FIELD OF THE INVENTION

The present invention relates to an improved process for preparing (2E)-3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-2-propenal of Formula I, which is an useful intermediate in the preparation of Pitavastatin calcium.

BACKGROUND OF THE INVENTION

Pitavastatin calcium is a synthetic lipid lowering agent that acts as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase inhibitor), chemically known as (3/?,55,6£)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid, calcium (2:1) salt of Formula II.

Pitavastatin calcium is being marketed under the brand name Livalo®, as an oral tablet in 1 MG, 2 MG and 4 MG strengths. Pitavastatin calcium is used to lower the lipid levels including cholesterol in blood and can be used for the prevention or treatment of hyperlipidemia and artheriosclerosis.

Pitavastatin was first time disclosed in US 4,761,419, US 5,011,930 and US 5,753,675. The process disclosed in these patents for the preparation of Pitavastatin is as shown below:-

wherein R is hydrogen or protecting group.

In the above processes, (2£)-3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-2-propenal of Formula I has been used as a key starting material to carry out the synthesis of Pitavastatin calcium and its analogs.

US 6,335,449 discloses a process for the preparation of (2£)-3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-2-propenal, which is as shown below:

The above process uses expensive reagents like diethylcyanoethylphosphonate and stronger reducing agents.

US 6,855,824 discloses a process for the preparation of (2E)-3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-2-propenal, which is as shown below:

wherein R7 and R8 each independently represent a hydrogen atom, an alkyl group optionally having substituents, an acyl group optionally having substituents or an aralkyl group optionally having substituents, or in combination represent an alkylene group, an arylene group or an aralkylene group; R9 represents an alkyl group optionally having substituents or an aryl group optionally having substituents; and X represents a halogen atom; R10 and R11 each independently represent a hydrogen atom, an alkyl group optionally having substituents, a cycloalkyl group optionally having substituents, an aryl group optionally having substituents or an aralkyl group optionally having substituents, or in combination represent an alkylene group, an arylene group or an aralkylene group.

The above process gives some amount of Z-isomer which needs extra purification for removal.

US 2006/0276653 Al, discloses a process for the preparation of (2E)-3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-2-propenal, which is as shown below:

wherein R is an alkyl group optionally having substituents.

The above process results in lower yields and therefore not economical.

As mentioned above, though there are number of processes available in the art, still there is a continuing need to identify alternative process for the manufacture of Pitavastatin propenaldehyde intermediate, such processes may, for example, when compared to previously known processes, be more convenient to use, be more suitable for large scale manufacture, give the product in a better yield, use less expensive reagents and / or be more environmentally friendly.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide an improved process for preparing (2£)-3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-2-propenal of Formula I, which is an useful intermediate in the preparation of Pitavastatin calcium with high yield and high purity.

Yet another objective of the present invention is to provide an improved process for preparing (2£)-3 -[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-2-propenal of Formula I, which is an useful intermediate in the preparation of Pitavastatin calcium, which is simple, industrially applicable and economically viable.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for preparing (2E)-3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-2-propenal of Formula I,

which comprises:

a) reacting 2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-carboxaldehyde of Formula III,
with a compound of Formula IVa or Formula IVb in an inert organic solvent,

wherein R1, R2, R3 represent phenyl or substituted phenyl, R4 represents an aliphatic residue selected from CM alkyl and R5 & R6 represent CM alkyl, aralkyl, phenyl or substituted phenyl to obtain a compound of Formula V,

b) converting the compound of Formula V with an aqueous base in a water miscible solvent to give a compound VI,

wherein M represents hydrogen or alkali metal c) treating the compound of Formula VI with a compound of Formula VII,

wherein X represents halogen and R represents CM alkyl in the presence of an organic base in an inert solvent to give a compound of Formula VIII, wherein R is as defined above d) reducing the compound of Formula VIII to give compound of Formula IX,

e) oxidizing the compound of Formula IX to give (2E)-3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-2-propenal of Formula I.

