Title of Invention	An improved process for the preparation of 4-fluoro-a-[2-methyl-loxopropyl]-?-oxo-N-ß-diphenylbenzenebutanamide,
Abstract	A novel process for the preparation of 4-fluoro-α-[2-methyl-l-oxopropyl]-Y-oxo-N-p-diphenylbenzenebutanamide also known as 2-[2-(4-fluorophenyl)-2-oxo-l-phenylethyl]-4-niethyl-3-oxo-pentanoic acid phenylamiclc of the formula I containing about 0.1% or less of α-[2-methyl-l-oxopropyl]-y-oxo-N-β-diphenylbenzene butanamide, about 0.05 % or less of difluoro -α-[2-methyl-l-oxopropyl]-Y-oxo-M-p-diphenylbenzene butanamide and about 0.1% or less of 3-[2-(4-Fluorophenyl)-2-oxo-1 -phenyl-ethoxy]-4-methyl-pent-2-enoic acid phenylamide.

Title of Invention

An improved process for the preparation of 4-fluoro-a-[2-methyl-loxopropyl]-?-oxo-N-ß-diphenylbenzenebutanamide,

Abstract

A novel process for the preparation of 4-fluoro-α-[2-methyl-l-oxopropyl]-Y-oxo-N-p-diphenylbenzenebutanamide also known as 2-[2-(4-fluorophenyl)-2-oxo-l-phenylethyl]-4-niethyl-3-oxo-pentanoic acid phenylamiclc of the formula I containing about 0.1% or less of α-[2-methyl-l-oxopropyl]-y-oxo-N-β-diphenylbenzene butanamide, about 0.05 % or less of difluoro -α-[2-methyl-l-oxopropyl]-Y-oxo-M-p-diphenylbenzene butanamide and about 0.1% or less of 3-[2-(4-Fluorophenyl)-2-oxo-1 -phenyl-ethoxy]-4-methyl-pent-2-enoic acid phenylamide.

