NOVEL INTERMEDIATES FOR THE PREPARATION OF HMG-CoA
REDUCTASE INHIBITORS
Field of the Invention
The present invention provides a process for preparing novel intermediates of
Formulae
Formula IV Formula V
wherein, R1can be hydrogen, C1-C4 alkyl, halogen, nitro, hydroxy, or C1-C4 alkoxy; Rx
can be selected from hydrophobic residue of HMG-CoA reductase inhibitors, which can
be effectively used for the preparation of HMG-CoA reductase inhibitors such as
rosuvastatin and pharmaceutically acceptable salts thereof.
Background of the Invention
HMG-CoA reductase inhibitors are the compounds which play a main role in the
synthesis of cholesterol, and subsequently they suppress the biosynthesis of cholesterol.
Therefore, they are useful in the treatment of hypercholesterolemia, hyperlipoproteinemia,
and atherosclerosis
Rosuvastatin calcium (Crestor®) is chemically known as bis[(E)-7-[4-(4-
fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino] pyrimidin-5 -yl](3R,5 S)-3 ,5-
dihydroxyhept-6-enoic acid], calcium salt.
Rosuvastatin was first disclosed in U.S. Patent No. 5,260,440, which also discloses
the process for the synthesis of rosuvastatin calcium.
Several processes have been reported in literature for the preparation of
rosuvastatin, such as WO 2004/014872, WO 2004/108691, WO 2005/042522, WO
2005/054207, WO 2005/077916, WO 2006/035277, WO 2007/041666, WO 2007/125547
or WO 2008/044243.
There remains a need in the art for processes for preparing rosuvastatin which are
cost effective, have fewer purification steps, are suitable for industrial scale preparation,
result in high yields and are environmentally friendly.
Summary of the Invention
The present invention provides a process for preparing novel intermediates of
Formulae
Formula IV Formula V
wherein, R1 can be hydrogen, C1-C4 alkyl, halogen, nitro, hydroxy, or C1-C4 alkoxy;
Rx is a hydrophobic residue of HMG-CoA reductase inhibitors including, for example:
Formula A Formula B Formula C
which can effectively be used for the preparation of HMG-CoA reductase inhibitors such
as rosuvastatin and pharmaceutically acceptable salts thereof.
One aspect of the present invention provides a process for preparing novel
intermediate of Formula IVa [Formula IV when Rx is Formula A]
H3C0 2S CH3
Formula IVa
wherein, R1can be hydrogen, C1-C4 alkyl, halogen, nitro, hydroxy, or C1-C4 alkoxy.
The process comprises the steps of:
(a) converting a compound of Formula la
Formula la
to a compound of Formula Ila,
Formula Ila
wherein, L is a leaving group;
(b) reacting a compound of Formula Ila with a compound of Formula III
Formula III
to give a compound of Formula IVa,
Formula IVa
wherein, R1 is same as defined above.
Another aspect of the present invention provides a process for the preparation of a
compound of Formula Va [Formula V when Rx is Formula A]
Formula Va
wherein, R1is as defined above.
The process comprises the steps of:
converting a compound of Formula la
Formula la
to a compound of Formula Ila,
Formula Ila
wherein, L is a leaving group;
reacting a compound of Formula Ila with a compound of Formula III
Formula III
to give a compound of Formula IVa,
Formula IVa
wherein, R1 is same as defined above;
(c) oxidizing a compound of Formula IVa to a compound of Formula Va.
Formula Va
Another aspect of the present invention provides a compound of Formula IVa and
a compound of Formula Va.
Formula IVa Formula Va
Another aspect of the present invention provides use of an intermediate of Formula
IVa or Formula Va, for preparing rosuvastatin or pharmaceutically acceptable salts
thereof.