In another embodiment of the present invention, the (2E)-3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-2-propenal of Formula I is converted to Pravastatin and its pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The process to prepare (2E)-3-[2-Cyclopropyl-4-(4-fluoro phenyl)quinolin-3-yl]-2-propenal of formula I comprises reacting 2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-carboxaldehyde of Formula III with phosphorane of Formula IVa or IVb in an inert organic solvent selected from acetonitrile, tetrahydrofuran; alcoholic solvents such as isopropyl alcohol, methanol, ethanol; methyl tert-butyl ether; toluene; halogenated hydrocarbons such as methylene chloride or ethylene chloride, optionally in the presence of a base at a temperature in the range of 0-100°C, preferably between 20-80°C to yield compound of Formula V. The preferred solvent is isopropanol.

The compound of formula V is treated with aqueous base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.; more preferably sodium hydroxide in water miscible solvent selected from ethanol, methanol, isopropyl alcohol, Tetrahydrofuran, etc. which is carried out at a temperature between 0-80°C, preferably at 0-30°C to yield compound of Formula VI.

The compound of Formula VI is treated with the compound of Formula VII, which is selected from methyl chloroformate, ethyl chloroformate, etc. in the presence of an organic base selected from trialkyl amines such as triethyl amine or pyridine in an inert solvent selected from methylene chloride, ethylene chloride toluene, hexanes, etc.; more preferably methylene chloride, at a temperature ranging from -50°C to 50°C; more preferably at 0-10°C to yield compound of Formula VIII. Optionally the compound of Formula VIII can be crystallized from a suitable organic solvent like hexane, heptane, ethyl acetate, toluene or mixtures thereof.

The compound of Formula VIII is reduced using a reducing agent, selected from Sodium borohydride, Lithium aluminium hydride, Diisobutylaluminium hydride, etc.; more preferably sodium borohydride in a suitable inert solvent selected from ethanol, methanol, tetrahydrofuran, toluene, methyl tert-butyl ether, isopropyl ether; more preferably ethanol, at a temperature ranging from -80°C to 80°C, more preferably -25°C to -25°C to yield compound of Formula IX.

(2£)-3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl-2-propenol of Formula IX is oxidized using an oxidizing agent selected from Pyridinium chlorochromate, 2,2,6,6-tetramethyl-1-piperidinyloxy, catalyzed sodium hypochlorite, tetrapropylammonium perruthenate with JV-methylmorpholine AT-oxide, Swern oxidation, 2,3-Dichloro-5,6-Dicyanobenzoquinone (DDQ), manganese dioxide, etc.; more preferably manganese dioxide in an inert solvent, selected from methylene chloride, ethylene chloride, toluene, acetone, etc. to yield compound of Formula I.

The present invention also relates to a process for the preparation of Pitavastatin calcium using the compound of Formula I, which is disclosed in our co-pending Indian patent application No. 1251 /CHE/2011.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

EXAMPLE 1

PREPARATION OF METHYL (2E)-3-[2-CYCLOPROPYL-4-(4-FLUOROPHENYL)-QUINOLIN-3-YL]ACRYLATE

2-Cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxaldehyde (10 g, 0.034 mole) was suspended in isopropyl alcohol (70 ml) and methyl(triphenyl phosphoranylidene)acetate (13.77 g, 0.041 mole) was added to it at 25-30°C The contents were heated to 78-80°C and the progress of the reaction was monitored by qualitative HPLC analysis till the carboxaldehyde starting material was left unreacted <0.2%. Thereafter, the reaction mass was partially concentrated and cooled to 0-5°C during which the product methyl (2E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]acrylate precipitated out. The product was isolated by filtration and dried at 40-45°C under reduced pressure till the water content is <0.1% w/w.

Yield: 12 g

1H NMR (CDCb, 300 MHz): 5 1.06-1.09 (m, 2H), 1.38-1.40 (m, 2H), 2.33-2.38 (m, 1H), 3.73 (s, 3H), 6.04 (d,J= 16.2 Hz, 1H), 7.19-7.25 (m, 4H), 7.33-7.36 (m, 2H), 7.61-7.65 (m, 1H), 7.78 (d, J= 16.2 Hz, 1H), 7.96(d, J= 8.7 Hz, 1H).