Full Text	FORM2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2006 PROVISIONAL SPECIFICATION (See section 10; rule 13) 1. Title of the invention. - "Novel process for (he preparation of 4-fluoro-a-[2-methyl-l- oxopropyl]-Y-oxo-N-p-diphenylbenzenebutanamide and products therefrom" 2. Applicant(s) (a) NAME : (b) NATIONALITY : (c) ADDRESS : ARCH PHARMALAES LIMITED An Indian Company "H" Wing, 4th floor, Tex Centre, Off Saki Vihar Road, Chandivali, Andheri (East), Mumbai-400 072, India. 3. PREAMBLE TO THE DESCRIPTION The following specification describes the invention. FIELD OF THE INVENTION The present invention relates to a novel process for the preparation of 4-fluoro-α-[2-methyl-l-oxopropyl]-Y-oxo-N-β-diphenylbenzenebutanamide of the formula I, a hey intermediate useful for the synthesis of Atorvastatin. The present invention in particular relates to a process for (he preparation of the compound of Formula 1 which is substantially free of impurities. BACKGROUND OF THE INVENTION One of the hey intermediates in the synthesis of Atorvastatin is as shown in formula I, hereinafter referred to as DKT 3. I This intermediate and its use in preparing Atorvastatin were disclosed in prior publications such as US 4681893, US 5124482, US 5216174, US 5097045. All these patents describe the process for the preparation of compound of formula I by reacting 4-rnethyl-3-oxo-N-phenyl-2-(phenylmethylene)pentamide with 4-fluorobenzaldehydc in the presence of a catalyst such as 3-benzy 1-5-(2-hydroxyethyl)-4-methylthiazolium chloride etc. DKT 3 has also been prepared by a different process by reacting 2-brorno-l-(4-fluorophenyl)-2-phenone (a compound of formula Tl) with 4-methyl-3-oxo-N-phenylpentamide (a compound of formula III) as disclosed in WO03/004457. Further an alternative route to I was disclosed in WO2006/021968. 2 X is CI or Br Following schematic representation depicts three different synthetic routes for the preparation of compound of the formula I. US 5124482: The compound of formula III v/as described in JOC, 1978, 43, 2087-2088, Synthesis 1992, 1213-1214, Chem.Pharm.Bull. 1987, 35, 1860-1870 3 US5124482 discloses that the preparation of compound of formula I requires the use of a catalyst selected from 3-benzyl-5-(2-hydroxyethyl)-4-methylthiaiolium chloride, 3,4-dimethyl-5-(2-hydro::y-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, l,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N,N,N,N-tetramethylethylcnediinine or the like. International application WO03/004457 discloses a process for making intermediate of formula I by using a highly polar solvent system comprising DMF, and water followed by chromatographic separation. An alternative process was described in international application WQ2006/021968, v.hich comprises a reaction between brorno-4-methyl-3-oxo pentanoic acid phenylamide and l-(4-fluoro phenyl)-2-phenyl ethanone. Other relevant references may include: KR 10-2004-0001435, J. Labelled Cpd.Radiopharm.42, 121-127, 1999, and KR 20050124322. Since the purity of Atorvastatin is controlled by the purity of DKT 3, it is important to control and minimize the impurities at this stage. There are two major impurities known that affect the purity of Atorvastatin. In the process described in US 5124432, the presence of trace amounts of water during the synthesis of DKT 3 results in the formation of two major impurities: c.-[2-methyl-l-oxopropyl]-y-oxo-N-p-diphenylberzene butanamide (abbreviated as "desfluoro" and shown by the formula IV); and difluoro- α-[2-methyl-l-oxopropyl]-y-oxo-N-P-diphenylberrzene butanamide (abbreviated as "difluoro" and is shown by the formula V). 4 alpha-[2-methyl-]-oxopropyl]-gamma-oxo-N-beta-diphenylben2enebutanamide IV difluoro-alpha-[2-niethyl-]-oxopropyl]-gamma-oxo-N-beta-diphenylben2enebutanamide V The prior literature has not consistently addressed the matter of impurities. For example, U85124482, WO03/004457 and KP 10-2004-0001435 do not specifically disclose the impurity profiles of the processes disclosed therein. The other relevant literature either does not mention or specify the level of O-alkylated impurity in atorvastatin. Formula VI (O-Alkylated Impurity) 5 The present inventors have surprisingly identified and characterised another impurity in DRT 3 to be 3-[2-(4-Fluorophenyl)-2-o>:o-l-phenyl-etho::y]-4-mcthyl-pent-2-enoic acid phenylarnide (hereinafter referred to as O-alkylated impurity, shown as formula VI) The present inventors have further found that the O-alkylated related impurity is a limitation to the yield and purity of DKT 3 and consequently provided an improved process for DKT 3 which results in higher purity and greater yield of the said critical intermediate for Aiorvastatin. The present invention provides processes for preparing DKT 3 with the desfluoro impurity about 0.1% or below; the difluoro impurity about 0.05 % or less and O-alkylated impurity of about 0.1% or less. Aiorvastatin is generally prepared by reaction known as Paal-Knorr pyrrole synthesis in which amine is reacted with the compound of the present invention of formula I .It involves addition of a primary amine to both leto groups of the diketone and the elimination of two moles of water to achieve the aromaticity. US patent 529S627 discloses the reaction between amine and diketone of the formula 1 in presence of pivalic acid as catalyst in temary mixture of heptane: THF: toluene. The product obtained is an acetonide protected 3, 5-dihydroxy-7-pyrrol-1-yl-heptanoic acid amide, which on further cleavage of acetonide was hydrolyzed to the carboxylic acid. US patent 5397792 discloses same kind of condensation using toluene/heptane/tetrahydrofuran in another ratio in the presence of pivalic acid as catalyst. US patent 5216174 described the Paal-Knorr reaction between tert butyl ester of acetonide protected 3, 5-dihydroxy-7-pyrmol-l-yl-heptanoic acid in solvents like hexane, toluene. Product formed is not isolated treated directly with an acid to remove the acetonide protecting group. WO2004/046105 discloses the reaction between ketal protected diprotected -7-amino-3,5-dihydroxy heptanol with diketone of formula I under acid catalyst conditions. The resulting heptanols are oxidized via the corresponding aldehyde 6 with or without isolation resulting into hetal protected diprotected -7-arnino-3. 