugs and surgery is generally the preferred method of including drugs and surgery in order to reduce the testicular androgen synthesis. However, this treatment can’t suppress other parts of the body for yielding the male hormone. Abiraterone is a therapeutic agent for prostate cancer with the English name for Abiraterone. It has not yet been marketed in China. It is developed by researchers coming from the British Royal Marsden Hospital located in southwest (world-renowned cancer research treatment center). It is kind of drug which is able to repress any part of the body for androgen production. It can not only reduce the levels of the prostate-specific antigen (PSA) which represents the tumor activity, but also helps to shrink the tumor. It can also apply to cancer patients who have been subject to chemotherapy in the past, revealing treatment hope. Previously, the patent of the Abiraterone was owned by British Cougar biopharmaceutical Company. But in 2009 Johnson Pharmaceutical acquire the Cougar Biological Company with $ 970 million, and thus getting the permission of the drug. The phase III clinical trial results have showed that the goods can significantly prolong patients with advanced prostate cancer including those who had used one or two docetaxel chemotherapy but still got deteriorating lives with a small drug side effects and good safety. Abiraterone is an oral administrated cytochrome oxidase P450 (CYP450) c17 inhibitor which can decrease the androgen levels through inhibiting the key enzyme in the androgen synthesis--CYP450c17, and also has inhibitory effect on the androgens coming from testis and other body parts. The above information is edited by the lookchem of Dai Xiongfeng.

How abiraterone works

Hormones are substances produced naturally in the body. They act as chemical messengers and help control the activity of cells and organs. Hormonal therapies interfere with the way hormones are made or how they work in the body. Most prostate cancers need the hormone testosterone to grow. Almost all testosterone in men is made by the testicles. A very small amount is made by the adrenal glands, which sit above the kidneys. Abiraterone reduces the amount of testosterone made by your body. This reduces testosterone levels and may shrink the prostate cancer or stop it growing. References Abiraterone acetate (Zytiga?) Abiraterone acetate (often shortened to abiraterone) is a hormonal therapy drug used to treat advanced prostate cancer. It is also known as Zytiga?.

Mechanism of Action

Abiraterone is an orally active inhibitor of the steroidal enzyme CYP17A1 (17 alpha-hydroxylase/C17,20 lyase). It inhibits CYP17A1 in a selective and irreversible manner via covalent binding mechanism. CYP17A1 is an enzyme that catalyzes the biosynthesis of androgen and is highly expressed in testicular, adrenal, and prostatic tumor tissue. More specifically, abiraterone inhibits the conversion of 17-hydroxyprognenolone to dehydroepiandrosterone (DHEA) by the enzyme CYP17A1 to decrease serum levels of testosterone and other androgens.Referenceshttp://www.drugbank.ca/drugs/DB05812

side effects

Like all treatments, abiraterone can cause side effects. Taking prednisolone as well as abiraterone will reduce the risk of side effects. Most men don’t have many problems with side effects. Possible side effects include: fluid retention, which can cause swelling in your ankles or hands High blood pressure during treatment happens in about 1 in 10 men (10%) Abiraterone can also cause the level of potassium in your blood to drop. This could make you feel tired and you may be at risk of a fast, irregular heartbeat. Tiredness (fatigue) and breathlessness from a drop in red blood cells (anaemia) Swelling of the legs or feet due to fluid build up (known as peripheral oedema) affects about 3 in 10 men (30%) Diarrhoea – drink plenty of fluids. Bladder infections affect just over 1 in 10 men (10%) Occasional side effects Between 1 and 10 in every 100 people have one or more of these. A mild effect on the liver that is unlikely to cause symptoms and will almost certainly go back to normal when you finish treatment. Heart problems, including a faster heart beat, a change to the heart rhythm and chest pain. Bone thinning (osteoporosis) can make bones more likely to break. High fat (cholesterol) levels in your blood – your doctor will check for this. An increased risk of getting an infection from a drop in white blood cells – it is harder to fight infections and you can become very ill. You may have headaches, aching muscles, a cough, a sore throat, or you may feel cold and shivery. If you have a severe infection this can be life threatening. Contact your treatment centre if you have any of these side effects or if your temperature goes above 38°C. A skin rash – you may develop a rash, which can be itchy. Speak to your doctor if you notice anything unusual.

