FIELD OF THE INVENTION
The present inventionvrelates to a process for the preparation of 4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N-p-diphenylbenzenebutanamide, the diketone intermediate of atorvastatin of Formula I,
v ■ .
Formula I
BACKGROUND OF THE INVENTION
U.S. Pat. Nos. 4,681,893, 5,124,482, 5,216,174, 5,097,045 disclose the process for
the preparation of atorvastatin including the process for the preparation of 4-fluoro-
a-[2methyl-l-oxopropyl]-y-oxo-N-p-diphenylbenzenebutanamide by reacting 4-
methyl-3 -bxo-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-dimethyl-5-(2-hydroxy-ethyl)-thiazolium iodide, 3-ethyl-4-(2-hydroxyethyl)-4-methylthiaz'olium 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'-tetramethylethylenedimine.
WO 09/144736 Al discloses a process for preparation of 4-fluoro-a-[2-methyl-l-oxopropylJ-y-oxo-N-p-diphenylbenzenebutanamide by reacting 2-halo-1 -(4-fluorophe]nyl)-2-phenylethanone with 4-methyl-3-oxo-N-phenylpentamide in the presence of base such as sodium carbonate, potassium carbonate, cesium carbonate,

diisopropylamine, triethylamine, metal hydroxide, sodium ethoxide, sodium hydride, n-butyl lithium, lithium diisopropylamide in C3-C5 alcohol as solvent. The final compound was isolated by layer separation, followed by concentrated under vacuum. '
WO 03/004457 discloses a process for preparation of 4-fluoro-a-[2-methyl-l-oxopropyl]-Y-oxo-N-p-diphenylbenzenebutanamide by reacting 2-bromo-l-(4-fluorophenyl)-2-phenone (a compound of Formula II) with 4-methyl-3-oxo-N-phenylpentamide by using a base comprising metal hydroxide, carbonate, hydrogen carbonate in suitable solvents like methanol, ethanol, dioxane, tetrahydrofuran, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide and the like.
WO 2012,143933, discloses a process for preparation of 4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N-P-diphenylbenzenebutanamide is obtained during Friedel-Crafts acylation, in situ halogenation in the presence of a solvent and nucleophilic substitution from 2-halo-1 -(4-fluorophenyl)-2-phenone with methyl-3-oxo-N-phenyl pentamide in presence of a base.
The processes as described in prior published references, involves the tedious and lengthy work up processes using one or more solvents, which effects the overall yield and, cost of the product. Also, isolation method as disclosed in prior art is cumbersome and time consuming. To avoid the above stated drawbacks, present invention provides a less time consuming, simple and cost effective process for preparation of 4-fluoro-a-[2-methyl-l-oxopropyl]-Y-oxo-N-P-diphenylbenzene butanamide wherein, the workup and isolation of product is simple as compared to the processes disclosed in prior published references.

OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved, cost effective and environment friendly process, for the preparation of 4-fluoro-a-[2-methyl-l-oxopropylJ-y-oxo-N^p-diphenylbenzenebutanamide of Formula I.
SUMMARY OF THE INVENTION
In the main aspect, present invention provides an improved process for the preparation of 4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N-p-diphenylbenzene biitanamide of Formula I.
Formula I
wherein said process comprising the steps of:
a) treating compound of Formula II with aniline in the presence of triethyl amine and hydrochloric acid under reflux condition to obtain compound of Formula III;
Formula II Aniline Formula III
r
b) reacting-fluorobenzene -with phenyl acetylchloride in the "presence "of anhydrous AICI3 at 2-8 °C to obtain compound of Formula IV;

Fluorobenzene Phenylacetyl chloride Formula IV
c) halogenation of compound of Formula IV to obtain the compound of ' Formula V;
Formula IV Formula V
Va = Cl Vb = Br
d) coupling compound of Formula III with compound of Formula V in the presence of K2CO3 and ethanol to obtain compound of Formula I;
Formula III Formula V
Formula I
e) isolating compound of Formula I; and
f) optionally converting compound of Formula I to atorvastatin.