5-dihydroxy -7-pyrrol-l-yl-heptanoic acid. OBJECT OF THE INVENTION: It is an object of the present invention to provide an improved process for the synthesis of the atorvastatin intermediate 4-fluoro-α-[2-methyl-l-oxcpropyl]-y-oxo-M-p-diphenylbenzenebutanamide. It is another object of the present invention to provide an improved process for the synthesis of the atorvastatin intermediate 4-fluoro-α-[2-methyl-l-oxopropyl]-Y-oxo-N-β-diphenylbenzenebuianamide that is substantially free of impurities. It is a further object of (the present invention to piovide an improved process for the synthesis of the atorvastatin intermediate 4-fluoro-α-[2-methyl-l-oxopropyl]-Y-oxo-11-p-diphenylbenzenebuianamide with O-alkylaied impurity of about 0.1% or less. It is yet another object of the present invention to provide an improved process for the synthesis of the atorvastatin intermediate 4-fluoro-α-[2-methyl-l-oxopropyl]-y-oxo-N-β-diphenylbencenebutanamide with high yield and purity. It is yet another object of the present invention to provide 3-[2-(4-Fluorophenyl)-2-oxo-l-phenyl-ethoxy]-4-methyl-pent-2-enoic acid phenylamide (hereinafter referred to as O-alhylated impurity, shown as formula VI). It is a further object of the present invention to synthesize atorvastatin in high yield and purity employing the intermediate 4-fluoio-α-[2-methyl-1-oxopropyl]-y-oxo-N-α-diphenylbenzenebutanamide with O-alhylated impurity of about 0.1% or less. 7 It is another object of the present invention to provide a process for the synthesis of compound of Formula III. SUMMARY OF THE INVENTION According to an aspect of the present invention there is provided an improved process for the synthesis of the atorvastatin intermediate 4-fluoro-α-[2-melhyl-l-oxopropyl]-y-oxo-TI-p-diphenylbenzenebutanamide, the said process comprising the step of: a) Reaction of a compound of Formula II and a compound of Formula III, in the presence of a base and isopropyl alcohol to obtain a compound of Formula I, wherein said compound of Formula I contains about 0.1% or less of O-alkylatecl compound of Formula VI as an impurity. According to yet another aspect of the present invention there is provided a process for the synthesis of compound of Formula III comprising the step of reaction of methyl isobutyryl acetate and aniline in the presence of a pyridine base. o o Methyl isobutyryl acetate and Aniline According to another aspect of the present invention there is provided a process for the synthesis of atorvastatin with a yield of about 70% or greater comprising the siep of reaction of the said compound of Formula I. 8 DETAILED DESCRIPTION OF THE INVENTION The present invention provides a process for making a hey intermediate for Atorvastatin viz 4-fluoro-α.-[2-methyl-l -oxopropyl]-y-oxo-N-β- diphenylbenzenebutanamide also referred to as DKT-3 at a higher yield and better impurity profile. One of the key intermediates in the Atorvastatin process is an intermediate called DKT 3, shown as Formula 1. There are three major impurities in the process for making DKT 3. These are: α-[2-methyl-l-oxopropyl]-y-oxo-N- p-diphenylbenzenebutanamicle (referred to herein as desfluoro compound of Formula IV ), difluoro α-[2-methyl-l-oxopropyl]-y-oxo-N-β-diphenylbenzenebutanamide (referred to herein as difluoro compound of Formula V), And Oalkylated compound shown as Formula VI. The process provided herein reduces these impurities to: about 0.1% or less; about 0.05% or less; and about 0.1% or less for compounds IV, V and VI respectively. In addition, the present process provides Intermediate I in yields of about 70% or greater. The general schematic for preparing the intermediate of formula I is shown below: X = CI or Br In one aspect, the halogen of the reactant is preferentially chlorine. The chloro compound is much more economical and environmental friendly. In addition, the process provides DKT 3 which leads to Atorvastatin having about 0.1% or less of desfluoro impurity, and about 0.05% or less of difluoro impurity. 9 The base may be selected from the group containing sodium carbonate, potassium carbonate, cesium carbonate, diisopropylethylamine, triethylarnine, or suitable mixture thereof, lithium diisopropylamide, sodium hydride, n-butyl lithium, sodium ethoxide, metal hydroxide, or a mixture thereof. The present inventors have surprisingly found that when the alcohol is isopropyl alcohol, the process yields intermediste of formula I with a significantly reduced amount of 3-[2-(4-F]uo]o-phenyl)-2-oxo-l-phenyl-elhoxy]-4-methy]-pent-2-enoic acid phenylamide as an impurity known as the O-alkylated impurity shown as formula VI below: O-alkylated Impurity (VI) In one aspect, the process provides for preparing DKT 3 wherein the O-alkylated impurity is about 0.1% or less. This result is accomplished by using isopropyl alcohol as the solvent, which is not specified in prior literature. For example, WG03/004457 discloses that polar solvents or solvent mixtures, for example alcohols (methanol or ethanol being specially preferred) or polar aprotic solvents, such as ethers, e.g. dioxane or THF or especially N,N -di-lower alkyl lower alkanoylamides, such as DMF or dimeihylaceiarnide, hexamethylphosphoric acid triamide or dimethyl sulfoxide, may be used. However, this reference does not indicate that the O-alkylated impurity is a problem, let alone suggests a solution to the problem. The inventors have tried to solve the O-alkylated impurity problem by carrying out the reaction in numerous solvents, such as the above mentioned solvents as well as others. For example, when acetone was used, the O-Alkylated impurity was found to be about 20-25%. When methanol was used, the O-Alkylated 10 impurity was found to be almost 50%. Other solvents such as DMF, DMSO, methyl ethyl ketone, methyl isobutyl ketone, n- butanol, toluene, and acetonitrile led to an impure product with many other impurities. The intermediate of formula 1 is further recrystallized from solvents such as isopropyl alcohol, methylene dichloride/hexane, ethyl acetate /hexane, etc. In one preferred method, the re-crystallization solvent is a mixture of isopropyl alcohol and methanol. The method of using isopropyl alcohol as a solvent has not only provided an unexpected reduction in the O-alkylated impurity, but also improved the yield of DKT 3 by about 30% wAv. The yield comparison v/as made against that of a process using acetone as the solvent. Additionally, a novel process is provided for the preparation of 4-mcthyl-3-oxo-N-phenylpentamide in appreciably good yield with reaction times significantly shortened. This process makes the Atorvastatin production economical and environmental friendly on an industrial scale. A process was described previously for the preparation of 4-methyl-3-oxo-N-phenylpentamide comprising of reaction between methyl-4-methyl -3-oxopentanoate and aniline (to be added in lots) using a solvent in presence of ethylene diamine as a base. The product isolation requires 10 days. The reported yield was 69%. In the present invention the same reaction is modified by changing the base to a pyridine base such as pyridine, picolines, lutidines -halogenated pyridines, which acts both as a solvent and as a base. The process results in a substantial increase in yield by 10% giving 79% wilh required purity of the substance making it commercially preferable. The reaction process has been shortened to about one 11 clay or less, compared to ten days described previously. This