Biological Activity

Description Abiraterone is a potent CYP17 inhibitor with IC50 of 2 nM in a cell-free assay. Features Approved for the treatment of docetaxel-treated castration-resistant prostate cancer. Targets?? CYP17 [1](Cell-free assay) 2 nM In vitro?? Abiraterone binds and inhibits wild-type and mutant androgen receptor (AR). Abiraterone inhibits in vitro proliferation and androgen receptor-regulated gene expression of androgen receptor-positive prostate cancer cells, which could be explained by androgen receptor antagonism in addition to inhibition of steroidogenesis. In fact, activation of mutant androgen receptor by eplerenone is inhibited by greater concentrations of Abiraterone. Abiraterone displaces ligand from both WT-AR and T877A with EC50 of 13.4 μM and 7.9 μM, respectively. [2]Abiraterone inhibits lyase activity with an IC50 of 5.8 nM in rat testis microsomes. Abiraterone acetate significantly inhibits T secretion (?48%) and in turn increased LH concentration (192%).[3] In vivo Abiraterone inhibits CYP17 with an IC50 of 72 nM, in human testicular microsomes. [4] Abiraterone fails to significantly reduce the size of any of the organs. [5] Abiraterone reduces the testosterone levels strongly, almost reaching the level of the orchiectomy control. The testosterone levels are reduced by Abiraterone for more than 95% compared to the control group. [6] References ??? [1] Attard G, et al. J Clin Oncol. 2008, 26(28), 4563-4571. ??? [2] Richards J, et al. Cancer Res. 2012, 72(9), 2176-2182. ??? [3] Duc I, et al. J Steroid Biochem Mol Biol. 2003, 84(5), 537-542. ??? [4] Hu Q, et al. J Med Chem. 2010, 53(15), 5749-5758. ??? [5] Bruno RD, et al. Steroids. 2011, 76(12), 1268-1279. ??? [6] Haidar S, et al. J Steroid Biochem Mol Biol. 2003, 84(5),555

Biological Activity

abiraterone (17-(3-pyridyl)androsta-5,16-dien-3β-ol) is a potent small-molecule inhibitor of cyp17 complex (17 alpha-monooxygenase) which is a member of the cytochrome p450 family consisting of 17 alpha-hydroxylase and c17,20-lyase and catalyzing the 17 alpha-hydroxylation of intermediates of steroid biosynthesis involved in testerone sysnthesis. abiraterone inhibits cyp17 complex by binding to the haem iron of cyp17a1, which forms a 60o angle above the haem plane and packs against the central i helix with 3β-oh interacting with aspargine 202 in the f helix. abiraterone is currently being investigated to treat late stage prostate cancer, in which it consistently suppresses testosterone levels, leads to significant reduction in psa level, and prolong life in patients with castration-resistant prostate cancer (crpc).natasha m. devore and emily e. scott. structures of cytochrome p450 17a1 with prostate cancer drugs abiraterone and tok-001. nature 2012; 482: 116-120farshid dayyani, gary e. gallick, christopher j. logothetis, paul g. corn. novel therapies for metastatic castrate-resistant prostate cancer. jnci j natl cancer inst (2011); 103(22): 1665-1675

Originator

Abiraterone,Cougar

Manufacturing Process

Diethyl(3-pyridyl)borane (3.38 g, 23 mmol) from Aldrich Chemical Co. Ltd. was added to a stirred solution of 3β-acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate (6.94 g, 15 mmol) in THF (75 ml) containing bis(triphenylphosphine)palladium(II) chloride (0.105 g, 0.15 mmol). An aqueous solution of sodium carbonate (2 M, 30 ml) was then added and the mixture heated, with stirring, by an oil bath at 80°C for 1 h, and allowed to cool. The mixture was partitioned between diethyl ether and water, the ether phase was dried (Na2CO3), filtered through a short plug of silica, and concentrated. Chromatography, on elution with light petroleum-diethyl ether (2:1), afforded the 3β-acetoxy-17-(3-pyridyl)androsta-5,16-diene (4.95 g, 84%) which crystallised from hexane, m.p. 144-145°C. To a solution of 3β-acetoxy-17-(3-pyridyl)androsta-5,16-diene (4.90 g, 12.5 mmol) in methanol (50 ml) was added an aqueous solution of sodium hydroxide (10% w/v, 10 ml) and the mixture heated, with stirring, on an oil bath at 80°C for 5 min, then allowed to cool. The mixture was poured into water, neutralised with hydrochloric acid (1 M), rebasified with saturated sodium bicarbonate solution, and extracted with hot toluene. The toluene extracts were combined, dried (Na2CO3), and concentrated. Chromatography, on elution with toluene-diethyl ether (2:1) afforded the 17-(3- pyridyl)androsta-5,16-dien-3β-ol (3.45 g, 79%) which crystallised from toluene, m.p. 228-229°C.

Therapeutic Function

Antiandrogen

InChI:InChI=1/C24H31NO/c1-23-11-9-18(26)14-17(23)5-6-19-21-8-7-20(16-4-3-13-25-15-16)24(21,2)12-10-22(19)23/h3-5,7,13,15,18-19,21-22,26H,6,8-12,14H2,1-2H3/t18-,19-,21-,22-,23-,24+/m0/s1

Synthetic route

abiraterone acetate (154229-18-2) → abiraterone (154229-19-3)

Conditions	Yield
With lithium hydroxide monohydrate In tetrahydrofuran; water at 0 - 20℃; for 48h; Inert atmosphere;	99%
With lithium hydroxide In tetrahydrofuran; methanol; water for 1h;	96%
With sodium hydroxide In methanol at 20℃; for 2h; Reagent/catalyst;	95.8%

C27H39NOSi → abiraterone (154229-19-3)

Conditions	Yield
With hydrogenchloride In methanol; water at 20 - 30℃; for 1.5h; pH=1 - 2;	96.6%
With tetrabutyl ammonium fluoride In dichloromethane at 20℃;	90%

3-((3S,8R,9S,10R,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)pyridine (1421704-60-0) → abiraterone (154229-19-3)

