Methods for the synthesis of activated ethylfumarates and their use as intermediates

Patent metadata

Field	Value
Publication number	US-2016159753-A1
Application number	US-201514949489-A
Country	US
Kind code	A1
Filing date	Nov 23, 2015
Priority date	Apr 27, 2012
Publication date	Jun 9, 2016
Grant date	—

Abstract

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.

First claim

What is claimed is:

1 . A method of preparing a diketopiperazine of Formula I (n=1-7) comprising:

mixing 4-nitrophenol, an inorganic metallic base, and ethyl fumaryl chloride in an organic solvent to produce a monoethyl fumarate ester;
adding an aminoalkyl-diketopiperazine;
wherein the mono-ethyl fumarate ester is reacted with the aminoalkyl-diketopiperazine in situ without purification.

2 . The method of claim 1 , wherein the organic solvent is selected from acetone, acetonitrile, ethyl acetate, tetrahydrofuran, and dichloromethane.

3 . The method of claim 1 , wherein the base is selected from sodium carbonate and sodium hydroxide.

4 . The method of claim 1 , wherein the base is provided in an amount of 1 to 2 equivalents based on the amount of 4-nitrophenol.

5 . 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.

6 . The method of claim 1 , wherein the inorganic metallic base is added as an aqueous mixture to a solution of 4-nitrophenol in the organic solvent.

7 . The method of claim 1 , wherein the ethyl fumaryl chloride is added to a mixture of 4-nitrophenol and the inorganic metallic base, with cooling.

8 . The method of claim 1 , wherein the aminoalkyl-diketopiperazine is added as a mixture in an inorganic solvent.

9 . The method of claim 8 , wherein the aminoalkyl-diketopiperazine-containing mixture further comprises a base selected from sodium carbonate and sodium hydroxide.

10 . The method of claim 8 , wherein the mixture is heated after addition of the aminoalkyl-diketopiperazine-containing mixture.

11 . The method of claim 1 , wherein the reaction is quenched with water.

12 . A method of preparing a diketopiperazine of Formula I (n=1-7) comprising:

mixing mono-ethyl fumarate with a proton scavenger and at least one of: diphenylphosphoryl azide, pivaloyl chloride, chlorosulfonyl isocyanate, and trifluoroacetic anhydride in an organic solvent to form a first reaction mixture; and
adding an aminoalkyl-diketopiperazine to form a second reaction mixture.

13 . The method of claim 12 , wherein the proton scavenger is selected from triethylamine, sodium carbonate, and sodium hydroxide.

14 . The method of claim 12 , wherein sodium carbonate is added with the aminoalkyl-diketopiperazine.

15 . The method of claim 12 , wherein the aminoalkyl-diketopiperazine is added without prior purification of the first reaction mixture.

16 . The method of claim 12 , wherein the organic solvent is selected from acetone, acetonitrile, ethyl acetate, tetrahydrofuran, and dichloromethane.

17 . The method of claim 12 , wherein the organic solvent is tetrahydrofuran.

18 . A method of preparing a diketopiperazine of Formula I (n=1-7) comprising:

mixing an aminoalkyl diketopiperazine of Formula II,

an inorganic metallic base, and an anhydride of mono-ethyl fumarate in an organic solvent.

19 . The method of claim 18 , wherein the anhydride of mono-ethyl fumarate is a mixed anhydride.

20 . The method of claim 18 , wherein the an inorganic metallic base is sodium carbonate.

Assignees

• Mannkind Corp

Inventors

• Kraft Kelly Sullivan
• Freeman John J
• Serwinski Paul
• Pavia Vincent
• Phansteil Otto
• Kaur Navneet

Classifications

• C07C67/30

  by modifying the acid moiety of the ester, such modification not being an introduction of an ester group · CPC title

• C07C67/39

  by oxidation of groups which are precursors for the acid moiety of the ester · CPC title

• C07C201/12

  by reactions not involving the formation of nitro groups · CPC title

• C07D241/08 Primary

  with oxygen atoms directly attached to ring carbon atoms · CPC title