FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(Section 10)
Process for preparation of Calcium salt of
Rosuvastatin
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANIES ACT, 1956,,
HAVING ITS REGISTERED OFFICE LOCATED AT MAHALAXMI
CHAMBERS, 2ND FLOOR, 22, BHULABHAI DESAI ROAD,
MUMBAI 400 026, MAHARASHTRA, INDIA
The following specification particularly describes the nature of the invention and the manner in which it is to be performed

Process for preparation of Calcium salt of Rosuvastatin
Field of Invention
The present invention relates to a process for the preparation of Rosuvastatin, a promising
HMG-CoA reductase inhibitor, to process steps and novel intermediates.
Background of the invention
HMG-CoA reductase inhibitors (also called (3-hydroxy-p-methylglutaryl-co-enzyme-A
reductase inhibitors and also called statins) are understood to be those active agents,
which may be preferably used to lower the low-density lipoprotein (LDL) particle
concentration in the blood stream of patients at risk for cardiovascular disease and thus
used for the prevention or treatment of hypercholesterolemia, hyperlipoproteinemia and
artheriosclerosis. A high risk level of LDL in the bloodstream has been linked to the
! formation of coronary lesions that obstruct the flow of blood and can rupture and promote
thrombosis.
Rosuvastatin, an antihyperchlolesterolemic drug used in the treatment of atherosclerosis
is chemically (E)-7-[4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]
pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium (2:1) salt having the
structural formula I.

Formula I
The prior art has been elaborated in a co-pending application number 325/MUM/2005. The above mentioned co-pending application discloses a commercially viable method of preparation for Rosuvastatin via novel intermediates.
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In continuation of Our work in this aspect, in this present invention relates another method of preparation of Rosuvastatin via novel intermediates and less expensive reagents by an early introduction of the correct absolute stereochemistry at C-5 (S) of side chain followed by regioselective chain extension using yet another side chain building blocks. The invention also relates to novel intermediates.
Detailed Description of the invention
The present invention concerns a process for the preparation of rosuvastatin comprising,
a) reacting a compound of formula (II)

Formula II
wherein, Rl, R2, R3 are substituted or unsubstituted phenyl and R4 is an aliphatic residue selected from C1-C4 alkyl;
with a compound of formula R-CH(=0) (Formula III) wherein R represents the following cyclic structure (formula IV) to obtain a compound of formula (V);

b). hydrolysing a compound of formula (V) to obtain a compound of formula (VI);

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c). treating a compound of formula (VI)

Formula VI
with an acid activating group and subsequently with a compound of formula VII that indroduces the radical of formula -CH2-COOR5 to obtain a compound of formula VIII

Formula VII
wherein, R5 represents C1-C4 alkyl; M is an alkali metal;
or in another variant of process, converting the compound of formula (VI) to its acid
halide of formula (IX)

Formula IX
wherein, X represents a halogen
and treating a resulting compound of formula (IX) with a compound of formula (X) to
obtain a compound of formula (VIII);
O H

Formula X
or in another variant of process, treating the compound of formula (IX) with a compound
of formula (VII) to obtain a compound of formula (VIII);
d). reducing a compound of formula (VIII) to obtain a compound of formula XI; Page 3 of 3

Formula VIII
e). hydrolyzing a compound of formula (XI) to obtain a compound of formula XII

Formula XI
f). resolving the resulting racemic compound of formula (XII), first converting the racemic compound to its diastereomeric salt using the (+) or (-) enantiomeric amine of the formula (XIII) and separating the mixture of diastereomeric salt into the individual diastereomers by chromatography or crystallization and then neutralizing the diastereomeric salt to give the enantiomerically pure product.

Formula XIII
wherein, R6 represent Cl-C4-alkyl which is optionally substituted by hydroxyl; R7 represent hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy; and g). treating the resulting compound of formula (XIV)

Formula XIV
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with an acid activating group and subsequently with a compound of formula (VII) that introduces the radical of formula -CH2-COOR5 to obtain a compound of formula (XV) or in another variant of process, esterifying a compound of formula (XIV)

Formula XIV
and condensing the resulting compound of formula (XVI)

Formula XVI
wherein R8 is an aliphatic residue selected from CI -C4 alkyl
with a compound of formula (X) to obtain a compound of formula (XV)

Formula X
h). reducing a compound of formula (XV) to obtain a compound of formula XVII

Formula XV
i). hydrolyzing a compound of formula (XVII) and converting into a salt of formula I thereof