is a significant advantage over the prior processes. The general scheme is shown as below. This process avoids the use of additional solvents like toluene which are difficult to remove. For example, use of toluene would require azeotropic distillation, whereas the pyridine base solvent needs only simple distillation. Further efficiencies are noted because the invented process requires addition of aniline in one portion compared to the prior art processes which required the addition of aniline in multiple portions. As a result, the present process has increased the yield by about 20% compared to prior processes, for example those that have utilized ethylenediamine. Thus, a novel process is provided to prepare a compound of formula III, comprising: reacting methyl-4-methyl -3-oxopentanoate with aniline in the presence of a pyridine base. In one aspect, the aniline is added in one continuous event. In another aspect, a process for mailing Aiorvastatin is provided wherein 4-methyl-3-oxo-N-phcnylpentamicle is prepared by reacting methyl-4-methyl -3-oxopentanoate with aniline in the presence of a pyridine base, and utilizing said 4-methyl-3-oxo-l J-phenylpentarnide to prepare DKT 3, and further utilizing DKT 3 to make atorvastatin. Aiorvastatin is generally prepared by reaction known as Paal-Knorr pyrole synthesis in which amine is reacted with the compound of the present invention of formula I .It involves addition of a primary amine to both keto groups of the diketone and the elimination of two moles of water to achieve the aromaticity. 12 "All the literature mentioned above and elsewhere in this application is hereby incorporated by reference." "The term atorvastatin includes atorvaslatin, and its pharmaceutically acceptable salts such as calcium, sodium, potassium, magnesium, zinc. among others, and any hydrates or solvates thereof. In addition, such atorvastatin may be present in an amorphous form or in one of its many polymorphic forms." The Atorvastatin thus prepared can be used to manufacture pharmaceutical compositions for administration. Said compositions may include tablets, capsules, solutions and suspensions among others. Solutions and suspensions may include those that arc intended for oral as well as parenteral administration. Methods for making and administering the pharmaceutical compositions are well-known in the pharmaceutical and medical arts. The following non limiting examples will illustrate the invention clearly. EXAMPLE 1: The mixture containing 300 ml Isopropyl alcohol 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 ofl2S gm of formula II in 125 ml Isopropyl alcohol 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 3-10 hrs with simultaneous monitoring on IIPLC. After HPLC complies, isopropyl alcohol is removed under vacuum keeping temp 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. This solid is then purified by using Isopropyl alcohol and methanol. Resulting purity found to be 99.69 % with 0.047% of DESFLUORO impurity, Difluoro almost nil and O-alkylated impurity to be 0.1% with yield of 73%. 13 EXAMPLE 2: The mixture containing 300 ml Isopropyl alcohol and 100 g of the formula 111 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 l28 gm of formula TI in 125 ml Isopropyl alcohol 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, potassium carbonate is removed by filtration followed by removal of isopropyl alcohol under vacuum keeping temp below 55°C followed by the addition of 600ml ethyl acetate at 40-45°C. 100ml water is charged and the organic layer is collected. Solvent is removed under vacuum when a solid mass is seen. This solid is then purified by using Isopropyl alcohol and methanol. Resulting purity found to be 99.77% with 0.076% of DESFLUORO impurity, E'ifluoro to be almost nil and O-alkylaled impurity to be 0.1% with yield of 73%. EXAMPLE 3: Reaction mixture containing 100 g methyl isobutyryl acetate and 100 ml of pyridine is heated at temperature of 110-115°C. 77.5g aniline is added slowly in about two hrs keeping reaction mass at 110-115°C. Completion of the reaction is monitored by TLC. Mixture of pyridine and methanol is distilled out at 85-90°C under reduced pressure. Contents are cooled to 35-40°C and water is added followed by pH adjustment to 1-1.5. Mass is cooled further to 10-20°C and product is filtered off. Wet cake obtained as 125-150 g (moisture content 20%, assay 98.5% by HPLC). 14 WE CLAIM: 1. An improved process for the synthesis of the alorvastatin intermediate 4-fluor&-α-[2-methyl-l-oxopropyl]-Y-oxo-N-β-diphenylben2enebutanamide, the said process comprising the step of: II (X is CI or Br) III Reaction of a compound of Formula II and a compound of Formula III, in the presence of a base and isopropyl alcohol to obtain a compound of Formula I, wherein said compound of Formula I contains about 0.1% or less of O-alhylated compound of Formula VI as an impurity. 2. The process for the synthesis of the atorvastalin intermediate 4-fluoro-α- [2-niediyl-l-oxopropyl]-y-oxo-N-β-cliphenyIbenzenebutanarnide as claimed in claim 1 wherein the base is selected from selected from the group containing sodium carbonate, potassium carbonate, cesium carbonate, diisopropyl ethyl amine, triethyl amine, 15 lith i umd i isopropy larnide, sodium hydride, n-butyl lithium, codium ethoxide, metal hydroxide, hydrogen carbonate, or a mixture thereof. 3. A process for the synthesis of compound of Formula III comprising the step of reaction of methyl isobutyryl acetate and aniline in the presence of a pyridine base. Methyl isobutyryl acetate and Aniline 1 16 4. The process as claimed in claim 3 wherein the said pyridine base is selected from the group consisting of: pyridine, picolines, halogenated pyridines, or lutidines. 5. A substantially pure compound of the formula I containing about 0.1% or less of a-[2-rnethyl-l -oxopropyl]-y-oxo-N-β-diphenylbercene butanamide, about 0.05 % or less of difluoro -α-[2-methyl-l-oxopropyl]-y-oxo-N-β-diphenylbenzene butanamide, and about 0.1% or less of O-alkylated impurity of formula VI. 6. The process for the synthesis of atorvaslatin with a yield of about 70% or greater comprising the step of reaction of the compound of Formula I as claimed in claim 5. 7. The compound 3-[2-(4-Fluorophenyl)-2-oxo-l-phenyl-ethoxy]-4-methyl-pent-2-enoic acid phcnylamide represented by formula VI. Formula VI 8. A pharmaceutical composition comprising a tablet, capsule, suspension or solution comprising substantially pure Atorvastatin containing about 0.1% or less of a-[2-methyl-l-oxopropyl]-y-oxo-Tl-p-dipheriylbenzene butanamide, about 0.05 % or less of difluoro -a-[2-methyl-l-o;-:opropyl]- y-oxo-N-β-diphenylbenzene butanamide and about 0.1% or less of 3-[2-(4- FIuorophenyl)-2-oxo-l-phenyI-ethoxy]-4-methyI-pent-2-enoic acid phenylamide. Dated this 29th day of May 2008, Abhishek Sen Of S. Majumdar & Co. Applicant's Agent 17

