FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
7-(SUBSTITUTED INDOLE)HEPT-6-ENOIC ACID AND SALTS THEREOF T.
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.

3. PREAMBLE TO THE DESCRIPTION
The present invention provides 7-(substituted indole)hept-6-enoic acid and
salts thereof. Further, the present invention provides pure fluvastatin and salts
thereof.

The following specification particularly describes the invention and the manner
in which it is to be performed.

4. DESCRIPTION
The present invention encompasses 7-(substituted indole)hept-6-enoic acid and salts thereof. The present invention further provides pure fluvastatin and salts thereof.
Fluvastatin is chemically known as [R,S-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid and is represented by following formula I.

/ CH3
H3C
Formula I
Fluvastatin, marketed under the name LESCOL, is a potent inhibitor of the enzyme 3-hydroxymethylglutaryl-coenzyme-A reductase (HMG CoA reductase) and is indicated for the treatment of Hypercholesterolemia as well as other diseases or conditions in which HMG CoA reductase is implicated.
There are several patents and patent applications cited in the literature, which refer to process for the preparation of fluvastatin such as U.S. Patent No. 4,739,073, U.S. Patent No. 5,354,772, U.S. Patent No. 6,743,926, U.S. Patent No. 5,189,164, WO 2006/109147 and WO 2007/023503. The polymorphs of fluvastatin are disclosed in U.S. Patent No. 6,696,479 and U.S. Patent No. 6,858,643. Further, U.S. application 2005/148784 provides a process for preparing intermediates of pharmaceuticals such as fluvastatin.
Like any synthetic compound, fluvastatin can contain extraneous compounds or impurities. These impurities may be, for example, starting materials, by-products


of the reaction, products of side reactions, or degradation products. Impurities in fluvastatin, or any active pharmaceutical ingredient ("API"), are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
The present inventors while developing a process for the preparation of fluvastatin isolated a compound of formula (II),
F
PR!

wherein R is an alkyl group and R1 is selected from the group of -H, an alkyl group or-M; wherein M is a pharmaceutically acceptable cation.
Scheme 1
Further, the inventors developed pure fluvastatin and salts thereof.
The compound of formula (II) was produced by the reaction of b-ketoester of formula III with a borane derivative of formula B(R)(R2)(R3), as depicted in scheme 1.



In one aspect of the present invention there is provided compound of formula (II),
wherein R is an alkyl group and R1 is selected from the group of -H, an alkyl group or -M; wherein M is a pharmaceutically acceptable cation.
The non-limiting examples of alkyl group are methyl, ethyl, propyl, i-propyl, n-butyl, /-butyl, f-butyl and the like. The non-limiting example of pharmaceutically acceptable cation include ammonium, alkali metals such as sodium, potassium and the like; alkaline earth metal such as magnesium, calcium and the like or trivalent cation such as aluminium and the like.
The specific compounds of the present invention include;
7-(6-ethyl-3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoic
acid;
Sodium 7-(6-ethyl-3-(4-fluorophenyl)-1 -isopropyl-1 H-indol-2-yl)-3,5-dihydroxy
hept-6-enoate;
Potassium 7-(6-ethyl-3-(4-fluorophenyl)-1 -isopropyl-1 H-indol-2-yl)-3,5-dihydroxy
hept-6-enoate;
7-(5-ethyl-3-(4-fluorophenyl)-1-isopropyl-1 H-indol-2-yl)-3,5-dihydroxyhept-6-enoic
acid;
7-(6-methyl-3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-
enoic acid;
7-(5-methyl-3-(4-fluorophenyl )-1 -isopropyl-1 H-indol-2-yl)-3,5-dihydroxyhept-6-
enoic acid;
tert-butyl 7-(6-ethyl-3-(4-fluorophenyl)-1 -isopropyl-1 H-indol-2-yl)-3,5-dihydroxy
hept-6-enoate;


methyl 7-(6-ethyl-3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxy
hept-6-enoate; and
pharmaceutically acceptable salts thereof.
The term "pharmaceutically acceptable salts" refers to those carboxylate salts formed with corresponding pharmaceutically acceptable cations.
In another aspect of the present invention there is provided pure fluvastatin and salts thereof. In this disclosure, fluvastatin and salts thereof, with a combined compound of formula II content of 0.5 % or less, is referred to as pure fluvastatin.
In another aspect of the present invention there is provided a pharmaceutical composition containing compound of formula II in association with a pharmaceutically acceptable excipient and/or carrier wherein the composition may comprise a preparation such as solid compositions, liquid compositions or other compositions for oral administration or as injections, liniments or suppositories etc. for parenteral administration.
The non-limiting examples of solid composition include compressed tablets, pills, capsules, dispersible powders, granules, hard capsules and soft capsules. The non-limiting examples of liquid composition include emulsions, solutions, suspensions, syrups and elixirs. The non-limiting examples of injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions.
In yet another aspect of the present invention there is provided a process for the preparation of compound of formula II,


F

R
wherein the said process includes steps of, (i) reacting compound of formula III,


/- (III)
wherein R1 is an alkyl group; with a borane derivative of formula (V),
B(R)(R2)(R3) (V) wherein R is an alkyl group; R2 and R3 are independently alkyl group or an alkoxy group; and
(ii) isolation of compound of formula II from the reaction mass thereof.
The compound of formula II can be prepared by adding a solution of b-ketoester of formula III in an organic solvent to a mixture of a reducing agent suspended into a mixture of an organic solvent and a borane derivative at -95 to -65°C and isolating the compounds of formula II from the reaction mass thereof.
The non-limiting examples of alkyl group are methyl, ethyl, propyl, i-propyl, n-butyl, /-butyl, f-butyl and the like. The non-limiting examples of alkoxy groups are methoxy, ethoxy, propoxy, i-propyloxy, n-butyloxy, /-butyloxy, f-butyloxy and the like. The non-limiting examples of borane derivatives include trimethyl borane,


triethyl borane, tri-t-butyl borane, dimethoxy ethyl borane, methoxydiethyl borane and the like. The non-limiting examples of organic solvent include polar aprotic solvent such as tetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, 1,4-dioxane, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, acetone and polar protic solvent such as methanol, ethanol, isopropanol and the like or mixtures thereof. The non-limiting examples of reducing agent include sodium borohydride, lithium aluminium hydride, sodium hydride and the like.
The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example-1
Preparation of tert-butyl 7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate (IV)
The B-ketoester III (8.9 kg) in tetrahydrofuran (35 L) and methanol (10 L) was added to a mixture of sodium borohydride (780g) suspended into a mixture of tetrahydrofuran and methanol and triethylborane (5L, 14%solution in tetrahydrofuran) at -85 to -75°C. After the completion of the reaction, it was quenched with saturated solution of sodium bicarbonate (1.7 Kg in 17 L) and a mixture of n-heptane (35 L), ethyl acetate (10 L) and water (80 L). The organic phase was separated and concentrated to residue under vacuum. This residue was dissolved in ethyl acetate (55 Lit) and stirred in a solution of 50 % hydrogen peroxide (10 L) at 20-25°C. The organic phase was separated and washed with brine (65 L), 10 % sodium sulfite solution (3X85 L) and then again with brine solution (65 L) at 20-25 °C. The organic layer was concentrated to residue under vacuum at 40-45 °C. The residue was slurried in a mixture of isopropanol:n-heptane (10 L) at 8-12 °C. The material was filtered, dried and recrystallized to obtain title compound.


Example-2
Isolation of 7-(6-ethyl-3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate sodium
The filtrate obtained after the crystallization of the ester IV was concentrated. About 400g of the residue obtained was refluxed with tertiary butyl methyl ether for 1-3 h and filtered. The filtrate was concentrated under vacuum to one-third the volume and filtered. The filtrate was concentrated and the residue was taken in ether again and stirred. The mass was filtered and the filtrate was concentrated. To the residue thus obtained was added 500 ml of n-Hexane, heated to reflux and filtered. The mother liquor was concentrated to obtain 80 g of the ester. The ester (80g) containing the impurity was passed through the silica gel column and the fractions obtained were concentrated. HPLC analysis confirmed the presence of impurity in one of the fractions. 5g of the residue obtained from the fraction containing the impurity was dissolved in methanol in a three-necked round bottom flask and about 450 mg of NaOH was added. The reaction mixture was stirred for 3-5h at RT and was concentrated after the disappearance of the starting material. The amount of required impurity present in the mixture was 4.25% as confirmed from the HPLC analysis, which was isolated by preparative HPLC.
Melting Point : 185-187 °C.
HPLC Purity : 80 %.
IR (KBr, cm"1) : 3360, 2967, 2933, 2874, 1648, 1567, 1499, 1428, 1371,
1352, 1216, 1170, 1183, 1157, 1104, 1069, 1055, 1013, 967 and 921.
1H NMR (400 MHz, CD3OD): 5 1.28 (3H, t, J=7.2 Hz), 1.49-1.54 (1H, m), 1.63-1.73 (7H, m), 2.28-2.36 (2H, m), 2.74 (2H, q, J=7.2 Hz), 3.94 - 4.0(1 H, m), 4.37 (1H, q, J= 6 Hz), 4.87 - 4.96 (1H, m), 5.70 (1H, dd, ^=16 Hz, J2=6.4 Hz), 6.68 (1H, d, J=16 Hz), 6.88 (1H, d, J=8 Hz), 7.10 - 7.14 (2H, m), 7.37 (1H, d, J= 10 Hz), 7.39 (1H, s), 7.40 - 7.42 (2H, m).
Mass(m/e): 440 (M++1).

We Claim:
1. A compound of formula (II),

wherein R is an alkyl group and R1 is selected from the group of -H, an alkyl group or-M; wherein M is a pharmaceutically acceptable cation.
2. A compound as claimed in claim 1, comprising of;
7-(6-ethyl-3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoic
acid;
Sodium 7-(6-ethyl-3-(4-fluorophenyl)-1 -isopropyl-1 H-indol-2-yl)-3,5-dihydroxy
hept-6-enoate;
Potassium 7-(6-ethyl-3-(4-fluorophenyl)-1 -isopropyl-1 H-indol-2-yl)-3,5-dihydroxy
hept-6-enoate;
7-(5-ethyl-3-(4-fluorophenyl)-1 -isopropyl-1 H-indol-2-yl)-3,5-dihydroxyhept-6-enoic
acid;
7-(6-methyl-3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-
enoic acid;
7-(5-methyl-3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-
enoic acid;
tert-butyl 7-(6-ethyl-3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxy
hept-6-enoate;
methyl 7-(6-ethyl-3-(4-fluorophenyl)-1-isopropyl-1 H-indol-2-yl)-3,5-dihydroxy
hept-6-enoate; and


pharmaceutically acceptable salts thereof.
3. Pure Fluvastatin and salts thereof with a combined compound of formula II content of 0.5 % or less.
4. A pharmaceutical composition comprising compound of formula II.
5. A process for the preparation of compound of formula II,

wherein the said process comprises of, (iii) reacting compound of formula III,
F

(HI)
wherein R1 is an alkyl group; with a borane derivative of formula (V),
B(R)(R2)(R3)
(V)
wherein R is an alkyl group; R2 and R3 are independently alkyl group or an alkoxy group; and
(i) isolation of compound of formula II from the reaction mass thereof.


6. The process of claim 5, wherein a borane derivative comprises of trimethyl borane, triethyl borane, tri-t-butyl borane, dimethoxy ethyl borane, methoxydiethyl borane and the like.
7. The process of claim 5, wherein compound of formula III,

(III)
wherein R1 is an alkyl group; is reacted with a borane derivative in presence of a reducing agent and a solvent which includes polar aprotic solvent and polar protic solvent or a mixture thereof.
8. A process of claim 7, wherein a reducing agent comprises of sodium borohydride, lithium aluminium hydride, sodium hydride and the like.
9. A process of claim 7, wherein a polar aprotic solvent comprises of tetrahydrofuran, dimethylsulfoxide, N,N-dimethyl formamide, 1,4-dioxane, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, acetone and the like
10. A process of claim 7, wherein a polar protic solvent comprises of methanol, ethanol, propanol and the like.




Abstract
The present invention encompasses /-(substituted indole)hept-6-enoic acid and salts thereof. The present invention further provides pure fluvastatin and salts thereof.