Conditions	Yield
With hydrogenchloride In methanol; water at 20 - 30℃; for 1h;	96.5%
Stage #1: 3-((3S,8R,9S,10R,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)pyridine With tetrabutyl ammonium fluoride In tetrahydrofuran Stage #2: With water In tetrahydrofuran	89%
With tetrabutyl ammonium fluoride In tetrahydrofuran	89%

C43H45NO → abiraterone (154229-19-3)

Conditions	Yield
With hydrogenchloride In methanol; water at 20 - 30℃; for 1h;	96.1%

C29H39NO2 → abiraterone (154229-19-3)

Conditions	Yield
With hydrogenchloride In methanol; water at 20 - 30℃; for 4h; pH=1 - 2;	94%

C20H27F3O4S + 3-Diethylboranylpyridine (89878-14-8) → abiraterone (154229-19-3)

Conditions	Yield
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In tetrahydrofuran; water at 20 - 75℃; for 0.5h;	88.8%

17-iodo-5,16-androstadien-3-ol (32138-69-5) + 3-Diethylboranylpyridine (89878-14-8) → abiraterone (154229-19-3)

Conditions	Yield
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; XPhos In 1,4-dioxane for 16h; Reflux;	75%
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In ethanol; water at 70 - 75℃; for 22h; Solvent; Reagent/catalyst; Temperature;	74.1%
With bis-triphenylphosphine-palladium(II) chloride In tetrahydrofuran for 24h; Suzuki Coupling; Reflux; Autoclave; Large scale;	72.1%

pyridin-3-ylzinc(II) bromide (220565-63-9) + 17-iodo-5,16-androstadien-3-ol (32138-69-5) → abiraterone (154229-19-3)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 20℃; for 5h;	74.5%

17-iodo-5,16-androstadien-3-ol (32138-69-5) + pyridin-3-ylmagnesium bromide (21970-14-9) → abiraterone (154229-19-3)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 35℃; for 5h; Temperature;	72.31%

3-Diethylboranylpyridine (89878-14-8) + 17-bromo-3β-hydroxy-5α-androstan-5,16-diene (106874-28-6) → abiraterone (154229-19-3)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; tert-butyl alcohol for 3h; Catalytic behavior; Solvent; Reagent/catalyst; Temperature; Suzuki Coupling; Inert atmosphere; Reflux; Large scale;	72%

17-iodo-5,16-androstadien-3-ol (32138-69-5) + 3-pyridylboronic acid (1692-25-7) → abiraterone (154229-19-3)

Conditions	Yield
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In water; N,N-dimethyl-formamide at 75 - 80℃; for 36h;	71.8%
With palladium on activated charcoal; sodium carbonate In dimethyl sulfoxide at 120℃; for 12h;

3-Diethylboranylpyridine (89878-14-8) + 17-iodoandrosta-5,16-dien-3β-ol 3-acetate → abiraterone (154229-19-3)

Conditions	Yield
Stage #1: 3-Diethylboranylpyridine; 17-iodoandrosta-5,16-dien-3β-ol 3-acetate With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In tetrahydrofuran; water for 5h; Reflux; Large scale; Stage #2: With sodium hydroxide In methanol at 25 - 35℃; for 7h; Reagent/catalyst; Large scale;	67.8%
Stage #1: 3-Diethylboranylpyridine; 17-iodoandrosta-5,16-dien-3β-ol 3-acetate With bis-triphenylphosphine-palladium(II) chloride; tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 0.333333h; Stage #2: With sodium carbonate In water at 65 - 70℃; for 1.25h;
Stage #1: 3-Diethylboranylpyridine; 17-iodoandrosta-5,16-dien-3β-ol 3-acetate With bis-triphenylphosphine-palladium(II) chloride; tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 0.333333h; Stage #2: In tetrahydrofuran at 65 - 70℃; for 1.25h;	34 g

3-(dimethylboryl)pyridine (1003865-86-8) + 17-iodo-5,16-androstadien-3-ol (32138-69-5) → abiraterone (154229-19-3)

Conditions	Yield
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate In methanol; water at 65 - 70℃; for 28h;	65%

C5H4INZn (718628-27-4) + 17-iodo-5,16-androstadien-3-ol (32138-69-5) → abiraterone (154229-19-3)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 20℃; for 4h;	52.5%

C20H27F3O4S + pyridin-2-ylboronic acid (197958-29-5) → abiraterone (154229-19-3)

Conditions	Yield
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In tetrahydrofuran; ethanol; water; toluene at 20 - 75℃; for 2.5h; Time; Suzuki Coupling;	51.6%

C26H38O3 → abiraterone (154229-19-3)

Conditions	Yield
With hydroxylamine hydrochloride In acetonitrile Reflux;	50%

3-Bromopyridine (626-55-1) + dehydroepiandrosterone-17-p-toluenesulfonyl hydrazone (34988-34-6) → abiraterone (154229-19-3)

