This application claims priority to Indian patent applications numbered 909/CHE/2011 filed on Mar 24, 2011

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of quinoline-3-carboxylate compounds which are useful intermediates in the preparation of HMG-CoA reductase inhibitors like Pitavastatin.

BACKGROUND OF THE INVENTION:

Quinoline-3-carboxylic acid compounds and their derivatives are useful intermediates for the preparation of various pharmaceutically active ingredients. Methyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate is one such intermediate useful for the preparation of, HMG-CoA reductase inhibitor, Pitavastatin.

Various processes were known in the art to produce quinoline-3-carboxylic acid compounds and their derivatives. For instance, WO 2010089770 patent application discloses condensation of 2-amino-4'-fluoro benzophenone with 3-cyclopropyl-3-oxopropanoate in the presence of a sulfuric acid catalyst in an acetic acid solvent to produce Methyl 2-cyclopropyl-4-(4' -fluorophenyl)quinoline-3-carboxylate.

US 6852862 patent claims a process to prepare quinoline-3-carboxylic acid compounds by reacting 2-aminophenyl ketone compound with a keto ester compound in presence of an acid catalyst in alcohol solvent characterized that the alcohol solvent was distilled off during the reaction.

Also the Heterocycles Vol; 50 No:l; 1999 pg. 479-483 discloses the synthesis of Ethyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-carboxylate by azeotropic dehydration of reaction mixture containing 2-amino-4'-fluoro-benzophenone, Ethyl 3-cyclopropyl-3-oxo propionate and methane sulfonic acid in benzene solvent.

The Chinese publication CN 101747265 discloses preparation of Methyl 2-cyclopropyl-4-(4'-fiuorophenyl)quinoline-3-caboxylate, the Pitavastatin intermediate, by cyclizing 2-amino-4'-fluoro-benzophenone and Methyl 3-cyclopropyl-3-oxo propionate in presence of catalytic amount of Zinc trifluoro sulfonate (Zn(OTf)2). The obtained intermediate was later converted to Pitavastatin. Though there exist several processes to prepare Quinoline-3-carboxylic acid compounds, still there is a need to develop a process, which is commercially feasible and more economical.

OBJECT AND SUMMARY OF THE INVENTION:

The main object of the present invention is to provide, an improved process for the preparation of quinoline-3-carboxylic acid ester compounds in pure form with good yield.
Another object of the present invention is to provide a process for the preparation of alkyl 2-cyclopropyl-4-(4' -fluorophenyl)quinoline-3-caboxylate compound.

One aspect of the present invention provides, an improved process for preparation of alkyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate comprising the steps of a) condensing 2-amino-4'-fluorobenzophenone with alkyl 3-cyclopropyl-3-oxopropionate in presence of an acid catalyst and dehydrating agent; and b) isolating alkyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to the process of preparation of quinoline-3-carboxylic acid ester compounds, which are useful intermediates in the preparation of various pharmaceutically active ingredients. Also the present invention further relates to the preparation of Pitavastatin starting from the quinoline-3-carboxylic acid compounds.

Accordingly, one aspect of the present invention provides, an improved process for the preparation of alkyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate comprising the steps of a) condensing 2-amino-4'-fluorobenzophenone with alkyl 3-cyclopropyl-3-oxopropionate in presence of an acid catalyst and dehydrating agent; and b) isolating alkyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate.

In one embodiment of the present invention, the alkyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate is selected from Methyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate, Ethyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate and Propyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate.

As per the present invention, alkyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate is prepared by condensing 2-amino-4'-fluorobenzophenone with alkyl 3-cyclopropyl-3-oxopropionate in presence of a dehydrating agent. The dehydrating agent may be selected from sodium sulfate, magnesium sulfate, Calcium sulfate, calcium chloride, Silicagel, Molecular sieves, Calcium oxide, Phosphorous pentoxide, PhosporoyI chloride, preferably sodium sulfate, Molecular sieves.

In another embodiment of the present invention alkyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate is prepared by condensing 2-amino-4'-fluorobenzophenone with alkyl 3-cyclopropyl-3-oxopropionate in presence of an acid catalyst. The acid catalyst may be selected from Hydrochloric acid, sulfuric acid, aceticacid, methane sulfonic acid, p-Toluene sulfonic acid, Trifluoro acetic acid, preferably methane sulfonic acid.

In one more embodiment of the present invention, alkyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate is prepared by condensing 2-amino-4'-fluorobenzophenone with alkyl 3-cyclopropyl-3-oxopropionate in an organic solvent. The organic solvent can be selected from alcohols, hydrocarbons and their mixtures.
Alcoholic solvent is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, preferably methanol, 2-propanol. Hydrocarbon solvent is selected from Benzene, Chloro benzene, Dichloro benzene, Toluene, Xylene, preferably Toluene.

In another aspect of the present invention, alkyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxyIate prepared as per the above procedures, is converted into HMG CoA reductase inhibitor Pravastatin by following conventional processes known in the art such as the processes mentioned in US 5856336, WO 2007132482, WO 2007125547, US 5273995.

