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:
A process for the preparation of Pitavastatin Calcium
2. APPLICANT (S)
(a) NAME: Enaltec Labs Pvt. Ltd.
(b) NATIONALITY:
An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS:
Enaltec Labs Pvt. Ltd., 17th Floor, Kesar Solitaire, Plot No. 5, Sector 19, Sanpada, Navi Mumbai - 400705, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

200278202
Technical field of the invention:
The present invention relates to an improved process for the preparation of Pritavastatin calcium represented by the following compound of formula (I).

Background of the invention:
Pravastatin calcium is chemically known as (+) monocalcium bis {(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5dihydroxy-6-heptenoate}. Pitavastatin calcium is represented by the following compound of formula (I):

It is an inhibitor of HMG-CoA reductase. It is a synthetic lipid-lowering agent for oral administration, indicated for the treatment of primary hyperlipidemia and mixed dyslipidemia as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) and commercially sold under the brand name LIVALO®.

Pravastatin is disclosed generically in U.S. patent number US5011930 and specifically in US5856336.
Moreover US patent numbers US 5,011,930 and US 5,856,336 discloses the process for preparation of Pitavastatin. US 5,856,336 discloses Pitavastatin is further conversion of Pitavastatin into Pitavastatin sodium salt wherein, reaction involves the reduction of the compound of formula (III) using DIBAL into the compound of formula (IV) which is on oxidation gives the compound of formula (V) which is reacted with (Z)-tributyl(2-ethoxyvinyl)stannane to obtain the compound of formula (VI); the compound of formula (VI) further converted under acidic condition into the compound of formula (VII) which is further converted in presence of n-BuLi into the compound of formula (VIII), reducing the compound of formula (VIII) using Na-Borohydride, Zn-Borohydride to give the compound of formula (II) (Pitavastatin) which is further converted into Pitavastatin sodium salt compound of formula (XI) as depicted in SCHEME-I.


The process disclosed in US'336 involves multiple steps for preparation of Pitavastatin (the compound of formula II). Also the process involves the use of n-BuLi which is difficult to use on a commercial scale as it is highly flammable liquid which catches fire spontaneously if exposed to air or in contact with water and releases flammable gases, which may ignite spontaneously.
PCT publication W09511898 generically discloses the preparation of HMG-CoA reductase inhibitor as depicted in SCHEME-II;

Wherein,
wherein ring X is a benzene ring, a substituted benzene ring or a substituted 5- or 6-membered heteroaromatic ring, each of R1 and R2 which are independent of each other, is hydrogen, C1-8 alkyl, C3.7 cycloalkyl, C1-3 alkoxy, butoxy, i-butoxy, sec-butoxy, tert-butoxy, R20R21N- (Wherein each of R20 and R21 which are independent of each other, is hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilyloxy, hydroxymethyl or -O(CH2)eOR22 (wherein R22 is hydrogen or C1-3 alkyl, and e is 1, 2, or 3); or R1 and R2 together form -CH=CH-CH=CH- or methylenedioxy, when they are at the o-position to each other;
R3 is hydrogen, C1-8 alkyl, C2-6alkenyl, C3-7, cycloalkyl, C5-7 cycloalkenyl.

each of R9a and R9brepresents a hydroxyl-protecting group and is independently
methoxymethyl, 2-methoxyethoxymethyl, tetrahydropyranyl, 4-
methoxytetrahydropyranyl, 1-ethoxyethyl, 1-methyl-l- methoxyethyl, allyl, benzyl, p-methoxybenzyl, triphenylmethyl, trimethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl, or R9a and R9b together form isopropylidene, cyclopentylidene, cyclohexylidene or benzylidene; and
Rio is methyl, ethyl, propyl, isopropyl, tert-butyl, tetrahydropyranyl, allyl, benzyl, triphenylmethyl, trimethylsilyl or tert-butyldimethylsilyl)
Y is P+R1;LR12R13Hal~ or P(W)R14R15 (wherein each of R11, R12 and R13 which are independent of one another, is methyl, ethyl, propyl, isopropyl, butyl, 2-chloroethyl, 2,2,2-trifluoroethyl, phenyl, methoxyphenyl, methylphenyl, pentafluorophenyl or benzyl, each of R14 and R15 which are independent of each other, is methyl, ethyl, propyl, isopropyl, butyl, 2-chloroethyl, 2,2,2- trifluoroethyl, phenyl, methoxyphenyl, methylphenyl, pentafluorophenyl, benzyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-chloroethoxy, 2,2,2- trifluoroethoxy, phenoxy, methoxyphenyloxy, methylphenyloxy, pentafluorophenyloxy or benzyloxy, or R14 and R15 together form a 5- or 6-membered ring, Hal is chlorine, bromine or iodine, and is O or S.
WO'898 further discloses that when Y in compound of formula XVII is P(0)Ph2, the yield of the condensation reaction and stereo selectivity (trans selectivity) will be excellent, and the compound of formula XIX can be obtain in good yield and purity.
WO'898 also discloses specifically the process for preparation of compounds represented by formulae XV(E), XV(Z) wherein, the compound of formula (XIII) is reacted with the compound represented by formula (XIV) in presence of n-BuLi as depicted in SCHEME-III;