Conditions	Yield
Stage #1: dehydroepiandrosterone-17-p-toluenesulfonyl hydrazone With tris-(dibenzylideneacetone)dipalladium(0); lithium tert-butoxide; XPhos In 1,4-dioxane at 20℃; for 0.0833333h; Stage #2: 3-Bromopyridine With tris-(dibenzylideneacetone)dipalladium(0) In 1,4-dioxane at 120℃; for 9h; Concentration; Temperature; Inert atmosphere;	43.1%
With tris-(dibenzylideneacetone)dipalladium(0); lithium tert-butoxide; XPhos In 1,4-dioxane for 4h; Inert atmosphere; Reflux;
With tris-(dibenzylideneacetone)dipalladium(0); lithium tert-butoxide; XPhos In 1,4-dioxane for 4h; Inert atmosphere; Reflux;
With tris-(dibenzylideneacetone)dipalladium(0); lithium tert-butoxide; XPhos In 1,4-dioxane for 4h; Reflux;

17-iodo-5,16-androstadien-3-ol (32138-69-5) + pyridin-3-ylzinc chloride (81745-82-6) → abiraterone (154229-19-3)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 20℃; for 7h;	35.7%

dehydroepiandrosterone (53-43-0) + 3α-hydroxy-androsten-(5)-one-(17) → abiraterone (154229-19-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 94 percent / NH2NH2*H2O, aq, NH2NH2*H2SO4 / ethanol / 120 h / Ambient temperature 2: 83 percent / I2, 1,1,3,3-tetramethylguanidine / tetrahydrofuran; diethyl ether / 1 h 3: 2 M aq. Na2CO3 / bis(triphenylphosphine)palladium(II) chloride / tetrahydrofuran / 96 h / 80 °C View Scheme

dehydroepiandrosterone-17-hydrazone (63015-10-1) → abiraterone (154229-19-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 83 percent / I2, 1,1,3,3-tetramethylguanidine / tetrahydrofuran; diethyl ether / 1 h 2: 2 M aq. Na2CO3 / bis(triphenylphosphine)palladium(II) chloride / tetrahydrofuran / 96 h / 80 °C View Scheme
Multi-step reaction with 5 steps 1: iodine; N,N,N',N'-tetramethylguanidine / tetrahydrofuran / 1 h / Cooling with ice 2: 1H-imidazole / dichloromethane / 1 h / 20 °C 3: n-butyllithium / tetrahydrofuran / 0.17 h / -78 - -65 °C 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; tetrahydrofuran / 15 h / Inert atmosphere; Reflux 5: tetrabutyl ammonium fluoride / tetrahydrofuran View Scheme
Multi-step reaction with 5 steps 1.1: iodine; N,N,N',N'-tetramethylguanidine / tetrahydrofuran 2.1: 1H-imidazole / dichloromethane / 1.17 h / 20 °C 3.1: triethyl borate / tetrahydrofuran / 0.17 h / -78 °C 3.2: 0.17 h / -65 °C 4.1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; tetrahydrofuran; toluene / Inert atmosphere; Reflux 5.1: tetrabutyl ammonium fluoride / tetrahydrofuran View Scheme

prasterone acetate (853-23-6) → abiraterone (154229-19-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 58 percent / 2,6-di-tert-butyl-4-methylpyridine / CH2Cl2 / 12 h 2: 84 percent / bis(triphenylphosphine)palladium(II) chloride, aq. Na2CO3 / tetrahydrofuran / 1 h / 80 °C 3: 79 percent / aq. NaOH / methanol / 0.08 h / 80 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 1.2: 2 h / -78 °C 2.1: bis-triphenylphosphine-palladium(II) chloride; sodium carbonate / tetrahydrofuran; water / 18 h / Inert atmosphere; Reflux 3.1: potassium hydroxide; methanol / 1.5 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: 2,6-dimethylpyridine / dichloromethane / -78 - -20 °C 2: sodium hydrogencarbonate; bis-triphenylphosphine-palladium(II) chloride / tetrahydrofuran; water / 1 h / 60 °C 3: potassium carbonate / methanol / 20 °C View Scheme

3β-acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate (115375-60-5) → abiraterone (154229-19-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 84 percent / bis(triphenylphosphine)palladium(II) chloride, aq. Na2CO3 / tetrahydrofuran / 1 h / 80 °C 2: 79 percent / aq. NaOH / methanol / 0.08 h / 80 °C View Scheme
Multi-step reaction with 2 steps 1: bis-triphenylphosphine-palladium(II) chloride; sodium carbonate / tetrahydrofuran; water / 18 h / Inert atmosphere; Reflux 2: potassium hydroxide; methanol / 1.5 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate; bis-triphenylphosphine-palladium(II) chloride / tetrahydrofuran; water / 1 h / 60 °C 2: potassium carbonate / methanol / 20 °C View Scheme

Et2 + 17-iodo-5,16-androstadien-3-ol (32138-69-5) + 3-Diethylboranylpyridine (89878-14-8) → abiraterone (154229-19-3)

Conditions	Yield
With sodium carbonate

diethyl ether (60-29-7) + 17-iodo-5,16-androstadien-3-ol (32138-69-5) + 3-Diethylboranylpyridine (89878-14-8) → abiraterone (154229-19-3)