The following examples should be cited merely to illustrate embodiments and are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention.

Examples

Example-1: Preparation of Methyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate

To a round bottom reaction flask, 2-amino-4'-fluorobenzophenone (25 gms) and Methyl 3-cyclopropyl-3-oxopropionate (18.92 gms) were added at room temperature. To the reaction mass Methane sulphonic acid (11.2 gms) and Isoprolyl alcohol (211 gms) were added followed by anhydrous sodium sulfate (25.0 gms) and refluxed the reaction mass for 5 hrs. After completion of the reaction, Toluene (211 gms) was added and filtered the reaction mass. The Toluene layer was washed with 4% sodium hydroxide solution followed by washing with brine solution. The Toluene layer was dried over sodium sulfate and concentrated. To the concentrated mass, toluene (35 ml) and heptanes (175 ml) were added. The reaction mass was stirred at 80 °C and then at RT. Reaction Mass was cooled to 0-10 °C. The obtained solid was filtered, washed with heptanes and dried. (yield: 83 %, Purity: 98.95 %)

Example-2: Preparation of Methyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate

To a round bottom reaction flask, 2-amino-4'-fluorobenzophenone (5 gms) and Methyl 3-cyclopropyl-3-oxopropionate (3.8 gms) were added at room temperature. To the reaction mass anhydrous sodium sulfate (5.0 gms) was added followed by the addition of Methane sulphonic acid (2.23 gms) and Methanol (4.5 ml). Reaction mass was heated at 65-70 °C for 3 hrs. After completion of the reaction, Toluene (43 ml) was added and filtered the reaction mass. The Toluene layer was washed with 4% sodium hydroxide solution followed by washing with brine solution. The Toluene layer was dried over sodium sulfate and concentrated. To the concentrated mass, toluene (15 ml) and heptanes (75 ml) were added. The reaction mass was stirred at 100°C and then at RT. Reaction Mass was cooled to 0-10 °C. The obtained solid was filtered, washed with heptanes and dried. (Yield: 84.5%, Purity: 99.65 %)

ExampIe-3:

Preparation of Methyl 2-cyclopropyI-4-(4'-fluorophenyI)quinoIine-3-caboxyIate
To a round bottom reaction flask 2-amino-4'-fluorobenzophenone (5 gms) and Methyl 3-cyclopropyl-3-oxopropionate (3.8 gms) were added at room temperature. To the reaction mass molecular sieves 3A (5.0 gms) were added followed by the addition of Methane sulphonic acid (2.23 gms) and Methanol (4.5 ml). Reaction mass was heated at 65 -70 °C for 3 hrs. After completion of reaction, Toluene (43 ml) was added and filtered the reaction mass. The Toluene layer was washed with 4% sodium hydroxide solution followed by washing with brine solution. The Toluene layer was dried over sodium sulfate and concentrated. To the concentrated mass, toluene (15 ml) and heptanes (75 ml) were added. The reaction mass was stirred at 80 °C and then at RT. The reaction mass was cooled, filtered and washed with heptanes. The obtained solid was dried. (Yield: 83.2%, Purity: 99.65 %).

We claim:

1. An improved process for the preparation of alkyl 2-cyclopropyl-4-(4'-
fluorophenyl)quinoline-3-caboxylate comprising the steps of

a) condensing 2-amino-4'-fluorobenzophenone with alkyl 3-cyclopropyl-3-
oxopropionate in presence of an acid catalyst and dehydrating agent; and

b) isolating alkyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate.

2. The process according to claim 1, wherein the alkyl 2-cycIopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate is selected from Methyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate, Ethyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate and Propyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate.

3. The process according to claim 2, wherein the alkyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate is Methyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-caboxylate.

4. The process according to claim 1, wherein the acid catalyst is selected from Hydrochloric acid, sulfuric acid, acetic acid, methane sulfonic acid, p-Toluene sulfonic acid and Trifluoro acetic acid.

5. The process according to claim 1, wherein the dehydrating agent is selected from sodium sulfate, magnesium sulfate, Calcium sulfate, calcium chloride, Silicagel, Molecular sieves, Calcium oxide, Phosphorous pentoxide and Phosporoyl chloride.

6. The process according to claim 1, wherein the condensation of 2-amino-4'-fluorobenzophenone with alkyl 3-cyclopropyl-3-oxopropionate is carried out in presence of alcoholic solvents, hydrocarbon solvents or mixtures thereof.

7. The process according to claim 6, wherein alcoholic solvent is selected from methanol, ethanol, 1-propanol, 2-propanol and butanol.

8. The process according to claim 6, wherein hydrocarbon solvent is selected from Benzene, Chloro benzene, Dichloro benzene, Toluene and Xylene.

9. The process according to any of the claims 1-8, wherein the obtained alkyl 2-cyclopropyl-4-(4'-fluorophenyl) quinoline-3-caboxylate is further converted into Pravastatin or pharmaceutically acceptable salts thereof.