Method for production of novel galeterone analogs and uses thereof
Galeterone and its C-3 analogs are of substantial interest because of their multi-target anticancer activities, including AR and Mnk degrading activities. Provided are novel procedures for gram-scale, high-yield synthesis of C-3 analogs of galeterone, including 3β-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene (galeterone 3β-imidazole) and 3β-(pyridine-4-ylmethoxy)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (galeterone 3β-pyridine methoxylate).
1. A process for preparing 3β-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene (2) and 3α-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene (5), the process comprising:
a first reaction comprising reacting a compound having Formula 1 (1)
to produce 3-azido-17-(1H-benzimidazole-1-yl) androsta-5,16-diene (7, 8); and
a second reaction comprising reacting the 3-azido-17-(1H-benzimidazole-1-yl) androsta-5,16-diene (7, 8) to produce 3-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene (2, 5),
wherein:
the first reaction comprises mesylation of the compound having Formula 1 (1) to produce a mesylate (4), and azidation of the mesylate (4) comprising contacting the mesylate (4) with (i) an alkali metal azide to produce 3α-azido-17-(1H-benzimidazole-1-yl) androsta-5,16-diene (7) or (ii) an organic azide to produce 3β-azido-17-(1H-benzimidazole-1-yl) androsta-5,16-diene (8), wherein the 3α-azido-17-(1H-benzimidazole-1-yl) androsta-5,16-diene (7) is produced in a yield of at least 60% with a standard deviation of 2%, and the 3β-azido-17-(1H-benzimidazole-1-yl) androsta-5,16-diene (8) is produced in a yield of at least 93% with a standard deviation of 2%, and
the second reaction comprises reduction of the 3α-azido-17-(1H-benzimidazole-1-yl) androsta-5,16-diene (7) and 3β-azido-17-(1H-benzimidazole-1-yl) androsta-5,16-diene (8) to produce an α-amine (9) and a β-amine (10), and cyclization of the α-amine (9) and β-amine (10) to produce the 3β-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene (2) and 3α-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene (5).
2. The process according to claim 1 , wherein the azidation comprises contacting the mesylate (4) with (i) the alkali metal azide or (ii) the organic azide, so as to perform the azidation in a stereo-selective manner to produce (i) the 3α-azido-17-(1H-benzimidazole-1-yl) androsta-5,16-diene (7) and (ii) the 3β-azido-17-(1H-benzimidazole-1-yl) androsta-5,16-diene (8).
3. The process according to claim 2 , wherein the azidation further comprises contacting the mesylate (4) with trimethylsilyl azide in the presence of boron trifluoride etherate and dichloromethane to produce the 3β-azido-17-(1H-benzimidazole-1-yl) androsta-5,16-diene (8).
4. The process according to claim 3 , wherein 15 equivalents of the trimethylsilyl azide and 27 equivalents of the boron trifluoride etherate are added for 1 equivalent of the mesylate (4).
5. The process according to claim 1 , wherein the reduction and the cyclization are performed in a stereo-retentive manner.
6. The process according to claim 1 , wherein the process produces a yield of the 3β-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene (2) of at least 62.8% with a standard deviation of 2%.
7. The process according to claim 1 , wherein the process produces a yield of the 3α-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene (5) of at least 28% with a standard deviation of 2%.