Formula XVII
wherein R and R5 have the meanings as defined.
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In reaction step (a), the reaction of a compound of formula (II) with a compound of
formula (III) is carried out in a suitable inert solvent, preferably toluene, and in a
temperature range from 60°C, to the boiling point of the solvent, preferably at the boiling
point of the solvent.
The saponification (step b) is carried out by treating the ester of formula (V) with a strong
base, such as an alkali metal hydroxide, preferably NaOH or KOH, in aqueous aliphatic
alcohol as solvent, preferably aqueous methanol, and in a temperature range from 25°C to
boiling point of solvent, preferably between 25°C to 35°C and acidifying the resulting
reaction mixture.
Formation of compound of formula (VIII) (step c) is carried out by treating the
compound of formula (VI) with an acid activating group, especially preferred one is the
use of 1,1-carbonyldiimidazole and condensing the resulting compound with alkali metal
salt of manoalkyl malonate (formula VII), preferably potassium monomethylmalonate or
potassium monoethylmalonate, in the presence of magnesium chloride, in an inert
solvent, preferably tetrahydrofuran, at temperature between 0 - 40°C, preferably at 0 -
35°C.
In another variant of process to prepare compound of formula (VIII) is carried out by
converting a compound of formula (VI) to a compound of formula (IX) in an inert
solvent, preferably dichloromethane, and in temperature range from 0°C to boiling point
of the solvent, preferably between 0°C to 28°C using oxalyl chloride or thionyl chloride
and subsequent treatment of a resulting of formula of (IX) with a compound of formula
(X) in the presence of a suitable base and in a suitable inert solvent, .especially
tetrahydrofuran, and in a temperature range from -78 C, to the boiling point of the
solvent, preferably at -78 to room temperature.
A suitable base is selected from an alkane alkali metal in presence of diisopropylamine,
alkali alkylsilazanes like LiHMDS or NaHMDS. Especially preferred is the use of n-
butyllithium in the presence of diisopropylamine.
In another variant of process to prepare compound of formula (VIII) is carried out by
condensing a compound of formula (IX) with an alkali metal salt of manoalkyl malonate
(Formula VII), preferably potassium monomethylmalonate or potassium
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monoethylmalonate, in the presence of magnesium chloride, in an inert solvent, preferably tetrahydrofuran, at temperature between 0 - 40°C, preferably at 0 -35°C.
The reduction of compound of formula (VIII), is carried out in a mixture of an inert solvent, such as an ether, preferably tetrahydrofuran and lower alkanol, preferably methanol, in the ratio of 4:1 volume/volume, and at temperature range from -78°C to 0°C, preferably at -65°C to 0°C.
A preferred reduction agent is a hydride, for example, an alkalimetal borohydride, especially sodium borohydride.
The saponification step e) is carried out by treating the ester of formula (XI) with a strong base, such as an alkali metal hydroxide, preferably NaOH or KOH, in aqueous aliphatic alcohol as solvent, preferably aqueous methanol, and in a temperature range from 25°C to boiling point of solvent, preferably between 25 C to 30°C and acidifying the resulting reaction mixture.
The resolution of racemate of compound of formula (XII) (step f) in to optically pure antipodes is earned out by means of known methods for the separation of entiomers, for example by means of preparative chromatography using chiral supports (HPLC) or by crystallization using optically pure precipitating agents, for example (+) or (-) phenylalkylamine or substituted phenylalkylamine, preferably (R)-l-phenylethylamine in alcoholic solvents such as lower alkanol, preferably ethanol and recrystallising from a mixture of ketonic solvent and lower alkanol, preferably mixture of acetone and methanol followed by neutralization.
Formation of compound of formula (XV) is carried out by treating the compound of formula (XIV) with an acid activating group, especially preferred one is the use of 1,1-carbonyldiimidazole and condensing the resulting compound with alkali metal salt of manoalkyl malonate (Formula VII), preferably potassium monomethylmalonate or potassium monoethylmalonate, in presence of magnesium chloride, in an inert solvent, preferred one is tetrahydrofuran, at temperature between 0 - 40°C, preferably at 0 -35°C. In another variant of process to prepare compound of formula (XV) is carried out by converting compound of formula XIV to a compound of formula XVI by esterification
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and condensing the resulting compound of formula (XVI) with a compound of formula
(X).
Esterification of compound of formula XIV is carried out, in lower alcoholic solvent,
especially C1-C3 alkanol, preferably methanol, in presence of acidic catalyst like
inorganic acids or p-toluensulphonic acid or acidic resins, and in a temperature range
from 0°C to boiling point of solvent, preferably between 0°C to 30°C.
Condensation step is carried out in the presence of a suitable base and in a suitable inert