In the other aspect, the present invention provides an isolated compound of Formula B,

Formula B
In yet another aspect, the present invention provides an improved process for the preparation of compound of Formula.I; wherein, compound of Formula I is free from the impurity of Formula B,

DETAILED DESCRIPTION
Brief description of the accompanying drawing
Fig. 1, represents the X-ray (powder) diffraction (XRPD) pattern of the crystalline form of 4-fluoro-a-[2methyl-l-oxopropyl]-Y-oxo-N-P-diphenylbenzenebutanamide of Formula I.
Fig. 2, represents the differential scanning calorimetry (DSC) pattern of the
crystalline form . of 4-fluoro-a-[2methyl-l-oxopropyl]-Y-oxo-N-(3-
diphenylbenzenebutanamide of Formula I.

In one embodiment, the present invention provides an improved process for the preparation of 4-fluoro-a-[2-methyl-l-oxopropyl]-Y-oxo-N-P-diphenylbenzene
butanamide of Formula I,
F

Formula I

wherein said process comprising the steps of:
a) treating compound of Formula II with aniline in the presence of triethyl amine and hydrochloric acid under reflux condition to obtain compound of Formula III;

O O


o + II I ► li J 50
NH
Formula II Aniline Formula III
b) reacting fluorobenzene with phenyl acetylchloride in the presence of anhydrous AICI3 at 2-8°C to obtain compound of Formula IV;

Fluorobenzene Phenylacetyl chloride

Formula IV

c) halogenation of compound of Formula IV to obtain the compound of Formula V;

Formula IV

Formula V
Va = Cl Vb = Br

d) coupling compound of Formula HI with compound of Formula V in the presence of K2CO3 and Ethahol to obtain compound of Formula I;


ONHO
Formula I

e) isolating compound of Formula I; and
f) optionally converting compound of Formula I to atorvastatin.

In another embodiment, the present invention provides the- process for the preparation of compound of Formula I, wherein phenyl acetyl chloride is prepared in-situ in reaction mixture by treating phenyl acetic acid with thionyl chloride.
i In another embodiment, the present invention provides a process for halogenation of compound of Formula IV to its. corresponding compound of Formula V in methylene chloride as solvent.
In another embodiment, compound of Formula I obtained herein is crystalline in nature.
In one another embodiment, compound of Formula I obtained herein may be amorphous in nature.
In one another embodiment, compound of Formula I is characterized by its XRPD pattern having peaks at diffraction angles at about 7.58, 8.97, 11.76, 12.36, 18.02, 18.70, 20.14, 22.57 and 25.17±0.2 degrees two-theta.
In one another embodiment compound of Formula I is characterized by its XRPD pattern having peaks at diffraction angles at about 7.58, 8.97, 10.47, 10.77, 10.96, 11.76, 12.67, 14.04, 14.65, 15.16, 15.72, 16.37, 18.02, 18.70, 18.89, 19.58, 20.14, 20:48, 20.66, 21.07, 21.42, 22.57, 22.88, 23.20, 23.46, 24.03, 24.63, 25.17, 25.48, 25.97, 26.81, 27.13, 27.53,28.33, 28.63, 28.95, 29.38, 30.36, 30.97, 31.82, 32.68, 32.99, 33.39, 33.97, 34.62, 36.41, 37.19, 38.64, 39.43 and 39.74 ±0.2 degrees two-theta.
In yet another embodiment, compound of Formula I is characterized,by its XRPD pattern as depicted in FIG-1.
In one another embodiment, compound of Formula I is characterized by its DSC curve having endothermic peaks at 200.97°C as depicted in FIG-2.

In yet another embodiment, compound of Formula I is characterized by its DSC curve as depicted in Fig. 2.
In a preferred embodiment, the present invention provides a substantially pure, crystalline form of compound of Formula I.
In a preferred embodiment, the compound of Formula I may be isolated from the
reaction mixture by purification, centrifugation, crystallization, filtration,
extraction or evaporation. : ■
In another embodiment,, the present invention provides the process for the preparation of compound of Formula B, wherein said process comprising the steps
of: ■ ■ - ■■ , .
i
a) treating compound of formula Wwith sodium methoxide in methanol at room temperature for 3 hours to obtain the compound of formula VI;



Formula VI

b) reacting compound of Formula VI with mesyl chloride and triethyl amine in methylene chloride for 1 hour to obtain the compound of Formula VII;

c) reacting compound of formula VII with compound of formula III in acetone and potassium carbonate to obtain the mixture of Compound of Formula I and Formula B; and