EXAMPLE 2

PREPARATION OF 3-[2-CYCLOPROPYL-4-(4-FLUOROPHENYL) QUINOUN-3-YL]-(2£)-PROPENOIC ACID

Methyl (2E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]acrylate (10 g, 0.028 mole) was dissolved in tetrahydrofuran (150) and was treated with aqueous sodium hydroxide (IN, 20ml) at 0-5°C. The reaction mixture was stirred at 25-30°C for 12 h for completion of hydrolysis which was monitored by TLC. Thereafter, solvent was evaporated under reduced pressure. The resulting mass was acidified and extracted with methylene chloride (2 x 100 ml). The organic layer was washed with water, dried and concentrated to give the title compound. Yield: 9 g

'H NMR (CDCb, 300 MHz): 8 1.05-1.11 (m, 2H), 1.24-1.28 (m, 2H), 2.35-2.50 (m, 1H), 5.93 (d,J= 15 Hz, 1H), 7.28-7.31 (m, 1H), 7.38-7.47 (m, 5H), 7.64 (d, J= 15 Hz, 1H), 7.69-7.74 (m, 2H), 7.90 (d, J= 9 Hz, 1H), 12.55 (brs, 1H).

EXAMPLE 3

PREPARATION OF 3-[2-CYCLOPROPYL-4-(4-FLUOROPHENYL) QUINOLIN-3-YL]-(2E)-PROPENOYL ETHYL CARBAMATE

3-[2-Cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-(2E)-propenoic acid (8 g, 0.024 mole) was suspended in methylene chloride (50 ml) and triethyl amine (4.2 ml, 0.030 mole) was added to it at 25-30°C. The resulting clear solution was cooled to 0-5°C and ethyl chloroformate (2.5 ml, 0.026 mole) was added to it slowly over a period of 10 min keeping the temperature below 5°C. The reaction mixture was stirred at 0-5°C for 30 min and water (50 ml) was added to it. The organic layer was separated and washed with aqueous sodium bicarbonate solution (5% w/v, 50 ml). Methylene chloride was distilled out under reduced pressure at 40-50°C to obtain the product as an oily residue which was crystallized from hexanes (50 ml) to obtain the product as white crystalline solid. Yield: 9 g

1H NMR (CDC13, 300 MHz): 5 1.07-1.13 (m, 2H), 1.35-1.62 (m, 5H), 2.34-2.37 (m, 1H), 4.34 (q, J = 7.2 Hz, 2H), 6.08 (d, J = 16.2 Hz, 1H), 7.21-7.26 {m, 4H), 7.35-7.37 (m, 2H), 7.64-7.69 (m, 1H), 7.91-7.98 (m, 2H).

EXAMPLE 4

PREPARATION OF 3-[2-CYCLOPROPYL-4-(4-FLUOROPHENYL) QUINOLIN-3-YL]-(2E)-PROPENOL

To a solution of 3-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-(2E)-propenoyl ethyl carbamates (5 g, 0.012 mole) in ethanol (50 ml) was added sodium borohydride (0.96 g, 0.025 mole) keeping the temperature between 0-5°C. The reaction mixture was stirred for 1 hr at 0-5°C. Thereafter, solvent was removed by distillation and water (100 ml) was added to it. The product was extracted using methylene chloride (50 ml x 2). The combined methylene chloride extracts was washed with saturated sodium bicarbonate (50 ml) and with water 100 ml. The organic layer was dried over sodium sulfate and evaporated to obtain the pure 3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-(2E)-propenol.

