Specification
FIELD OF THE INVENTION
The present invention relates to novel organic acid salt of Pitavastatin alkyl ester of Formula I.
wherein R represents C1.3 alkyl; X represents monobasic or dibasic acid
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 (3i?,5iS',6£0-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid, calcium (2:1) salt.
Pitavastatin 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.
In view of the importance of Pitavastatin as a Lipid-lowering agent, several synthetic methods have been reported in the literature to prepare Pitavastatin, some of which are as summarized below.
US 4,761,419, US 5,011,930, US 5,753,675 discloses a process, which is as shown below:
wherein R is hydrogen or protecting group.
US 6,835,838 B2 discloses a process for the preparation of Pitavastatin calcium, which is as shown below:
However, it has been observed that the above process of lactonization resuhs in ~10-15% of unreacted Pitavastatin ethyl ester and therefore resuhs in low yield. Further, -10% of Pitavastatin acid results during the above lactonization process and therefore does not produce a single product which is required to keep adequate control for an intermediate through specifications to have consistently better quality of the finished product.
US 6,875,867 B2 discloses a process for the preparation of Pitavastatin arginine salt, which is as shown below.
During the above process Trifluoroacetic acid or hydrochloric acid is used to break the acetonide and the product Pitavastatin ester formed in situ converted to its corresponding alkali salt by treating with base, such as sodium hydroxide.
It is known that Pitavastatin is enantiomerically pure compound having two chiral centers in side chain of the molecule. All four isomers of Pitavastatin can be separated by HPLC and the Pitavastatin is (3R, 5S)-isomeT.
The process shown above carries out diastereomeric purification of Pitavastatin calcium through its lactone hydrochloride intermediate or forming different salts of Pitavastatin like arginine salt, which makes the process economically unviable.
Further, it is well understood from the prior art that crystallization of Pitavastatin esters to remove diastereomers is practically a difficult process because of their lesser solubility in most of the organic solvents as compared to the required (3R, 55)-isomer.
However, the present inventors have now found that the diastereomer can be reduced by making Pitavastatin alkyl ester as organic acid sah, which is industrially feasible.
OBJECTIVE OF THE INVENTION
The objective of the present invention is to provide Pitavastatin alkyl ester organic acid salt.
Yet another objective of the present invention is to provide an improved process for
preparing(3/,55',6£)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3,5-
dihydroxy-6-heptenoic acid, calcium salt (2:1) using Pitavastatin alkyl ester organic acid salt, which is simple, industrially applicable and economically viable.
SUMMARY OF THE INVENTION
The present invention relates to novel organic acid salt of Pitavastatin alkyl ester of Formula I.
wherein R represents C1.3 alkyl; X represents monobasic or dibasic acid
The present invention also relates to a process to prepare organic acid salt of Pitavastatin alkyl ester of Formula I, which comprises: a) reacting Pitavastatin ester of Formula III,
wherein R represents C1.3 alkyl with an organic acid in the presence of inert solvent; b) isolating the compound of Formula I.
The present invention also relates to a process for preparing (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3,5-dihydroxy-6-heptenoic acid, calcium salt (2:1) of Formula II, which comprises:
a) reacting Pitavastatin alkyl ester of Formula III,
wherein R represents C1.3 alkyl with an organic acid selected from monobasic acid or dibasic acid in the presence of inert solvent to obtain organic acid salt of Pitavastatin alkyl ester of Formula;
wherein R represents C1.3 alkyl; X represents monobasic or dibasic acid
b) optionally, purifying the compound of Formula I;
c) treating compound of formula I with aqueous inorganic base to obtain pure Pitavastatin alkyl ester of Formula III;
d) hydrolyzing Pitavastatin alkyl ester of formula III with strong base to obtain the corresponding alkali metal salt of compound of Formula IV;
wherein M represents Na, K, Li
e) treating compound of formula IV with a calcium source to obtain Pitavastatin calcium of Formula II; and
f) isolating the Pitavastatin calcium of Formula II.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel organic acid salt of Pitavastatin alkyl ester of Formula I.
wherein R represents C1.3 alkyl; X represents monobasic or dibasic acid
The organic acid salt of Pitavastatin ester is selected from trifluoroacetic acid, trifluoromethane sulfonic acid, acetic acid, methanesulfonic acid, perchloric acid, periodic acid, oxalic acid, mandelic acid, malic acid, tartaric acid, camphorsulfonic acid, benzenesulfonic acid, p-toluenebenzenesulphonic acid, 4-nitrobenzenesulfonic acid etc.