Yet another aspect of the present invention provides a process for the preparation
of rosuvastatin calcium having the following formula:
the process comprises the steps of:
converting a compound of Formula la
Formula la
to a compound of Formula Ila;
H,C0 2S \ CH3
Formula Ila
wherein, L is a leaving group;
reacting a compound of Formula Ila with a compound of Formula III
Formula III
to give a compound of Formula IVa
Formula IVa
wherein, R1 is same as defined above;
oxidizing a compound of Formula IVa to a compound of Formula Va;
Formula Va
condensing a compound of Formula Va with a compound of Formula VI,
Formula VI
wherein, R can be hydrogen, alkyl, cycloalkyl, arylalkyl, aryl or
carbonylbenzyloxy (cbz), preferably alkyl, more preferably, tertiary butyl; P1
and P2 can be hydrogen or a protecting group wherein, preferably P1 and P2
combines to form structure represented as
wherein, R4 and R5 can be alkyl group, alkoxy group or can combine together
to form a cyclic hydrocarbon chain or a carbonyl group,
to give a compound of Formula Vila
Formula Vila
wherein, P1, P2 and R are as defined above;
(e) de-protecting or hydrolyzing a compound of Formula Vila to give a
compound of Formula Villa;
(f converting a compound of Formula Villa to an amine salt; and
(g) converting an amine salt of a compound of Formula Villa to rosuvastatin
calcium.
According to yet another aspect of the present invention there is provided a
pharmaceutical composition comprising:
a) rosuvastatin calcium of Formula
b) one or more compounds selected from
Formula IVa Formula Va
wherein, R1is as defined above.
Compounds listed in component (b) may be present in amounts up to 2% by
weight with respect to the total weight of components (a) and (b) when determined by
HPLC. Preferably, compounds listed in component (b) may be present in amounts 0.2%
by weight. The compound in component (a), i.e., the active ingredient is preferably present
in amounts greater than 95% by weight, preferably greater than 98%, and more preferably
in amounts greater than 99% with respect to the total weight of components (a) and (b)
when determined by HPLC.
According to yet another aspect of the present invention, there is provided
rosuvastatin calcium, prepared according to the process described above, wherein
rosuvastatin calcium has purity of more than 99.0% and compounds of Formula IVa and
Formula Va are present in amounts less than 0.10%. Preferably, rosuvastatin calcium has
purity of more than 99.5% when determined by HPLC and the compounds of Formula IVa
and Formula Va are present in amounts less than 0.05%.
Other objects, features, advantages and aspects of the present invention will
become apparent to those of ordinary skill in the art from the following detailed
description.
Detailed Description of the Invention
As used herein, "pharmaceutically acceptable salts" refers to the addition salts
using cations capable of forming such salts. The term "a cation capable of forming a
pharmaceutically acceptable salt" refers to alkali metal ion (e.g., lithium, sodium,
potassium or cesium), alkaline earth metal ion (e.g., beryllium, magnesium or calcium),
ammonium ion or amine salts (e.g., methyl amine, ethyl amine, n-propyl amine, isopropyl
amine, n-butyl amine, tertiary butyl amine, or the like). The pharmaceutically acceptable
salts can be crystalline, semi crystalline, or amorphous in nature.
As used herein, "alkyl group" refers to straight, branched, or cyclic hydrocarbon,
(e.g., methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tertbutyl,
cyclobutyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, cyclopentyl, n-hexyl,
isohexyl or the like). "Halogen" means fluorine, chlorine, bromine and iodine.
As used herein, room temperature is meant to indicate a temperature range of about
25°C to about 35°C.
As used herein, the term "protecting group" refers to hydroxyl protecting groups
described in Protective Groups in Organic Synthesis by Greene and Wuts or Protecting
Groups by Carey and Sundberg. The preferred hydroxyl protecting groups are ethers (e.g.,
methyl ether, methoxy methyl ethers, methoxyethoxymethyl ethers, methyl thiomethyl
ethers, benzyloxymethyl ethers, tetrahydropyranyl ether, ethoxyethyl ethers, benzyl ethers,
2-naphthyl ethers, p-methoxybenzyl ethers, o-Nitrobenzyl ethers, p-Nitobenzyl ethers,
trityl ethers, tri methyl silyl ethers, triethyl silyl ethers, triisopropyl silyl ethers, phenyl
dimethyl silyl ethers or t-butyldimethylsilyl ethers), acetonides (isopropylidenes),
cycloalkylidene ketals or benzylidene acetals (e.g., p-methoxybenzylidenes, or the like).