The process disclosed in WO'898 for the preparation of compound of formulae XV(E), XV(Z) is carried out in presence of n-BuLi which is highly flammable liquid which catches fire spontaneously if exposed to air or in contact with water and releases flammable gases, which may ignite spontaneously, thus difficult to use on a commercial scale. Further, this reaction is carried out at -78°C. It is difficult to maintain the negative temperature up to -78°C which makes this process economically and industrially less feasible.
Indian patent number 2,553,46 discloses the process for preparation of Pitavastatin calcium (the compound of formula I) wherein, the compound of formula (XII) is reacted with triphenyl phosphine to get the compound of formula (XIII) which is further reacted with the compound of formula (XIV) to obtain the compound of formula (XV) which is converted into organic amine salt of Pitavastatin represented by the formula (XVI). Organic amine salt of the Pitavastatin further converted into Pitavastatin calcium (the compound of formula I) using CaCl2 as depicted in SHEME-III;


The condensation of compound of formula (XIII) and compound of formula (XIV) as per the process disclosed in IN'346 is conducted at around the temperature of 70°C which promotes impurity formation and makes this process commercially less feasible. Moreover, the process involves preparation of amine salt of Pitavastatin represented by compound of formula (XVI) which is subsequently converted into Pitavastatin calcium salt represented by compound of formula (I) results in multiple stage process which makes the process cumbersome industrially not viable.
Hence, there is a continuous need to develop simple, commercially advantageous and industrially viable process for the preparation of the Pitavastatin calcium (the compound of formula I). The Process should avoids the use of hazardous reagents like n-BuLi, involves the less number of reaction steps and reduces overall reaction time. This creates need to develop environment friendly process with minimum or no use of hazardous reagents or solvent, cost effective and economically more feasible.

The process as per present invention is advantageous over cited prior art as the process involves the condensation of the compound of formula (XIII) and the compound of formula (XIV) at room temperature and provides the compound of formula (XV) with good yield and purity. As the reaction is carried out at room temperature which makes the process industrially feasible.
Further, In the process of present invention for preparation Pitavastatin calcium; the compound of formula (I) from the compound of formula (XV) involves the use of water as a solvent while prior art processes involves the use of different organic solvents. Use of only water as a solvent is advantageous in economic, environmental safety, health safety perspectives.
The process of present invention for the preparation of Pitavastatin calcium represented by compound of formula (I) avoids multiple steps which makes this process economically viable and industrially feasible.
Object of the invention:
i) An object of the present invention is to provide an improved process for
the preparation of Pitavastatin calcium (the compound of formula (I)) involving less number of reaction steps.
ii) Another object of the present invention is to provide an improved process for the preparation of Pitavastatin calcium (the compound of formula (I)) involving carrying out the reaction at a shorter duration of time.
iii) Further object of the present invention is to provide an improved process for producing Pitavastatin calcium (the compound of formula (I)) avoiding

the use of hazardous reagent such as n-BuLi thereby rendering the process commercially feasible.
iv) Further object of the present invention is to provide an improved process for producing Pitavastatin calcium (the compound of formula (I)) from the compound of formula (XV) using water as a solvent.
v) Yet another object of the present invention is to provide an improved process for producing Pitavastatin calcium (the compound of formula (I)) with good yield and purity.
Summary of the invention:
In accordance with an aspect of the present invention is to provide a process for preparing Pitavastatin calcium (the compound of formula I) comprising the steps of;
a. reacting the compound of formula (XIII) with the compound of formula
(XIV) in solvent and in presence of a base to obtain the compound of formula
(XV),

b. deprotecting the compound of formula (XV) using acid in presence of a water
as a solvent to obtain the compound of a formula (XVII),


c. hydrolyzing the compound of formula (XVII) using base in presence of a
water as a solvent to obtain Pitavastatin; the compound of formula (II),

d. converting pitavastatin ( the compound of formula (II)) into Pitavastatin
calcium (the compound of formula (I)) using calcium chloride and water as a
solvent,