solvent, especially tetrahydrofuran, and in a temperature range from -78°C to the boiling
point of the solvent, preferably at room temperature. A suitable base is selected from an
alkane alkalimetal in the presence of diisopropylamine, alkali alkylsilazanes like
LiHMDS or NaHMDS. Preferred one is the use of n-butyllithium in the presence of
diisopropylamine.
The reduction of compound of formula XV (step h), is carried out in a mixture of an inert
solvent, preferably tetrahydrofuran and a lower alkanol, preferably methanol, in the ratio
of 4:1 volume/volume, and at temperatures from -78°C to 0°C, preferably at -78°C to -
70°C. To split the corresponding boronic ester the reaction mixture is then treated with
methanol, and in a temperature range from 0 C to the boiling point of solvent, preferably
in range of 0°C to 40°C.
A preferred reduction agent is an alkalimetal borohydride in the presence of a di-Cl-C7-
alkyl-Cl-C4 alkoxy-borane, especially sodium borohydride in the presence of
diethylmethoxyborane.
The isolation of compound of formula I (step i), is carried out by saponification of a
compound of formula XVII using a base, such as an alkali metal hydroxide, preferably
NaOH and followed by treatment with aqueous calcium chloride solution.
The present invention also relates to a novel compound of formula VI or its acid chloride
and process of making it.
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Formula VI
The starting material of formula III may be prepared, for example, as described in Bioorganic & Medicinal Chemistry 1997, 437.
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1. Preparation of ethyl (2E)-3-{4-(4-flurophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino] pyrimidin-5 -yl} aerylate
To a solution of N-[4-(4-flurophenyl)-5-formyl-6-isopropylpyrimidin-2-yl]-N-methylmethylsulfonamide (55g; 156mmol) in 700ml of toluene, 60.2g of (carbethoxymethylene).triphenylphosphorane (172mmol) was added at 25 - 29°C. The reaction mixture was refluxed for 6 hours. After completion of reaction (TLC; disappearance of starting material), reaction mixture was cooled between 25 -28°C and 500ml of n-hexane was added and stirrer for 15 minutes. The separated solid was removed by filtration and the filtrate was distilled under reduced pressure to remove the solvents. The oily mass obtained after removal of solvents was purified through silica gel column to obtain ethyl (2E)-3-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl) amino]pyrimidin-5-yl}acrylate as a solid.
'H NMR (400MHz. CDC13): 1.27-1.3 (9H, m, -CH(CH3)2, -CH2CH3), 3.33-3.4 (1H, m, -CH(CH3)2, 3.49 (3H, s, -NCH3), 3.55 (3H, s, -S02CH3), 4.19 (2H, q, -OCH2CH3), 5.81 (1H, d, J=16.10), 5.81 (1H, d, C=CHCOOCH2), 7.10 (2H, t, Ar-H), 7.59 (2H, dd, Ar-H), 7.68 (1H, d, J=16.10, -CH=CHCOOCH2).
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13C NMR (400MHz. CDC13): 14.32, 21.97, 30.01, 32.29, 42.44, 60.76, 115.45, 115.67,
118.81, 125.71, 132.04, 132.73, 133.67, 133.71, 139.17, 157.97, 162.51, 164.33, 165.01,
165.50,175.15
Example 2. Preparation of (2E)-3-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methyl
sulfonyl) amino]pyrimidin-5-yl}acrylic acid
A solution of ethyl (2E)-3-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methyl
sulfonyl)amino]pyrimidin-5-yl}acrylate 20g (47.5 mmol) in methanol (200ml). To this
solution, NaOH (2.09g; 52.25mmol)) in 50ml of water was added in drop wise over the
period of approximately 15 minutes at temperature between 25°C to 29°C. After stirring
at this temperature for further 8 hours, to the reaction mixture 200 ml of tert-butyl methyl
ether was added followed by 50ml of water. The aqueous layer was separated and the
organic layer was washed with 50ml of water. The aqueous layers were combined and the
pH was adjusted to approximately 3-4 by acidification and extracted twice to 200ml of
dichloromethane. The combined organic layers were washed with 100 ml saturated NaCl
solution, dried over anhydrous Na2SO4 and filtered. The filtrate obtained was evaporate
to dryness under vacuum to obtain (2E)-3-{4-(4-flurophenyl)-6-isopropyl-2-[methyl
(methylsulfonyl)amino]pyrimidin-5-yl}acrylic acid as a white solid. The structure of the
product has been conformed by NMR, Mass.
'H NMR (400MHz, CDC13) 5= 1.23 (6H, d, -CH(CH3)2); 3.33-3.4 (1H, m, -CH(CH3)2);
3.45 (3H, s, -NCH3); 3.52 (3H, s, -SO2CH3); 5.8 (1H, d, J=16.34, =CH-COOH); 7.06
(2H, t, Ar-H), 7.53 (2H, dd, Ar-H); 7.75 (1H, d, J=16.10, -CH=CH-COOH); 9.8 (1H, br.
s, COOH).
Example 3 Preparation of methyl (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl
(methylsulfonyl)amino]pyrimidin-5-yl}-3-oxo-4-pentenoate
Method 1:
To a solution of (2E)-3-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)
amino]pyrimidin-5-yl}acrylic acid (2.0g; 5.06mmol) in 8 ml of tetrahydrofuran (THF),
1,1-carbonyldiimidazole (0.98g; 6.07mmol) was added in portions over a period of 5
minutes and stirred between 25°C and 29°C under nitrogen atmosphere. After stirring for
2 hours, this solution was added to a preformed mixture of monomethyl malonate
potassium salt (0.79g; 5.06mmol), magnesium chloride (0.482g; 5.06mmol and
Page 10 of 10

