FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patent Rules, 2006
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION: AN IMPROVED PROCESS FOR THE
PREPARATION OF KEY INTERMEDIATE OF ATORVASTATIN.
2. APPLICANT:
(a) NAME: ARCH PHARMALABS LIMITED
(b) NATIONALITY: INDIAN
(c) ADDRESS: ARCH PHARMALABS LIMITED,
541-A, ARCH HOUSE, MAROL-MAROSHI ROAD, ANDHERI (EAST), MUMBAI-400059
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE:
An improved process for the preparation of key intermediate of Atorvastatin. FIELD OF THE INVENTION:
The present invention relates to an advanced and improved process over the
prior art for the preparation of 4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N-
p-diphenylbenzenebutanamide of the formula I commercially referred as
DKT III, a key intermediate for the synthesis of Atorvastatin and
pharmaceutically acceptable salts thereof. The process disclosed herein
relates to an efficient and economical process for the preparation of
substantially pure 4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N-J5-
diphenylbenzenebutanamide of the formula I comprising the key raw materials comprising compound of formula II, herein referred as DK II and compound of formula III referred as DKT-I

The invention especially relates to a process for the preparation of a key intermediate for Atorvastatin, 4-fluoro-a-[2-methyl-l-oxopropyl]-Y-oxo-N-p-diphenylbenzenebutanamide of formula I with better yield and higher

purity obtained by nucleophilic substitution reaction of substantially pure 2-chIoro-l-(4-fluorophenyl)-2-phenone compound of formula II, with methyl 4-methyl-3-oxopentaonate of formula III. The process is illustrated below in scheme 1:

The requisite purity of compound of formula II also referred as DK-II is achieved by distillation of said crude compound of formula II.
BACKGROUND OF THE INVENTION:
4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N-p-diphenylbenzenebutanamide of formula I hereinbefore and hereinafter referred to as DKT III, is a key intermediate for the preparation of Atorvastatin of formula ATV and its pharmaceutically acceptable salts.

US 4681893, US 5124482, US 5216174, US 5097045 disclose the process for the preparation of Atorvastatin represented by ATV and the process

for the preparation of compound of formula I comprising contacting 4-
methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentamide with 4-
fluorobenzaldehyde in the presence of a catalyst such as 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride, 3,4-dimethyI-5-(2-hydroxy-ethyl)-thiazolium iodide, 3-ethyl-4-(2-hydroxyethyl)-4-methylthiazolium bromide, thiamine hydrochloride and the base selected from N,N-diisopropylethylamine, pyridine, N,N-dimethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N,N,N\N'-tetramethylethylenedimine as illustrated herein below:

WO03/004457 (hereinafter referred as '457) discloses the process for
preparing 4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N-p-dipheny
lbenzenebutanamide comprising contacting 2-bromo-l-(4-fluorophenyl)-2-phenone with 4-methyI-3-oxo-N-phenylpentamide by using a highly polar solvent system comprising DMF, ethanol and methanol as illustrated herein below. Product is isolated by precipitation with solvent like n-hexane. The remaining soluble material is recovered by chromatographic separation. The compound is obtained as diastereoisomeric mixture in a ratio of about 3:1 to 4:1 including unknown impurities. In case of mixture of ratio 3:1 and 4:1 the yield of DKT III is 75% and 80% respectively and the other impurity constituents of the remaining 20-25% mixture have neither been isolated nor characterized.


The said '457 application comprises the use of 2-bromo-l-(4-ffuorophenyl)-2-phenone instead of corresponding chloro compound of formula II used herein in the instant patent application. The bromo compound used in '457 is very expensive compared to compound of formula II used for the same purpose in the instant application. Furthermore, preparation of bromo substituted compound in place of chloro substituted compound of Formula II is industrially unsafe as it comprises use of bromine which is unsafe for industrial use.
WO2006/021968, discloses a process for DKT III comprising a reaction between bromo -4-methyl-3-oxo pentanoic acid phenylamide and l-(4-fluoro phenyl)-2-phenyl ethanone as illustrated herein below:

CN101307009A and US8163959B2 discloses a method for the preparation of DKT III comprising a-chlorination of 4-fluorobenzene benzyl ketone of formula IIA in the solvent to obtain 2-chloro-l-(4-fluorophenyl)-2-phenone of formula II with isobutyryl acetanilide of formula IH in the presence of a base to obtain the DKT m of formula I as illustrated herein below:


The drawback associated with the process disclosed therein is low purity profile of resulting DKT III (about 97%).
Moreover, purity of Atorvastatin is dependent on the purity of DKT III, it is, therefore, important to control impurities at this stage which intern depends upon the purity profile of compound of formula II.
Inventors of the present invention have observed that 2-chloro-l-(4-fluorophenyl)-2-phenone of formula II obtained by the chlorination of compound of formula IIA is liquid having impurity profile as depicted in HPLC chromatograph represented by figure-I given hereinbelow. If compound of such an impurity profile is used as a starting material then it will result into the formation of crude DKT-III of Formula-I having impurity profile as expressed by a HPLC chromatograph of Figure-H given herein below.