In accordance with another aspect of the present invention is to provide a process for preparing Pitavastatin calcium (the compound of formula (I)):


comprising the steps of,
step e) reacting the compound of formula (XIII) with the compound of formula (XIV) to give the compound of formula (XV),

Step f) Converting compound of formula (XV) to Compound of formula (I) via compound of formula (II),


Detail description of the invention:
The compound of formula XIII can be prepared by the process disclosed in W09511898.
In accordance with an aspect of the present invention is to provide the process for the preparation of Pitavastatin calcium (the compound of formula (I)):

comprising the steps of,
a. reacting the compound of formula (XIII) with the compound of formula
(XIV) in an organic solvent and in presence of base to obtain the compound
of formula (XV),

b. deprotecting the compound of formula (XV) using acid in presence of a water
as a solvent to obtain the compound of a formula (XVII),

,1
c. hydrolyzing the compound of formula (XVII) using base in presence of a
water as a solvent to obtain Pitavastatin the compound of formula (II),

d. converting pitavastatin the compound of formula (II) into Pitavastatin
calcium the compound of formula (I) using calcium chloride and water as a
solvent,

In accordance with an embodiment of the present invention, the organic solvent used in the step a) is selected from DMSO (dimethyl sulfoxide) and sulfolane or any combination thereof.

In accordance with another embodiment of the present invention, the base used in the step a) is sodium hydride, sodium carbonate, potassium carbonate or any combination
thereof.
In accordance with yet another embodiment of the present invention, the base used in the step a) is sodium hydrides or potassium carbonate.
In accordance with another embodiment of the present invention in the step a) sodium hydrides is used as a base and DMSO or sulfolane is used as solvent.
In accordance with another embodiment of the present invention in the step a) potassium carbonate is used as a base and sulfolane is used as solvent.
The compound of formula (XIII) is reacted with the compound of formula (XIV) in an organic solvent and in presence of base at a temperature in the range of 20-40°C for the period of 2 to 13 hours.
The compound of formula (XV) can be isolated by steps of concentration, slurring in alcohol selected from group consisting of methanol, ethanol, propanol or isopropanol followed by filtration or centrifugation and drying optionally at a temperature in the range of 45-50°C.
The compound of formula (XV) can be optionally purified by using alcohol selected from methanol, ethanol, propanol, and isopropanol or any combination thereof.
In accordance with an embodiment of the present invention; the acid used in step b) for deprotecting the compound of formula (XV) is selected from hydrochloric acid (HCI) and sulfuric acid (H2SO4).
Deprotection of the compound of formula (XV) using acid is carried out in water as a solvent at a temperature in the range of 20-40°C for the period of 1 to 5 hours.

The compound of formula (XVII) is not isolated and reaction mass is used for next
step, step c).
In accordance with an embodiment of the present invention, the base used for step c) is selected from sodium hydroxide or potassium hydroxide.
Hydrolysis of the compound of formula (XVII) using base is carried out in water as a solvent at a temperature in the range of 20-40°C for the period of 1 to 5 hours to obtain Pitavastatin (the compound of formula (II)).
Pitavastatin (the compound of formula (II)) is not isolated and reaction mass is washed with cyclohexane and diisopropyl ether followed by adjusting pH to 7.8 to 8.2 using concentrated HC1 and treatment with calcium chloride to provide Pitavastatin calcium (the compound of formula (I)).
Pitavastatin calcium (the compound of formula (I)) is isolated by steps of filtration or centrifugation and drying
Pitavastatin calcium (the compound of formula (I)) is dried at a temperature in the
range of 45-50°C.
In accordance with an embodiment step a), step b), step c) and step d) is carried out at a temperature in the range of 20-40°C
In accordance with an embodiment, Pitavastatin (the compound of formula (II)) is not
isolated.
In accordance with another embodiment, Pitavastatin (the compound of formula (II)) is optionally isolated and purified.
In accordance with another embodiment, Pitavastatin (the compound of formula (I)) is optionally further recrystallized using suitable solvent or combination of solvents.