triethylamine which was stirred for further 2 hours at 25 -28°C. The resulted reaction
mixture was stirred for 24 hours at 35°C. The reaction mixture was cooled»to
approximately to 27°C and filtered. The residue was washed twice with 25ml of THF and
combined with the filtrate. The combined filtrate was concentrated under vacuum and the
residue obtained was dissolved in 60ml of ethyl acetate, washed with 30ml of 1 N
hydrochloric acid, thrice with 40ml of saturated NaHC03 followed by saturated NaCl
solution, dried over anhydrous Na2SO4. The filtrate obtained after the filtration was
concentrated under reduced pressure to obtain methyl (4E)-5-{4-(4-flurophenyl)-6-
isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}-3-oxo-4-pentenoate as a
yellow colored solid.
'H NMR (400MHZ, CDC13): 1.26 (6H, d, -CH(CH3)3); 3.3-3.38 (1H, m, -CH(CH3)3);
3.49 (3H, s, -NCH3); 3.55 (3H, s, -S02CH3); 3.7 (3H, s, OCH3); 4.94 (1H, s); 5.72 (1H, d,
J=15.85, Ar-CH=CH-); 7.08 (2H, t, Ar-H); 7.42 (1H, d, J=15.85* Ar-CH=CH-); 7.61
(2H, dd, Ar-H), 11.79 (1H, s, enol-OH).
Method 2:
a). Preparation of (2E)-3-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)
amino]pyrimidin-5-yl}-2-propenoyl chloride
To a solution of (2E)-3-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)
amino]pyrimidin-5-yl}acrylic acid (2.0g; 5.06mmol) in 20ml of dichloromethane oxalyl
chloride (0.77g ; 6.07mmol) was added in drop wise over a period of 5 minutes at 0 -5°C
with stirring under nitrogen atmosphere. The reaction mixture was allowed to warm up
and stirred at 25°C to 29°C. After stirring for 2 hours, the reaction mixture was
concentrated under reduced pressure and swapped trice with 20ml dichloromethane to
obtained (2E)-3-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]
pyrimidin-5-yl}-2-propenoyl chloride as a solid.
b). Preparation of methyl (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl
(methylsulfonyl)amino]pyrimidin-5-yl}-3-oxo-4-pentenoate
To a solution of monomethyl malonate potassium salt (0.79g; 5.06mmol), magnesium
chloride (0.482g; 5.06mmol) was added followed by triethylamine (0.5l g) and the
suspension was stirred for 2 hours at 25 -28°C. To this, solution of (2E)-3-{4-(4-
flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}-2-propenoyl
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chloride (2.06g, 5.0mmol) in 10ml of THF was added and stirred for 24 hours at
30-35°C. The reaction mixture was cooled, filtered and then residue was washed twice
with 25ml of THF. The filtrate was concentrated by evaporation, taken up in 60ml of
ethyl acetate, washed with 30ml of IN hydrochloric acid, thrice with 40ml of saturated
NaHCO3 solution followed by saturated NaCl solution and dried over anhydrous Na2S04.
The filtrate after filtration was concentrated under reduced pressure to obtain methyl
(4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}-
3-oxo-4-pentenoate as yellow colored solid.
Example 4 Preparation of racemic methyl (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-
[methyl(methylsulfonyl)amino]pyrimidin-5-yl}-3-hydroxy-4-pentenoate
To a solution of methyl (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methyl
sulfonyl)amino]pyrimidin-5-yl}-3-oxo-4-pentenoate (1.5g; 3.325mmol) in 15ml of
THF/methanol (4:1) was cooled to -65°C under nitrogen atmosphere with stirring. To this
stirred solution, NaBH4 (0.154g; 3.99mmol) was added in portion and solution was stirred
for further 1-2 hours at -65°C. To this 1ml of acetic acid in 15ml water followed by 15ml
ethyl acetate was added and stirred for 5min. The layers were separated and aqueous
layer was extracted twice with 30ml of ethyl acetate. The combined organic phases are
washed twice with 30ml saturated NaHCO3 solution and then with 30ml saturated NaCl
solution, dried over anhydrous Na2S04, filtered. The filtrate was concentrated under
reduced pressure to obtained methyl (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-
[methyl(methylsulfonyl) amino]pyrimidin-5-yl}-3-hydroxy-4-pentenoate as solid.
'H NMR (400MHz, CDC13): 1.21 (6H, d, -CH(CH3), 2.3-2.5 (2H, m, CH2-COO); 3.27-
3.34 (1H, m, -CH(CH3)3), 3.49 (3H, s, -NCH3), 3.54 (3H, s, -SO2CH3); 3.68 (3H, s, -
OCH3); 4.52-5.56 (1H, m, >CH-OH); 5.45 (1H, d, J=16.10, =CHCOO), 6.64 (1H, d, J=
16.10, CH=CHCOO); 7.07 (2H, t, Ar-H), 7.6 (2H, dd; Ar-H),
Example 5 Preparation of racemic (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl
(methylsulfonyl)amino]pyrimidin-5-yl}-3-hydroxy-4-pentenoic acid
To a stirred solution, of racemic methyl (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-
[methyl(methylsulfonyl)amino]pyrimidin-5-yl}-3-hydroxy-4-pentenoate (12g; 26.6
