Process for producing a hydrate of a hydrochloride salt of 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid
A process for producing a hydrate of a hydrochloride salt of 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid of the formula: wherein the process comprises the following step: recrystallizing the hydrochloride salt of 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid, in the presence of hydrochloric acid and a recrystallization solvent; wherein the recrystallization solvent is methanol, ethanol, 2-propanol, diethyl ether, ethyl acetate, benzene, toluene, acetone, dichloromethane, chloroform, hexane, dimethylformamide, acetonitrile, or water; or mixed solvent thereof.
1. A compound:
or a pharmaceutically acceptable salt thereof.
2. A process for producing a hydrate of a hydrochloride salt of 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid, wherein 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl)diacetic acid is of the formula:
wherein the process comprises the following step:
recrystallizing a hydrochloride salt of 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl)bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl)diacetic acid, wherein 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid is of the formula:
in the presence of hydrochloric acid and a recrystallization solvent;
wherein the recrystallization solvent is water; or
wherein the recrystallization solvent is a mixture of water and one or more additional solvents selected from the group consisting of acetone, acetonitrile, benzene, chloroform, dichloromethane, diethyl ether, N,N-dimethylformamide, ethanol, ethyl acetate, hexane, isopropanol, methanol, and toluene.
3. The process of claim 2 , wherein the hydrate of the hydrochloride salt of 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid is 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl)bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl)diacetic acid is a hydrate of 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl)bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl)diacetic acid monohydrochloride.
4. The process of claim 2 , wherein the process further comprises the following step:
deprotecting di-tert-butyl 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl)bis(azanediyl))bis(ethane-2,1-diyl))bis((tert-butoxycarbonyl)azanediyl))diacetate of the formula:
with hydrochloric acid, to produce a hydrochloride salt of 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl)bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid, wherein 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis(azanediyl))diacetic acid is of the formula:
5. The process of claim 4 , wherein the process further comprises the following step:
reacting 2-acetylnaphtho[2,3-b]furan-4,9-dione of the formula:
with tert-butyl N-(tert-butoxycarbonyl)-N-(2-isocyanatoethyl)glycinate of the formula:
in the presence of a base, and a reductant in a solvent, to produce di-tert-butyl 2,2′-((((((2-acetylnaphtho[2,3-b]furan-4,9-diyl)bis(oxy))bis(carbonyl))bis(azanediyl))bis(ethane-2,1-diyl))bis((tert-butoxycarbonyl)azanediyl))diacetate of the formula:
wherein the base is selected from the group consisting of calcium hydride, cesium carbonate, cyclohexyldimethylamine, N,N-diisopropylethylamine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, lutidine, N-methylmorpholine, N-methylpiperidine, N-methylpyrrolidine, potassium carbonate, pyridine, sodium acetate, sodium carbonate, sodium hydride, triethylamine, tripropylamine, and tributylamine, or a mixture thereof;
wherein the reductant is selected from the group consisting of formic acid, iron(II) ion, oxalic acid, sodium, sodium dithionite, tin(II) ion, and zinc, or a mixture thereof; and
wherein the solvent is selected from the group consisting of acetonitrile, benzene, chlorobenzene, chloroform, 1,2-dichloroethane, dichloromethane, dimethylsulfoxide, N,N-dimethylformamide, 1,4-dioxane, N-methyl-2-pyrrolidone, propionitrile, tetrahydrofuran, toluene, and water, or a mixture thereof.
6. The process of claim 5 , wherein the base is N,N-diisopropylethylamine or triethylamine.
7. The process of claim 5 , wherein the reductant is sodium dithionite.
8. The process of claim 2 , wherein the recrystallization solvent is water.