Conditions	Yield
With sodium carbonate In tetrahydrofuran; bis(triphenylphosphine)palladium(II) dichloride

dehydroepiandrosterone (53-43-0) → abiraterone (154229-19-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: toluene-4-sulfonic acid / tetrahydrofuran / Inert atmosphere; Reflux 2: 1H-imidazole / dichloromethane / 2 h / 20 °C / Inert atmosphere 3: water; tris-(dibenzylideneacetone)dipalladium(0); XPhos; lithium tert-butoxide / 1,4-dioxane / 5 h / Inert atmosphere; Reflux 4: tetrabutyl ammonium fluoride / tetrahydrofuran View Scheme
Multi-step reaction with 4 steps 1: toluene-4-sulfonic acid / tetrahydrofuran / Inert atmosphere; Reflux 2: 1H-imidazole / dichloromethane / 3 h / 20 °C / Inert atmosphere 3: water; tris-(dibenzylideneacetone)dipalladium(0); XPhos; lithium tert-butoxide / 1,4-dioxane / 6 h / 90 °C / Inert atmosphere 4: tetrabutyl ammonium fluoride / tetrahydrofuran View Scheme
Multi-step reaction with 6 steps 1: hydrazinium sulfate; hydrazine hydrate / ethanol; water / 72 h / 20 °C 2: iodine; N,N,N',N'-tetramethylguanidine / tetrahydrofuran / 1 h / Cooling with ice 3: 1H-imidazole / dichloromethane / 1 h / 20 °C 4: n-butyllithium / tetrahydrofuran / 0.17 h / -78 - -65 °C 5: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; tetrahydrofuran / 15 h / Inert atmosphere; Reflux 6: tetrabutyl ammonium fluoride / tetrahydrofuran View Scheme

3-((tert-butyldimethylsilyl)oxy)-17-iodo-5,16-androstadiene (1426400-02-3) → abiraterone (154229-19-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: n-butyllithium / tetrahydrofuran / 0.17 h / -78 - -65 °C 2: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; tetrahydrofuran / 15 h / Inert atmosphere; Reflux 3: tetrabutyl ammonium fluoride / tetrahydrofuran View Scheme
Multi-step reaction with 3 steps 1.1: triethyl borate / tetrahydrofuran / 0.17 h / -78 °C 1.2: 0.17 h / -65 °C 2.1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; tetrahydrofuran; toluene / Inert atmosphere; Reflux 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran View Scheme

3-((tert-butyldimethylsilyl)oxy)-5,16-androstadien-17-boronic acid (1426400-03-4) → abiraterone (154229-19-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; tetrahydrofuran / 15 h / Inert atmosphere; Reflux 2: tetrabutyl ammonium fluoride / tetrahydrofuran View Scheme

dehydroepiandrosterone-17-p-toluenesulfonyl hydrazone (34988-34-6) → abiraterone (154229-19-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1H-imidazole / dichloromethane / 2 h / 20 °C / Inert atmosphere 2: water; tris-(dibenzylideneacetone)dipalladium(0); XPhos; lithium tert-butoxide / 1,4-dioxane / 5 h / Inert atmosphere; Reflux 3: tetrabutyl ammonium fluoride / tetrahydrofuran View Scheme
Multi-step reaction with 3 steps 1: 1H-imidazole / dichloromethane / 2 h / 20 °C / Inert atmosphere 2: tris-(dibenzylideneacetone)dipalladium(0); XPhos; lithium tert-butoxide / 1,4-dioxane / 15 h / 110 °C / Inert atmosphere 3: tetrabutyl ammonium fluoride / tetrahydrofuran View Scheme
Multi-step reaction with 3 steps 1: 1H-imidazole / dichloromethane / 2.17 h / 20 °C / Inert atmosphere 2: caesium carbonate; dichloro bis(acetonitrile) palladium(II); 1,3-bis-(diphenylphosphino)propane / 1,4-dioxane / 110 °C 3: tetrabutyl ammonium fluoride / tetrahydrofuran View Scheme

5-dehydroepiandrosterone 2,4,6-trimethylbenzenesulfonyl hydrazone → abiraterone (154229-19-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1H-imidazole / dichloromethane / 3 h / 20 °C / Inert atmosphere 2: water; tris-(dibenzylideneacetone)dipalladium(0); XPhos; lithium tert-butoxide / 1,4-dioxane / 6 h / 90 °C / Inert atmosphere 3: tetrabutyl ammonium fluoride / tetrahydrofuran View Scheme
Multi-step reaction with 3 steps 1: 1H-imidazole / dichloromethane / 3 h / 20 °C / Inert atmosphere 2: tris-(dibenzylideneacetone)dipalladium(0); lithium tert-butoxide; XPhos / water; 1,4-dioxane / 6 h / 90 °C / Inert atmosphere 3: tetrabutyl ammonium fluoride / tetrahydrofuran View Scheme

BOC-glycine (4530-20-5) + abiraterone (154229-19-3) → tert-butoxycarbonylaminoacetic acid 10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ester

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; Inert atmosphere;	98%

abiraterone (154229-19-3) → 17-(3-pyridine)-4,16-dieneandrost-3-one (154229-21-7)

