# US 7,612,203 B2 · Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof

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- Number: US 7,612,203 B2
- Document ID: US7612203B2
- Status: Granted
- Kind: B2
- Application number: 11/360,289
- Filed: 2006-02-22
- Published: 2006-11-16
- Granted: 2009-11-03
- Earliest claimed: 2005-02-22
- Assignees: Teva Pharmaceutical Industries Ltd.
- Inventors: Valerie Niddam-Hildesheim; Anna Balanov; Natalia Shenkar
- Web page: https://patentgrep.com/patent/US7612203B2

## CPC

- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- A61P 3/06: Antihyperlipidemics
- C07F 7/1892: {by reactions not provided for in C07F7/1876 - C07F7/1888}
- C07F 7/1896: {Compounds having one or more Si-O-acyl linkages}
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The present invention provides rosuvastatin and intermediates thereof having a low level of alkylether impurity and processes for the preparation thereof.

## Claims

### Claim 1

A process of preparing the compound of formula I having the structure:
comprising the steps of:
a) combining a compound of formula IV:
wherein R is a carboxyl protecting group, with a C1-C5 alcohol to obtain a solution;
b) cooling the solution at a temperature of about −10° C. to about 30° C.;
c) combining the solution of step b) with a solution of methanesulfonic acid in a C1-C5 alcohol:water mixture having a ratio of about 6 to about 30 (v/v) to obtain a reaction mixture; and
d) heating the reaction mixture at a maximum temperature of about 35° C. to obtain the compound of Formula I.

### Claim 2 (depends on 1)

The process of claim 1, wherein the C1-C5 alcohol of step a) is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol and amyl alcohol.

### Claim 3 (depends on 2)

The process of claim 2, wherein the C1-C5 alcohol of step a) is methanol, ethanol, or isopropanol.

### Claim 4 (depends on 1)

The process of claim 1, wherein step b) comprises cooling the solution to a temperature of about 0° C. to about 20° C.

### Claim 5 (depends on 1)

The process of claim 1, wherein the C1-C5 alcohol:water mixture in step c) has a ratio of about 20:6 (v/v).

### Claim 6 (depends on 1)

The process of claim 1, wherein the solution of methanesulfonic acid in the C1-C5 alcohol:water mixture is added drop-wise to the solution of step b).

### Claim 7 (depends on 1)

The process of claim 1, wherein step d) comprises heating the reaction mixture to a temperature of about 20° C. to about 35° C.

### Claim 8 (depends on 1)

The process of claim 1, wherein step d) comprises heating the reaction mixture to a temperature of about 30° C.

### Claim 9 (depends on 1)

The process of claim 1, wherein step d) comprises heating the reaction mixture for a period of about 2 to about 10 hours.

### Claim 10 (depends on 6)

A process of preparing rosuvastatin and salts thereof having about 0.02% to about 0.2% area by HPLC of Rosu-alkylether
wherein R1 is a C1-C8 linear or branched alkyl, and M is H or a metal cation, comprising carrying out the process of claim 6 and converting the obtained compound to rosuvastatin or a salt thereof.

### Claim 11

A process of preparing a compound of formula II-ether having the structure:
comprising converting the compound of formula I-ether
wherein R is a carboxyl protecting group that is not methyl ester and R1 is a C1-C8 linear or branched alkyl, into the compound of Formula II-ether.

### Claim 12

A process of obtaining a compound of formula II having the structure:
wherein R is a carboxyl protecting group, and R1 is a C1-C8 linear or branched alkyl;
having about 0.02% to about 1.5% area by HPLC of a compound of formula II-ether having the structure:
wherein R is a carboxyl protecting group, and R1 is a C1-C8 linear or branched alkyl;
said process comprising:
a) combining the compound of formula II
with an organic solvent selected from the group consisting of aromatic hydrocarbons, C1-C5 alcohols, esters, ketones, ethers, C5-C8 linear or branched hydrocarbons, nitrites, mixtures thereof, and mixtures of any of these with water, to obtain a reaction mixture;
b) heating the reaction mixture at a temperature of about 25° C. to about 110° C. to obtain a solution;
c) cooling the solution to a temperature of about −10° C. to about 20° C. to obtain a precipitate; and
d) recovering the compound of Formula II.

### Claim 13 (depends on 12)

The process of claim 12, wherein the organic solvent is selected from the group consisting of toluene, benzene, acetone, ethylacetate, methylacetate, tetrahydrofuran, methyl-tertbutylether, heptane, hexane, acetonitrile, mixtures of alcohols, acetonitrile, and acetone with water, THF, EtOAc or MTBE, and a mixture of toluene and heptane.

### Claim 14 (depends on 13)

The process of claim 13, wherein the organic solvent is toluene.

### Claim 15 (depends on 12)

The process of claim 12, wherein step b) comprises heating the reaction mixture at a temperature of about 40° C. to about 90° C.

### Claim 16 (depends on 12)

The process of claim 12, further comprising the step of seeding the solution prior to step c).