In another embodiment of the present invention, the process to prepare organic acid salt of Pitavastatin alkyl ester of Formula I,
wherein R represents Cu alkyl; X represents monobasic or dibasic acid comprises, reacting Pitavastatin ester in an organic solvent selected from C1-C5 alcohol such as methanol, ethanol, butanol; Cs-Cg esters such as ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate; Cs-Cg ketones such as methyl ethyl ketone, methyl isobutyl ketone, acetone; Ce-Cio aromatic hydrocarbons such as toluene; ethers such as tetrahydrofiiran, methyl ethyl ether; acetonitrile and mixture thereof, with an organic acid selected from monobasic or dibasic acid, such as trifluoroacetic acid, trifluoromethane sulfonic acid, acetic acid, methanesulfonic acid, perchloric acid, periodic acid, oxalic acid, mandelic acid, malic acid, tartaric acid, camphorsulfonic acid, benzenesulfonic acid, p-toluenebenzene sulphonic acid, 4-nitrobenzene sulfonic acid; preferably frifluoroacetic acid at temperature below 15°C, preferably at 0-5°C, for 15 min to 2 hr, preferably 15-20 min. Non-polar solvent selected from hexane, heptane, cyclohexane ethers such as diisopropyl ether etc., is added and isolated the organic acid salt of Pitavastatin alkyl ester of Formula I.
The organic acid salt of formula I is prepared by combining organic acid and ester compound of III in molar ratio within the range from 1.25:1 to 0.8:1; preferably 1.1:1.
In another aspect, the present invention provides Pitavastatin ester organic acid salt of formula I, containing less than -0.3% of its anti-isomer of formula 1(a), Pitavastatin lactone salt of formula V and Pitavastatin acid salt of formula VI.
The present invention also provides Pitavastatin ester of Formula III, having -0.3% of diastereomeric purity.
wherein X represents monobasic or dibasic acid
In another embodiment of the present invention, the process for preparing (3/,55,6£)-7-[2-cyclopropyl-4-(4-fIuorophenyl)quinoline-3-yl]-3,5-dihydroxy-6-heptenoic acid, calcium (2:1) salt of Formula II, comprises, reacting Pitavastatin ester in an organic solvent selected from C1-C5 alcohol such as methanol, ethanol, butanol; C3-C8 esters such as ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate; C3-C8 ketones such as methyl ethyl ketone, methyl isobutyl ketone, acetone; Ce-Cio aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, methylethyl ether; acetonitrile and mixture thereof, with an organic acid selected from monobasic or dibasic acids, such as trifluoroacetic acid, trifluoromethane sulfonic acid, acetic acid, methanesulfonic acid, perchloric acid, periodic acid, oxalic acid, mandelic acid, malic acid, tartaric acid, camphorsulfonic acid, benzenesulfonic acid, p-toluenebenzenesulphonic acid, 4-nitrobenzenesulfonic acid; preferably trifluoroacetic acid at temperature below 15°C, preferably at 0-5°C, for 15 min to 2 hr, preferably 15-20 min. Non-polar solvent selected from hexane, heptane, cyclohexane ethers such as diisopropyl ether, etc. is added and isolated the organic acid salt of Pitavastatin alkyl ester of Formula I. Optionally, purifying the obtained organic acid salt of Pitavastatin alkyl ester of Formula I using organic solvent or from a mixture of solvent, selected from ethanol, methanol, isopropyl alcohol, tert-butyl alcohol, ethyl acetate, isopropyl acetate, tetrahydrofuran, toluene, acetonitrile, water, hexanes, heptane, pentane, cyclohexane etc.
Organic acid compound of formula I is treated with aqueous inorganic base selected from sodium bicarbonate, potassiimi bicarbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodiimi carbonate, lithium hydroxide, lithium bicarbonate, lithium carbonate; in the presence of an organic solvent selected from ethyl acetate, isopropyl acetate, toluene, tetrahydrofuran, acetonitrile and water is added to obtain Pitavastatin alkali ester of formula III.
Pitavastatin alkali ester of formula III is then treated with strong base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium hydroxide, etc. to obtain Pitavastatin alkali salt of Formula IV, which is then in situ converted to Pitavastatin calcium of Formula II by treating with a source of calcium selected from calcium chloride, calcium acetate, calcium carbonate.
In another aspect, the Pitavastatin ethyl ester of Formula III of the present invention is prepared by process, which comprises preparing a solution of Pitavastatin keto ester of
Formula VII, in an organic solvent or a mixture of organic solvents, selected from the group consisting of an etheral solvent selected from Ci-Cg ethers or cyclic ethers such as diethyl ether, dimethyl ether, tetrahydrofiiran; alcoholic solvent selected from C1-C4 alcohol such as methanol, ethanol, butanol, and protic solvents such as toluene, alkyl esters such as ethyl acetate, methyl acetate, and adding to a solution of mixture of dialkylalkoxyborane, selected from diethylmethoxyborane, dimethylmethoxyborane, dimethylethoxyborane and a hydride ion source, selected from sodium borohydride, potassium borohydride, lithium borohydride and sodium triacetoxyborohydride, in a mixture of three or more organic solvents, group consisting of an ethereal solvent selected from Ci-Cg ethers or cyclic ethers such as diethyl ether, dimethyl ether, tetrahydrofiiran; alcoholic solvents selected from C1-C4 alcohol such as methanol, ethanol, butanol and protic solvents such as toluene, alkyl ester such as ethyl acetate, methyl acetate, propyl acetate at low temperature in the range of -50°C to -95°C, more preferably -70°C to -80°C. Thereafter, the reaction mass is stirred at same temperature. Reaction is quenched at -80°C to -50°C by adding quenching agents to the reaction mass.