The hydroxyl group of the compound of Formula la can be displaced by a
suitable leaving group to give a compound of Formula Ila using the procedures known to a
person of ordinary skill in the art. For example, the reaction can be carried out in the
presence of a base in a solvent. A suitable leaving group can be defined as a group which
can be easily displaced by the reaction with an appropriate reagent. A suitable leaving
group includes halo (e.g., bromo, chloro, or the like), alkyl sulphonyloxy (e.g.,
methylsulphonyloxy, triflouro methylsuphonyloxy, or the like), aryl suphonyloxy (e.g.,
benzyl suphonyloxy, p-tolyl suphonyloxy, or the like), phosphate (e.g., diphenyl
phosphate, or the like) or phosphite (diphenyl phosphate, or the like). The solvent can be
selected from halogenated solvents (e.g., dichloromethane, chloroform, carbon
tetrachloride, or the like), ketones (e.g., acetone, 2-butanone, methyl isobutyl ketone,
methyl ethyl ketone, or the like), esters (e.g., ethyl acetate, methyl acetate, tertiary butyl
acetate, or the like), nitriles (e.g., acetonitrile or the like), aprotic polar organic solvents
(e.g., dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, or the like). The base
can be selected from organic base (e.g., triethylamine, diisopropylethylamine,
diisopropylamine, pyridine, dimethylaminopyridine, or the like), inorganic base (e.g.,
sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium
bicarbonate or potassium bicarbonate), or a mixture thereof.
A compound of Formula Ila can be reacted with a compound of Formula III,
(wherein, R 1is as defined above, preferably methyl) to give a compound of Formula IVa.
The reaction can be carried out in the presence of a base with or without a solvent. The
base can be selected from organic base (e.g., triethylamine, isopropylethylamine,
diisopropylamine, pyridine, dimethylaminopyridine, or the like), inorganic base (e.g.,
sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium
bicarbonate, or potassium bicarbonate), or a mixture thereof. A suitable solvent can be
selected from halogenated solvents (e.g., dichloromethane, chloroform, carbon
tetrachloride, or the like), ketones (e.g., acetone, 2-butanone, methyl isobutyl ketone,
methyl ethyl ketone, or the like), esters (e.g., ethyl acetate, methyl acetate, tertiary butyl
acetate, or the like), nitriles (e.g., acetonitrile or the like), aprotic polar organic solvents
(e.g., dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, or the like).
The sulfide of Formula IVa can be oxidized to the sulfone of Formula Va. The
oxidation can be carried out using procedures generally known to a person of ordinary
skill in the art. For example, the reaction can be carried out using a suitable oxidizing
agent in a solvent. A suitable oxidizing agent can be selected from permanganates (such
as potassium permanganate or the like), meta-chloro per benzoic acid, sodium
hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydroperoxide
or oxone K SO 'K SC 'K SC ) . The oxidizing agent can be used in the presence of an
appropriate catalyst. An appropriate catalyst can be selected from ammonium molybdate
or alkali metal tungstate, such as sodium tungstate. The solvent can be selected from
halogenated solvents (e.g., dichloromethane, chloroform, carbon tetrachloride, or the like),
ketones (e.g., acetone, 2-butanone, methyl isobutyl ketone, methyl ethyl ketone, or the
like), esters (e.g., ethyl acetate, methyl acetate, tertiary butyl acetate, or the like) or
alcoholic solvent (e.g., methanol, ethanol, 1-propanol or 2-propanol), or a mixture thereof,
optionally in the presence of phase transfer catalysts selected from alkyl ammonium
halides (e.g., tetrabutyl ammonium bromide, or the like).