Conditions	Yield
With aluminum isopropoxide In toluene; butanone Inert atmosphere; Reflux;	97%
With aluminum isopropoxide In cyclohexanone; toluene for 2h; Dean-Stark; Reflux;	90%
With aluminum isopropoxide; butanone In toluene for 16h; Oppenauer Oxidation; Reflux; Dean-Stark;	85%

acetic anhydride (108-24-7) + abiraterone (154229-19-3) → abiraterone acetate (154229-18-2)

Conditions	Yield
With dmap In acetone at 20 - 65℃; for 1h;	95.3%
With pyridine; dmap; triethylamine at 0 - 20℃; for 5h;	95%
With pyridine In acetonitrile Reflux; Large scale;	91.6%

succinic acid mono-tert-butyl ester (15026-17-2) + abiraterone (154229-19-3) → C32H43NO4

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 6h; Inert atmosphere;	95%

1,1'-carbonyldiimidazole (530-62-1) + abiraterone (154229-19-3) → C28H33N3O2

Conditions	Yield
Stage #1: abiraterone With triethylamine In dichloromethane for 0.166667h; Stage #2: 1,1'-carbonyldiimidazole With dmap In dichloromethane Reflux;	92%

chloroacetyl chloride (79-04-9) + abiraterone (154229-19-3) → abiraterone chloroacetic acid ester

Conditions	Yield
Stage #1: abiraterone With pyridine; calcium chloride In tetrahydrofuran at 0℃; for 0.0833333h; Stage #2: chloroacetyl chloride In tetrahydrofuran at 0 - 20℃; for 10.5h; Solvent; Reagent/catalyst; Concentration; Temperature;	91.3%

acetyl chloride (75-36-5) + abiraterone (154229-19-3) → abiraterone acetate (154229-18-2)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In diethyl ether at 20℃; for 4h;	85.1%
With 2-(Dimethylamino)pyridine; triethylamine In diethyl ether; ethanol; hexane; water	84%
With triethylamine In ethyl acetate at 5 - 20℃; for 2h;	83%

[2-(tert-butoxycarbonyl-isopropylamino)acetylamino]acetic acid + abiraterone (154229-19-3) → [2-(tert-butoxycarbonylisopropylamino)acetylamino]acetic acid 10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ester

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; Inert atmosphere;	84%

abiraterone (154229-19-3) → 17β-(3-pyridyl)androst-5-en-3β-ol

Conditions	Yield
With hydrazine hydrate; acetic acid In ethanol at 80℃; for 16h;	83%

n-tetradecyloxy isopropenyl ether + abiraterone (154229-19-3) → C41H65NO2

Conditions	Yield
With dichloro-acetic acid In dichloromethane at 20℃; Schlenk technique;	83%

Acetic anhydride-d6 (16649-49-3) + abiraterone (154229-19-3) → (3β)-17-(3-pyridyl)androst-5,16-dienyl d3-acetate

Conditions	Yield
With dmap In acetone at 55 - 65℃; for 2h;	82.4%

[Ru(2,2’:6’,2’’-terpyridine)(6,6'-dimethyl-2,2'-dipyridyl)Cl]Cl (1449222-32-5) + abiraterone (154229-19-3) → [Ru(2,2':6',2''-terpyridine)(6,6'-dimethyl-2,2'-biquinoline)(abiraterone)]Cl2

Conditions	Yield
In ethanol; water at 80℃; for 20h; Inert atmosphere;	81.5%

4-Nitrophenyl chloroformate (7693-46-1) + abiraterone (154229-19-3) → abiraterone 4-nitrobenzene carbonate

Conditions	Yield
With dmap at 20℃;	80.6%
In tetrahydrofuran at 0℃; for 3h; Reflux;	69%

1-methylpiperidine-4-carboxylic acid hydrochloride (71985-80-3) + abiraterone (154229-19-3) → [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl] 1-methylpiperidine-4-carboxylate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	80%

triisopropylsilyl chloride (13154-24-0) + abiraterone (154229-19-3) → 3-((3S,8R,9S,10R,13S,14S)-10,13-dimethyl-3-((triisopropylsilyl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)pyridine

Conditions	Yield
Stage #1: abiraterone With 1H-imidazole In dichloromethane at 0℃; for 0.166667h; Stage #2: triisopropylsilyl chloride In dichloromethane at 20℃; for 44h;	80%

abiraterone (154229-19-3) → 17-(3-pyridyl)-3,6-dioxoandrosta-4,16-diene (154229-33-1)

Conditions	Yield
With dipyridine chromium(VI) oxide In dichloromethane at 20℃; for 4h;	75%

4-((9Z,12Z)-octadeca-9,12-dien-1-yloxy)-4-oxobutanoic acid + abiraterone (154229-19-3) → (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl linoleylsuccinate

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane for 14h; Inert atmosphere; Cooling with ice;	60%

