# US 8,784,847 B2 · Synthesis of 1-amino-1,3,3,5,5,-cyclohexane mesylate

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- Number: US 8,784,847 B2
- Document ID: US8784847B2
- Status: Granted
- Kind: B2
- Application number: 13/138,883
- Filed: 2010-04-16
- Published: 2012-04-26
- Granted: 2014-07-22
- Earliest claimed: 2009-04-17
- Assignees: MERZ PHARMA GmbH & CO. KGaA
- Applicants: Markus Henrich; Simona Negura; Gergely Tasi; Pal Kocsan; Federico Sbrogio; Michael Pyerin; Herbert Koller
- Inventors: Markus Henrich; Simona Negura; Gergely Tasi; Pal Kocsan; Federico Sbrogio; Michael Pyerin; Herbert Koller
- Web page: https://patentgrep.com/patent/US8784847B2

## CPC

- C07C 303/32: of salts of sulfonic acids
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/16: Otologicals
- C07C 29/40: with compounds containing carbon-to-metal bonds
- C07C 209/16: with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C 209/68: from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C 209/84: Purification
- C07C 209/86: Separation
- C07C 211/35: containing only non-condensed rings
- C07C 2601/14: The ring being saturated
- Y10T 428/2982: Particulate matter [e.g., sphere, flake, etc.]
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

Process for manufacturing 1-amino-1,3,3,5,5-pentamethylcyclohexane mesylate comprising step (i): (i) reacting 1-amino-1,3,3,5,5-pentamethylcyclohexane with methane sulfonic acid in a solvent or a mixture of two or more solvents selected from anisole, cumene, pentane, hexane, heptane, isooctane, methyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl ethyl ketone, methyl isopropylketone, methyl isobutyl ketone, dimethyl sulphoxide, tetrahydrofuran, methyltetrahydrofuran, 1,1-diethoxypropane, 1,1-dimethoxymethane, and 2,2-dimethoxypropane.

## Claims

### Claim 1

A process for manufacturing 1-amino-1,3,3,5,5-pentamethylcyclohexane mesylate comprising step (i):
(i) reacting 1-amino-1,3,3,5,5-pentamethylcyclohexane with methane sulfonic acid in a solvent of anisole or methyl ethyl ketone or a solvent mixture of anisole or methyl ethyl ketone with one or more solvents selected from the group consisting of cumene, pentane, hexane, heptane, isooctane, methyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl isopropylketone, methyl isobutyl ketone, dimethyl sulphoxide, tetrahydrofuran, methyltetrahydrofuran, 1,1-diethoxypropane, 1,1-dimethoxymethane, and 2,2-dimethoxypropane; wherein the reaction results in the formation of a product of 1-amino-1,3,3,5,5-pentamethylcyclohexane mesylate.

### Claim 2 (depends on 1)

The process according to claim 1, wherein the solvent is anisole, or the solvent mixture is anisole with one or more solvents selected from the group consisting of cumene, pentane, hexane, heptane, isooctane, methyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl isopropyl ketone, methyl isobutyl ketone, dimethyl sulphoxide, tetrahydrofuran, methyltetrahydrofuran, 1,1-diethoxypropane, 1,1-dimethoxymethane, and 2,2-dimethoxypropane; and optionally methyl ethyl ketone.

### Claim 3 (depends on 1)

The process according to claim 1, wherein the solvent further includes water dissolved therein.

### Claim 4 (depends on 3)

The process according to claim 3, wherein the solvent is methyl ethyl ketone and water or the solvent mixture is methyl ethyl ketone, water and one or more solvents selected from the group consisting of tetrahydrofuran, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, methyl isopropyl ketone, and methyl isobutyl ketone.

### Claim 5 (depends on 3)

The process according to claim 3, wherein the solvent includes from 0.1 to 10% by weight water based on the total amount of water and solvent.

### Claim 6 (depends on 1)

The process according to claim 1, wherein in step (i) the ratio of the volume of solvent to the weight of 1-amino-1,3,3,5,5-pentamethylcyclohexane is from 5:1 to 50:1 (ml/g).

### Claim 7 (depends on 1)

The process according to claim 1, wherein the temperature within step (i) is from −20° C. to 120° C.

### Claim 8 (depends on 1)

The process according to claim 1, wherein the temperature within step (i) is from 0° C. to 60° C.

### Claim 9 (depends on 8)

The process according to claim 8, wherein the solvent is anisole or methyl ethyl ketone in a solvent mixture with one or more solvents selected from the group consisting of cumene, pentane, hexane, heptane, isooctane, methyl isopropyl ketone, methyl isobutyl ketone, tetrahydrofuran, and mixtures thereof, and wherein the solvent optionally further includes water dissolved therein.

### Claim 10 (depends on 1)

The process according to claim 1, further comprising step (ii):
(ii) isolating 1-amino-1,3,3,5,5-pentamethylcyclohexanemesylate crystalline product from the reaction mixture of step (i) by crystallization.

### Claim 11 (depends on 10)

The process according to claim 10, wherein the crystallization in step (ii) is achieved by reducing the temperature of the reaction mixture of step (i), adding anti-solvents, or distilling off partially the solvent used in step (i).