The sulfone of Formula Va can be condensed with the aldehyde of Formula VI
to give a compound of Formula Vila. The condensation can be carried out in the presence
of a base selected from metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, or
the like), metal carbonates (e.g., potassium carbonate, sodium carbonate, cesium
carbonate, lithium carbonate, or the like), alkyl lithium (e.g., methyl lithium, n-butyl
lithium, or the like), metal alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium
propoxide, sodium tertiarybutoxide, potassium methoxide, potassium ethoxide,
magnesium t-butoxide, or the like), metal disilazides (e.g., sodium
bis(trimethylsilyl)azanide, lithium bis(trimethylsilyl)azanide, or the like) or a mixture
thereof in a solvent selected from ethers (e.g., diethylether, tetrahydrofuran, or the like),
polar aprotic solvents (e.g., acetonitrile, dimethyl formamide, dimethyl sulfoxide, dimethyl
acetamide, or the like) or mixtures thereof .
The process is characterized by the fact that the compound of Formula Vila
formed by the condensation reaction as described above may or may not be isolated.
A compound of Formula Vila can be deprotected and/or hydrolyzed to give a
compound of Formula Villa. Deprotection and hydrolysis can proceed under the similar
conditions. Deprotection can be carried out by the methods known to person ordinary skill
in the art or as described in Protecting Groups by Carey & Sundberg. Particularly, the
step can be carried out using an acid such as hydrochloric acid, hydrobromic acid, acetic
acid or trifluoroacetic acid, or a base such as sodium hydroxide or potassium hydroxide.
A compound of Formula Villa can be converted into an amine salt by reacting
it with an organic amine in a solvent. As used herein, amine salts refers to salts of primary
amine (e.g., methyl amine, ethyl amine, n-propyl amine or n-butyl amine), secondary
amine salts (e.g., 2-propyl amine, 2-butyl amine, or the like) or tertiary amine salts (e.g.,
tertiary butyl amine or the like) or cyclic amine salts (e.g., cyclohexyl amine or the like),
morpholine or pyrolidine. Preferably, amine salt can be selected from primary amine salt,
such as methyl amine salt, or tertiary amine salt such as tertiary butyl amine salt. The
amine salts can be crystalline, semi crystalline or amorphous in nature. The solvent used
in this step can be selected from halogenated solvents (e.g., dichloromethane, chloroform,
carbon tetrachloride, or the like), ketones (e.g., acetone, 2-butanone, methyl isobutyl
ketone, methyl ethyl ketone, or the like), nitrile (e.g., acetonitrile or the like), esters (e.g.,
ethyl acetate, methyl acetate, tertiary butyl acetate, or the like) or alcoholic solvent (e.g.,
methanol, ethanol, 1-propanol or 2-propanol) or mixtures thereof.
An amine of Formula Villa can be converted into a HMG-CoA reductase inhibitor,
rosuvastatin calcium thereof using the conditions known to a person ordinary skill in the
art. For example, the procedures described in U.S. Patent No. 5,260,440, WO
2004/014872; WO 2004/108691; WO 2005/042522; WO 2005/054207; WO
2005/077916; WO 2006/035277; WO 2007/041666; WO 2007/125547 or WO
2008/044243. Particularly, using the procedures described in this application.
Having thus described the invention with reference to the particular preferred
embodiment and illustrative examples, those in the art can appreciate the modifications to
the invention as described and illustrated that do not depart from the spirit and the scope of
the invention as disclosed in the specifications. The examples are set forth to aid the
understanding of the invention but are not intended to and should not be construed to limit
its scope in any way.
Starting Materials
Preparation of Tert- 3,5-Dideoxy-2,4 -O-(l-Methylethylidene)-L -Ervt r -
Hexuronate:
t r t-Butyl 2,4-dideoxy-3,5-0-(l-methylethylidene)-D-ery tAro-hexonate
(commercially available; 20 g) was added to a pre cooled (0°C to 5°C) mixture of 2,2,6,6-
tetramethylpiperidine-l-oxyl (0.04 g), potassium bromide (1.92 g), and sodium
bicarbonate (18 g) in dichloromethane (120 mL) and stirred at 0°C to 5°C for 15 minutes.