Full Text

FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2006
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - "Novel process for (he preparation of 4-fluoro-a-[2-methyl-l-
oxopropyl]-Y-oxo-N-p-diphenylbenzenebutanamide and products therefrom"

2. Applicant(s)
(a) NAME :
(b) NATIONALITY :
(c) ADDRESS :

ARCH PHARMALAES LIMITED
An Indian Company
"H" Wing, 4th floor, Tex Centre, Off Saki Vihar Road, Chandivali, Andheri (East), Mumbai-400 072, India.

3. PREAMBLE TO THE DESCRIPTION

The following specification describes the invention.

FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of 4-fluoro-α-[2-methyl-l-oxopropyl]-Y-oxo-N-β-diphenylbenzenebutanamide of the formula I, a hey intermediate useful for the synthesis of Atorvastatin. The present invention in particular relates to a process for (he preparation of the compound of Formula 1 which is substantially free of impurities.
BACKGROUND OF THE INVENTION
One of the hey intermediates in the synthesis of Atorvastatin is as shown in formula I, hereinafter referred to as DKT 3.

I This intermediate and its use in preparing Atorvastatin were disclosed in prior publications such as US 4681893, US 5124482, US 5216174, US 5097045. All these patents describe the process for the preparation of compound of formula I by reacting 4-rnethyl-3-oxo-N-phenyl-2-(phenylmethylene)pentamide with 4-fluorobenzaldehydc in the presence of a catalyst such as 3-benzy 1-5-(2-hydroxyethyl)-4-methylthiazolium chloride etc.
DKT 3 has also been prepared by a different process by reacting 2-brorno-l-(4-fluorophenyl)-2-phenone (a compound of formula Tl) with 4-methyl-3-oxo-N-phenylpentamide (a compound of formula III) as disclosed in WO03/004457. Further an alternative route to I was disclosed in WO2006/021968.
2

X is CI or Br

Following schematic representation depicts three different synthetic routes for the preparation of compound of the formula I.
US 5124482:

The compound of formula III v/as described in JOC, 1978, 43, 2087-2088, Synthesis 1992, 1213-1214, Chem.Pharm.Bull. 1987, 35, 1860-1870
3

US5124482 discloses that the preparation of compound of formula I requires the use of a catalyst selected from 3-benzyl-5-(2-hydroxyethyl)-4-methylthiaiolium chloride, 3,4-dimethyl-5-(2-hydro::y-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, l,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N,N,N,N-tetramethylethylcnediinine or the like.
International application WO03/004457 discloses a process for making intermediate of formula I by using a highly polar solvent system comprising DMF, and water followed by chromatographic separation.
An alternative process was described in international application WQ2006/021968, v.hich comprises a reaction between brorno-4-methyl-3-oxo pentanoic acid phenylamide and l-(4-fluoro phenyl)-2-phenyl ethanone. Other relevant references may include: KR 10-2004-0001435, J. Labelled Cpd.Radiopharm.42, 121-127, 1999, and KR 20050124322.
Since the purity of Atorvastatin is controlled by the purity of DKT 3, it is important to control and minimize the impurities at this stage. There are two major impurities known that affect the purity of Atorvastatin. In the process described in US 5124432, the presence of trace amounts of water during the synthesis of DKT 3 results in the formation of two major impurities: c.-[2-methyl-l-oxopropyl]-y-oxo-N-p-diphenylberzene butanamide (abbreviated as "desfluoro" and shown by the formula IV); and difluoro- α-[2-methyl-l-oxopropyl]-y-oxo-N-P-diphenylberrzene butanamide (abbreviated as "difluoro" and is shown by the formula V).
4

alpha-[2-methyl-]-oxopropyl]-gamma-oxo-N-beta-diphenylben2enebutanamide
IV
difluoro-alpha-[2-niethyl-]-oxopropyl]-gamma-oxo-N-beta-diphenylben2enebutanamide
V The prior literature has not consistently addressed the matter of impurities. For example, U85124482, WO03/004457 and KP 10-2004-0001435 do not specifically disclose the impurity profiles of the processes disclosed therein. The other relevant literature either does not mention or specify the level of O-alkylated impurity in atorvastatin.

Formula VI (O-Alkylated Impurity)
5
The present inventors have surprisingly identified and characterised another impurity in DRT 3 to be 3-[2-(4-Fluorophenyl)-2-o>:o-l-phenyl-etho::y]-4-mcthyl-pent-2-enoic acid phenylarnide (hereinafter referred to as O-alkylated impurity, shown as formula VI)

The present inventors have further found that the O-alkylated related impurity is a limitation to the yield and purity of DKT 3 and consequently provided an improved process for DKT 3 which results in higher purity and greater yield of the said critical intermediate for Aiorvastatin.
The present invention provides processes for preparing DKT 3 with the desfluoro impurity about 0.1% or below; the difluoro impurity about 0.05 % or less and O-alkylated impurity of about 0.1% or less.
Aiorvastatin is generally prepared by reaction known as Paal-Knorr pyrrole synthesis in which amine is reacted with the compound of the present invention of formula I .It involves addition of a primary amine to both leto groups of the diketone and the elimination of two moles of water to achieve the aromaticity.
US patent 529S627 discloses the reaction between amine and diketone of the formula 1 in presence of pivalic acid as catalyst in temary mixture of heptane: THF: toluene. The product obtained is an acetonide protected 3, 5-dihydroxy-7-pyrrol-1-yl-heptanoic acid amide, which on further cleavage of acetonide was hydrolyzed to the carboxylic acid. US patent 5397792 discloses same kind of condensation using toluene/heptane/tetrahydrofuran in another ratio in the presence of pivalic acid as catalyst.
US patent 5216174 described the Paal-Knorr reaction between tert butyl ester of acetonide protected 3, 5-dihydroxy-7-pyrmol-l-yl-heptanoic acid in solvents like hexane, toluene. Product formed is not isolated treated directly with an acid to remove the acetonide protecting group.
WO2004/046105 discloses the reaction between ketal protected diprotected -7-amino-3,5-dihydroxy heptanol with diketone of formula I under acid catalyst conditions. The resulting heptanols are oxidized via the corresponding aldehyde
6

