# US 9,040,696 B2 · Method for preparing rosuvastatin salts

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- Number: US 9,040,696 B2
- Document ID: US9040696B2
- Status: Granted
- Kind: B2
- Application number: 13/989,821
- Filed: 2011-11-29
- Published: 2013-10-24
- Granted: 2015-05-26
- Earliest claimed: 2010-11-29
- Assignees: Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag
- Applicants: Marta Porcs-Makkay; Ferenc Lorant Bartha; Gyorgy Krasznai; Balazs Volk; Gyorgy Ruzsics; Laszlo Pongo; Gyula Lukacs; Tibor Szabo; Jozsef Barkoczy; Jozsef Debreczeni; Adrienn Keszthelyi; Angela Pandur; Eniko Molnar; Matyas Milen; Maria Tothne Lauritz
- Inventors: Marta Porcs-Makkay; Ferenc Lorant Bartha; Gyorgy Krasznai; Balazs Volk; Gyorgy Ruzsics; Laszlo Pongo; Gyula Lukacs; Tibor Szabo; Jozsef Barkoczy; Jozsef Debreczeni; Adrienn Keszthelyi; Angela Pandur; Eniko Molnar; Matyas Milen; Maria Tothne Lauritz
- Web page: https://patentgrep.com/patent/US9040696B2

## CPC

- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- A61P 3/06: Antihyperlipidemics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is related to methods for the preparation of pharmaceutically acceptable salts of (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3R,5S,6E)-dihydroxy-hept-6-enoic acid, intermediates thereof and methods for producing said intermediates.

## Claims

### Claim 1

A method for the preparation of a rosuvastatin product, which method is one of the following methods I to V:
I) for the preparation of rosuvastatin ammonium salt of Formula (II),
wherein R1, R2 and R3 independently represent hydrogen or a straight, branched or cyclic saturated alkyl group comprising 1 to 6 carbons atoms or NR1R2 together represents a saturated heterocyclic group having 5, 6 or 7 carbon atoms and one nitrogen atom,
which comprises
reacting a rosuvastatin amide of Formula (III)
wherein R4 and R5 independently from each other represent hydrogen or a straight, branched or cyclic alkyl group comprising 1 to 6 carbon atoms or NR4R5 together represents a saturated 5, 6 or 7-membered heterocyclic group having one nitrogen atom,
in water or in a homogeneous mixture of water and a water-miscible organic solvent,
with an amine of the Formula (X)
wherein R1, R2 and R3 independently from each other represent hydrogen or a straight, branched or cyclic alkyl group comprising 1 to 6 carbon atoms, or R1 and R2 with the nitrogen attached thereto comprises a saturated 5, 6 or 7-membered heterocyclic group having one nitrogen atom;
or
II) for the preparation of rosuvastatin calcium salt of Formula (IV)
which comprises
a) reacting a rosuvastatin amide of Formula (III),
wherein R4 and R5 each independently represents hydrogen or a straight, branched or cyclic saturated alkyl group comprising 1 to 6 carbon atoms or NR4R5 together forms a saturated 5, 6 or 7-membered heterocyclic group having one nitrogen atom,
in water or in a homogeneous mixture of water and a water-miscible organic solvent,
with an amine of Formula (X)
wherein R1, R2 and R3 independently represent hydrogen or a straight, branched or cyclic alkyl group comprising 1 to 6 carbon atoms or R1 and R2 together with a nitrogen atom attached thereto form a saturated 5, 6 or 7-membered heterocyclic group having one nitrogen;
b) transforming the rosuvastatin ammonium salt of Formula (II) obtained in step a),
wherein R1, R2 and R3 each independently from each other represents hydrogen or a straight, branched or cyclic saturated alkyl group comprising 1 to 6 carbon atoms or R1 and R2 together with the nitrogen attached thereto form a saturated 5, 6 or 7-membered heterocyclic group having one nitrogen atom,
into rosuvastatin calcium salt of Formula (IV) or a hydrate form thereof;
or
III) for the preparation of rosuvastatin zinc (2:1) salt of Formula (V)
which comprises
a) reacting a rosuvastatin amide of Formula (III),
wherein R4 and R5 each independently from each other represents hydrogen or a straight, branched or cyclic alkyl group having 1 to 6 carbon atoms or NR4R5 together represents a saturated 5-, 6- or 7-membered heterocyclic group having one nitrogen,
in water or in a homogeneous mixture of water and a water-miscible organic solvent,
with an amine of Formula (X)
wherein R1, R2 and R3 each independently from each other represents hydrogen or a straight, branched or cyclic alkyl group having one to six carbon atoms or R1 and R2 with a nitrogen atom attached thereto form a saturated 5, 6 or 7-membered heterocyclic group having one nitrogen atom;
b) transforming rosuvastatin ammonium salt of Formula (II) obtained in step a)
wherein R1, R2 and R3 each independently from each other represents hydrogen or a straight, branched or cyclic alkyl group having 1 to 6 carbon atoms or R1 and R2 together with the nitrogen atom attached thereto form a saturated 5, 6 or 7-membered heterocycylic group having one nitrogen atom into rosuvastatin zinc (2:1) salt of Formula (V);
or
IV) for the preparation of rosuvastatin TBA salt of Formula (IIa) in crystalline Form II,
which comprises
a) reacting a rosuvastatin amide of Formula (III),
wherein R4 and R5 each independently from each other represents hydrogen or a straight, branched or cyclic alkyl group having 1 to 6 carbon atoms or wherein NR4R5 together represents a saturated 5-, 6- or 7-membered heterocyclic group having one nitrogen atom,
in water or in a homogeneous mixture of water and a water-miscible solvent,
with an amine of Formula (X)
wherein R1, R2 and R3 each independently from each other represents hydrogen or a straight, branched or cyclic alkyl group having 1 to 6 carbon atoms or R1 and R2 together with the nitrogen atom attached thereto form a saturated 5, 6 or 7-membered heterocycylic group having one nitrogen,
b) purifying crude rosuvastatin TBA salt obtained in step a) by crystallization;
c) mixing the aqueous suspension of the purified rosuvastatin TBA salt of the Formula (IIa) thus obtained with tert-butylamine and
d) crystallizing rosuvastatin TBA salt crystalline Form (II) of the Formula (IIa) fractionally;
or
V) for the preparation of rosuvastatin TBA salt of Formula (IIa),
which comprises
reacting a rosuvastatin amide of Formula (III),
wherein R4 and R5 each independently from each other represents hydrogen or a straight, branched or cyclic alkyl group having 1 to 6 carbon atoms or wherein NR4R5 together represents a saturated 5-, 6- or 7-membered heterocyclic group having one nitrogen atom,
in water or in a homogeneous mixture of water and a water-miscible solvent,
with an amine of Formula (X)
wherein R1, R2 and R3 each independently from each other represents hydrogen or a straight, branched or cyclic alkyl group having 1 to 6 carbon atoms or wherein R1 and R2 together with the nitrogen atom attached thereto form a saturated 5, 6 or 7-membered heterocycylic group having one nitrogen.

