# US 10,870,628 B2 · Formation of N-protected 3,6-bis-(4-aminobutyl)-2,5-diketopiperazine through a cyclic α-N-protected amino ester

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- Number: US 10,870,628 B2
- Document ID: US10870628B2
- Status: Granted
- Kind: B2
- Application number: 16/806,298
- Filed: 2020-03-02
- Published: 2020-06-25
- Granted: 2020-12-22
- Earliest claimed: 2013-03-15
- Assignees: MannKind Corporation
- Applicants: MannKind Corporation
- Inventors: John J. Freeman; Otto Phanstiel; William Elliot Bay; Kelly Sullivan Kraft
- Web page: https://patentgrep.com/patent/US10870628B2

## CPC

- C07D 241/08: with oxygen atoms directly attached to ring carbon atoms
- C07D 241/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 241/10: having three double bonds between ring members or between ring members and non-ring members
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A method for the synthesis of N-protected 3,6-aminoalkyl-2,5-diketopiperazines is provided. The method includes obtaining a cyclic α-N protected active amino ester and adding it to a mixture of an amine catalyst in an organic solvent.

## Claims

### Claim 1

A method for the synthesis of a compound according to Formula I:
the method comprising adding a cyclic amino compound according to the following formula:
to a catalyst in an organic solvent selected from THF, dioxane, and ethanol, and heating the mixture for a period of 2 to 6 hours,
wherein the cyclic amino compound is added over a period of greater than one hour,
wherein R is a C3 to C5 N-protected alkyl amine,
wherein the protecting group (PG) is selected from the group consisting of amide forming protecting groups and carbamate forming protecting groups,
wherein n is from 2-4, and
wherein X is selected from C, P, and S.

### Claim 2 (depends on 1)

The method of claim 1, wherein the mixture is heated to a temperature of up to 75° C.

### Claim 3 (depends on 1)

The method of claim 1, wherein the organic solvent is THF.

### Claim 4 (depends on 1)

The method of claim 1, wherein the catalyst is an amine catalyst.

### Claim 5 (depends on 4)

The method of claim 4, wherein the amine catalyst is benzamindoxine.

### Claim 6 (depends on 5)

The method of claim 5, wherein the mixture comprises a co-catalyst selected form hydroxybenzotriazole and hydroxysuccinimide.

### Claim 7 (depends on 6)

The method of claim 6, wherein the co-catalyst is present in an amount of about 0.2 equivalents that of the catalyst.

### Claim 8 (depends on 1)

The method of claim 1, wherein the wherein the catalyst is present in an amount of 0.25 to 2.5 equivalents based on the amount of the cyclic amino compound.

### Claim 9 (depends on 8)

The method of claim 8, wherein the organic solvent is selected from THF and ethanol.

### Claim 10 (depends on 1)

The method of claim 1, wherein the PG is selected from trifluoroacetyl, Cbz, and Boc.

### Claim 11 (depends on 1)

The method of claim 1, wherein X is C.

### Claim 12 (depends on 11)

The method of claim 11, wherein PG is trifluoroacetyl.

### Claim 13 (depends on 12)

The method of claim 12, wherein the organic solvent is selected from THF and ethanol.

### Claim 14 (depends on 13)

The method of claim 13, wherein PG is Cbz.

### Claim 15

A method for the synthesis of a diketopiperazine according to Formula II,
the method comprising mixing a cyclic amino compound according to the following formula:
with a catalyst in an organic solvent selected from THF, dioxane, and ethanol, and heating the mixture for a period of 2 to 6 hours, and removing the PG after formation of diketopiperazine,
wherein R is a C4 N-protected alkyl amine,
wherein the protecting group (PG) is selected from the group consisting of amide forming protecting groups and carbamate forming protecting groups, and
wherein X is selected from C, P, and S.

### Claim 16 (depends on 15)

The method of claim 15, wherein the mixture is heated to a temperature of up to 75° C.

### Claim 17 (depends on 16)

The method of claim 16, wherein the organic solvent is THF.

### Claim 18 (depends on 15)

The method of claim 15, wherein the amine catalyst is benzamindoxine.

### Claim 19 (depends on 8)

The method of claim 8, wherein the mixture comprises a co-catalyst selected form hydroxybenzotriazole and hydroxysuccinimide.

### Claim 20 (depends on 19)

The method of claim 19, wherein the PG is selected from trifluoroacetyl, Cbz, and Boc.