with or without isolation resulting into hetal protected diprotected -7-arnino-3. 5-dihydroxy -7-pyrrol-l-yl-heptanoic acid.
OBJECT OF THE INVENTION:
It is an object of the present invention to provide an improved process for the synthesis of the atorvastatin intermediate 4-fluoro-α-[2-methyl-l-oxcpropyl]-y-oxo-M-p-diphenylbenzenebutanamide.
It is another object of the present invention to provide an improved process for the synthesis of the atorvastatin intermediate 4-fluoro-α-[2-methyl-l-oxopropyl]-Y-oxo-N-β-diphenylbenzenebuianamide that is substantially free of impurities.
It is a further object of (the present invention to piovide an improved process for the synthesis of the atorvastatin intermediate 4-fluoro-α-[2-methyl-l-oxopropyl]-Y-oxo-11-p-diphenylbenzenebuianamide with O-alkylaied impurity of about 0.1% or less.
It is yet another object of the present invention to provide an improved process for the synthesis of the atorvastatin intermediate 4-fluoro-α-[2-methyl-l-oxopropyl]-y-oxo-N-β-diphenylbencenebutanamide with high yield and purity.
It is yet another object of the present invention to provide 3-[2-(4-Fluorophenyl)-2-oxo-l-phenyl-ethoxy]-4-methyl-pent-2-enoic acid phenylamide (hereinafter referred to as O-alhylated impurity, shown as formula VI).
It is a further object of the present invention to synthesize atorvastatin in high yield and purity employing the intermediate 4-fluoio-α-[2-methyl-1-oxopropyl]-y-oxo-N-α-diphenylbenzenebutanamide with O-alhylated impurity of about 0.1% or less.
7

It is another object of the present invention to provide a process for the synthesis of compound of Formula III.
SUMMARY OF THE INVENTION
According to an aspect of the present invention there is provided an improved process for the synthesis of the atorvastatin intermediate 4-fluoro-α-[2-melhyl-l-oxopropyl]-y-oxo-TI-p-diphenylbenzenebutanamide, the said process comprising the step of:
a) Reaction of a compound of Formula II and a compound of Formula III, in the presence of a base and isopropyl alcohol to obtain a compound of Formula I, wherein said compound of Formula I contains about 0.1% or less of O-alkylatecl compound of Formula VI as an impurity.
According to yet another aspect of the present invention there is provided a process for the synthesis of compound of Formula III comprising the step of reaction of methyl isobutyryl acetate and aniline in the presence of a pyridine base.

o o
Methyl isobutyryl acetate
and
Aniline According to another aspect of the present invention there is provided a process for the synthesis of atorvastatin with a yield of about 70% or greater comprising the siep of reaction of the said compound of Formula I.
8

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for making a hey intermediate for
Atorvastatin viz 4-fluoro-α.-[2-methyl-l -oxopropyl]-y-oxo-N-β-
diphenylbenzenebutanamide also referred to as DKT-3 at a higher yield and better
impurity profile. One of the key intermediates in the Atorvastatin process is an
intermediate called DKT 3, shown as Formula 1. There are three major impurities
in the process for making DKT 3. These are: α-[2-methyl-l-oxopropyl]-y-oxo-N-
p-diphenylbenzenebutanamicle (referred to herein as desfluoro compound of
Formula IV ),
difluoro α-[2-methyl-l-oxopropyl]-y-oxo-N-β-diphenylbenzenebutanamide
(referred to herein as difluoro compound of Formula V),
And Oalkylated compound shown as Formula VI.
The process provided herein reduces these impurities to: about 0.1% or less; about
0.05% or less; and about 0.1% or less for compounds IV, V and VI respectively.
In addition, the present process provides Intermediate I in yields of about 70% or
greater.
The general schematic for preparing the intermediate of formula I is shown below:

X = CI or Br
In one aspect, the halogen of the reactant is preferentially chlorine. The chloro compound is much more economical and environmental friendly. In addition, the process provides DKT 3 which leads to Atorvastatin having about 0.1% or less of desfluoro impurity, and about 0.05% or less of difluoro impurity.
9

The base may be selected from the group containing sodium carbonate, potassium carbonate, cesium carbonate, diisopropylethylamine, triethylarnine, or suitable mixture thereof, lithium diisopropylamide, sodium hydride, n-butyl lithium, sodium ethoxide, metal hydroxide, or a mixture thereof.
The present inventors have surprisingly found that when the alcohol is isopropyl alcohol, the process yields intermediste of formula I with a significantly reduced amount of 3-[2-(4-F]uo]o-phenyl)-2-oxo-l-phenyl-elhoxy]-4-methy]-pent-2-enoic acid phenylamide as an impurity known as the O-alkylated impurity shown as formula VI below:

