# US 12,110,275 B2 · Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl] piperazin-1-yl]ethyl pyridine-3-carboxylate

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- Number: US 12,110,275 B2
- Document ID: US12110275B2
- Status: Granted
- Kind: B2
- Application number: 18/239,337
- Filed: 2023-08-29
- Published: 2023-12-14
- Granted: 2024-10-08
- Earliest claimed: 2020-06-30
- Assignees: Imbria Pharmaceuticals, Inc.
- Applicants: Imbria Pharmaceuticals, Inc.
- Inventors: Neil Buckley; Dan Belmont; Bryan Hauser; Myoung Goo Kim; Kumar Kannan
- Web page: https://patentgrep.com/patent/US12110275B2

## CPC

- C07D 213/803: Processes of preparation
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention provides methods of chemical synthesis of the pharmacological agent 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate, also called CV-8972. The methods entail formation of a free base form of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethanol, also called CV-8814, as intermediate without producing a salt form of CV-8814.

## Claims

### Claim 1

A method for preparing a compound of Formula (X):
the method comprising the steps of:
reacting a compound of Formula (1):
with a compound of Formula (2):
with sodium triacetoxyborohydride, in the presence of acetic acid and 2-methyltetrahydrofuran to produce a free base form of a compound of Formula (IX):
and
reacting the free base form of a compound of Formula (IX) with a compound of Formula (3):
in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 4-(dimethylamino)pyridine in dichloromethane to produce the compound of Formula (X).

### Claim 2 (depends on 1)

The method of claim 1, wherein the step of reacting the free base form of the compound of Formula (IX) with the compound of Formula (3) produces a free base form of the compound of Formula (X).

### Claim 3 (depends on 2)

The method of claim 2, wherein the method further comprises converting the free base form of the compound of Formula (X) to a salt form of the compound of Formula (X).

### Claim 4 (depends on 3)

The method of claim 3, wherein the salt form of the compound of Formula (X) is monohydrate.

### Claim 5 (depends on 3)

The method of claim 3, further comprising converting the free base form of the compound of Formula (X) to a HCl salt of the compound of Formula (X).

### Claim 6 (depends on 3)

The method of claim 3, wherein the step of converting the free base form of the compound of Formula (X) to the salt form of the compound of Formula (X) is performed at about 50° C.

### Claim 7 (depends on 3)

The method of claim 3, wherein the method further comprises converting the salt form of the compound of Formula (X) from a first crystal form to a second crystal form.

### Claim 8 (depends on 7)

The method of claim 7, wherein the step of converting the salt form of the compound of Formula (X) from the first crystal form to the second crystal form comprises one selected from the group consisting of precipitating the salt form of the compound of Formula (X), changing the solvent of the salt form of the compound of Formula (X), and incubating the salt form of the compound of Formula (X), at about 60° C.

### Claim 9 (depends on 1)

The method of claim 1, wherein the step of reacting the compound of Formula (1) and the compound of Formula (2) is performed at from about 15° C. to about 25° C.

### Claim 10 (depends on 1)

The method of claim 1, wherein the step of reacting the compound of Formula (1) and the compound of Formula (2) does not comprise dichloromethane.

### Claim 11 (depends on 1)

The method of claim 1, further comprising a solvent exchange to Methyl tert-Butyl Ether (MTBE), and recrystallization from MTBE/n-heptane after the step of reacting the compound of Formula (1) and the compound of Formula (2) is complete to form the free base form of a compound of Formula (IX).

### Claim 12 (depends on 1)

The method of claim 1, wherein the step of reacting the free base form of the compound of Formula (IX) with the compound of Formula (3) is performed at from about 20° C. to about 25° C.

### Claim 13 (depends on 1)

The method of claim 1, wherein the method does not comprise producing a salt form of the compound of Formula (IX).

### Claim 14 (depends on 1)

The method of claim 1, wherein the method does not comprise use of dioxane, ethylacetate, or potassium carbonate.