Upstream product

• 32138-69-5 17-iodo-5,16-androstadien-3-ol 
• 89878-14-8 3-Diethylboranylpyridine 
• 115375-60-5 3β-acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate 
• 29163-23-3 3β-formyl-oxy-5-androsten-17-one 
• 1429742-48-2 3β-formyloxyandrosta-5,16-diene-17-yl trifluoromethanesulphonate 
• 1429742-49-3 3β-formyloxy-17-(3-pyridyl)androsta-5,16-diene 
• 626-55-1 3-Bromopyridine 
• 21970-14-9 pyridin-3-ylmagnesium bromide 
• 42151-23-5 (3S)-3-tert-butyldimethylsilyloxyandrost-5-en-17-one 
• 1421704-59-7 C₃₀H₄₇NO₂Si 
• 1193-82-4 racemic methyl phenyl sulfoxide 
• 979-02-2 16-dehydropregnenolone acetate 
• 34988-34-6 dehydroepiandrosterone-17-p-toluenesulfonyl hydrazone 
• 53-43-0 dehydroepiandrosterone 

Downstream Products

• 154229-18-2 abiraterone acetate 
• 186826-68-6 3β-Acetoxy-16-(3β-acetoxyandrosta-5,16-dien-17-yl)-17-(3-pyridyl)androsta-5,16-diene 
• 154229-21-7 17-(3-pyridine)-4,16-dieneandrost-3-one 

Relevant academic research and scientific papers

Synthesis and biological evaluation of analogs of didehydroepiandrosterone as potential new anticancer agents

The synthesis, cytotoxicity and inhibition of CDK8 by thirteen analogs of cortistatin A are reported. These efforts revealed that the analogs with either a 6- or 7-isoquinoline or 5-indole side chain in the 17-position are the most promising anti-proliferative agents. These compounds showed potent cytotoxic effects in CEM, HeLa and HMEC-1 cells. All three compounds exhibited IC50 values 10μM. The most interesting 10l analog exhibited an IC50 value of 0.59 μM towards the human dermal microvascular endothelial cell line (HMEC-1), significantly lower than the reference standard 2-methoxyestradiol. At a concentration at 50 nM the most potent 10h compound reduced the activity of CDK8 to 35percent.

A new method for the synthesis of abiraterone drug catalyzed by Pd-NPs@Zn-MOF as efficient reusable catalyst

The present work provides a novel process for the preparation of abiraterone drug in a Suzuki–Miyaura coupling approach by a new heterogeneous palladium catalyst, Pd-NPs@Zn-MOF, which has been synthesized by one-step encapsulation in nanoporous metal–organic framework Zn-MOF under a temperature control program for the first time. Pd-NPs@Zn-MOF were characterized by transmission electron microscopy (TEM), X-Ray powder diffraction (XRD), BET surface area analysis, inductively coupled plasma (ICP)-optical emission spectrometry (OES), and X-ray photoelectron spectroscopy (XPS).

PRODRUGS OF ABIRATERONE

The present invention relates to compounds of formula (I), or their isotopic forms, stereoisomers, tautomers, or pharmaceutically acceptable salt(s) thereof as prodrugs of abiraterone. The present invention also describes method of making such compounds, pharmaceutical compositions comprising such compounds and the use of the compounds of formula (I).

Preparation method of abiraterone

The invention provides a preparation method of abiraterone, and belongs to the technical field of medicine synthesis. The preparation method comprises the following steps: by taking a compound 17-bromoandrostane-5, 16-diene-3beta-alcohol as an initial raw material, carrying out borylation reaction on the initial raw material and boric acid ester under the action of an accelerant to obtain an intermediate compound 2; and allowing the compound 2 and a pyridyl compound to be subjected to a coupling reaction under the action of a catalyst to obtain the abiraterone. According to the method, the yield and the purity of abiraterone are remarkably improved by adjusting the synthesis route, the ratio of the reaction raw materials and other process parameters; the preparation method disclosed by the invention is simple and easy to implement and mild in condition, the yield of the obtained product is as high as 95%, the purity of the product is as high as 99.8%, and the stipulation of the drug quality standard is met.

Synthetic method of abiraterone acetate and intermediate thereof (by machine translation)

The invention relates to a synthesis method of abiraterone acetate and a dragon intermediate thereof. In the synthesis method of abiraterone acetate intermediate, a compound of formula (I), a chloro reagent and a base are chlorinated to obtain the abiraterone acetate intermediate of formula (II). The mass ratio of the compound of the formula (I) to the base is 1: (1.5 -3). The structure of the compound of formula (I) and abiraterone acetate is as follows. To the synthesis method, the occurrence probability of side reactions in the chlorination reaction process can be reduced while the high reaction activity is maintained, so that the yield and purity of the abiraterone acetate intermediate can be improved, and the process is simple. (by machine translation)

Slow-, tight-binding inhibition of CYP17A1 by abiraterone redefines its kinetic selectivity and dosing regimen