O-alkylated Impurity (VI) In one aspect, the process provides for preparing DKT 3 wherein the O-alkylated impurity is about 0.1% or less. This result is accomplished by using isopropyl alcohol as the solvent, which is not specified in prior literature. For example, WG03/004457 discloses that polar solvents or solvent mixtures, for example alcohols (methanol or ethanol being specially preferred) or polar aprotic solvents, such as ethers, e.g. dioxane or THF or especially N,N -di-lower alkyl lower alkanoylamides, such as DMF or dimeihylaceiarnide, hexamethylphosphoric acid triamide or dimethyl sulfoxide, may be used. However, this reference does not indicate that the O-alkylated impurity is a problem, let alone suggests a solution to the problem.
The inventors have tried to solve the O-alkylated impurity problem by carrying out the reaction in numerous solvents, such as the above mentioned solvents as well as others. For example, when acetone was used, the O-Alkylated impurity was found to be about 20-25%. When methanol was used, the O-Alkylated
10

impurity was found to be almost 50%. Other solvents such as DMF, DMSO, methyl ethyl ketone, methyl isobutyl ketone, n- butanol, toluene, and acetonitrile led to an impure product with many other impurities.
The intermediate of formula 1 is further recrystallized from solvents such as isopropyl alcohol, methylene dichloride/hexane, ethyl acetate /hexane, etc. In one preferred method, the re-crystallization solvent is a mixture of isopropyl alcohol and methanol.
The method of using isopropyl alcohol as a solvent has not only provided an unexpected reduction in the O-alkylated impurity, but also improved the yield of DKT 3 by about 30% wAv. The yield comparison v/as made against that of a process using acetone as the solvent.
Additionally, a novel process is provided for the preparation of 4-mcthyl-3-oxo-N-phenylpentamide in appreciably good yield with reaction times significantly shortened. This process makes the Atorvastatin production economical and environmental friendly on an industrial scale.
A process was described previously for the preparation of 4-methyl-3-oxo-N-phenylpentamide comprising of reaction between methyl-4-methyl -3-oxopentanoate and aniline (to be added in lots) using a solvent in presence of ethylene diamine as a base. The product isolation requires 10 days. The reported yield was 69%.
In the present invention the same reaction is modified by changing the base to a pyridine base such as pyridine, picolines, lutidines -halogenated pyridines, which acts both as a solvent and as a base. The process results in a substantial increase in yield by 10% giving 79% wilh required purity of the substance making it commercially preferable. The reaction process has been shortened to about one
11

clay or less, compared to ten days described previously. This is a significant advantage over the prior processes. The general scheme is shown as below.

This process avoids the use of additional solvents like toluene which are difficult to remove. For example, use of toluene would require azeotropic distillation, whereas the pyridine base solvent needs only simple distillation. Further efficiencies are noted because the invented process requires addition of aniline in one portion compared to the prior art processes which required the addition of aniline in multiple portions. As a result, the present process has increased the yield by about 20% compared to prior processes, for example those that have utilized ethylenediamine.
Thus, a novel process is provided to prepare a compound of formula III, comprising:
reacting methyl-4-methyl -3-oxopentanoate with aniline in the presence of a pyridine base. In one aspect, the aniline is added in one continuous event. In another aspect, a process for mailing Aiorvastatin is provided wherein 4-methyl-3-oxo-N-phcnylpentamicle is prepared by reacting methyl-4-methyl -3-oxopentanoate with aniline in the presence of a pyridine base, and utilizing said 4-methyl-3-oxo-l J-phenylpentarnide to prepare DKT 3, and further utilizing DKT 3 to make atorvastatin.
Aiorvastatin is generally prepared by reaction known as Paal-Knorr pyrole synthesis in which amine is reacted with the compound of the present invention of formula I .It involves addition of a primary amine to both keto groups of the diketone and the elimination of two moles of water to achieve the aromaticity.
12

"All the literature mentioned above and elsewhere in this application is hereby incorporated by reference."
"The term atorvastatin includes atorvaslatin, and its pharmaceutically acceptable salts such as calcium, sodium, potassium, magnesium, zinc. among others, and any hydrates or solvates thereof. In addition, such atorvastatin may be present in an amorphous form or in one of its many polymorphic forms."
The Atorvastatin thus prepared can be used to manufacture pharmaceutical compositions for administration. Said compositions may include tablets, capsules, solutions and suspensions among others. Solutions and suspensions may include those that arc intended for oral as well as parenteral administration. Methods for making and administering the pharmaceutical compositions are well-known in the pharmaceutical and medical arts.
The following non limiting examples will illustrate the invention clearly.
EXAMPLE 1:
The mixture containing 300 ml Isopropyl alcohol 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 ofl2S gm of formula II in 125 ml Isopropyl alcohol 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 3-10 hrs with simultaneous monitoring on IIPLC. After HPLC complies, isopropyl alcohol is removed under vacuum keeping temp 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. This solid is then purified by using Isopropyl alcohol and methanol. Resulting purity found to be 99.69 % with 0.047% of DESFLUORO impurity, Difluoro almost nil and O-alkylated impurity to be 0.1% with yield of 73%.
13

