PROCESS FOR PREPARING ENANTIOMERICALLY PURE FLUVASTATIN
SODIUM AND A NOVEL POLYMORPHIC FORM THEREOF
Field of the Invention
Provided are processes for preparing enantiomerically pure fluvastatin sodium. Also
provided are pharmaceutical compositions comprising enantiomerically pure fluvastatin sodium.
In addition, provided is a novel polymorphic form of enantiomerically pure fluvastatin sodium.
Background of the Invention
Fluvastatin sodium is the monosodium salt of a racemic mixture of (3R,5S) and (3S,5R)
erythro-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid
of Formula A.
(Figure Removed)
FORMULA A
Fluvastatin sodium is a cholesterol lowering agent, which acts through the inhibition of
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. It is indicated as an adjunct to
diet to reduce elevated total cholesterol (Total-C), LDL-C, TG and Apo B levels, and to increase
HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson
Type Ila and lib) whose response to dietary restriction of saturated fat and cholesterol and other
non-pharmacological measures has not been adequate. It is also indicated to slow the
progression of coronary atherosclerosis in patients with coronary heart disease as part of a
treatment strategy to lower total and LDL cholesterol to target levels. Fluvastatin sodium is the
first entirely synthetic HMG-CoA reductase inhibitor, and is in part structurally distinct from the
fungal derivatives of this therapeutic class.
A process for preparing racemic fluvastatin sodium, which involves lyophilization of an
aqueous solution of fluvastatin sodium, has been reported. Also previously reported is a process
lor preparation of enantiomerically pure (3S, 5R) or (3R, 5S) forms of fluvastatin sodium which
comprises resolution of racemic fluvastatin sodium by High Performance Liquid
C'hromalography (1IP1 C) and by using chiral auxiliaries.
Processes of forming enantiomerically pure fluvastatin sodium have also been reported.
Crystalline hydrates of enantiomerically enriched (3R,5S) or (3S,5R) of fluvastatin sodium
referred to as Forms A, B1, B2, C, D and E have also been reported.
However, previously reported processes to prepare enantiomerieally pure fluvastatin
sodium involve purification through column chromatography, use of large quantity of solvents
and toxic reagents which generate significant amount of toxic effluents and side-products. The
yields obtained are low and the processes are not viable on commercial scale. Accordingly,
there remains a need for novel forms of fluvastatin sodium, as well as improved processes of
preparing enantiomerieally pure fluvastatin sodium.
Brief Description of the Figures
Figure 1 is an XRD spectrum of Form I of the enantiomerieally pure (3R,5S) enantiomer
of fluvaslatin sodium.
Figure 2 is an FT1R spectrum of Form I of the enantiomerieally pure (3R,5S) enantiomer
of fluvastatin sodium.
Summary of the Invention
Hnantiomerically pure (3R,5S) E-fluvastatin sodium can now be prepared in excellent
yields and in fewer steps by processes which do not utilize toxic reagents, as compared to
previously known processes. The processes are easily scalable on commercial scale. Also
provided is novel Form I of the enantiomerieally pure (3R,5S) fluvastatin sodium.
Thus in one aspect, provided are processes for preparing (3R,5S) enantiomer of
iluvastatin sodium of formula I,
(Figure Removed)
FORMULA
which comprises:
a) reacting an aldehyde of Formula la
FORMULA la
(Figure Removed)
FORMULA Ib
to form a compound of Formula Ic,
(Figure Removed)
wherein RI is hydrogen or a hydroxy protecting group, R2 is aryl, aralkyl
or alkyl and RB is hydrogen or CM alkyl;
b) (i) reducing the compound of Formula Ic, wherein RI is hydrogen and RB is
hydrogen or CM alkyl, to form a diol of Formula Id,
(Figure Removed)
(ii) deprotecting the compound of Formula Ic, wherein RI is a hydroxy
protecting group and Rj is hydrogen or CM alkyl, to form a compound of
Formula Ic'
(Figure Removed)
and reducing the compound of Formula Ic' to form a diol of Formula Id,
(Figure Removed)
( i i i ) reducing the compound of Formula Ic, wherein RI is a hydroxy protecting
group and R3 is hydrogen or C1-4 alkyl, to form a compound of Formula Ic"
FORMULAIC"
and deprotecting the compound of Formula Ic" to form a diol of Formula Id,
and
c) converting the diol of Formula Id to enantiomerically pure (3R,5S) enantiomer of
tluvastatin sodium of Formula I by contacting the diol of Formula Id with one or
more sodium-containing compounds.