### Claim 17 (depends on 12)

The process of claim 12, wherein step b) further comprises maintaining the solution at a temperature of about 20° C. to about 60° C. for about one hour prior to step c).

### Claim 18 (depends on 12)

The process of claim 12, wherein step c) comprises cooling the solution to a temperature of about 0° C. to about 5° C.

### Claim 19

A process for preparing rosuvastatin and salts thereof having about 0.02% to about 0.2% area by HPLC of Rosu-alkylether of the structure:
wherein R1 is a C1-C8 linear or branched alkyl, and M is H or a metal cation, said process comprising
a) combining a compound of formula II:
wherein R is a carboxyl protecting group, and R1 is a C1-C8 linear or branched alkyl, with an organic solvent selected from the group consisting of aromatic hydrocarbons, C1-C5 alcohols, esters, ketones, ethers, C5-C8 linear or branched hydrocarbons, nitrites, mixtures thereof, and mixtures of any of these with water, to obtain a reaction mixture;
b) heating the reaction mixture at a temperature of about 25° C. to about 110° C. to obtain a solution;
c) cooling the solution to a temperature of about −10°0 C. to about 20° C. to obtain a precipitate; and
d) recovering the compound of Formula II; and
e) converting the recovered compound into rosuvastatin or a salt thereof.

### Claim 20

A process of preparing the compound of formula III-ether having the structure:
wherein R1 is a C1-C8 linear or branched alkyl, and M is H or a metal cation;
said process comprising converting the compound of formula II-ether
wherein R is a carboxyl protecting group, and R1 is a C1-C8 linear or branched alkyl, into the compound of formula III-ether.

### Claim 21

A process for preparing Rosuvastatin or salts thereof having about 0.02% to about 0.2% area by HPLC of the compound of formula III-ether having the structure:
wherein R1 is a C1-C8 linear or branched alkyl, and M is H or a metal cation, said process comprising the steps of:
a) obtaining one or more samples of one or more batches of the compound of formula I
wherein R is a carboxyl protecting group that is not methyl ester;
b) measuring the level of the compound of formula I-ether:
wherein R is a carboxyl protecting group that is not methyl ester and R1 is a C1-C8 linear or branched alkyl in each of the samples;
c) selecting a batch from step a) having a level of the compound of formula I-ether, in an amount of about 0.02% to about 0.2% area by HPLC, based on the measurement of the samples from the batches; and
d) preparing Rosuvastatin having about 0.02% to about 0.2% area by HPLC of the compound of formula III-ether using the selected batch.

### Claim 22

A process for preparing Rosuvastatin having about 0.02% to about 0.2% area by HPLC of the compound of formula III-ether having the structure:
wherein R1 is a C1-C8 linear or branched alkyl, and M is H or a metal cation, said process comprising the steps of:
a) obtaining one or more samples of one or more batches of the compound of formula II
wherein R is a carboxyl protecting group;
b) measuring the level in each of the samples of the compound of formula II-ether having the structure:
wherein R is a carboxyl protecting group, and R1 is a C1-C8 linear or branched alkyl;
c) selecting a batch from step a) having a level of the compound of formula II-ether of about 0.02% to about 0.2% area by HPLC, based on the measurement of the samples from the batches; and
d) preparing Rosuvastatin having about 0.02% to about 0.2% area by HPLC of the compound of formula III-ether using the selected batch.

### Claim 23 (depends on 22)

The process of claim 22, wherein when the level measured in step b) is higher than about 0.02% to about 0.2% area by HPLC, the process further comprises
b1) combining the compound of formula II:
with an organic solvent selected from the group consisting of aromatic hydrocarbons, C1-C5 alcohols, esters, ketones, ethers, C5-C8 linear or branched hydrocarbons, nitrites, mixtures thereof, and mixtures of any of these with water, to obtain a reaction mixture;
b2) heating the reaction mixture at a temperature of about 25° C. to about 110° C. to obtain a solution;
b3) cooling the solution to a temperature of about −10° C. to about 20° C. to obtain a precipitate; and
b4) recovering the compound of Formula II containing about 0.02% to about 0.2% area by HPLC of the compound of formula II-ether.

### Claim 24

A process for preparing a pharmaceutical formulation comprising Rosuvastatin having about 0.02% to about 0.2% area by HPLC of the compound of formula III-ether having the structure:
wherein R1 is a C1-C8 linear or branched alkyl, and M is H or a metal cation, said process comprising the steps of:
a) obtaining one or more samples of one or more batches of Rosuvastatin;
b) measuring the level of the compound of formula III-ether in each of the samples;
c) selecting a batch of Rosuvastatin having a level of the compound of formula III-ether of about 0.02% to about 0.2% area by HPLC, based on the measurement of the samples from the batches;
d) preparing Rosuvastatm having about 0.02% to about 0.2% area by HPLC of the compound of formula III-ether using the selected batch; and
e) preparing a formulation comprising the Rosuvastatin prepared in step d).