Compounds suitable as precursors to compounds that are useful for imaging amyloid deposits
The present invention relates to novel derivatives that are suitable as precursors to compounds that are useful for imaging amyloid deposits in living patients, their compositions, methods of use and processes to make such compounds. The compounds deriving from these precursors are useful in methods of imaging amyloid deposits in brain in vivo to allow antemortem diagnosis of Alzheimer's disease by positron emission tomography (PET) as well as measuring clinical efficacy of Alzheimer's disease therapeutic agents. Furthermore, the present invention also discloses the precursor compounds in crystalline form.
1. A process for making [5-(5-ethoxymethoxy-benzofuran-2-yl)-6-nitro-pyridin-2-yl]-methyl-carbamic acid tert-butyl ester or salt thereof, wherein the process comprises reacting 5-ethoxymethoxy-benzofuran-2-boronic acid and (5-bromo-6-nitro-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester in the presence of a palladium catalyst and base in a solvent.
2. The process according to claim 1 , wherein the palladium catalyst is dichlorobis(triphenylphosphine)palladium(II).
3. The process according to claim 1 , wherein the base is triethylamine.
4. The process according to claim 1 , wherein the solvent is ethanol.
5. The process according to claim 1 , wherein the [5-(5-ethoxymethoxy-benzofuran-2-yl)-6-nitro-pyridin-2-yl]-methyl-carbamic acid tert-butyl ester or salt thereof is in crystalline form.
6. The process according to claim 1 , wherein said 5-ethoxymethoxy-benzofuran-2-boronic acid is made by a process comprising:
a. converting 5-methoxybenzofuran to benzofuran-5-ol with a deprotection reagent in a solvent;
b. converting benzofuran-5-ol to 5-ethoxymethoxy-benzofuran with a base and a protection reagent in a solvent; and
c. converting 5-ethoxymethoxy-benzofuran to 5-ethoxymethoxy-benzofuran-2-boronic acid by a process comprising deprotonating 5-ethoxymethoxy-benzofuran with a base and mixing the deprotonated product with a trialkylborate in a solvent.
7. The process according to claim 6 , wherein the deprotection reagent for converting 5-methoxybenzofuran to benzofuran-5-ol in a solvent is boron tribromide.
8. The process according to claim 7 , wherein the solvent is dichloromethane.
9. The process according to claim 6 , wherein the base for converting benzofuran-5-ol to 5-ethoxymethoxy-benzofuran with a protection reagent in a solvent is sodium hydride.
10. The process according to claim 6 , wherein the protection reagent for converting benzofuran-5-ol to 5-ethoxymethoxy-benzofuran with a base is chloromethyl ethyl ether and the solvent is dimethylformamide.
11. The process according to claim 6 , wherein the base for converting 5-ethoxymethoxy-benzofuran to 5-ethoxymethoxy-benzofuran-2-boronic acid with a trialkylborate in a solvent is n-butyllithium.
12. The process according to claim 6 , wherein the trialkylborate for converting 5-ethoxymethoxy-benzofuran to 5-ethoxymethoxy-benzofuran-2-boronic acid with a base is triisopropyl borate and the solvent is tetrahydrofuran.
13. The process according to claim 1 , wherein said (5-bromo-6-nitro-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester is made by a process comprising:
a. converting 6-nitro-pyridin-2-ylamine to 5-bromo-6-nitro-pyridin-2-ylamine by a process comprising bromination of 6-nitro-pyridin-2-ylamine in a solvent using a bromination reagent;
b. converting 5-bromo-6-nitro-pyridin-2-ylamine to (5-bromo-6-nitro-pyridin-2-yl)-carbamic acid tert-butyl ester by a process comprising combining 5-bromo-6-nitro-pyridin-2-ylamine and di-tert-butyl dicarbonate in a solvent in the presence of a base; and
c. converting (5-bromo-6-nitro-pyridin-2-yl)-carbamic acid tert-butyl ester to (5-bromo-6-nitro-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester by a process comprising alkylating (5-bromo-6-nitro-pyridin-2-yl)-carbamic acid tert-butyl ester in a solvent using an alkylating agent in the presence of a base.
14. The process according to claim 13 , wherein the bromination reagent for converting 6-nitro-pyridin-2-ylamine to 5-bromo-6-nitro-pyridin-2-ylamine in a solvent is N-bromosuccinimide.
15. The process according to claim 14 , wherein the solvent is acetonitrile.
16. The process according to claim 13 , wherein the base for converting 5-bromo-6-nitro-pyridin-2-ylamine to (5-bromo-6-nitro-pyridin-2-yl)-carbamic acid tert-butyl ester with di-tert-butyl dicarbonate is sodium bis(trimethylsilyl)amide.
17. The process according to claim 16 , wherein the solvent is tetrahydrofuran.
18. The process according to claim 13 , wherein the alkylating agent for converting (5-bromo-6-nitro-pyridin-2-yl)-carbamic acid tert-butyl ester to (5-bromo-6-nitro-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester is methyl iodide.
19. The process according to claim 18 , wherein the base is 1,8-diazabicyclo[5.4.0]undec-7-ene and the solvent is dimethylformamide.
20. A process for making 2-(2-[ 18 F]-fluoro-6-methylamino-pyridin-3-yl)-benzofuran-5-ol or a salt thereof, wherein the process comprises reacting [5-(5-ethoxymethoxy-benzofuran-2-yl)-6-nitro-pyridin-2-yl]-methyl-carbamic acid tert-butyl ester or salt thereof prepared according to the process of claim 1 , with a source of 18 F-fluoride.