Formula'B Formula I
d) isolating the compound of Formula B.
In another embodiment, the compound of Formula B is isolated from the reaction mixture column chromatography.
In furthermore embodiment, there is provided a substantially pure compound of Formula I, wherein said compound of Formula I is substantially free of impurities of Formulas A, B, C, D and E, and wherein each impurity is less than about 0.15% w/w or total impurity less than about 1% w/w, more specifically less than about 0.15% w/w of any impurity;
<




Formula A

Formula C
DKT-III diastereomer


F ,

Formula D . and

In another embodiment, the present invention provides an isolated compound of Formula B;

In a preferred embodiment, there is provided a substantially pure compound of Formula I, wherein said compound of Formula I is substantially free of impurity B;


In one another embodiment, the compound of Formula I "prepared as per the process of the present invention is characterized with purity above 99%, preferably above'
99.5%, and more preferably above 99.9%.
■KT
In yet another embodiment, the present invention provides an improved process for the preparation of compound of Formula I which in turn can be used for preparing Atorvastatin.
The present invention can be illustrated by the following examples, which are not to limit the scope of invention.
Example-1: Synthesis of 4-methyl-3-oxo-N-phenylpentanamide of Formula III
Methyl isobutyl acetate (500 g) was charged with Aniline (405 g) and triethylamine (125 g) at'room temperature. Temperature raise to 110-130°C. Methanol generated in reaction was distilled out along with TEA at the temperature 110-130 °C. After completion of reaction, reaction mass cooled to 30-35°C and water (1800 ml) is added. PH of reaction mas was adjusted 1.0 to 1.5 using Hydrochloric acid aqueous solution. The precipitated mass was cooled and filter. The filter mass .is washed with water to give wet cake of 4-methyl-3-oxo-N-phenylpentanamide of Formula III. The wet cake was used as such for next step. (Moisture content-23%, 715 g, 77%)
Example-2: Synthesis of l-(4-fluorophenyl)-2-phenylethanone of Formula IV
Fluorobenzene (164.0 g) was charged in RBF and cooled to 2-8°C. Aluminium chloride (208 g) was added at 2 to 8°C. Then phenyl acetyl chloride (230 g) was added drop wise by maintaining temperature 2-8°C. Reaction is monitored by TLC and then quenched in IN Hydrochloric acid solution (2.0 ltr). Precipitated solid was filtered and recrystallized in cyclohexane to get l-(4-fluorqphenyl)-2-phenylethanone of Formula IV (250 g, yield-77%).

Example-3: Example-3: Synthesis of 2-chIoro-l-(4-fluorophenyl)-2-phenylethanone of Formula Va
l-(4-fluorbphenyl)-2-phenylethanone (50.0 g) of Formula IV was charged in , methylene chloride (150 ml) at room temperature. Sulfuryl chloride (35.Og) was added at 10-15°C.After completion of reaction, water (50 ml) is added to reaction mass. Stirred and layers are separated. Organic layer was washed with sodium bicarbonate aq. solution. The organic layer was distilled out and degassed to get oily mass4o get 2-Chloro-l-(4-fluorophenyl)-2-phenylethanone (53.5 g, 92.0%) of formula Va.
r
ExampIe-4: Synthesis of 2-bromo-l-(4-fluorophenyl)-2-phenyIethanone of Formula Vb
l-(4-fluorpphenyl)-2-phenylethanone (210.0 g) of Formula IV was charged in methylene dichloride (600 ml) at room temperature. Catalytic hydrobromic acid in acetic acid (2.0 g) was added and then cooled to 15°C. Bromine was added at 15-30°C. After completion of reaction, water (250 ml) was added to reaction mass. Reaction mass was stirred and layers were separated. Organic layer was washed with sodium Meta bisulphite and sodium bicarbonate aq. solution. The organic layer finally distilled out and degassed to get oily mass to get 2-bromo-l-(4-fluorophenyI)-2-phenylethanone (270 g, 94.0%) of Formula Vb.
Example-5: Synthesis of 4-fluoro-a-[2methyM-oxopropyl]-y-oxo-N-P-diphenylbenzenebutanamide of Formula I
4-methyl-3-oxo-N-phenylpentanamide (175 g) of Formula III and 2-bromo-l-(4-fluorophenyl)-2-phenylethanone (250 g) of Formula Vb was charged in ethanol at 20 to 30 °C. Potassium carbonate (175 g) was added to the reaction mass. Reaction mass was stirred at 30-40°C till complete conversion. After completion of reaction, water (500 ml) was charged in to the reaction mass and precipitated solid was filtered. Crude wet solid was charged in water (850 ml) again and stirred. Crude material was purified in Ethanol and dried to get pure 4-fluoro-a-[2methyl-l-