FIGURE II
DKT-III represented by HPLC chromatograph of Figure-II can not be used as such for the preparation of Atorvastatin, therefore, it becomes essential to purify by crystallization to achieve the high purity to meet the specification of DKT III as well as of Atorvastatin therefrom.
Several factors are usually considered while developing a purification step at plant scale, including the dynamic capacity of the matrix. Therefore, crystallization as purification mode at plant level is less preferred over the distillation. Reason for this is that crystallization as a purification mode is multi-operational and multi-functional process as it could be guessed from the following figure which represents various operations that too without charcoalisation and filtration through a filtering mode like hyflo super eel, calcite etc , which otherwise will increase two more unit operations.

Figure - Steps in Recrystallization*

* indicating crystallization without charcoalisation, which otherwise increase two more unit operations viz charcoalisation followed by filtration to remove charcoal.
Furthermore, crystalisation step results in lower yield as some material remains in the solvent. In view of above, therefore, there is a dire need to develop a process that will produce substantially pure DKT III which can be used as such without purification for the preparation of Atorvastatin.
Inventors of the present invention disclose herein a process for the preparation of substantially pure DKT-III of Formula I comprising using substantially pure compound of Formula II obtained by industrially viable purification process of distillation avoiding multistep crystallization of DKT

Figure in
III. Desired purity of compound of Formula II which is suitable for preparing substantially pure DKT- III of Formula I which does not require purification and as such can be used for the preparation of Atorvastatin is achieved by industrially viable distillation process. Substantially pure distilled 2-chloro-l-(4-fluorophenyl)-2~phenone of formula II as indicated by the HPLC chromatograph (Figure IH) when contacted with compound of formula III yields DKT HI with high purity profile (Figure IV) that does not require additional purification by crystallization as confirmed by the chromatographs given herein below:



FIGURE IV
DISCREPTION OF THE FIGURES:
Figure I represents crude DK II of formula II before purification by
distillation.
Figure II represents crude DKT III with about 97% purity obtained by using
crude DK II represented by Figure I.
Figure III represents substantially pure DK II of formula II after distillation.
Figure IV represents substantially pure DKT III obtained by using distilled
DKII.
ADVANTAGES OF THE PRESENT INVENTION:
1) Process of the present invention comprises purification of DK- II by high vacuum distillation before it is used for preparing DKT HI avoiding purification of DKT-III by recrystalisation at latter stage making the process high yielding and cost effective.
2) Process of the present invention comprises high vacuum distillation of crude DK II of formula II to obtain substantially pure DK- II compound of formula H.

3) Use of distilled DKII results into high yield of substantially pure DKT III that does not require additional recrystallisation.
4) Avoiding crystallization at a later stage not only reduces the operational steps but also reduces cost of the project.
OBJECT OF THE INVENTION:
First aspect of the present invention is to provide an improved process for the synthesis of Atorvastatin key intermediate 4-fmoro-a-[2-methyI-l-oxopropyl]-y-oxo-N-P-diphenyIbenzenebutanamide of formula I.
Second aspect of the present invention is to provide an improved process for the synthesis of the Atorvastatin key intermediate 4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N-p-diphenylbenzenebutanamide of formula I that is substantially free of impurities.
Third aspect of the present invention is to provide an improved process for the synthesis of the Atorvastatin key intermediate 4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N-P-diphenylbenzenebutanamide with high yield and purity.
Forth aspect of the invention is to provide an improved process for the synthesis of the Atorvastatin key intermediate 4-fluoro-a-[2-methyl-l-oxopropylj-y-oxo-N-P-diphenylbenzenebutanamide of formula I, comprising the steps of: i) chlorinating the compound of formula ILA to obtain compound of formula II;

ii) distilling crude DK II of formula II obtained from step I to obtain
substantially pure DK- II; iii) contacting DK II obtained from step ii with compound of formula III
in a solvent in the presence of a base to prepare the compound of
formula I; iv) isolating the compound of formula I.
Fifth aspect of the present invention is to synthesize atorvastatin of formula ATV in high yield and purity, comprising the steps of:
i) chlorinating the compound of formula DA in a solvent optionally
in the presence of a base and or halogen carrier to obtain the DK II
of formula II; ii) distilling DK II of formula II obtained from step I; iii) contacting DK II obtained from step ii with compound of formula
m in a solvent in the presence of a base to prepare the compound
of formula I; iv) isolating the compound of formula I; v) employing the compound of formula I obtained from the step iv for
the preparation of Atorvastatin.
Sixth aspect of the present invention is to synthesize atorvastatin salt in high yield and purity, comprising the steps of:
i) chlorinating the compound of formula IIA in a solvent optionally in the presence of a base and or halogen carrier to obtain the DK II of formula II; ii) distilling DK II of formula II obtained from step I;