The quenching agent is selected from water, acetic acid, aqueous hydrochloric acid, acetone, sodium bicarbonate, aqueous acetic acid buffer or mixture thereof Preferred agents are acetic acid buffer or acetic acid. After quenching the reaction mass is diluted with water and extracted with solvents like ethyl acetate, toluene, methylene chloride preferably with ethyl acetate. Distillation of solvents results Pitavastatin ethyl ester having (3S,5S)-diastereomer ~1 %.
Preferably, the total volume of solvent used for the reaction of Pitavastatin keto ester of Formula VII and dialkylalkoxyborane is about 10 volumes to 80 volumes (based on per gram of Pitavastatin keto ester of Formula VII) in the reaction mixture, more preferably 30-40 volumes; the source of hydride ion is present in an amount of 1 to about 4 equivalents (based on per mole of Pitavastatin keto ester of Formula VII).
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 ETHYL (i,55,
Documents
Application Documents
| # |
Name |
Date |
| 1 |
2458-CHE-2011 FORM-2 19-07-2011.pdf |
2011-07-19 |
| 1 |
abstract2458-CHE-2011.jpg |
2013-02-06 |
| 2 |
2458-CHE-2011 FORM-1 19-07-2011.pdf |
2011-07-19 |
| 2 |
2458-CHE-2011 CORRESPONDENCE OTHERS 05-11-2012.pdf |
2012-11-05 |
| 3 |
2458-CHE-2011 DESCRIPTION (PROVISIONAL) 19-07-2011.pdf |
2011-07-19 |
| 3 |
2458-CHE-2011 FORM-3 05-11-2012.pdf |
2012-11-05 |
| 4 |
2458-CHE-2011 CORRESPONDENCE OTHERS 19-07-2011.pdf |
2011-07-19 |
| 4 |
2458-CHE-2011 CORRESPONDENCE OTHERS 11-07-2012.pdf |
2012-07-11 |
| 5 |
2458-CHE-2011 DESCRIPTION(COMPLETE) 11-07-2012.pdf |
2012-07-11 |
| 5 |
2458-CHE-2011 OTHER DOCUMENT 12-08-2011.pdf |
2011-08-12 |
| 6 |
2458-CHE-2011 ABSTRACT 11-07-2012.pdf |
2012-07-11 |
| 6 |
2458-CHE-2011 FORM-1 12-08-2011.pdf |
2011-08-12 |
| 7 |
2458-CHE-2011 CLAIMS 11-07-2012.pdf |
2012-07-11 |
| 7 |
2458-CHE-2011 CORRESPONDENCE OTHERS 12-08-2011.pdf |
2011-08-12 |
| 8 |
2458-CHE-2011 FORM-5 11-07-2012.pdf |
2012-07-11 |
| 8 |
2458-CHE-2011 FORM-2 11-07-2012.pdf |
2012-07-11 |
| 9 |
2458-CHE-2011 FORM-5 11-07-2012.pdf |
2012-07-11 |
| 9 |
2458-CHE-2011 FORM-2 11-07-2012.pdf |
2012-07-11 |
| 10 |
2458-CHE-2011 CORRESPONDENCE OTHERS 12-08-2011.pdf |
2011-08-12 |
| 10 |
2458-CHE-2011 CLAIMS 11-07-2012.pdf |
2012-07-11 |
| 11 |
2458-CHE-2011 ABSTRACT 11-07-2012.pdf |
2012-07-11 |
| 11 |
2458-CHE-2011 FORM-1 12-08-2011.pdf |
2011-08-12 |
| 12 |
2458-CHE-2011 DESCRIPTION(COMPLETE) 11-07-2012.pdf |
2012-07-11 |
| 12 |
2458-CHE-2011 OTHER DOCUMENT 12-08-2011.pdf |
2011-08-12 |
| 13 |
2458-CHE-2011 CORRESPONDENCE OTHERS 19-07-2011.pdf |
2011-07-19 |
| 13 |
2458-CHE-2011 CORRESPONDENCE OTHERS 11-07-2012.pdf |
2012-07-11 |
| 14 |
2458-CHE-2011 DESCRIPTION (PROVISIONAL) 19-07-2011.pdf |
2011-07-19 |
| 14 |
2458-CHE-2011 FORM-3 05-11-2012.pdf |
2012-11-05 |
| 15 |
2458-CHE-2011 FORM-1 19-07-2011.pdf |
2011-07-19 |
| 15 |
2458-CHE-2011 CORRESPONDENCE OTHERS 05-11-2012.pdf |
2012-11-05 |
| 16 |
abstract2458-CHE-2011.jpg |
2013-02-06 |
| 16 |
2458-CHE-2011 FORM-2 19-07-2011.pdf |
2011-07-19 |