oxopropyl]-Y-oxd-N-P-diphenylbenzehebutanamide of Formula I (262 g, 74.0% yield).
Example-6: Synthesis of , 441uoro-a-[2methyl-l-oxopropyl]-Y-oxo-N-P-diphenylbenzenebutanamide of formula I
4-methyl-3-oxo-N-phenylpentanamide (41.0 g) of formula III and 2-Chloro-l-(4-fluorophenyI)-2-phenylethanone (48.6 g) of formula Va was charged in ethanol at 20 to 30°C. Potassium carbonate (40.0 g) was added to the reaction mass. Reaction >. \ mass is stirred at 30-40°C till complete conversion. After completion of reaction, water (120 ml) is charged in to the reaction mass and precipitated solid is filtered. Crude solid is charged in water (200 ml) again and stirred. Crude material is purified in ethanol and dried to get. pure 4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N-p-diphenylbenzenebutanamide of Formula I (60.0 g, 73.8% yield).
Example-7: Synthesis of {l-(4-fluorophenyl)-2-hydroxy-2-phenylethanone} of Formula VI
To a solution of compound of Formula Vb (30 g, 0.1023 M) in methanol (600ml) was added sodium methoxide 30% (92.10g, 0.5117 M) dropwise at 0-5°C in 30 min. After addition of sodium methoxide, reaction mixture was stirred at room temperature for 3 hours. Reaction mixture was monitored by TLC and after completion of reaction mixture was quenched by concentrated hydrochloric acid (40ml) at 0°C (adjusting pH at 2). Reaction mixture was concentrated on rotavapour at 40PC under high vacuum to remove the methanol. After removal of methanol the compound was precipitated and precipitate was filtered on Buchner funnel and dried in air oven at 50°C for lh to get compound of Formula VI as off white solid (20 g, 85% yield).
Example-8: Synthesis of {2-(4-fluorophenyl)-2-oxo-l-phenylethyl methanesulfonate} Formula VII:
To a solution of compound of Formula VI (20g, 0.0869 M) in 200ml methylene chloride was added triethyl amine (18.16ml, 0.134M). Reaction mixture was cooled

to 0°C and mesyl chloride (8.74ml, 0.1130 M) was added dropwise. Reaction mixture was stirred at 0°C for lh and monitored by TLC. After completion of reaction mixture was diluted by water (200 ml) and methylene chloride (200ml). Organic layer was separated in separating funnel and organic layer was washed by saturated sodium bicarbonate solution (200 ml) arid brine solution (200ml). Organic
layer was concentrated on rota vapour under high vacuum at 40°C to get the
* -
* compound of Formula VII as off white semisolid. (17 g, 63.4% yield).
Example-9: Synthesis of {4-(4-Fluorophenyl)-2-isobutyryl-N, 3-diphenyl-2H-oxete-2-carboxamide} of Formula B: • ~
To a solution of 4-methyl-3-oxo-N-phenylpentanamide of Formula III (8g, 0.0389M)' in acetone (80 ml) was added potassium carbonate (8g, 0.058 M) and compound of Formula VII (12g, 0.0389 M) at room temperature. Reaction mixture was: heated at 45 °C for overnight. Reaction mixture was monitored by TLC and after completion of reaction mixture was diluted by water (100ml) arid ethyl acetate (200ml). Reaction mixture was separated in separating funnel to separate the ethyl acetate layer. Ethyl acetate layer was separated and concentrated to get desired compound which was further purified using column chromatography. Compound of Formula I & other non-polar impurities of the compound were removed using methylene chloride and hexane as mobile phase in Agela column chromatography instrument. After removing the compound of Formula I and non-polar impurities in 10 to 100% (methylene dichloride/hexane) as eluent, the resultant compound was eluted in 5% (methanol/ methylene dichloride) to get 4g compound of Formula B, which was further purified using glass column in 10-15% ethyl acetate/hexane as eluent to get compound of Formula B (500mg) which was again crystalized by isopropyl ether to get 400 rhg of compound of Formula B as white solid (400 mg, Purity-97.08%).
CHARACTERIZATION:
1HNMR (400MHZ, DMSO-d6): 5 8.015 (s,lH), 7.418-7.399 (d, J=7.6Hz, 2H),
7.355-7.337 (d, J=7.2Hz, 2H), 7.303-7.231 (m, 4H), 7.226-7.156 (m, 4H), 7.134-
* -