iii) contacting DK II obtained from step ii with compound of formula
III in a solvent in the presence of a base to prepare the compound
of formula I; iv) isolating the compound of formula I; v) employing the compound of formula I obtained from the step iv for
the preparation of atorvastatin of formula ATV; vi) employing atorvastatin obtained from step v for the preparation of
pharmaceutically acceptable salts of atorvastatin.
SUMMARY OF THE INVENTION
Disclosed herein is an improved process for the synthesis of DKT III of formula I comprising the steps of:
contacting substantially pure distilled 2-chloro-l-(4-fluorophenyl)-2-phenone of formula II with 4-methyl-3-oxo-N-phenylpentamide of formula HI in the presence of a base in a solvent resulting into high purity DKT III of formula I.
DETAILED DISCREPTION OF THE INVENTION:
The words contacting or contacted used hereinabove and hereinbelow mean
reacting, mixing, heating, refluxing, treating, stirring, condensing and the
like.
The invention will now be described in detail in connection with certain
general and preferred embodiments, so that various aspects thereof may be
more fully understood and appreciated without limiting the scope of the
invention.
In a general embodiment of the present invention disclosed herein is a
process for the preparation of DKT III of formula I comprising the steps of:

i) chlorinating the compound of formula IIA in a solvent optionally
in the presence of a base and or halogen carrier to obtain the DKII
of formula II; ii) distilling crude DK II obtained in step i) to obtain substantially
pure said DKTII of formula II; iii) contacting DK II obtained from step ii with compound of formula
III in a solvent in the presence of a base to prepare the compound
of formula I; iv) isolating the compound of formula I.
The reaction scheme is illustrated hereinbelow:

Chlorinating agent used for the preparation of DKT-II of Formula II is
chlorine.
Solvent used for the chlorination is any solvent that will not inhibit the
chlorination preferably halogenated solvents selected from the group
comprising aliphatic hydrocarbon like methyl chloride, methylene
dichloride, chloroform, carbontetrachloride, ethylenedichloride and mixture
thereof. The Preferable solvent is methylenedichloride.
The base used for the chlorination is any base that will not inhibit chlorination preferably organic amine selected from the group comprising

alkyl amines like methylamine, diethylamine, triethylamine and the like. Preferably base is triethylamine.
The solvent used for the reaction of DK II of formula II with compound of formula HI to prepare DKT III of formula I is any solvent that will not inhibit the reaction. The said solvent is a polar solvent comprising amide solvent, alcoholic solvent, ketonic solvent. Preferably solvent is an alcoholic solvent comprising C3-C5 linear or branched alcohols selected from the group comprising propanol, isopropanol, butanol, isobutanol,t-butanol,pentanol, isopentanol,t-pentanol and mixture thereof. More preferably solvent is isopropanol.
The base used for the reaction compound of formula II with compound of formula III to prepare compound of Formula I is an inorganic or organic base selected from the group comprising sodium carbonate, potassium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, lithium diisopropylamide, sodium hydride, n-butyl lithium, sodium ethoxide, metal hydroxide, or a mixture thereof. Preferably base is potassium carbonate.
DKT III so obtained is further converted into Atorvastatin by the processes known in the prior art. Which is further converted into it pharmaceutically acceptable salts comprising contacting with suitable salt. Particularly Atorvastatin calcium by contacting Atorvastatin with calcium source selected from the group comprising calcium acetate, calcium chloride and like.
Following examples will explain the invention in details:

Preparation of 4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N-p-diphenylbenzenebutanamide
EXAMPLE 1:
The mixture containing 300 ml isopropanol and 100 g of the formula III is cooled to 10-15°C. Potassium carbonate 94 g is charged into the above contents keeping the temperature 10-15°C. A solution of distilled 128 gm of formula II in 125 ml isopropanol is then added slowly in 2-3 hrs keeping temperature at 10-15°C. Temperature is allowed to reach at 25-30°C.Temperature is further raised to 40-45°C and then maintained for 8-10 hrs with simultaneous monitoring on HPLC. After HPLC complies, isopropanol is removed under vacuum keeping temperature below 55°C followed by the addition of 600ml ethyl acetate at 40-45°C. 600ml water is charged and the organic layer is collected. Solvent is removed under vacuum when a solid mass is seen. Solid is filtered off and washed with isopropanol. Yield obtained is 79% with purity of 99.74%.
Preparation of (4R-cis)-l,l-dimethylethyl-6-{2[2-fluorophenyl)-5-(l-methyIethyI)-3-phenyI-4-[(phenylamino) carbonyl]-lH-pyrrol-l-yI]}-2,2-dimethyI-l,3-dioxane-4-acetate
Example 2:
58g (4R-cis)-1,1 -dimethylethyl-6-(2-aminomethyl)-2,2-dimethyl-1,3-
dioxane-4-acetate is charged with 480 ml of cyclohexane at RT followed by the addition of 84 g of DKT III and 12 g of pivalic acid at RT. The reaction mass is heated to reach at 78°C and water is removed azeotropically.

Reaction is maintained for 62 hrs and is monitored. After the completion, reaction mass is quenched with sodium bicarbonate solution. Organic layer separated is washed thoroughly till it is free from acidity. Cyclohexane from the organic layer is recovered under vacuum. Residue so obtained is dissolved in isopropanol and product is isolated by the addition of water at 30-35°C.Product is further purified from isopropanol.
Preparation of Atorvastatin calcium
Example 3
40.0g (4R-cis)-1,1 -dimethylethyl-6-{2[2-fiuorophenyl)-5-( 1 -methylethyl)-3-
phenyl-4-[(phenylamino) carbonyl]-1 H-pyrrol-1 -yl]} -2,2-dimethyl-1,3-
dioxane-4-acetate is taken into 641 ml methanol. Heat the contents to 45-50°C till it gives a clear solution. Add 10.0 g at 20-26°C of hydrochloric acid. Reaction is maintained for 6 hrs, reaction is monitored on HPLC. After complete conversion it is added with solution of 7.0g NaOH dissolved in 65ml water at 23-26°C till the pH of 12-12.5 is reached. Contents are slowly heated to reach at 35-40°C and then maintained for 6 hrs. Completion of the reaction is followed by concentration of reaction mass under vacuum. Concentrated mass thus obtained is diluted with aqueous methanol and extracted with methyl tert butyl ether at 30-32°C.Aqueous layer is collected and given the washing with mixture containing n-hexane and cyclohexane (l:lv/v).pH of aqueous layer is adjusted to 8.2-8.4 using sodium hydroxide solution at 30-32°C. Finally calcium acetate 6.0g dissolved in 194 ml water is added to aqueous at 47-50°C till turbidity is observed. Contents are further heated till salt is precipitated. Product is filtered off and dried.

CLAIMS:
1. A process for preparing a compound of Formula I

comprising the steps of:
A) distillation of reaction mixture containing compound of formula II to
obtain substantially pure said compound of formula II;

B) contacting the compound of formula II obtained in step a) with compound of formula HI in the presence of a base and an organic solvent to yield a compound of formula I.
2. The process of claim 1 wherein solvent is C3-C5 alcohol selected from the group comprising n-propanol, isopropanol, n-butanol, isobutanol, t-butanol,n-pentanol, isopentanol, t-pentanol and mixture thereof.
3. The process of claim 2 wherein C3-C5 alcohol is isopropanol.

4. The process of claim 1 wherein base is select from the group comprising sodium carbonate, potassium carbonate, cesium carbonate, diisopropylefhylamine, triethylamine, lithium diisopropylamide, metal hydroxide, butyl lithium, sodium ethoxide and mixture thereof.
5. The process of claim 4 wherein base is potassium carbonate.
6. The process of claim 1 wherein solvent is isopropanol; and the base is potassium carbonate.
7. A process of preparing atorvastatin, comprising the steps of:

with a compound of formula III

(A) contacting the substantially pure compound of formula II obtained by distillation of the reaction mixture containing crude of the said compound of formula II;
in the presence of a base and organic solvent to yield a compound of formula
I;
(B) employing the compound of formula I to synthesize atorvastatin.

8. The process of claim 7 wherein the organic solvent is isopropanol; and the base is potassium carbonate.
9. A process of preparing atorvastatin calcium, comprising the steps of:

with a compound of formula III

(A) contacting the substantially pure compound of formula II obtained by distillation of the reaction mixture containing crude of the said compound of formula II;
in the presence of a base and organic solvent to yield a compound of formula
I;
(B) employing the compound of formula I to synthesize atorvastatin; and
(C) contacting the said atorvastatin with calcium source to yield calcium salt of atorvastatin.
10. The process of claim 9 wherein the organic solvent is isopropanol; and the base is potassium carbonate and calcium source is calcium acetate.