Aqueous sodium hypochlorite (10%; 40 mL) was added slowly to the resulting mixture
and stirred at 0°C to 5°C for 30 minutes. Sodium bicarbonate (18 g) was added to the
mixture and stirred at 0°C to 5°C for 10 minutes, followed by the slow addition of aqueous
sodium hypochlorite (10%; 40 ml) in 30 minutes at 0°C to 5°C. The reaction mixture was
stirred at 0°C to 5°C for 30 minutes. After completion of the reaction, the reaction
mixture was filtered through hyfio bed and washed with dichloromethane (20 mL). The
filtrate was washed with aqueous sodium thiosulphate (10%>; 100 mL). The organic layer
was separated and washed with de-ionized water (100 mL) and finally washed with
aqueous solution of sodium chloride (10%>; 100 mL). The organic layer was separated and
concentrated under vacuum at 40°C to give tert-butyl 3,5-dideoxy-2,4 -O-(lmethylethylidene)-
L-ery tAro-hexuronate.
Dry weight: 19.2 g.
EXAMPLES
Example 1: N-r4-(4-Fluorophenvn-5-(r(5-Methyl-l,3,4-Thiadiazol-2-
Yl)SulfanyllMethyl|-6-(Propan-2-Yl)Pyrimidin-2-Yll -N-Methylmethanesulfonamide
Diisopropyl ethyl amine (84.12 g) was slowly added to a mixture of N-[4-(4-
fluorophenyl)-5-(hydroxymethyl)-6-(propan-2-yl)pyrimidin-2-yl]-Nmethylmethanesulfonamide
(commercially available; 100 g) and dimethyl aminopyridine
(5 g) and diphenyl chlorophosphate (123.2 g) in dichloromethane (500 mL) at 0°C to 5°C.
The reaction mixture was stirred for 30 minutes at the same temperature to give [4-(4-
fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]methyl
diphenyl phosphate. To this mixture was added 2-mercapto-5-methyl-l,3,4-thiadiazole
(41 g) at 0°C to 5°C followed by slow addition of diisopropyl ethyl amine (36.5 g). The
resultant mixture was stirred for 2 hours at 0°C to 5°C. After completion of the reaction,
the mixture was quenched with de-ionized water (500 mL) and acidified to pH 3.5 using
hydrochloric acid (6N). The organic layer was separated and washed with sodium
bicarbonate (5%) at room temperature. The organic layer was separated and
dichloromethane was recovered at 45°C to give oily residue. Methanol (300 mL) was
added to resulting oily residue and the mixture was stirred at room temperature for one
hour to give N-[4-(4-fluorophenyl)-5-{[(5-methyl-l,3,4-thiadiazol-2-yl)sulfanyl]methyl}-
6-(propan-2-yl)pyrimidin-2-yl ]-N-methylmethanesulfonamide, which was filtered, washed
with methanol (100 mL) and dried at 45°C for 2 hours.
Dry Weight: 115 g
Example 2 : N-r4-(4-Fluorophenyl)-5- (IY5-Methyl-1 ,3,4-Thiadiazol-2-YnSulfonvH
Methyl) -6-(Propan-2-Yl)Pyrimidin-2-Yll -N-Methylmethanesulfonamide
Ammonium molybdate (26.5 g) was added to a mixture of N-[4-(4-fluorophenyl)-
5-{[(5-methyl-l,3,4-thiadiazol-2-yl)sulfanyl]methyl}-6-(propan-2-yl)pyrimidin-2-yl ]-Nmethylmethanesulfonamide
(Example 1; 100 g), tetra butyl ammonium bromide (5 g) and
hydrogen peroxide (30%; 600 mL) in dichloromethane (200 mL) at 0°C to 5°C. The
mixture was stirred for 10 hours to 12 hours at 0°C to 5°C. After the completion of the
reaction, the dichloromethane layer was separated and washed with aqueous solution of
sodium metasulfite (2%; 500 mL). The dichloromethane layer was again separated and
washed with aqueous solution of sodium bicarbonate (5%; 500 mL) and stirred for 10
minutes. The dichloromethane layer was finally separated and recovered under vacuum at
35°C to 45°C to give a residue. Methanol (300 mL) was added to the resulting residue and
stirred at room temperature to give N-[4-(4-fluorophenyl)-5 -{[(5-methyl- 1,3,4-thiadiazol-
2-yl)sulfonyl]methyl} -6-(propan-2-yl)pyrimidin-2-yl] -N-methylmethanesulfonamide,
which was filtered, washed with methanol (100 mL) and dried under vacuum at 45°C for 2
hours.
