METHODS FOR THE SYNTHESIS OF ACTIVATED ETHYLFUMARATES AND THEIR USE AS INTERMEDIATES
Disclosed embodiments relate to improved methods for the synthesis of activated fumarate intermediates and their use in chemical synthesis. Disclosed embodiments describe the synthesis of activated fumarate esters including those derived from activating groups including: 4-nitrophenyl, diphenylphophoryl azide, pivaloyl chloride, chlorosulfonyl isocyanate, p-nitrophenol, MEF, trifluoroacetyl and chlorine, for example, ethyl fumaroyl chloride and the subsequent use of the activated ester in situ. Further embodiments describe the improved synthesis of substituted aminoalkyl-diketopiperazines from unisolated and unpurified intermediates allowing for improved yields and reactor throughput.
1 . A method of preparing a functionalized diketopiperazine comprising:
in a first reaction vessel, mixing a diketopiperazine according to the following formula
with sodium hydroxide in a first organic solvent to form a deprotected aminoalkyl-diketopiperazine;
in a second reaction vessel, mixing 4-nitrophenol and a second organic solvent;
adding a mixture of sodium hydroxide and water to the second reaction vessel;
cooling the second reaction vessel;
adding ethyl fumaryl chloride over a period of 1 minute to 60 minutes;
adding contents of the first reaction vessel to contents of the second reaction vessel to form a combined reaction mixture;
heating the combined reaction mixture;
cooling the combined reaction mixture;
quenching the combined reaction mixture with water; and
isolating a functionalized diketopiperazine according to the following formula
2 . The method of claim 1 , wherein PG is trifluoroacetyl.
3 . The method of claim 1 , wherein the first organic solvent is selected from acetone, acetonitrile, ethyl acetate, tetrahydrofuran, and dichloromethane.
4 . The method of claim 1 , wherein the second organic solvent is selected from acetone, acetonitrile, ethyl acetate, tetrahydrofuran, and dichloromethane.
5 . The method of claim 1 , wherein the first organic solvent and second organic solvent are the same.
6 . The method of claim 5 , wherein the first organic solvent and second organic solvent are acetone.
7 . The method of claim 1 , wherein mixing the diketopiperazine with sodium hydroxide comprises mixing at room temperature.
8 . The method of claim 7 , wherein mixing at room temperature comprises mixing at room temperature for at least 10 minutes.
9 . The method of claim 1 , wherein cooling the 4-nitrophenol mixture comprises cooling to a temperature of 10° C. to 25° C.
10 . The method of claim 1 , wherein the ethyl fumaryl chloride is added as a solution in a third organic solvent.
11 . The method of claim 10 , wherein the ethyl fumaryl chloride is added over a period of 5 minutes to 10 minutes.
12 . The method of claim 11 , wherein the contents of the second reaction vessel are stirred for a period of at least 15 minutes after addition of the ethyl fumaryl chloride.
13 . The method of claim 1 , wherein the ethyl fumaryl chloride is provided in an amount of 0.5 to 2 equivalents based on the amount of 4-nitrophenol in the second reaction vessel.
14 . The method of claim 1 , wherein the sodium hydroxide is provided in an amount of 1 to 2 equivalents based on the amount of 4-nitrophenol in the second reaction vessel.
15 . The method of claim 1 , wherein the sodium hydroxide is provided in the first reaction vessel in an amount of 2 to 3 equivalents based on the amount of diketopiperazine.
16 . The method of claim 1 , wherein heating the combined reaction mixture comprises heating to a temperature of 30° C. to 75° C.
17 . A method of preparing a diketopiperazine of Formula I (n=1-7) comprising:
mixing 4-nitrophenol, sodium hydroxide in an amount of about 1.1 equivalents based on the 4-nitrophenol, and acetone to form a first mixture;
cooling the first mixture to a temperature of about 20° C.;
adding ethyl fumaryl chloride in acetone to the first mixture over a period of at least 5 minutes to achieve a mixture having a pH of 7-8;
adding a crude mixture of an aminoalkyl-diketopiperazine according to the following formula
in acetone to the first mixture to form a combined reaction mixture;
heating the combined reaction mixture to a temperature of 30° C. to 75° C. for a period of 10 minutes to 2 hours to form the diketopiperazine of Formula I.
18 . The method of claim 17 , wherein the ethyl fumaryl chloride is provided in an amount of less than 1 equivalent based on the amount of 4-nitrophenol in the first mixture.
19 . The method of claim 17 , wherein the aminoalkyl-diketopiperazine is provided in an amount of less than 0.5 equivalents based on the amount of ethyl fumaryl chloride in the first mixture.
20 . The method of claim 17 , wherein the first mixture is stirred at room temperature for a period of at least 15 minutes after addition of the ethyl fumaryl chloride.