# US 12,215,081 B2 · Pharmaceutical intermediate

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- Number: US 12,215,081 B2
- Document ID: US12215081B2
- Status: Granted
- Kind: B2
- Application number: 17/609,034
- Filed: 2020-05-20
- Published: 2022-07-07
- Granted: 2025-02-04
- Earliest claimed: 2019-05-22
- Assignees: Zaklady Farmaceutyczne Polpharma S.A.
- Applicants: Zaklady Farmaceutyczne Polpharma S.A.
- Inventors: Adam Haluszczuk; Dorota Pogoda
- Web page: https://patentgrep.com/patent/US12215081B2

## CPC

- C07D 211/58: attached in position 4
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

This invention relates to 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate and a process for the preparation of 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate comprising treating 4-(4-fluorobenzylamino)-1-methylpiperidine with water. The invention also relates to a process for the preparation of pimavanserin comprising reacting 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate with 1-isobutoxy-4-(isocyanatomethyl)benzene; to a process for the preparation of a pimavanserin acid addition salt comprising reacting 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate with 1-isobutoxy-4-(isocyanatomethyl)benzene and converting pimavanserin into a pimavanserin acid addition salt, pimavanserin and pimavanserin acid addition salts obtainable by the process, and to the use of 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate for preparing pimavanserin or an acid addition salt thereof.

## Claims

### Claim 1

4-(4-Fluorobenzylamino)-1-methylpiperidine trihydrate.

### Claim 2

A process for the preparation of 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate comprising treating 4-(4-fluorobenzylamino)-1-methylpiperidine with water.

### Claim 3 (depends on 2)

A process as claimed in claim 2, comprising:
(i) dissolving 4-(4-fluorobenzylamino)-1-methylpiperidine in water to form a solution;
(ii) cooling the solution obtained in step (i) to precipitate 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate; and
(iii) isolating the 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate from the solution.

### Claim 4 (depends on 2)

A process as claimed in claim 2, comprising treating 4-(4-fluorobenzylamino)-1-methylpiperidine with, or dissolving 4-(4-fluorobenzylamino)-1-methylpiperidine in, a water/alcohol mixture or a water/organic solvent mixture or an aqueous inorganic salt solution.

### Claim 5 (depends on 3)

A process as claimed in claim 3, wherein in step (ii) the solution is cooled to below 20° C.

### Claim 6 (depends on 2)

A process as claimed in claim 2, wherein prior to treating 4-(4-fluorobenzylamino)-1-methylpiperidine with water or prior to dissolving 4-(4-fluorobenzylamino)-1-methylpiperidine in water to form a solution, the process further comprises the step of preparing 4-(4-fluorobenzylamino)-1-methylpiperidine by reacting together 1-methyl-4-piperidone and 4-fluorobenzylamine or 4-fluorobenzaldehyde and 1-methylpiperidin-4-amine, in the presence of a reducing agent.

### Claim 7 (depends on 3)

A process as claimed in claim 3, comprising treating 4-(4-fluorobenzylamino)-1-methylpiperidine with, or dissolving 4-(4-fluorobenzylamino)-1-methylpiperidine in, a water/alcohol mixture or a water/organic solvent mixture or an aqueous inorganic salt solution.

### Claim 8 (depends on 3)

A process as claimed in claim 3, wherein prior to treating 4-(4-fluorobenzylamino)-1-methylpiperidine with water or prior to dissolving 4-(4-fluorobenzylamino)-1-methylpiperidine in water to form a solution, the process further comprises the step of preparing 4-(4-fluorobenzylamino)-1-methylpiperidine by reacting together 1-methyl-4-piperidone and 4-fluorobenzylamine or 4-fluorobenzaldehyde and 1-methylpiperidin-4-amine, in the presence of a reducing agent.