Dry weight: 100 g
Example 3: e -ButvHT4R.6S -6- ((E )-2-r4-(4-Fluorophenvn-2-rMethyl(Methylsulfonvn
Aminol-6-(Propan-2-Yl)Pyrimidin-5-YllEthenyl|-2,2-Dimethyl-l,3-Dioxan-4-YllAcetate
Lithium bis(trimethylsilyl)azanide in terahydrofuran (23% w/w; 268 mL) was
added to a pre cooled mixture of N-[4-(4-fluorophenyl)-5 -{[(5-methyl- 1,3,4-thiadiazol-2-
yl)sulfonyl]methyl}-6-(propan-2-yl)pyrimidin-2-yl ]-N-methylmethanesulfonamide
(Example 2; 100 g) and t rt-butyl 3,5-dideoxy-2,4-0-(l-methylethylidene)-L-erythrohexuronate
(54.4 g) in tertrahydrofuran (800 mL) at -60°C to -70°C. After the completion
of the reaction, the mixture was washed with saturated aqueous solution of ammonium
chloride and the temperature is allowed to rise to 20°C to 25°C. The reaction mixture was
extracted twice with ethylacetate (250 mL + 150 mL). The combined ethylacetate layers
were washed with aqueous solution of sodium bicarbonate (5%; 500 mL) and brine (500
mL). The organic layer was separated and concentrated under vacuum at 40°C to 45°C to
give residue. Methanol (700 ml) was added to the resulting residue and stirred at 20°C to
25°C for 2 hours. The product was filtered, washed with methanol (100 mL) and dried at
40°C to 45°C for 4 hours to 5 hours.
Dry weight: 52.4 g
Alternate Method for 7¾rt-Butyl r(4i?,6^-6 -((E )-2-r4-(4-Fluorophenvn-2-
rMethyl(MethylsulfonvnAmino1-6-(Propan-2-YnPyrimidin-5-Y11Ethenyl|-2,2-Dimethyl-
1.3-Dioxan-4-YHAcetate
Sodium methoxide (12.8 g) was added in lots to a pre cooled mixture of N-[4-(4-
fluorophenyl)-5-{[(5-methyl-l,3,4-thiadiazol-2-yl)sulfonyl]methyl}-6-(propan-2-
yl)pyrimidin-2-yl ]-N-methylmethanesulfonamide (100 g) and tert-butyl 3,5-dideoxy-2,4-
0-(l-methylethylidene)-L-erythro-hexuronate (60 g) in tertrahydrofuran (500 mL) at -
15°C to 10°C. After the completion of the reaction, the mixture was quenched with
saturated aqueous solution of ammonium chloride. To the resultant mixture,
dichloromethane (500 mL) was added and the pH of the mixture was adjusted to 5.0 to 7.0
using dilute hydrochloric acid (2N). The organic layer was washed with aqueous solution
of sodium bicarbonate (5%; 200 mL). The organic layer was separated and concentrated
under vacuum at 40°C to 45°C to give residue. Methanol (1000 mL) was added to the
resulting residue and stirred at 20°C to 25°C for 2 hours. The product was filtered,
washed with methanol (100 mL) and dried at 40°C to 45°C for 4 hours to 5 hours.