mmol) in 120ml of methanol, a solution of aqueous sodium hydroxide (1.17g; 29.3mmol
in 25ml water) was added slowly at temperature between 27-29°C and stirred for further
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1-2 hours. After completion of reaction (TLC; disappearance of starting material), 25ml of water and 120ml tert-butyl methyl ether were added. The organic layer was separated and washed with 25ml water. The aqueous layers were combined and the pH was adjusted to approximately 3-4 by acidification and extracted twice to 100ml of dichloromethane. The combined organic layers were washed with 50 ml saturated NaCl solution, dried over anhydrous Na2SO4, filtered. The filtrate obtained was evaporated to dryness under vacuum to obtain racemic (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}-3-hydroxy-4-pentenoic acid as off-white solid. The structure of the product has been conformed by NMR.
'H NMR (400MHz, CDC13): 1.3 (6H, d, -CH(CH3)3), 3.34-3.41 (1H, m, -CH(CH3)3), 3.47 (3H, s, -NCH3), 3.56 (3H, s, -SO2CH3), 5.85 (1H, d, J=16.34, =CHCOOH), 7.12 (2H, t, J=8.29, Ar-H), 7.59 (2H, dd, J=8.05, 5.51, Ar-H), 7.8 (1H, d, J=16.34, -CH=CHCOOH), 10.79 (1H, br., -COOH).
13C NMR (400MHz, CDCI3): 21.96, 32.37, 33.03,42.45, 115.56, 115.77, 118.39, 124.88,
132.04, 132.13, 133.60, 133.59, 141.59, 158.13, 162.57, 164.60, 165.07, 170.91, 175.23.
Example 6. Preparation of (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl
(methylsulfonyl)amino]pyrimidin-5-yl}(3S)-3-hydroxy-4-pentenoic acid
To a solution of racemic (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methyl
sulfonyl)amino]pyrimidin-5-yl}-3-hydroxy-4-pentenoic acid in ethanol, (R)-l-phenyl
ethylamine was added at 25-29°C. The reaction mixture was cooled to 0°C and stirred for
another 3 hours. The solid precipitated was filtered and washed with tert-butyl methyl
ether, dried under vacuum. The solid obtained after drying was recrystallised from 5
volumes of methanol - acetone mixture (1:4 ratio by v/v) to get (R)-l-phenylethylamine
salt of (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]
pyrimidin -5-yl}(3S)-3-hydroxy-4-pentenoic acid.
The crystallised salt was taken in methanol and treated with aqueous sodium hydroxide
solution at 25 -28°C with stirring. After stirring for 1 hour, water was added followed by
tert-butyl methyl ether. The organic layer was separated and the aqueous layer was
acidified (pH of 3-4) and extracted with dichloromethane. After removal of solvent under
vacuum, (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]
pyrimidin-5-yl} (3S)-3-hydroxy-4-pentenoic acid was obtained as a solid.
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'H NMR (400MHZ, CDC13): 1.3 (6H, d, -CH(CH3)3), 3.34-3.41 (1H, m, -CH(CH3)3), 3.47 (3H, s, -NCH3), 3.56 (3H, s, -S02CH3), 5.85 (1H, d, J=16.34, =CHCOOH), 7.12 (2H, t, J=8.29, Ar-H), 7.59 (2H, dd, J=8.05, 5.51, Ar-H), 7.8 (1H, d, J=16.34, -CH=CHCOOH), 10.79 (1H, br s, -COOH).
13C NMR (400MHz, CDC13): 21.96, 32.37, 33.03, 42.45, 115.56, 115.77, 118.39, 124.88,
132.04, 132.13, 133*60, 133.59, 141.59, 158.13, 162.57, 164.60, 165.07, 170.91, 175.23.
Example 7 Preparation of methyl (6E)-7-{4-(4-flurophenyl)-6-isopropyl-2-[methyl
(methylsulfonyl)amino]pyrimidin-5-yl}(5S)-5-hydroxy-3-oxo-6-heptenoate
To a solution of (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)
amino]pyrimidin-5-yl}(3S)-3-hydroxy-4-pentenoic acid (2.0g; 4.57mmoI) in 8ml of THF,
1,1 -carbonyldiimidazole (0.885g, 5.48mmol) was added in portions over a period of 5
minutes and stirred between 25°C and 29°C under nitrogen atmosphere. After stirring for
2 hours, this solution was added to a preformed mixture of monomethyl malonate
potassium salt (0.71g; 4.57mmol), magnesium chloride (0.435g; 4.57mmol) and
triethylamine (0.46g; 4.57mmol) which was stirred for further 2 hours at 25 -28°C. The
resulted reaction mixture was stirred for 24 hours at 30 - 35°C. The reaction mixture was
cooled and filtered and then residue is washed twice with 25ml of THF. The filtrate was
concentrated by evaporation, taken up in 60ml of ethyl acetate, washed with 30ml of IN
hydrochloric acid, thrice with 40ml of saturated NaHC03 solution followed by saturated
NaCl solution, dried over anhydrous Na2S04. The filtrate obtained after filtration was
concentrated under reduced pressure to obtain yellow colored oily mass, which was
purified through column to obtain methyl (6E)-7-{4-(4-flurophenyl)-6-isopropyl-2-
[methyl(methylsulfonyl) amino]pyrimidin-5-yl}(5S)-5-hydroxy-3-oxo-6-heptenoate.
'H NMR (400MHz, CDC13): 5 =1.2 (6H, d, -CH(CH3)2); 2.6 (2H, d, (OH)CH-CH2-
