# US 10,865,180 B2 · Process for the preparation of l-Norepinephrine bitartrate monohydrate having high enantiomeric purity

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- Number: US 10,865,180 B2
- Document ID: US10865180B2
- Status: Granted
- Kind: B2
- Application number: 16/537,324
- Filed: 2019-08-09
- Published: 2020-02-13
- Granted: 2020-12-15
- Earliest claimed: 2019-08-09
- Assignees: Harman Finochem Limited
- Applicants: Harman Finochem Limited
- Inventors: Vijay Trimbak Kadam; Nareesh Saranapu; Amin Rashid Shaikh; Harpreet Singh Minhas; Gurpreet Singh Minhas
- Web page: https://patentgrep.com/patent/US10865180B2

## CPC

- C07C 213/04: by reaction of ammonia or amines with olefin oxides or halohydrins
- C07C 213/10: Separation; Purification; Stabilisation; Use of additives
- C07C 213/02: by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention, discloses optically pure compounds of l-Norepinephrine and its acid addition salts and hydrates and process for the preparation thereof. Specifically, the present invention discloses optically pure compounds of l-Norepinephrine bitartrate, its process of preparation and pharmaceutical compositions comprising the same.

## Claims

### Claim 1

A process for the preparation of optically pure l-Norepinephrine bitartrate monohydrate, wherein the process comprises;
a) treating dl-Norepinephrine base with D-(−)-tartaric acid in the presence of water and an organic solvent to obtain crude l-Norepinephrine bitartrate;
b) converting the l-Norepinephrine bitartrate obtained in step (a) into l-Norepinephrine base;
c) treating the l-Norepinephrine base obtained in step (b) with L-(+)-tartaric acid and water to obtain l-Norepinephrine Bitartrate monohydrate having an optical purity of greater than 99%.

### Claim 2 (depends on 1)

The process as claimed in claim 1, wherein step (b) comprises converting the l-Norepinephrine bitartrate obtained in step (a) into l-Norepinephrine base by treating with ammonia.

### Claim 3 (depends on 1)

The process as claimed in claim 1, wherein step (b) comprises:
a first step of converting the l-Norepinephrine bitartrate obtained in step (a) into l-Norepinephrine base by treating with ammonia;
a second step of treating the l-Norepinephrine base obtained in the first step with D-(−)-tartaric acid to obtain pure l-Norepinephrine bitartrate; and
a third step of converting the l-Norepinephrine bitartrate obtained in the second step into l-Norepinephrine base by treating with aqueous ammonia solution.

### Claim 4 (depends on 1)

The process as claimed in claim 1, further comprising:
d) purifying the l-Norepinephrine Bitartrate monohydrate obtained in step (c) from a water/IPA mixture to obtain l-Norepinephrine Bitartrate monohydrate having an optical purity of greater than 99.5%.

### Claim 5 (depends on 1)

The process as claimed in claim 1, wherein the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetonitrile, dioxane, dimethylformamide, dimethylsulphoxide, halogenated solvents, and mixtures thereof.

### Claim 6 (depends on 1)

The process as claimed in claim 1, wherein the organic solvent is a halogenated solvent selected from the group consisting of dichloromethane, chloroform, and mixtures thereof.

### Claim 7 (depends on 1)

The process as claimed in claim 1, further comprising, prior to step (a), a step of preparing the dl-Norepinephrine base by:
a) reacting catechol with chloroacetyl chloride in the presence of a Lewis acid to obtain a compound of Formula II;
b) reacting the compound of Formula II with Hexamine;
c) converting the product of step (b) into the hydrochloride salt of a ketone of formula IV; and
d) hydrogenating the ketone of formula (IV) to obtain dl-Norepinephrine of formula V;

### Claim 8 (depends on 1)

A pharmaceutical composition comprising:
l-Norepinephrine bitartrate monohydrate having an optical purity of more than 99.5%, prepared by the method of claim 1; and
one or more pharmaceutically acceptable carrier(s).

### Claim 9

A process for the preparation of optically pure l-Norepinephrine bitartrate monohydrate, wherein the process comprises;
a) treating dl-Norepinephrine base with D-(−)-tartaric acid in the presence of water and an organic solvent to obtain crude l-Norepinephrine bitartrate;
b) converting the l-Norepinephrine bitartrate obtained in step (a) into l-Norepinephrine base by performing:
a first step of converting the l-Norepinephrine bitartrate obtained in step (a) into l-Norepinephrine base;
a second step of treating the l-Norepinephrine base obtained in the first step with D-(−)-tartaric acid to obtain pure l-Norepinephrine bitartrate; and
a third step of converting the l-Norepinephrine bitartrate obtained in the second step into l-Norepinephrine base by treating with aqueous ammonia; and
c) treating the l-Norepinephrine base obtained in the third step with L-(+)-tartaric acid and water to obtain l-Norepinephrine Bitartrate monohydrate having an optical purity of greater than 99%.