In accordance with another embodiment, Pitavastatin calcium (the compound of formula (I)) is optionally further recrystallized using suitable solvent or combination
of solvents.
In accordance with an embodiment of the present invention is to provide the process for the preparation of Pitavastatin calcium (the compound of formula (I)):

comprising the steps of,
step e) reacting the compound of formula (XIII) with the compound of formula (XIV) in solvent selected form DMSO (dimethyl sulfoxide) or sulfolane and in presence of base selected from sodium hydrides or potassium carbonate to obtain the compound
of formula (XV),

Step f) Converting compound of formula (XV) to Compound of formula (I) via compound of formula (II),


wherein,
compound of formula (XV) is treated with hydrochloric acid (HCI) or sulfuric acid (H2SO4) in water at 20-40°C for the period of 1 to 5 hours, followed by treatment with sodium hydroxide or potassium hydroxide at a temperature in the range of 20-40°C for the period of 1 to 5 hours to give Pitavastatin (the compound of formula (II)), further reaction mixture washed with cyclohexane and diisopropyl ether followed by adjusting pH to 7.8 to 8.2 using concentrated HCI and treatment with calcium chloride to provide Pitavastatin calcium (the compound of formula (I)).
In accordance with an embodiment, Pitavastatin (the compound of formula (II)) is not
isolated.
In accordance with another embodiment, Pitavastatin (the compound of formula (II)) is isolated and purified.

Pitavastatin (the compound of formula (I)) is optionally further recrystallized using suitable solvent or combination of solvents.
Pitavastatin (the compound of formula (II)) is isolated, purified by recrystallization or column chromatography and dried.
Pitavastatin calcium (the compound of formula (I)) is isolated by steps of filtration or centrifugation and drying.
Examples:
The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.

In a 2.0-Liter, 4-necked round bottom flask equipped with a mechanical stirrer, a thermometer and a condenser ((2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl)methyl) triphenylphosphonium bromide (15gm), sodium hydride (1.45gm), tert-butyl (4R-cis)-6-formaldehydel-2,2-dimethyl-l,3-dioxane-4-acetate (6.89 gm) and DMSO (105 ml) was charged and the reaction mixture was stirred for a period of 2 to 13 hours at a temperature in the range of 25-35°C. After consumption of starting material, water (1050 ml) and toluene (210 ml) was added and reaction mixture was

stirred for 30 min. Layers were separated and toluene layer was distilled under vacuum to obtain residue which was further treated with IPA (Isopropyl alcohol, 75 ml) and methanol (75 ml), filtered and dried in oven at 45 °C to produce white color compound of formula (XV).

In a 2.0-Liter, 4-necked round bottom flask equipped with a mechanical stirrer, a thermometer and a condenser; ((2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl)methyl) triphenylphosphonium bromide (15 gm), sodium hydride (1.0gm), tert-butyl (4R-cis)-6-formaldehydel-2,2-dimethyl-l,3-dioxane-4-acetate (6.89 gm) and sulfolane (105 ml) was charged. The reaction mixture was stirred for a period of 2 to 13 hours at a temperature in the range of 25-35°C. After consumption of starting material, water (1050 ml) and toluene (210 ml) was added and reaction mixture was stirred for 30 min. Layers were separated and toluene layer was distilled under vacuum to obtain residue which was further treated with IPA (75 ml) and methanol (75 ml), filtered and dried in oven at 45°C to produce white color compound of formula (XV).. Yield: 10.27 gm (80.0%), Purity: 97.65%.