The processes can include one or more of the following embodiments. For example, the
reduction of the compound of Formula Ic or the compound of Formula Ic' in step b)(i) or b)(iii)
can be carried out in the presence of one or more reducing agent selected from one or more
borohydride. Suitable borohydrides can be selected from sodium borohydride, potassium
borohydride, calcium borohydride or mixtures thereof.
In another aspect, provided are compounds of Formula Ic,
(Figure Removed)
wherein RI is hydrogen or a hydroxy protecting group and R3 is hydrogen or CM alkyl group.
In yet another aspect, provided are processes for preparing compounds of Formula Ic or
compounds of Formula Ic' comprising the steps of:
a) reacting an aldehyde of Formula la
(Figure Removed)
with a |i-hydroxyester of Formula Ib
(Figure Removed)
b
to form a condensation product of Formula Ic,
(Figure Removed)
wherein RI is hydrogen or a hydroxy protecting group, RI is aryl, aralkyl
or alkyl, and RT, is hydrogen or C1-4 alkyl; and
optionally deprotecting the compound of Formula Ic, wherein RI is a hydroxy
protecting group, to form a compound of Formula Ic'.
FORMULA Ic'
In another aspect, provided are processes for preparing enantiomerically pure (3R,5S)-
fluvastatin sodium of Formula I,
(Figure Removed)
a) (i) reducing the compound of Formula Ic, wherein RI is hydrogen and RI is
hydrogen or C1-4 alkyl, to form a diol of Formula Id,
(Figure Removed)
FORMULA Id
( i i ) deprotecting the compound of Formula Ic, wherein RI is a hydroxy
protecting group and Ra is hydrogen or CM alkyl, to form a compound of
Formula Ic'
(Figure Removed)
FORMULA Ic'
and reducing the compound of Formula Ic' to form a diol of Formula Id,
( i i i ) reducing the compound of Formula Ic, wherein RI is a hydroxy protecting
group and R ) is hydrogen or CM alkyl, to form a compound of Formula Ic"
(Figure Removed)
FORMULA Ic"
and deprotecting the compound of Formula Ic" to form a diol of Formula Id,
and
b) convening the diol of Formula Id to enantiomerically pure (3R,5S) enantiomer of
fluvastatin sodium of Formula I
FORMULA I
by contacting the diol of Formula Id with one or more sodium-containing compounds.
In another aspect, provided is Form I of enantiomerically pure (3R,5S) fluvastatin
sodium. Form I of enantiomerically pure (3R,5S) fluvastatin sodium can include one or more of
the following embodiments. For example, Form I of enantiomerically pure (3R,5S) fluvastatin
sodium can exhibit an XR1) spectrum having 26 values at about: 6.6, 9.9, 11.4, and 30.9. Form I
of enantiomerically pure (3R,5S) fluvastatin sodium can also exhibit an XRD pattern having 20
values at about 3.3, 6.6. 8.8, 9.9, 11.4, 13.2, 19.0, 21.9, 29.6 and/or 30.9. Form I of
enantiomerically pure (3R,5S) enantiomer of fluvastatin sodium can exhibit an FTIR spectrum
as depicted in Figure 2. The Form I of enantiomerically pure (3R,5S) enantiomer of fluvastatin
sodium can have a moisture content of below about 5 % w/w.
In another aspect, provided are pharmaceutical compositions comprising a
therapeutically effective amount of Form 1 of enantiomerically pure (3R, 5S) fluvastatin sodium
and optionally one or more pharmaceutically acceptable diluents or excipients.