EXAMPLE 2:
The mixture containing 300 ml Isopropyl alcohol and 100 g of the formula 111 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 l28 gm of formula TI in 125 ml Isopropyl alcohol 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, potassium carbonate is removed by filtration followed by removal of isopropyl alcohol under vacuum keeping temp below 55°C followed by the addition of 600ml ethyl acetate at 40-45°C. 100ml water is charged and the organic layer is collected. Solvent is removed under vacuum when a solid mass is seen. This solid is then purified by using Isopropyl alcohol and methanol. Resulting purity found to be 99.77% with 0.076% of DESFLUORO impurity, E'ifluoro to be almost nil and O-alkylaled impurity to be 0.1% with yield of 73%.
EXAMPLE 3:
Reaction mixture containing 100 g methyl isobutyryl acetate and 100 ml of pyridine is heated at temperature of 110-115°C. 77.5g aniline is added slowly in about two hrs keeping reaction mass at 110-115°C. Completion of the reaction is monitored by TLC. Mixture of pyridine and methanol is distilled out at 85-90°C under reduced pressure. Contents are cooled to 35-40°C and water is added followed by pH adjustment to 1-1.5. Mass is cooled further to 10-20°C and product is filtered off. Wet cake obtained as 125-150 g (moisture content 20%, assay 98.5% by HPLC).
14

WE CLAIM:
1. An improved process for the synthesis of the alorvastatin intermediate 4-fluor&-α-[2-methyl-l-oxopropyl]-Y-oxo-N-β-diphenylben2enebutanamide, the said process comprising the step of:

II (X is CI or Br)
III
Reaction of a compound of Formula II and a compound of Formula III, in the presence of a base and isopropyl alcohol to obtain a compound of Formula I, wherein said compound of Formula I contains about 0.1% or less of O-alhylated compound of Formula VI as an impurity.

2. The process for the synthesis of the atorvastalin intermediate 4-fluoro-α-
[2-niediyl-l-oxopropyl]-y-oxo-N-β-cliphenyIbenzenebutanarnide as
claimed in claim 1 wherein the base is selected from selected from the
group containing sodium carbonate, potassium carbonate, cesium
carbonate, diisopropyl ethyl amine, triethyl amine,
15

lith i umd i isopropy larnide, sodium hydride, n-butyl lithium, codium ethoxide, metal hydroxide, hydrogen carbonate, or a mixture thereof.
3. A process for the synthesis of compound of Formula III comprising the step of reaction of methyl isobutyryl acetate and aniline in the presence of a pyridine base.
Methyl isobutyryl acetate and

Aniline

1
16
4. The process as claimed in claim 3 wherein the said pyridine base is selected from the group consisting of: pyridine, picolines, halogenated pyridines, or lutidines.
5. A substantially pure compound of the formula I containing about 0.1% or less of a-[2-rnethyl-l -oxopropyl]-y-oxo-N-β-diphenylbercene butanamide, about 0.05 % or less of difluoro -α-[2-methyl-l-oxopropyl]-y-oxo-N-β-diphenylbenzene butanamide, and about 0.1% or less of O-alkylated impurity of formula VI.

6. The process for the synthesis of atorvaslatin with a yield of about 70% or greater comprising the step of reaction of the compound of Formula I as claimed in claim 5.
7. The compound 3-[2-(4-Fluorophenyl)-2-oxo-l-phenyl-ethoxy]-4-methyl-pent-2-enoic acid phcnylamide represented by formula VI.

Formula VI
8. A pharmaceutical composition comprising a tablet, capsule, suspension or
solution comprising substantially pure Atorvastatin containing about 0.1%
or less of a-[2-methyl-l-oxopropyl]-y-oxo-Tl-p-dipheriylbenzene
butanamide, about 0.05 % or less of difluoro -a-[2-methyl-l-o;-:opropyl]-
y-oxo-N-β-diphenylbenzene butanamide and about 0.1% or less of 3-[2-(4-
FIuorophenyl)-2-oxo-l-phenyI-ethoxy]-4-methyI-pent-2-enoic acid
phenylamide.
Dated this 29th day of May 2008,

Abhishek Sen
Of S. Majumdar & Co. Applicant's Agent
17

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=TbuK28CLqBWrAJqetXybTg==&loc=vsnutRQWHdTHa1EUofPtPQ==

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Patent Number

279634

Indian Patent Application Number

1152/MUM/2008

PG Journal Number

05/2017

Publication Date

03-Feb-2017

Grant Date

27-Jan-2017

Date of Filing

29-May-2008

Name of Patentee

ARCH PHARMALABS LIMITED

Applicant Address

"H" WING, 4TH FLOOR, TEX CENTRE, OFF SAKI VIHAR ROAD, CHANDIVALI. ANDHERI (EAST), MUMBAI-400072, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	PAI, GANESH GURPUR	"H" WING, 4TH FLOOR, TEX CENTRE, OFF SAKI VIHAR ROAD, CHANDIVALI. ANDHERI (EAST), MUMBAI-400072, INDIA
2	NANDA, KISHORE	"H" WING, 4TH FLOOR, TEX CENTRE, OFF SAKI VIHAR ROAD, CHANDIVALI. ANDHERI (EAST), MUMBAI-400072, INDIA
3	ANJANEYULU,A.	"H" WING, 4TH FLOOR, TEX CENTRE, OFF SAKI VIHAR ROAD, CHANDIVALI. ANDHERI (EAST), MUMBAI-400072, INDIA
4	GHOGARE, B.N.	"H" WING, 4TH FLOOR, TEX CENTRE, OFF SAKI VIHAR ROAD, CHANDIVALI. ANDHERI (EAST), MUMBAI-400072, INDIA
5	CHAUDHARI, N.P.	"H" WING, 4TH FLOOR, TEX CENTRE, OFF SAKI VIHAR ROAD, CHANDIVALI. ANDHERI (EAST), MUMBAI-400072, INDIA

PCT International Classification Number

C07D207/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA