Process for preparing b-[(7α, 17β)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-trien-3-yl]-boronic acid and process intermediates
AssigneeIndustriale Chimica S.R.L.
InventorsRoberto Lenna, Andrea Fasana
Life of this patent
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Abstract
The present invention relates to a process for preparing B-[(7α,17β)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-trien-3-yl]-boronic acid, also known as Fulvestrant-3-boronic acid or ZB716, whose structure is shown below:
Claims9
A process for the synthesis of B-[(7α,17β)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5 (10)-trien-3-yl]-boronic acid (compound ZB716), comprising the following steps:
- a) reaction of Fulvestrant, (7α,17β)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-estra-1,3,5 (10)-trien-3,17-diol, intermediate N-7 of the process, with a triflating agent, to obtain intermediate N-6, (7α, 17β)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-estra-1,3,5 (10)-trien-17-ol 3-triflate:
- b) reaction of intermediate N-6 with an acylating reagent to obtain an intermediate of general formula N-5,
- wherein R is selected from a linear or branched C1-C7 alkyl radical, an aromatic radical and a heterocyclic radical;
- c) reaction of intermediate N-5 with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane to obtain the intermediate of general formula N-4,
- d) reaction of intermediate N-4 with an inorganic base to give the mixture made of intermediate N-3, (7α, 17β)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-estra-1,3,5 (10)-trien-17-ol, and compound ZB716, B-[(7α, 17β)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5 (10)-trien-3-yl]-boronic acid:
- e) reaction of the mixture made of intermediate N-3 and compound ZB716 with KHF2 to obtain intermediate N-1, potassium (7α,17β)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-estra-1,3,5 (10)-trien-17-ol-3-trifluoroborate:
- f) treatment of intermediate N-1 with an inorganic base to give compound ZB716, B-[(7α, 17β)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5 (10)-trien-3-yl]-boronic acid:
A compound (7α, 17β)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-estra-1,3,5 (10)-trien-17-acyloxy 3-triflate, of general formula:
- wherein R is selected from a linear or branched C1-C7 alkyl radical, an aromatic radical and a heterocyclic radical.
The compound (7α, 17β)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-estra-1,3,5 (10)-trien-17-acyloxy, of general formula:
- wherein R is selected from a linear or branched C1-C7 alkyl radical, an aromatic radical and a heterocyclic radical.
Dependencies are inferred from the claim text.