In yet another aspect, provided are methods of antagonizing HMG-CoA in mammal,
which comprises administering to the mammal a therapeutically effective amount of Form I of
enantiomerically pure (3R.5S) fluvastatin sodium.
Detailed Description of the Invention
Processes lor preparing (3R,5S) enantiomer of fluvastatin sodium of Formula I are
provided.
(Figure Removed)
'he process comprises the steps of:
a) reacting an aldehyde of Formula la
(Figure Removed)
with a |'i-hydroxyester of Formula Ib,
(Figure Removed)
to form a compound of Formula Ic,
(Figure Removed)
wherein RI is hydrogen or a hydroxy protecting group, R2 is aryl, aralkyl
or alkyl and R.i is hydrogen or C 1-4 alkyl;
( i ) reducing the compound of Formula Ic, wherein RI is hydrogen and R^ is
hydrogen or C1-4 alkyl, to form a diol of Formula Id,
(Figure Removed)
( i i ) deprotecting the compound of Formula Ic, wherein RI is a hydroxy
protecting group and Rj is hydrogen or C1-4 alkyl, to form a compound of
Formula Ic'
(Figure Removed)
and reducing the compound of Formula Ic' to form a diol of Formula Id,
( i i i ) reducing the compound of Formula Ic, wherein RI is a hydroxy protecting
group and R3 is hydrogen or C1-4 alkyl, to form a compound of Formula Ic"
FORMULA Ic"
and deprotecting the compound of Formula Ic" to form a diol oi" Formula Id,
and
c) converting the diol of l;ormula Id to enantiomerically pure (3R,5S) enantiomer of
fluvastatin sodium of formula I by contacting the diol of Formula Id with one or more
sodium-containing compounds.
The aldehyde of formula la can be prepared by previously reported methods (for
example, U.S. Patent Nos. 4,739,073 and 5,354,772). The aldehyde of Formula 1 can be
condensed with a [}-hydroxyester of Formula Ib (wherein RI can be hydrogen or a hydroxy
protecting group, Ri can be aryl, aralkyl or alkyl, and R) can be hydrogen or C1-4 alkyl) to form
a compound of Formula Ic. The condensation reaction can be carried out in presence of one or
more organic solvents, for example, polar aprotic solvents, aromatic hydrocarbon solvents,
halogenated hydrocarbon solvents, acetonitrile, ethers or mixtures thereof. The reaction can be
carried out at temperatures between about 40 °C to the reflux temperature of the one or more
solvents used. After completion of the condensation reaction, the one or more solvents can be
removed, and the product thus obtained can be contacted with one or more antisolvents, for
example, cyclohexane, to yield a compound of Formula Ic, wherein RI and R3 are as defined
earlier.
In one embodiment, the compound of Formula Ic, wherein RI can be hydrogen and RB
can be hydrogen or CM alkyl, can be reduced to form a diol of Formula Id. In another
embodiment, the compound of Formula le, wherein RI can be a hydroxy protecting group and
RI can be hydrogen or CM alkyl, can be deprotected to form a compound of Formula Ic1 and the
compound of Formula Ic' can then be reduced to form a diol of Formula Id. In yet another
embodiment, the compound of Formula Ic, wherein RI can be a hydroxy protecting group and
RS can be hydrogen or C|.4 alkyl, can be reduced to form a compound of Formula Ic" and the
compound of Formula Ic" can then be deprotected to form a diol of Formula Id.
Compounds of Formula Ic or Formula Ic", wherein RI is a hydroxy protecting group, can
he deproteeted by conventional processes (for example, by addition of one or more acids) to
form compounds of formula Ic' or compounds Formula Id respectively. When trialkylsilyl
groups are used as protecting agents, acid hydrolysis of the product can be conveniently carried
out in order to deprotect trialkylsilyl groups.
Compounds of Formula Ic (wherein R] is hydrogen) or Formula Ic' can be reduced using
OIK' or more trialkylboranes and optionally one or more metal borohydrides to form compounds
of Formula Ic" or compounds Formula Id respectively. Such reduction reactions can also be
carried out in presence of one or more organic solvents, for example, one or more C1-4 ethers
U'.tf., tetrahydrofuran, 1,4-dioxane, diethylether or mixture thereof), one or more CM alcohols
(t'.tf.. methanol, elhanol, n-propanol, isopropanol, n-butanol, isobutanol, /er/-butanol or mixtures
(hereof), or mixtures thereof. The reactions can also be carried out at low temperatures, for
example, from about 10 to about -80 "C. Suitable borohydrides include, for example, one or
more of sodium borohydride, potassium borohydride, calcium borohydride, or mixtures thereof.
Borohydride, if used in excess, can be quenched (using, for example one or more lower alcohols,
c.i,'., methanol, ethanol) after completion of the reduction reaction. The reaction mixture can
then be basified and extracted with one or more suitable organic solvents (e.g., ethyl acetate,
toluene, dichloromethane, dichloroethane, chloroform, hydrocarbons, including lower alkanes
and cycloalkanes, such as eyclohexane). The organic layer can be dried and concentrated under
vacuum to obtain a residue, which can be purified by crystallization or column chromatography
to yield enantiomerically pure (3R,5S)-diol of Formula Id.
The (3R,5S)-diol of Formula Id can be contacted with one or more sodium-containing
compounds, for example, sodium hydroxide, to form enantiomerically pure (3R,5S)-fluvastatin
sodium of Formula I. This reaction can also be carried out in presence of one or more organic
solvents and water. Suitable organic solvents include, for example, one or more CM alcohols
U'.,V'" methanol, ethanol, n-propanol, isobutanol, n-butanol, isobutanol, /er/-butanol or mixtures
thereof).
Compounds of Formula Ic, wherein RI is hydrogen or a hydroxy protecting group and Rj
is hydrogen or C1-4 alkyl group, are also provided.
Also provided are processes for preparing compounds of Formula Ic or compounds of
Formula Ic' comprising the steps of:
a) reacting an aldehyde of Formula la with a p-hydroxyester of Formula Ib to form a
condensation product of Formula Ic,
wherein RI is hydrogen or a hydroxy protecting group, R2 is aryl, aralkyl
or alkyl, and RI is hydrogen or CM alkyl; and
b) optionally deprotecting the compound of Formula Ic, wherein RI is a hydroxy
protecting group, to form a compound of Formula Ic'.
In yet a further aspect, provided are processes for preparation of enantiomerically pure
(3R,5S)-fluvastatin sodium comprising the steps of:
a) (i) reducing the compound of Formula Ic, wherein RI is hydrogen and Rj is
hydrogen or CM alkyl, to form a diol of Formula Id,
and
(Figure Removed)
deprotecting the compound of Formula Ic, wherein RI is a hydroxy
protecting group and R3 is hydrogen or C1-4 alkyl, to form a compound of
Formula Ic'
(Figure Removed)
and reducing the compound of Formula Ic1 to form a diol of Formula Id,
(Hi) reducing the compound of Formula Ic, wherein R] is a hydroxy protecting
group and RI is hydrogen or CM alkyl, to form a compound of Formula Ic"
(Figure Removed)
and deprotecting the compound of Formula Ic" to form a diol of Formula Id,
h) converting the diol of Formula Id to enantiomerically pure (3R,5S) enantiomer of
lluvastatin sodium of Formula I
FORMULA I
by contacting the did of Formula Id with one or more sodium-containing
compounds.
In yet another aspect, Form I of enantiomerically pure (3R,5S) fluvastatin sodium is
provided. Form 1 of enantiomerically pure (3R,5S) fluvastatin sodium can exhibit an XRD
spectrum having one or more 20 values at about: 6.6, 9.9, 11.4, and/or 30.9. Form I of
enantiomerically pure (3R,5S) fluvastatin sodium can also exhibit an XRD spectrum having one
or more 26 values at about: 3.3, 6.6, 8.8, 9.9, 11.4, 13.2, 19.0, 21.9, 29.6 and/or 30.9. Form I of
enantiomerically pure (3R,5S) fluvastatin sodium can also exhibit an XRD spectrum having one
or more 20 values at about: 3.3,6.6,8.8,9.9, 11.4, 13.2, 16.3, 16.9, 17.6, 18.1, 19.0, 19.9,20.5,
20.8, 21.2, 21.9, 22.5. 22.9, 23.2, 23.9, 24.7, 25.0, 25.6, 26.3, 26.8, 27.1, 28.1, 29.2, 29.6, 30.0,
30.9, 31.6, 32.0, 32.5, 33.0, 33.0, 35.5, 35.9, 36.5, 37.1 and/or 37.5. An example of an XRD
spectrum of Form 1 of enantiomerically pure (3R,5S) fluvastatin sodium is depicted in Figure 1.
Form I of enantiomerically pure (3R,5S) fluvastatin sodium can also have a moisture
content below about 5 % w/w. An example of an FTIR spectrum of Form I of enantiomerically
pure (3R,5S) fluvastatin sodium is depicted in Figure 2.
In yet another aspect, pharmaceutical compositions comprising therapeutically effective
amounts of Form 1 of enantiomerically pure (3R, 5S) fluvastatin sodium optionally containing
one or more pharmaceutically acceptable diluents or excipients are provided.
In yet another aspect, methods of antagonizing HMG-CoA in mammal, which comprises
administering to the mammal therapeutically effective amounts of Form I of enantiomerically
pure (3R, 5S) fluvastatin sodium are also provided.
Powder XRD spectra of the samples can be determined by using a X-Ray Diffractometer
manufactured by Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu
target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100
mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A.
FT-IR spectra of the samples can be determined by using a Perkin Elmer instrument, 16
PC, SCAN: 16scans, 4.0 cm"1, according to the USP 25, general test methods page 1920,
infrared absorption spectrum by potassium bromide pellet method.
While the present invention has been described in terms of its specific embodiments,
certain modifications and equivalents will be apparent to those skilled in the art and are included
within the scope of the present invention. The examples are provided to illustrate particular
aspects of the disclosure and do not limit the scope of the present invention as defined by the
claims.
Examples
Hxample 1: Synthesis of Methyl (3S.6E)-7-[3-(4-fluorophenyl)-l-isopropyl-l//-indol-2-yl]3-
[(/c'/7-butvl-dimethylsiiyl)oxvJ-5-oxohept-6-enoate
The title compound is a compound of Formula Ic, wherein R\ is ^r/-butyldimethylsilyl
and R3 is methyl.
(Figure Removed)
A mixture of i-(41-fluorophenyl)-l-isopropyl indole-2-carboxyaldehyde (1.0 g) and 1-
inethyl-(3R)-3-[(/c'r/-butyl-dimethylsilyl)oxy]-5-oxo-6-triphenylphosphoranylidene-hexanate
(3.0 g) in acetonitrile (60 mL) was refluxed at 81 to 83 °C for 48 hours, cooled to room
temperature and concentrated under vacuum (40-100 mmHg) at 40 to 45 °C to yield a crude oil.
The crude oil was suspended in cyelohexane (30 mL) and concentrated, forming a residue. The
residue was suspended in cyelohexane (30 mL) and stirred for 1 hour. The solids thus obtained
were filtered, washed with cyelohexane (20 mL) and the combined filtrate and washings were
concentrated to yield the title compound as an oil.
Yield: 1.53 g.
'VNMR (8, CDCh): 199 .94, 172.11 163.1, 140.12, 131.88, 123.45, 64.58, 51.432, 25.98,
20.77, 18.52. 'HNMR (8, CDC13): 0.07 [(CH3)2Si, 6H, s ], 0.90 [(CH3).3C-, 9H, s ], 1.74 to 1.77
KCHiht1-, 6H, two singlets], 2.60 [-CH2- , 2H , mj, 2.82 [-CH2-, 2H, mj, 3.61 (OCH3, 3H, s ) ,
4.6 [-CH(CH2)2-. 111. mL 4.72 to 5.0 [--CH(CH3)2 , 1H, m] , 6.37 to 6.47 f-CH=CH-CO-,!H,
dd|, 7.76 to 7.73 CH-CM-CO-, 1H, dd], 7.58 to 7.20 [ArH, 8 H, m]. MS m/z: [M+l]+ 538.6,
421,279. For C ' 3iH4 0lN04Si. Found: C 69.32; H 7.47; F 3.47; N 2.67; O 11.52; Si 5.55
Example 2: Synthesis of Methyl (3S,6E)-7-[3-(4-fluorophenyl)-l-isopropyl-l//-indol-2-yl]3-
hydroxy-5-oxohept-6-cnoate
The title compound is a compound of Formula Ic\ wherein R3 is methyl.
TBDMSO, OCH, OCH,
A solution ofmethanesulphonic acid (0.25 mL) in water (5.0 mL) was added to (3S,6E)-
7-|3-(4-fluorophenyl)-1 -isopropyl-1 //-indol-2-yl]3-[(/er/-butyl-dimethylsilyl) oxy]-5-oxohept-6-
enoate (2.0 g) in methanol (30 mL) at 15 °C. The reaction mixture was stirred for 6 hours at 30
to 35°C and concentrated under vacuum. The residue thus obtained was extracted with
dichloromethane (100 mL), and washed with water (50 mL) and then with aqueous sodium
bicarbonate (1% w/v; 30 mL). The solution was concentrated under vacuum to yield the title
compound as thick oil.
Yield: 1.5 g.
1 5 CNMR (6, CDC13): 200.76, 172.23, 165.33, 141.38, 131.78, 126.19, 123.6, 121.53, 64.35,
51.58, 48.27, 20.72. 'HNMR (8, CDC13 ): 1.63 to 1.67 [(CH3)2C-, 6H, two singlets], 2.55 to
2.67 (CH2, 2H, m), 2.82 to 2.95 |-CH2-, 2H, m], 3.72 (OCH3, 3H, s), 4.12 [-CHOH-, 1H, m],
4.67 |-CH(CH3)2, 1H, m], 5.65 [-OH, 1H, broad] 6.51 to 6.55 [-CH=CH-CO-,1H, dd], 7.76 to
7.73 1-CH=CH-C()-,1H, dd], 7.58 to 7.20 [ArH, 8H, m]. MS m/z: [M+l]+ 424. For
C':.sH26FNO4, Found : C 70.95; H 6.24; F 4.52; N 3.27; 0 15.02
Example 3: Synthesis of Methyl (3/?.5y)-7-[3-(4-fluorophenvl)-l-isopropvl-l/y-indol-2-yl]-3,5-
dihydroxyheptanoate
The title compound is a compound of Formula Id, wherein R3 is methyl.
OCH, OCH,
To a solution of methyl (3S,6E)-7-[3-(4-fluorophenyl)-l-isopropyl-l//-indol-2-yl]3-
hydroxy-5-oxohept-6-cnoale (1.5 g) in anhydrous tetrahydrofuran (20 mL) and (6 mL) of
methanol, was added a solution of diethylmethoxyborane (2 mL, 1M in tetrahydrofuran) at -
78°C, and the mixture was stirred at the same temperature for 30 minutes. To the mixture was
added sodium borohydride (0.5 g) and the mixture was stirred for another 3 hours. Acetic acid
(2.5 mL) was added thereto, and the mixture was adjusted to pH 8 with saturated sodium
bicarbonate and extracted with ethyl acetate. The organic layer was washed with water, dried
and evaporated ethyl acetate under reduced pressure. To the resulting residue, methanol was
added and the mixture was evaporated under reduced pressure. The resulting residue was
subjected to column chromatography of silica gel eluting with methylene chloride/ ether (3:1) to
give (1.5 g) of title compound as oil which was finally purified by column chromatography, to
give a yield of 1.2 g.
l R ( K B r ) ( c m " ' ) : 3468,3458,3391, 1707, 1535, 1258, 1216, 1118. l3 CNMR (5, CDCf,): 173.7,
164.8, 140.7, 136.6, 134.9, 120.4, 116.4, 115.6, 112.8,71.4,52.1,48.27,43.3.21.9. HNMR
U\ CDCl.,): 1.53 to 1.61 [(CH,,)iC-, 6H, two singlets], 1.95 to 2.01 (CH2, 2H, m), 2.45 to 2.61
|-CHr, 2H, m|. 3.00 (OCHj, 3H, s), 4.27 |-CHOHC(H)=C(H)-, 1H, m], 4.33 [-CH2CHOHCH2-,
111. m], 4.7 K'H(CH,)2, 1H, m], 5.8 [-CH=CH-CHOH-,1H, dd], 6.89 [-CH=CH-CHOH-,1H,
dd|. 7.38 to 7.57 | ArLL 8 Fl, m]. MS m/z: [M+l]+ 426. For C25H28F4NO , Found: C 70.66; H
66.56;O 15.03;N 32.98; F 4.45.
Lxample 4: Synthesis of sodium (3/?.5iS)-7-[3-(4-fluorophenyl)-l-isopropyl-l//-indol-2-yl]-3,5-
d i h ydrox yheptanoate
The title compound is a compound of Formula I.
Aqueous sodium hydroxide (6 mL, 0.25N) was added to a solution of methyl (3R,5S)-7-
[ i-(4-tluorophenyl)-l-isopropyl-l//-indol-2-yl]-3,5-dihydroxyheptanoate (0.60 g) in methanol
(20 mL) at room temperature and stirred for 2 hours. The solution was concentrated to remove
the organic solvent under vacuum at 35 to 40 °C, forming a residue. Water (20 mL) was added
to the residue and the mixture was stirred. The aqueous layer was washed with ethyl acetate (2 x
50 mL) and filtered through a celite bed. The aqueous layer was then concentrated under
vacuum at 40 "C to yield t i t l e compound as a white solid.
Yield: 0.4 g.
Moisture content: below 5 % w/w.
!R(KBr)(cm-l): 3407, 1573, 1346, 1216, 1107. 13CNMR (8, CD3OD): 180.6, 166.43, 141.0,
136.6, 129.8, 122.7, 120.6, 119.98,71.8,68.5,48.5,44.8,24.3,22.0. 'HNMR (8, CD3OD):
1.53 to 1.59 [(CH,)2C-,6H, two singlets], 1.97 to 2.12 (CH2, 2H, m), 2.34 to 2.55 |-CH2-, 2H,
m|, 2.35 [OH, IH, broad], 3.09 [OH, IH, broad] , 4.34 [-CHOHC(H)=C(H)-, IH, m] , 4.23 [-
CH2CHOHCH2-, IH, in] , 4.68 [-CH(CH3)2, IH, m], 6.34 [-CH=CH-CHOH-, IH, dd], 6.76 [-
CH=CH-CHOH-, IH, dd], 7.28 to 7.59 [ArH, 8H, m]. MS m/z: [M+2 -Na] 412.1, [M - H2O]
3')4.2. For C24H2.sO4FN, Found: C 66.57; H 5.9; O 14.7; N 32.24; F.
XRD spectrum as per Figure 1
FTIR spectrum as per Figure 2.

WE CLAIM:
A process for preparing (3R,5S) enantiomer of fluvastatin sodium of Formula I,
(Figure Removed)
FORMULA
which comprises:
a) reacting an aldehyde of Formula la
(Figure Removed)
FORMULA la
with a fl-hydroxyester of Formula Ib,
(Figure Removed)
FORMULA Ib
to form a compound of Formula Ic,
(Figure Removed)
wherein RI is hydrogen or a hydroxy protecting group, Ra is aryl, aralkyl
or alkyl and R3, is hydrogen or C 1.4 alkyl;
(i) reducing the compound of Formula Ic, wherein RI is hydrogen and R3 is
hydrogen or C1-4 alkyl, to form a diol of Formula Id,
(Figure Removed)
deprotecting the compound of Formula Ic, wherein RI is a hydroxy
protecting group and RI is hydrogen or C1-4 alkyl, to form a compound of
Formula Ic'
or
(Figure Removed)
and reducing the compound of Formula Ic' to form a diol of Formula Id,
( i i i ) reducing the compound of Formula Ic, wherein RI is a hydroxy protecting
group and R) is hydrogen or CM alkyl, to form a compound of Formula
(Figure Removed)
FORMULA Ic"
and deprotecting the compound of Formula Ic" to form a diol of Formula Id,
and
c) converting the diol of Formula Id to enantiomerically pure (3R,5S) enantiomer of
fluvastatin sodium of Formula I by contacting the diol of Formula Id with one or
more sodium-containing compounds.
2. The process oi claim 1, wherein the reduction of the compound of Formula Ic or the
compound of Formula Ic' in step b)(i) or b)(iii) is carried out in the presence of one or more
reducing agent selected from one or more borohydrides.
3. The process of claim 2, wherein the one or more borohydride is selected from sodium
borohydride, potassium borohydride, calcium borohydride or mixtures thereof.
4. A compound of Formula Ic,
FORMULA Ic
wherein RI is hydrogen or a hydroxy protecting group and RB is hydrogen or CM alkyl group.
5. A process for preparation of a compound of Formula Ic or a compound of Formula Ic'
comprising the steps of:
a) reacting an aldehyde of Formula la
FORMULA la
with 'd hydroxyester of Formula Ib
(Figure Removed)
FORMULA Ib
to form a condensation product of Formula Ic,
(Figure Removed)
FORMULA Ic
wherein RI is hydrogen or a hydroxy protecting group, R3 is aryl, aralkyl
or alkyl, and Rj is hydrogen or C1-4 alkyl; and
optionally deprotecting the compound of Formula Ic, wherein RI is a hydroxy
protecting group, to form a compound of Formula Ic'.
(Figure Removed)
6. A process for preparation of the enantiomerically pure (3R,5S)-fluvastatin sodium of
Formula I,
(Figure Removed)
FORMULA I
comprising the steps of:
a) (i) reducing the compound of Formula Ic, wherein RI is hydrogen and
hydrogen or C1-4 alkyl, to form a diol of Formula Id,
(Figure Removed)
or
(ii) deprotecting the compound of Formula Ic, wherein RI is a hydroxy
protecting group and Rj is hydrogen or C1-4 alkyl, to form a compound of
Formula Ic'
or
FORMULA Ic'
and reducing the compound of Formula Ic' to form a diol of Formula Id,
( i i i ) reducing the compound of Formula Ic, wherein RI is a hydroxy protecting
group and R3 is hydrogen orC1-4 alkyl, to form a compound of Formula Ic"
(Figure Removed)
and deprotecting the compound of Formula Ic" to form a diol of Formula Id,
h) converting the diol of Formula Id to enantiomerically pure (3R,5S) enantiomer of
lluvastatin sodium of Formula I
FORMULA I
by contacting the dioi of Formula Id with one or more sodium-containing compounds.
7. Form I of enantiomerically pure (3R,5S) fluvastatin sodium.
8 The Form 1 of enantiomerically pure (3R,5S) fluvastatin sodium of claim 7 exhibiting an
XRD spectrum having 29 values at about: 6.6, 9.9, 11.4, and 30.9.
7 The Form I of enantiomerically pure (3R,5S) enantiomer of fluvastatin sodium of claim
7 exhibiting FTIR spectrum as depicted in Figure 2.
10. The Form 1 of enantiomerically pure (3R,5S) enantiomer of fluvastatin sodium of claim
7 having a moisture content of below about 5 % w/w.
1 1 . Form 1 of enantiomerically pure (3R,5S) fluvastatin sodium of claim 7 exhibiting an
XRD pattern having 20 values at about 3.3, 6.6, 8.8, 9.9, 11.4, 13.2, 19.0, 21.9, 29.6 and/or 30.9.
12. A pharmaceutical composition comprising a therapeutically effective amount of Form I
of enantiomerically pure (3R, 5S) fluvastatin sodium and optionally one or more
pharmaceutical ly acceptable diluents or excipients.
13. A method of antagonizing HMG-CoA in mammal, which comprises administering to the
mammal a therapeutically effective amount of Form I of enantiomerically pure (3R,5S)
lluvastatin sodium.