C(O)); 3.3 (1H, m, -CH(CH3)2); 3.43 (2H, s, (O)C-CH2COO-); 3.47 (3H, s -NCH3); 3.52
(3H, s, -S02CH3); 3.7, (3H, s, -COOCH3); 4.61 (1H, m, >CH-OH); 5.4 (1H, dd, J=16,
=CH-CH(OH); 6.6 (1H, d, 15.85, Ar-CH-CH); 7.1 (2H, t, Ar-HO; 7.6 (2H, dd, Ar-H).
Example 8 Preparation: of methyl (6E)-7-{4-(4-flurophenyl)-6-isopropyl-2-
[methyl(methylsulfonyl)amino]pyrimidin-5-yl}(3R,5S)-3,5-dihydroxyhept-6-enoate
Methyl (6E)-7-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]
pyrimidin-5-yl}(5S)-5-hydroxy-3-oxo-6-heptenoate (lg; 2.03mmol) was taken in 10ml
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dry THF/methanol (4:1) and cooled to -78°C under nitrogen atmosphere. To this stirred solution, diethylmethoxyborane (1 M in THF; 0.223g; 2.23mmol) was added drop wise over a period of ~5 minutes. After stirring at that temperature for 30 minutes, NaBH4 (0.076g; 2.23mmol) was added at -78°C and stirred at -78°C for 3-4 hours. To this reaction mixture, 1ml of acetic acid was added in drop wise followed by 10ml of ethyl acetate and 10ml of water. After stirring for 10 minutes at -78°C, the reaction mixture allowed reach 25-28°C. The layers were separated and the aqueous layer was extracted twice with 30ml of ethyl acetate. The combined organic layers were washed twice with 30ml saturated NaHCO3 solution and then with saturated NaCl solution, dried over anhydrous Na2SO4. The reaction mixture was filtered and the solvents were removed by distillation under vacuum. The oily product thus obtained was swapped thrice with 30ml of methanol to remove borate complex and concentrated to obtained oily mass, which after column purified provided methyl (6E)-7-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsuIfonyl)amino]pyrimidin-5-yl}(3R,5S)-3,5-dihydroxyhept-6-enoate. 'H NMR (400MHz, CDC13): 5 =1.2 (6H, d, -CH(CH3)2); 1.39 -1.56 (2H, m, >CH2); 2.4 (2H, CH-CH2-COO); 3.3 (1H, m, -CH(CH3)2); 3.48 (3H, s -NCH3); 3.53 (3H, s, -SO2CH3); 3.7, (3H, s, -COOCH3); 4.16 (1H, m, >CH-OH); 4.42 (1H, m, >CH-OH); 5.4 (1H, dd, 5=16, =CH-CH(OH); 6.6 (1H, d, 15.85, Ar-CH=CH); 7.1 (2H, t, Ar-H); 7.6 (2H, dd, Ar-H).
Example 9 Preparation of calcium salt of (2:l)-(+)-7-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}(3R,5S)-3,5-dihyroxy-(E)-hept-6-enoic acid
To a solution of methyl (6E)-7-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methyl sulfonyl)amino]pyrimidin-5-yl}(3R,5S)-3,5-dihydroxyhept-6-enoate (2g, 4.04mmol) in 30ml of acetonitrile, 0.25N solution of NaOH (17.7ml; 4.44mmol) was added over a period of 5 minutes at temperature between 26-29°C with stirring. After stirring for 3-4 hours, 30ml tert-butyl methyl ether was added followed by 10ml of water. The layers were separated and organic layer was extracted with 20ml of water. The combined aqueous layers were concentrated by evaporation under reduced pressure to its half volume. To the concentrated aqueous layer, a 1 M solution of CaCl2.2H20 (2.02ml, 2.02mmol) was added drop wise with stirring at 25-28°C. After stirred for 45 minutes,
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the precipitate formed was filtered and washed with water to get Rosuvastatin Calcium as a white solid.
Example 10 Preparation of tert-butyl (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}-3-oxo-4-pentenoate Diisopropylamine (7.4g; 73.2mmol) was taken in 100ml of dry THF and cooled to -5°C to 0°C with stirring under nitrogen atmosphere. To this stirred solution n-butyllithium (1.6M in hexane; 47ml; 73.2mmol) was added in drop wise manner over a period of approximately 30 minutes at temperature between -5°C to +5°C under nitrogen atmosphere. The reaction mixture was then allowed to reach +10°C (in the course of 10 minutes) and maintained at that temperature for 30 min. Again the reaction mixture was cooled to around -65°C, tert-butyl acetate (8.5g; 73.2mmol) was added in drop wise over a period of 20 minutes and stirred out at that temperature for 40 min. To this, a solution of (2E)-3-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}-2-propenoyl chloride (25.lg; 61mmol) in 100ml of dry THF was added in one lot at -65°C. The reaction mixture was stirred out at temperature between -60°C and -65°C, the reaction mixture allowed to warm up to -5°C (in time interval of ~45 minutes) and stirred at that temperature for further 30 minutes. The reaction mixture quenched with drop wise addition of acetic acid (50ml) and stirred for -10 minutes. To this 200ml of ethyl acetate was added followed by 200ml of water and stirring is carried out for -10 minutes. The layers were separated and the aqueous layer was extracted twice with 200ml of ethyl acetate. The combined organic layers were washed twice with 300ml saturated NaHCO3 solution and then with saturated NaCl solution, dried over anhydrous Na2S04, filtered. The filtrate was distilled under reduced pressure to obtained tert-butyl (4E)-5-{4-(4-fluropehenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}-3-0X0-4-pentenoate as an oily mass.
Example 11 Preparation of racemic (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl}-3-hydroxy-4-pentenoic acid To a stirred solution of tert-butyl (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl}-3-hydroxy-4-pentenoate (28.5g; 57mmol) in 200ml of methanol, a solution of aqueous sodium hydroxide (2.54g; 63.5mmol in 50ml water) was added slowly at temperature between 27-29°C. The reaction mixture was
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heated and refluxed for 6-10 hours. After completion of reaction (completion of reaction was monitored by TLC, ethyl acetate: hexane 3:7), 50ml of water and 200ml of tert-butyl methyl ether were added. The organic layer was separated and washed with 100ml water. The aqueous layers were combined and the pH was adjusted to approximately between 3-4 by acidification and extracted twice with 200ml of dichloromethane. The combined organic layers were washed with 100ml saturated NaCl solution, dried over anhydrous Na2S04. The filtrate obtained after filtration was evaporated to dryness under vacuum to obtain racemic (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin -5-yl}-3-hydroxy-4-pentenoic acid as white solid. The structure of the product has been conformed by NMR.
'H NMR (400MHz, CDC13): 1.2 (6H, d, -CH(CH3)3), 2.5 (1H, m, -CH2-COOH), 3.3 (1H, m, -CH(CH3)3), 3.49 (3H, s, -NCH3), 3.54 (3H, s, -S02CH3), 4.58 (l h, s, >CH-OH), 5.46 (1H, d, J=15.98, =CHCOOH), 6.7 (1H, d, J=15.85, -CH=CHCOOH), 7.1 (2H, t, Ar-H), 7.59 (2H, dd, Ar-H).
13C NMR (400MHz, CDC13): 21.55, 32.11, 33.10, 40.40, 42.73, 68.09, 114.96, 115.16, 120.86, 124.22, 131.99, 132.08, 134.27, 134.30, 137.32,157.34, 161.99, 163.53, 164.47, 174.82, 176.81.
Example 12 preparation of methyl (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl) amino]pyrimidin-5-yl}(3S)-3-hydroxy-4-pentenoate Methanol (25ml) was taken in a 100ml three necked round bottomed flask and cooled to -5°C with stirring. To this acetyl chloride (0.588g; 7.488mmol) was added drop wise in such a way that the temperature remains between -5°C to +5°C over a period of approximately 10 minutes. After stirring for 30 minutes at 0°C, a solution of (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}(3S)-3-hydroxy-4-pentenoic acid (4.2g; 9.6mmol) in 15ml of methanol was added drop wise over a period of -10 minutes at 0°C and stirred at that temperature for further 30 minutes. Then the reaction mixture was allowed to reach 20 - 25°C and stirred for 3-4 hours at 25 -29°C. Again the reaction mixture was cooled to 0°C and 3g of powered NaHC03 was added in portions. The reaction mixture was filtered and to the filtrate 50ml of ethyl acetate and 30ml of water were added. The layers were separated and the aqueous layer was extracted twice with 30ml of ethyl acetate. The combined organic
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layers were washed with 50ml of saturated NaHC03 solution, 50 ml of saturated NaCl solution and dried over anhydrous Na2S04. Methyl (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl}(3S)-3-hydroxy-4-pentenoate was obtained as solid after complete removal of solvent by distillation under vacuum. 'H NMR (400MHz, CDCl3): 1.2 (6H, d, -CH(CH3)3), 2.4-2.5 (2H, m, -CH2COOMe), 3.1 (1H, d, >CH-OH), 3.34-3.41 (1H, m, -CH(CH3)3), 3.48 (3H, s, -NCH3), 3.54 (3H, s, -SO2CH3), 3.7 (3H, s, -COOCH3), 4.6 (1H, s, >CH-OH), 5.5 (1H, dd, J=16.10, 5.12 =CHCOOCH3), 6.6 (1H, d, J=16.10, -CH=CHCOOMe), 7.1 (2H, t, Ar-H), 7.6 (2H, dd, Ar-H).
13C NMR (400MHz, CDC13): 21.54, 32.03, 33.04, 40.31, 51.85, 68.15, 114.89, 115.10, 121.00, 123.73, 132.00, 132.09, 134.32, 137.71, 157.27, 161.94, 164.42, 172.38, and 174.79.
Example 13 Preparation of tert-butyl (6E)-7-{4-(4-flurophenyl)-6-isopropyl-2-
[methyl(methylsulfonyl) amino]pyrimidin-5-yl}(5S)-5-hydroxy-3-oxo-6-heptenoate
To a solution of diisopropylamine (0.9g; 8.87mmol) in 10ml of dry tetrahydrofuran,
n-butyllithium (1.6M in hexane; 6ml; 8.87mmol) was added at 0°C under nitrogen
atmosphere, with stirring in drop wise over a period of ~10 minutes. The reaction mixture
was then allowed to warm up to +10°C (in time interval of-10 minutes) and maintained
at that temperature for 30 minutes. Again the reaction mixture was cooled to - 65°C and
tert-butyl acetate (1.03g; 8.87mmol) was added drop wise over a period of ~5 minutes.
After stirred for another 40 minutes, the resulting solution was transferred to a solution of
methyl (4E)-5-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]
pyrimidin -5 -yl}(3S)-3-hydroxy-4-pentenoate (lg; 2.2 mmol) in 5ml of dry THF at 0 C. The reaction mixture was allowed to reach to 20°C and stirred at that temperature for ~4 hours. 1ml of acetic acid was added in drop wise to the reaction mixture followed by 10ml of ethyl acetate and 10ml of water. After stirring for 10 minutes, the layers were separated and the aqueous phase was extracted twice with 30ml of ethyl acetate. The combined organic layers were washed twice with 30ml saturated NaHC03 solution and then with saturated NaCl solution, dried over anhydrous Na2S04. The filtrate obtained after filtration was distilled under vacuum to remove the solvent completely, tert-butyl (6E)-7-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}-
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(5R)-5-hydroxy-3-oxo-6-heptenoate was obtained as an orange oily mass and was taken as it is for next step.
Example 14 Preparation of tert-butyl (6E)-7-{4-(4-fIurophenyl)-6-isopropyl-2-
[methyl(methyl sulfonyl) amino]pyrimidin-5-yl}(3R,5S)-3,5-dihydroxyhept-6-enoate
tert-butyl (6E)-7-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]
pyrimidin-5-yl}(5S)-5-hydroxy-3-oxo-6-heptenoate (lg; 1.87mmol) was taken in 10ml of dry THF/methanol (4:1 v/v) and cooled to -78°C under nitrogen atmosphere with stirring. To this stirred solution, diethylmethoxyborane (1 M in THF; 2.1g; 2.05mmol)) was added drop wise over a period of ~5 minutes. After stirring for at that temperature for further 30 minutes, NaBH4 (0.08g; 2.05mmol) was added at -78°C. The reaction mixture was stirred at -78°C for 3-4 hours. To the reaction mixture 1ml of acetic acid was added in drop wise followed by 10ml of ethyl acetate and 10ml of water. After stirring for 10 minutes at -78°C the reaction mixture was allowed reach 25 -28°C. The layers were separated and the aqueous layer was extracted twice with 30ml of ethyl acetate. The combined organic phases were washed twice with 30ml saturated NaHC03 solution and then with saturated NaCl solution, dried over anhydrous Na2S04. The reaction mixture was filtered and the solvent was removed by distillation under vacuum. The oily product thus obtained was swapped thrice with 30ml of methanol to remove borate complex and concentrated to obtain an oily mass, which after column purification provided tert-butyl (6E)-7-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}(3R,5S)-3,5-dihydroxyhept-6-enoate as a solid.
'H NMR (400MHZ, CDC13): 1.23 (6H, d, -CH(CH3)3, 1.40-1.50 (11H, m, -C(CH3)3, -CH2), 2.34 (2H, d, -CH2COO), 3.35 (1H, d, >CH-OH), 3.31-3.38 (1H, m, -CH(CH3)3), 3.49 (3H, s, -NCH3), 3.54 (3H, s, -S02CH3), 3.76 (H, s, -OH), 3.86 (H, s, -OH), 4.41 (1H, d, >CH-OH), 4.42 (1H, t, >CH-OH), 5.42 (1H, dd, J=l 15.98 =CHCOO), 6.6 (1H, d, J=16.10, -CH=CHCOO), 7.06 (2H, t, Ar-H), 7.6 (2H, dd, Ar-H).
Example 15 Preparation of Calcium (2:l)-(+)7-[4-(4-flurophenyl)-6-isopropyl-2[N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-.(3R,5S)-dihydroxy-(E)-6-heptenoic acid A solution of tert-butyl (6E)-7-{4-(4-flurophenyl)-6-isopropyl-2-[methyl(methyl sulfonyl)amino]pyrimidin-5-yl}(3R,5S)-3,5-dihydroxyhept-6-enoate (2g; 3.72 mmol) in 30ml of acetonitrile of 0.25 M solution of NaOH (14.9ml; 3.72 mmol) was added over a
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period of 5 minutes at temperature between 26 -29°C with stirring. After stirred for 3-4 hours, 30 ml of tert-butyl methyl ether was added followed by 10ml pf water. The layers were separated and the organic layer was extracted with 20ml of water. The combined aqueous layers were concentrated by evaporation under reduced pressure to its half volume. To the concentrated aqueous layer, 1 M solution of CaCl2.2H20 (1.86ml; 1.86 mmol) was added drop wise with stirring at 25 - 28°C. After stirred for 45 minutes, the precipitate formed was filtered and washed with water to get Rosuvastatin Calcium as a white solid.
Claims
1. A process for the manufacture of Rosuvastatin of formula I, according to the present invention, comprising

a) reacting a compound of formula (II)

Formula II
wherein, Rl, R2, R3 are substituted or unsubstituted phenyl and R4 is an aliphatic residue selected from C1-C4 alkyl;
with a compound of formula R-CH(=0) (Formula III) wherein R represents the following cyclic structure (formula IV) to obtain a compound of formula (V);
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