In a 2.0-Liter 4-necked round bottom flask equipped with a mechanical stirrer, a thermometer and a condenser ((2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl)methyl) triphenylphosphonium bromide (15gm), potassium carbonate (15.38gm), tert-butyl (4R-cis)-6-formaldehydel-2,2-dimethyl-l,3-dioxane-4-acetate (6.89 gm) and sulfolane (105 ml) was charged. The reaction mixture was stirred for a period of 2 to 13 hours at a temperature in the range of 25-35°C. After consumption of starting material, water (1050 ml) and toluene (210 ml) was added and reaction mixture was stirred for 30 min. Layers were separated and toluene layer was distilled under vacuum to obtain residue which was further treated with IPA (75 ml) and methanol (75 ml), filtered and dried in oven at 45°C to produce white color compound of formula (XV)..
Yield: 10.91 (85.00%), Purity: 99.57%.
Example-4: Preparation of Pitavastatin Calcium (I)


Into a 3-Liter, 3-necked round bottom flask equipped with a mechanical stirrer, thermometer and condenser; compound of formula (XV) (50 gm), water (250 ml) and HC1 solution in water (17.62 ml concentrated HC1 in 125 ml water) was charged and reaction mass was stirred at 25-30°C for a period of 2 hours. After consumption of compound of formula (XV), sodium hydroxide solution (12.60gm in 125 ml of water) was added and reaction mass was stirred at 25-30°C for a period of 2 hours followed by cyclohexane (250 ml) and diisopropyl ether (250 ml) washing were given to reaction mass to give Pitvastatin (compound of Formula (I) in the reaction mixture. The pH of the reaction mixture was adjusted to 7.8 to 8.2 using concentrated HC1 and treatment with calcium chloride (11.21 gm) in water was given followed by filtration and drying at 45°C to afford the calcium salt of Pitavastatin (the compound of formula I).
Yield: 39.24 (92.00%), Purity: 99.91%.

We Claim :

1. A process for preparing Pitavastatin calcium (compound of formula I) comprising the steps of;
a. reacting the compound of formula (XIII) with the compound of formula
(XIV) in solvent and in presence of a base at a temperature in the range of
20-25°C to obtain the compound of formula (XV),

b. deprotecting the compound of formula (XV) using acid in presence of a
water as a solvent to obtain the compound of a formula (XVII),

c. hydrolyzing the compound of formula (XVII) using base in presence of a
water as a solvent to obtain pitavastatin the compound of formula (II),


d. converting Pitavastatin the compound of formula (II) into Pitavastatin calcium the compound of formula (I) using calcium chloride and water as a solvent,

2. The process as claimed in claim 1 wherein organic solvent used in the step a)
is selected from DMSO and sulfolane or any combination thereof.
3. The process as claimed in claim 1 wherein base used in the step a) is selected
from sodium hydride and potassium carbonate.
4. The process as claimed in claim 1 wherein the acid used in step b) for
deprotecting the compound of formula (XV) is selected from Hydrochloric
acid (HCI) and sulfuric acid (H2SO4).
5. The process as claimed in claim 1 wherein the base used for step c) is selected
from sodium hydroxide or potassium hydroxide.

6. The process as claimed in claim 1 wherein Pitavastatin (the compound of
formula (II)) is not isolated in step c) and reaction mass is washed with
cyclohexane and diisopropyl ether followed by adjusting pH to 7.8 to 8.2
using concentrated HC1 and treatment with calcium chloride in step d) to
provide Pitavastatin calcium (the compound of formula (I)).
7. The process as claimed in claim 1, wherein step a), step b), step c) and step d) is carried out at a temperature in the range of 20-40°C.
8. A process for preparing Pitavastatin calcium (compound of formula I)

comprising the steps of;
step e) reacting the compound of formula (XIII) with the compound of formula (XIV) in solvent selected form DMSO (dimethyl sulfoxide) or sulfolane and in presence of base selected from sodium hydrides or potassium carbonate to obtain the compound of formula (XV),


Step f) Converting compound of formula (XV) to Compound of formula (I) via compound of formula (II),

wherein,
compound of formula (XV) is treated with hydrochloric acid (HO) or sulfuric acid (H2SO4) in water at 20-40°C for the period of 1 to 5 hours, followed by treatment with sodium hydroxide or potassium hydroxide at a temperature in the range of 20-40°C for the period of 1 to 5 hours to give Pitavastatin (the compound of formula (II)), further reaction mixture washed with cyclohexane and diisopropyl ether followed by adjusting pH to 7.8 to 8.2 using concentrated HC1 and treatment with calcium chloride to provide Pitavastatin calcium (the compound of formula (I)).
9. The process as claimed in claim 8, Pitavastatin (the compound of formula (II)) is not isolated.

10. The process as claimed in claim 8, Pitavastatin (the compound of formula (II)) is isolated, purified by recrystallization or column chromatography and dried.