Dry weight: 60 g
Example 4 : (3R,5S,6E)-7-r4-(4-Fluorophenvn-2-rMethyl(MethylsulfonvnAminol-6-
(Propan-2-Yl)Pyrimidin-5-Y11-3,5-Dihvdroxyhept-6-Enoic Acid - 2-Methylpropan-2-
Amine (1:1)
Hydrochloric acid (2 N; 60 mL) was added to a solution of tert-butyl [(4i?,65)-6-
{(E)-2-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-
yl]ethenyl}-2,2-dimethyl-l,3-dioxan-4-yl]acetate (Example 3; 50 g) in acetonitrile (500
mL) at room temperature and stirred at the same temperature for 3 hours. After
completion of the reaction, aqueous solution of sodium hydroxide (10%; 90 mL) was
added to the reaction mixture at room temperature and the temperature of the mixture was
allowed to rise to 40°C to 45°C. The pH of the reaction mixture was adjusted to 12 to
12.8 using aqueous solution of sodium hydroxide (10%). Acetonitrile was recovered
completely under vacuum at 45°C to 50°C. De-ionized water (250 mL) was added to the
resulting residue at room temperature. Methyl tert-butyl ether (200 mL) was added to the
mixture and stirred for 10 minutes. Layers were separated and methyl tert-butyl ether
(200 mL) was added to the aqueous layer and stirred for 10 minutes. Layers were
separated and aqueous layer was cooled to 5°C to 10°C and adjusted to a pH of 3.5 to 4.0
using hydrochloric acid (2N). Dichloromethane was added to the resulting mixture and
stirred for 10 minutes to 15 minutes. Dichloromethane was recovered completely under
vacuum at 35°C to 40°C. Acetonitrile (500 mL) was added to the resulting residue and
mixture was cooled to 0°C to 5°C. To this cooled layer, tert-butyl amine (7 g) was slowly
added for 30 minutes at 0°C to 5°C and stirred for 2 hours at 10°C to 15°C. The product
was filtered, washed with acetonitrile (50 mL) and dried under vacuum at 45°C for 3
hours.
Dry weight: 40 g
Alternate Method:
Hydrochloric acid (0.02 N; 15 mL) was added to a solution of tert-butyl
(3R,5S,6E)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-
yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate (Example 3; 15 g) in acetonitrile (150 mL)
at 25°C to 30°C and stirred at the same temperature for 2 hours. After completion of the
reaction, aqueous solution of sodium hydroxide (1.55g in 30 mL) was added to the
reaction mixture at 25°C to 30°C and stirred for 2.0 hours at 30°C to 35°C. Acetonitrile
was recovered completely under vacuum at 40°C to 45°C. De-ionized water (30 mL) was
added to the resulting residue at room temperature. Methyl tert-butyl ether (30 mL) was
added to the mixture and stirred for 10 minutes. Layers were separated; methyl tert-butyl
ether (30 mL) was added to the aqueous layer and stirred for 10 minutes. Layers were
separated; the aqueous layer was cooled to 0°C to 5°C and added acetonitrile (75 ml) and
sodium chloride (25 g) adjusted pH of 3.5 to 4.0 using hydrochloric acid (2N) at 0°C to
5°C. Organic layer was separated and cooled to 0°C to 5°C. To this pre-cooled organic
layer, tert-butyl amine ( 1.9 g) was slowly added in 20 minutes at 0°C to 5°C and stirred
for 1 hour at room temperature. The resulting mixture was cooled to 5°C to 10°C, filtered,
washed with acetonitrile (30 mL) and dried under vacuum at 40°C to 45°C for 4 hours.
Dry weight: 12 g
Example 5 : Rosuvastatin Calcium
Aqueous solution of sodium hydroxide (0.72 g in 10 mL) was added to a
solution of (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-
(propan-2-yl)pyrimidin-5 -yl] -3,5-dihydroxyhept-6-enoic acid -2-methylpropan-2-amine
(10 g) in de-ionized water (50 mL) at room temperature and stirred for 2 hours to 3 hours
at 20°C to 30°C. The reaction mixture was extracted twice with methyl tertiary butyl ether
(2 X 40 mL) at room temperature. The pH of aqueous layer was adjusted to 9.1 using
hydrochloric acid (2N). Residual solvents were recovered under vacuum at 35°C to 45°C
(~10 mL). The mixture was filtered through 0.45 micron paper and the filtrate was
preserved. The filtrate was slowly added in 20 minutes to a solution of calcium acetate
( 1.99 g) in de-ionized water (20 mL) at room temperature. The resulting mixture was
stirred at room temperature for one hour, filtered, washed with de-ionized water (20 mL)
and dried under vacuum at 45°C.