Substantial evidence underscores the clinical efficacy of inhibiting CYP17A1-mediated androgen biosynthesis by abiraterone for treatment of prostate oncology. Previous structural analysis and in vitro assays revealed inconsistencies surrounding the nature and potency of CYP17A1 inhibition by abiraterone. Here, we establish that abiraterone is a slow-, tight-binding inhibitor of CYP17A1, with initial weak binding preceding the subsequent slow isomerization to a high-affinity CYP17A1-abiraterone complex. The in vitro inhibition constant of the final high-affinity CYP17A1-abiraterone complex ( ( Ki? = 0.39 nM )yielded a binding free energy of -12.8 kcal/mol that was quantitatively consistent with the in silico prediction of 214.5 kcal/mol. Prolonged suppression of dehydroepiandrosterone (DHEA) concentrations observed in VCaP cells after abiraterone washout corroborated its protracted CYP17A1 engagement. Molecular dynamics simulations illuminated potential structural determinants underlying the rapid reversible binding characterizing the two-step induced-fit model. Given the extended residence time (42 hours) of abiraterone within the CYP17A1 active site, in silico simulations demonstrated sustained target engagement even whenmost abiraterone has been eliminated systemically. Subsequent pharmacokineticpharmacodynamic (PK-PD) modeling linking time-dependent CYP17A1 occupancy to in vitro steroidogenic dynamics predicted comparable suppression of downstream DHEA-sulfate at both 1000- and 500-mg doses of abiraterone acetate. This enabled mechanistic rationalization of a clinically reported PK-PD disconnect, inwhich equipotent reduction of downstreamplasma DHEAsulfate levels was achieved despite a lower systemic exposure of abiraterone. Our novel findings provide the impetus for reevaluating the current dosing paradigmof abiraterone with the aim of preserving PD efficacy while mitigating its dose-dependent adverse effects and financial burden. SIGNIFICANCE STATEMENT With the advent of novel molecularly targeted anticancer modalities, it is becoming increasingly evident that optimal dose selection must necessarily be predicated on mechanistic characterization of the relationships between target exposure, drug-target interactions, and pharmacodynamic endpoints. Nevertheless, efficacy has always been perceived as being exclusively synonymous with affinity-based measurements of drug-target binding. This work demonstrates how elucidating the slow-, tight-binding inhibition of CYP17A1 by abiraterone via in vitro and in silico analyses was pivotal in establishing the role of kinetic selectivity in mediating time-dependent CYP17A1 engagement and eventually downstream efficacy outcomes.

Method for preparing abiraterone acetate

The invention provides a method for preparing abiraterone acetate. Specifically, the invention relates to an improved method for synthesizing abiraterone or a derivative thereof through a key 3 beta-benzoyloxy intermediate. According to the process, intermediate DHEA 3-benzoyloxy ester is a solid, the intermediate with higher purity can be obtained through a crystallization method, and the processoperability is high. Meanwhile, benzoyl is strong in electric negative force, easy to react with hydroxyl and high in acylation rate, and a six-membered ring structure is twisted in a space structureof a benzoyl functional group, so that elimination reaction is not easy to perform, and generation of process byproducts is effectively avoided.

Preparation method of abiraterone acetate

The invention provides a preparation method of abiraterone acetate: dissolving an alkenyl iodide (17-iodoandrostane-5,16-diene-3[beta]-acetate or 17-iodoandrostane-5,16-diene-3[beta]-hydroxyl), a compound (I), an aryl boride (diethyl(3-pyridyl)borane), a compound (II), pyridine-3-boronic acid or pyridine-3-boronic acid pinacol ester, an alkaline substance, and a Pd/C catalyst in an organic solvent, and performing a reaction at 60-120 DEG C for 3-12 h; after the reaction is finished, carrying out post-treatment on the reaction liquid to obtain the abiraterone acetate and recycling the Pd catalyst; wherein the compound (I) and compound (II) are represented as the formulas as follows. The method is high in yield, is less in impurity and has convenience of recycling the noble metal catalyst and obtaining raw materials, is simple in operation, is available to industrial production, and has great application value.

STEROIDAL COMPOUND, COMPOSITION CONTAINING THE SAME AND USE THEREOF

Provided in the present invention are a steroidal compound, a composition containing the same and a use thereof. Specifically, disclosed in the present invention are a steroidal compound as shown in formula (I) and a drug composition containing the same, or a crystal form, a pharmaceutically acceptable salt, a hydrate or solvate, a stereoisomer, a prodrug, a metabolite or an isotopic variant thereof. The compound according to the present invention can be used as a CYP17 enzyme inhibitor, and has better pharmacokinetic parameters, which can improve drug concentration of the compound in an animal, thereby improving the efficacy and safety of the drug, and in turn the compound may be applied in the preparation of the drug for treating CYP17 enzyme-related diseases (such as prostate cancer).

Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2

Inhibition of androgen biosynthesis is clinically effective for treating androgen-responsive prostate cancer. Abiraterone is a clinical first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1) required for androgen biosynthesis. However, abiraterone also causes hypertension, hypokalemia, and edema, likely due in part to off-target inhibition of another steroidogenic cytochrome P450, CYP21A2. Abiraterone analogs were designed based on structural evidence that B-ring substituents may favorably interact with polar residues in binding CYP17A1 and sterically clash with residues in the CYP21A2 active site. The best analogs increased selectivity of CYP17A1 inhibition up to 84-fold compared with 6.6-fold for abiraterone. Cocrystallization with CYP17A1 validated the intended new contacts with CYP17A1 active site residues. Docking these analogs into CYP21A2 identified steric clashes that likely underlie decreased binding and CYP21A2 inhibition. Overall, these analogs may offer a clinical advantage in the form of reduced side effects.