### Claim 2 (depends on 1)

The method according to claim 1, which is the method I.

### Claim 3 (depends on 2)

The method according to claim 2, wherein the rosuvastatin amide of Formula (III) is rosuvastatin n-butylamide of Formula (IIIa)

### Claim 4 (depends on 2)

The method according to claim 2, wherein the rosuvastatin amide of Formula (III) is rosuvastatin N,N-dimethylamide of Formula (IIIb)

### Claim 5 (depends on 2)

The method according to claim 2, wherein the rosuvastatin amide of Formula (III) is rosuvastatin pyrrollidinylamide of Formula (IIIc)

### Claim 6 (depends on 2)

The method according to claim 2, wherein in the compound of Formula (X), R1 is 1-butyl or 2,2-dimethyl-ethyl and R2 and R3 are hydrogen.

### Claim 7 (depends on 2)

The method according to claim 2, wherein for each mole of the compound of Formula (III) 1 to 30 molar equivalents of the compound of Formula (X) are reacted.

### Claim 8 (depends on 2)

The method according to claim 2, wherein the reaction is carried out at a temperature between 80 and 140° C.

### Claim 9 (depends on 1)

The method according to claim 1, which is the method II.

### Claim 10 (depends on 9)

The method according to claim 9, wherein in the compound of Formula (X), R1 is 2,2-dimethylethyl, and R2 and R3 are hydrogens.

### Claim 11 (depends on 9)

The method according to claim 9, wherein in the compound of Formula (X), R1 is 1-butyl, and R2 and R3 are hydrogens.

### Claim 12 (depends on 9)

The method according to claim 9, wherein the rosuvastatin ammonium salt of Formula (II) is transformed into the rosuvastatin calcium salt of Formula (IV).

### Claim 13 (depends on 1)

The method according to claim 1, which is the method III.

### Claim 14 (depends on 13)

The method according to claim 13, wherein in the compound of Formula (X), R1 is 2,2-dimethylethyl, and R2 and R3 are each hydrogens.

### Claim 15 (depends on 13)

The method according to claim 13, wherein in the compound of Formula (X), R1 is 1-butyl, and R2 and R3 are each hydrogens.

### Claim 16 (depends on 1)

The method according to claim 1, which is the method IV.

### Claim 17 (depends on 1)

The method according to claim 1, which is the method V.

### Claim 18

A crystalline Form II rosuvastatin t-butylammonium salt of Formula (IIa)
which has the following X-ray diffraction lines measured by CuKα radiation (±0.2° 2Θ): 18.654 degrees 2Θ; or 18.654 and 15.803 degrees 2Θ; or 11.282, 15.803 and 19.832 degrees 2Θ; or has the powder X-ray diffractogram of FIG. 1.

### Claim 19 (depends on 18)

The crystalline Form II rosuvastatin t-butylammonium salt of Formula (IIa) according to claim 18, which has the following X-ray diffraction lines measured by CuKα radiation (±0.2° 2Θ): 18.654 and 15.803 degrees 2Θ.

### Claim 20 (depends on 18)

The crystalline Form II rosuvastatin tert-butylammonium salt of Formula (IIa) according to claim 18, which has the following X-ray diffraction lines measured by CuKα radiation (±0.2° 2Θ): 11.282, 15.803 and 19.832 degrees 2Θ.

### Claim 21 (depends on 18)

The crystalline Form II rosuvastatin t-butylammonium salt of Formula (IIa) according to claim 18, which has the following X-ray diffraction lines measured by CuKα radiation: (±0.2° 2Θ): 18.654 degrees 2Θ.

### Claim 22 (depends on 18)

The crystalline Form II rosuvastatin t-butylammonium salt of Formula (IIa) according to claim 18, which has the powder X-ray diffractogram of FIG. 1.