# US 10,501,403 B2 · Method for preparation of (S)-N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride

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- Number: US 10,501,403 B2
- Document ID: US10501403B2
- Status: Granted
- Kind: B2
- Application number: 16/347,514
- Filed: 2017-11-03
- Published: 2019-09-19
- Granted: 2019-12-10
- Earliest claimed: 2016-11-04
- Assignees: St Pharm Co., Ltd.
- Applicants: St Pharm Co., Ltd.
- Inventors: Yeong Hun Kim; Hyun Woo Baek; Hyeon Jin Lee; Sang Kyu Kang; Sun Ki Chang; Geun Jho Lim
- Web page: https://patentgrep.com/patent/US10501403B2

## CPC

- C07C 211/27: having amino groups linked to the six-membered aromatic ring by saturated carbon chains
- C07C 41/30: by increasing the number of carbon atoms, e.g. by oligomerisation
- C07C 209/22: by substitution of other functional groups
- C07C 213/00: Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C 217/62: linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
- C07C 247/10: and containing rings
- C07C 269/06: by reactions not involving the formation of carbamate groups
- C07C 271/20: to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07B 2200/07: Optical isomers
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention relates to a novel method for preparing (S)—N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride.

## Claims

### Claim 1

A method for preparing (S)—N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride, comprising the following steps:
(1) preparing a compound of Formula 2 by Grignard coupling of a compound of Formula 1;
(2) preparing a compound of Formula 3 by azide substitution of the compound of Formula 2 in a reaction with sodium azide;
(3) preparing an aziridine derivative of Formula 4 having an amino group protected by an amino-protecting group by cyclization of the compound of Formula 3 using triphenylphosphine;
(4) preparing a compound of Formula 5 by ring opening of the compound of Formula 4;
(5) preparing a compound of Formula 6 by a reaction for removing the amino-protecting group of the compound of Formula 5:
wherein X is bromo or chloro, and
R is C1-6 alkyl.

### Claim 2 (depends on 1)

The method of claim 1, wherein step (1) comprises the following steps:
(1-1) preparing a Grignard compound by reacting the compound of Formula 1 with a metallic or organometallic compound; and
(1-2) reacting the Grignard compound with a compound of Formula 7:

### Claim 3 (depends on 1)

The method of claim 1, wherein step (1) is performed using tetrahydrofuran (THF), 1,4-dioxane, diethylether, or a mixture thereof as a solvent.

### Claim 4 (depends on 2)

The method of claim 2, wherein step (1-1) is performed at a temperature of 20° C. to 60° C.

### Claim 5 (depends on 2)

The method of claim 2, wherein step (1-2) is performed at a temperature of −20° C. to 30° C.

### Claim 6 (depends on 2)

The method of claim 2, wherein step (1-2) is performed by further comprising a Lewis acid.

### Claim 7 (depends on 1)

The method of claim 1, wherein step (2) is performed using dimethylformamide as a solvent.

### Claim 8 (depends on 1)

The method of claim 1, wherein step (2) is performed at a temperature of 70° C. to 100° C.

### Claim 9 (depends on 1)

The method of claim 1, wherein step (3) comprises the following steps:
(3-1) forming an aziridinyl group of Formula 3-1 by cyclization by triphenylphosphine; and
(3-2) introducing a protecting group to an amino group by reacting the compound including the aziridinyl group obtained by step (3-1) with di-tert-butyl dicarbonate:
wherein R is the same as defined in claim 1.

### Claim 10 (depends on 9)

The method of claim 9, wherein step (3-2) is performed by further comprising a catalyst selected from 4-dimethylaminopyridine and iodine (I2), or an alkaline substance selected from triethanolamide (TEA), N,N-diisopropylethylamine (DIEA), and NaHCO3.

### Claim 11 (depends on 1)

The method of claim 1, wherein step (3) is performed using acetonitrile, toluene, or a mixture thereof as a solvent.

### Claim 12 (depends on 9)

The method of claim 9, wherein step (3-1) is performed at a temperature of 55° C. to 70° C.

### Claim 13 (depends on 9)

The method of claim 9, wherein step (3-2) is performed at a temperature of 20° C. to 30° C.

### Claim 14 (depends on 1)

The method of claim 1, wherein step (4) is performed using acetonitrile, tetrahydrofuran, toluene, or a mixture thereof as a solvent.

### Claim 15 (depends on 1)

The method of claim 1, wherein step (4) is performed at a temperature of 45° C. to 55° C.

### Claim 16 (depends on 1)

The method of claim 1, wherein the reaction of step (5) is performed with trifluoroacetic acid, hydrochloric acid, methanolic hydrochloric acid, or a mixture thereof.

### Claim 17 (depends on 1)

The method of claim 1, wherein step (5) is performed using methanol, dichloromethane, tetrahydrofuran, or a mixture thereof as a solvent.

### Claim 18 (depends on 1)

The method of claim 1, wherein the reaction of step (5) is performed with acetyl chloride in a methanol solvent.

### Claim 19 (depends on 1)

The method of claim 1, wherein step (5) is performed at a temperature of 45° C. to 55° C.

### Claim 20 (depends on 1)

The method of claim 1, wherein steps (4) and (5) further comprise either step (4-1) or (5-1), respectively, for independently crystallizing the prepared compounds, or both steps.