Dry Weight: 8.0 g
HPLC purity (%): 99.8

We Claim:
1. A process for the preparation of a compound of Formula IVa
Formula IVa
wherein, R1is hydrogen, C1-C4 alkyl, halogen, nitro, hydroxy, or C1-C4 alkoxy;
such process comprising the steps of:
(a) converting a compound of Formula la
to a compound of Formula Ila,
H3C0 2S CH
Formula Ila
wherein, L is a leaving group; and
reacting a compound of Formula Ila with a compound of Formula III
Formula III
to give a compound of Formula IVa.
A process for the preparation of a compound of Formula Va
Formula Va
wherein R1is hydrogen, C1-C4 alkyl, halogen, nitro, hydroxy or C1-C4 alkoxy,
such process comprising the steps of:
(a) converting a compound of Formula la
Formula la
to a compound of Formula Ila,
Formula Ila
wherein, L is a leaving group;
reacting a compound of Formula Ila with a compound of Formula III
Formula III
to give a compound of Formula IVa, and
Formula IVa
c) oxidizing a compound of Formula IVa to a compound of Formula Va.
3. A compound of Formula IVa or a compound of Formula Va.
Formula IVa Formula Va
4. Use of an intermediate of Formula IVa or Formula Va for preparing rosuvastatin or
pharmaceutically acceptable salts thereof.
5. A process for the preparation of rosuvastatin calcium of formula
comprising the steps of:
(a) converting a compound of Formula la
Formula la
to a compound of Formula Ila;
Formula Ila
wherein 'L' is a leaving group
reacting a compound of Formula Ila with a compound of Formula III
Formula III
to give a compound of Formula IVa;
Formula IVa
oxidizing a compound of Formula IVa to a compound of Formula Va;
Formula Va
condensing a compound of Formula Va with a compound of Formula VI,
Formula VI
wherein R is alkyl, cycloalkyl, arylalkyl, aryl or carbonylbenzyloxy (cbz); P1
and P2 are hydrogen or a protecting group, wherein, P1 and P2 combines to
form structure represented as
wherein, R4 and R5 is alkyl group, alkoxy group or can combine together to
form a cyclic hydrocarbon chain or a carbonyl group, to give a compound of
Formula Vila;
Formula Vila
(e) de-protecting or hydrolyzing a compound of Formula Vila to give a
compound of Formula Villa;
(f) converting a compound of Formula Villa to an amine salt; and
(g) converting an amine salt of a compound of Formula Villa to rosuvastatin
calcium.
6. The process according to claim 5, wherein 'L' is leaving group selected from a
group consisting of alkyl sulphonyloxy, aryl suphonyloxy, phosphate or phosphite groups.
7. The process according to claim 6, wherein 'L' is diphenyl phosphate.
8. The process according to claim 5, wherein R1is Ci-C4alkyl.
9. The process according to claim 5, wherein the step (b) is reacted in the presence of
a base selected from triethylamine, diisopropylethylamme, diisopropylamine, pyridine or
dimethylaminopyridine.
10. The process according to claim 9, wherein an organic base is
diisopropylethylamme.
11. The process according to claim 5, wherein the step (c) is performed using an
oxidizing agent selected from a group consisting of permanganates, meta-chloro per
benzoic acid, sodium hypochlorite, hydrogen peroxide, tert-butyl hydrogen peroxide,
cumene hydroperoxide or oxone (2KHS05 KHS0 4K2S0 4) in the presence of transition
metal catalysts.
12. The process according to claim 11, wherein oxidation is performed using hydrogen
peroxide in the presence of ammonium molybdate.
13. The process according to claim 5, wherein P1and P2 are acetonide (isopropylidene)
group.
14. The process according to claim 5, wherein an amine salt is selected from a group
consisting of methyl amine, ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine
or tert-butyl amine.
15. The process according to claim 14, wherein an amine salt is tert-butyl amine salt.
16. The process according to claim 5, wherein an amine salt is treated with a base and
then converted to rosuvastatin calcium by treatment with calcium hydroxide.
17. Rosuvastatin calcium, prepared according to claim 5, wherein rosuvastatin calcium
has purity more than 99.5% when determined by HPLC.