### Claim 12 (depends on 10)

The process according to claim 10, wherein in step (ii) the temperature is reduced to a temperature within the range of −20° C. to 50° C.

### Claim 13 (depends on 1)

The process according to claim 1, further comprising at least one of the steps (iii) to (v) subsequent to step (i):
(iii) re-crystallizing the product formed in step (i) from a mixture of one or more solvents selected from the group consisting of anisole, cumene, pentane, hexane, heptane, isooctane, methyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, dimethyl sulphoxide, tetrahydrofuran, methyltetrahydrofuran, 1,1-diethoxypropane, 1,1-dimethoxymethane, and 2,2-dimethoxypropane;
(iv) adding 1-amino-1,3,3,5,5-pentamethylcyclohexane mesylate in any one of the preceding steps (i) or (iii);
(v) de-agglomerating and/or milling the product formed in any one of the preceding steps (i), (iii), or (iv).

### Claim 14 (depends on 10)

The process according to claim 10, further comprising at least one of the steps (iii) to (v) subsequent to steps (i) or (ii):
(iii) re-crystallizing the product formed in step (i) or step (ii) from a mixture of one or more solvents selected from the group consisting of anisole, cumene, pentane, hexane, heptane, isooctane, methyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, dimethyl sulphoxide, tetrahydrofuran, methyltetrahydrofuran, 1,1-diethoxypropane, 1,1-dimethoxymethane, and 2,2-dimethoxypropane;
(iv) adding 1-amino-1,3,3,5,5-pentamethylcyclohexane mesylate in any one of the preceding steps (i) to (iii);
(v) de-agglomerating and/or milling the product formed in any one of the preceding steps (i) to (iv).

### Claim 15 (depends on 13)

The process according to claim 13, wherein in step (i) and/or step (iii) said solvent is anisole or methyl ethyl ketone or the solvent mixture is anisole or methyl ethyl ketone and one or more solvents selected from the group consisting of cumene, methyl isopropyl ketone, methyl isobutyl ketone, tetrahydrofuran, n-butyl acetate, and mixtures thereof; and optionally further includes water, and wherein in step (i) and/or step (iii) the temperature is from 60° C. to 120° C.

### Claim 16 (depends on 14)

The process according to claim 14, wherein in step (i) and/or step (iii) said solvent is anisole or methyl ethyl ketone or the solvent mixture is anisole or methyl ethyl ketone and one or more solvents selected from the group consisting of cumene, methyl isopropyl ketone, methyl isobutyl ketone, tetrahydrofuran, n-butyl acetate, and mixtures thereof; and optionally further includes water, and wherein in step (i) and/or step (iii) the temperature is from 60° C. to 120° C.

### Claim 17 (depends on 1)

The process according to claim 1, further comprising steps (a) to (c) prior to step (i):
(a) converting isophorone to 3,3,5,5-tetramethylcyclohexanone;
(b) converting 3,3,5,5-tetramethylcyclohexanone 1,3,3,5,5-pentamethylcyclohexanol:
(c) converting 1,3,3,5,5-pentamethylcyclohexanol to 1-amino-1,3,3,5,5-pentamethylcyclohexane.

### Claim 18 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17)

The process according to any one of claims 1 to 17, further comprising step (vii):
(vii) converting 1-amino-1,3,3,5,5-pentamethylcyclohexane mesylate obtained according to any one of the preceding claims to 1-amino-1,3,3,5,5-pentamethylcyclohexane.

### Claim 19

A process for the crystallization and/or re-crystallization of 1-amino-1,3,3,5,5-pentamethylcyclohexane mesylate comprising reacting a mixture of 1-amino-1,3,3,5,5-pentamethylcyclohexane and methane sulfonic acid and/or 1-amino-1,3,3,5,5-pentamethylcyclohexane mesylate with anisole as a solvent or a solvent mixture of anisole and at least one additional solvent selected from the group consisting of cumene, pentane, hexane, heptane, isooctane, methyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl ethyl ketone, methyl isopropylketone, methyl isobutyl ketone, dimethyl sulphoxide, tetrahydrofuran, methyltetrahydrofuran, 1,1-diethoxypropane, 1,1-dimethoxymethane, and 2,2-dimethoxypropane to form a reaction mixture; allowing the reaction to proceed, and reducing the temperature of the reaction mixture to obtain the crystallized and/or re-crystallized 1-amino-1,3,3,5,5-pentamethylcyclohexane mesylate.

### Claim 20 (depends on 5)

The process according to claim 5, wherein the solvent includes from 0.1 to 8% by weight water based on the total amount of water and solvent.

### Claim 21 (depends on 5)

The process according to claim 5, wherein the solvent includes from 0.1 to 5% by weight water based on the total amount of water and solvent.

### Claim 22 (depends on 5)

The process according to claim 5, wherein the solvent includes from 0.1 to 4% by weight water based on the total amount of water and solvent.

### Claim 23 (depends on 5)

The process according to claim 5, wherein the solvent includes from 0.1 to 2% by weight water based on the total amount of water and solvent.

### Claim 24 (depends on 5)

The process according to claim 5, wherein the solvent includes from 0.1 to 1% by weight water based on the total amount of water and solvent.