7.098 (dd> 2H), 3.128-3.024 (m, IH), 1.114-1.096 (d, J=7.2Hz, 3H), 1.072-1.055 (d, J=6.8Hz, 3H).
13C NMR (400MHZ, DMSO-d6):5 204.18, 165.56, 163.85, 161.39, 157.99, 137.00, 135.85, 131.74, 130.7, 130.63, 128.52, 128.39, 128.25, 126.95, 126.92, 125.97, 125.84, 125.01, 115.42, 115.25,93.23,39.73, 17.43, 17.19.
MS calculated C26H22FNO3 [M+HJ+: 416.45,found:416.36, [M-Hj-413.9

WE CLAIM
1. An improved process for the preparation of 4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N-P-diphenylbenzenebutanamide of Formula I.
F

Formula I
wherein said process comprising the steps of:
a) treating compound of Formula II with aniline in the presence of triethyl amine and hydrochloric acid under reflux condition to obtain compound of Formula HI;



O'
O O
Formula II

Aniline

U ° 6
Formula III

b) reacting fluorobenzene with phenyl acetylchloride in the presence of anhydrous AICI3 at 2-8°C to obtain compound of Formula IV;

Fluorobenzene Phenylacetyl chloride Formula IV
c) halogenation of compound of Formula IV to obtain the compound of
Formula V;
O r^% O


Formula IV Formula V
Va - CI Vb = Br
d) coupling compound of Formula III with compound of Formula V in the
presence of K2CO3 and ethanol to obtain compound of Formula I;

F

e) isolating compound of Formula I; and
f) optionally converting compound of Formula I to atorvastatin.
2. A compound of Formula B;


3. The process as claimed in claim 1, wherein .compound of Formula I is substantially free pf impurity B, wherein impurity B is less than about
0.15% w/w,

Formula B

Formula A Formula B Formula C
4. The process as claimed in claim 1, wherein compound of Formula I is substantially free of impurities of Formula A, B, C, D and E, wherein each impurity is less than about 0.15% w/w,

Formula D ■ ana Formula E
5. The process as claimed in claim 1, wherein compound of Formula I is characterized by X-ray powder diffraction (XRD) pattern having peaks at about 7.58, 8.97, 11.76, 12.367, 18.02, 18.70, 20.14, 22.57 and 25.17±0.2 degrees two-theta.
6. The process as claimed in claim 1, wherein compound of Formula I is characterized by DSC with endotherm peak at 200.97°C.
7. The process as claimed in claim 1, wherein compound of Formula I obtained therein is crystalline in nature and characterized by at least one of:
a) an X-ray powder diffraction (XRPD) pattern having peaks at 7.58, 8.97, 11.76, 12.367, 18.02, 18.70, 20.14, 22.57 and 25.17 ±0.2 degrees two-theta, and
b). melting endotherms of 200.97°C as measured by differential scanning calorimetry.
8. The process as claimed in claim 1, wherein said compound of Formula I is crystalline in nature and characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Fig. 1; and by differential scanning calorimetry (DSC) as depicted in Fig. 2.
9. The process as claimed in claim 1, wherein said compound of Formula I is used for the preparation of atorvastatin.
10. A process for the preparation of 2-(4-(4-fluorophenyl)-3-phenyl-2H-oxet-2-yl)-4-methyl-3-oxo-N-phenylpentanamide of Formula B,

wherein said process comprising the steps of: a) treating compound of formula Vb with sodium methoxide in methanol at room temperature for 3 hours to obtain the compound of formula VI;
Formula Vb Formula VI
b) reacting compound of Formula VI with methyl chloride and triethyl amine in methylene chloride for 1 hour to obtain the compound of Formula VII;
Formula VI Formula VII
c) reacting compound of formula VII with compound of formula III in Acetone and potassium carbonate to obtain the mixture of Compound of Formula I and Formula B; and
Formula VII Formula III
Formula B - Formula I
d) isolating the compound of Formula B.