Yield: 3.6 g

1H NMR (CDCI3, 300 MHz): 5 0.83-0.89 (m, 2H), 1.01-1.04 (m, 2H), 2.42-2.46 (m, 1H), 4.14 (brs, 1H), 5.78-5.87 (m, 1H), 6.60 (d, J = 16.2 Hz, 1H), 7.14-7.35 (m, 6H), 7.56-7.60 (m, 1H), 7.95 (d, J= 8.4 Hz, 1H).

EXAMPLE 5

PREPARATION OF (2E)-3-[2-CYCLOPROPYL-4-(4-FLUOROPHENYL QUINOLIN-3-YL-2-PROPENAL
3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-(2E)-propenol (5g,0.015 mole) was dissolved in toluene (50 ml) at 25-30°C and manganese dioxide (active, 10 g) was added to it. The reaction mixture was stirred for 12 h at 25-30°C. The progress of the reaction was monitored by TLC and after completion of the reaction, the reaction mixture was filtered through hyflo and toluene was evaporated under reduced pressure at 40-50°C to obtain the product as a semi solid. The product was further crystallized from hexane-ethyl acetate (20 ml, 9:1 v/v). Yield: 4.8 g

*H NMR (300 MHz, CDCI3): S 1.08-1.34 (m, 2H), 1.42-1.61 (m, 2H), 2.33-2.36 (m, 1H), 6.56-6.49 (m, 1H), 7.22-7.27 (w, 4H), 7.27-7.37 (m, 2H), 7.56 (d, J= 15.6 Hz, 7.66-7.97 (m, 1H), 7.99 (d, J = 6 Hz, 1H), 9.50, (d, J= 7.8 Hz, 1H).

WE CLAIM:

1. A process for preparing (2E)-3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-2-propenal of Formula I,

which comprises:

a) reacting 2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-carboxaldehyde of Formula III,

with a compound of Formula IVa or Formula IVb in an inert organic solvent,

wherein R1, R2, R3 represent phenyl or substituted phenyl, R4 represents an aliphatic residue selected from C1-4 alkyl and R5 & R-6 represent C1-4 alkyl, aralkyl, phenyl or substituted phenyl to obtain a compound of Formula V,

b) converting the compound of Formula V with an aqueous base in a water miscible solvent to give a compound VI,

wherein M represents hydrogen or alkali metal, c) treating the compound of Formula VI with a compound of Formula VII,

wherein X represents halogen and R represents C1-4 alkyl

in the presence of an organic base in an inert solvent to give a compound of Formula VIII,

wherein R is as defined above, d) reducing the compound of Formula VIII to give compound of Formula IX,

e) oxidizing the compound of Formula IX to give (2£)-3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-2-propenal of Formula I.

2. The process according to claim 1, wherein compound of formula I is further converted to Pitavastatin.

3. The process according to claim 1, wherein the inert organic solvent used in step (a) is selected from the group consisting of acetonitrile, Tetrahydrofuran, isopropyl alcohol, methanol, ethanol, methyl tert-butyl ether, toluene, methylene chloride and ethylene chloride.

4. The process according to claim 1, wherein aqueous base used in step (b) is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide.

5. The process according to claim 1, wherein water miscible solvent is selected from the group consisting of ethanol, methanol, isopropyl alcohol and Tetrahydrofuran.

6. The process according to claim 1, wherein organic base is trialkylamine.

7. The process according to claim 1, wherein inert solvent used in step (c) is selected from the group consisting of methylene chloride, ethylene chloride toluene and hexanes.

8. The process according to claim 1, wherein reducing agent used in step (d) is selected from the group consisting of Sodium borohydride, Lithium aluminium hydride and Diisobutylaluminium hydride.

9. The process according to claim 1, wherein compound of Formula IX is oxidized using an oxidizing agent selected from Pyridinium chlorochromate, 2,2,6,6-tetramethyl-1-piperidinyloxy catalyzed sodium hypochlorite, tetrapropylammonium perruthenate with TV-methylmorpholine Af-oxide, DDQ and manganese dioxide or by Swern oxidation.

10. A process for the preparation of Pravastatin from compound of formula I, characterised in that compound of formula I is prepared by any of the preceding claims.