FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"AN IMPROVED PROCESS FOR THE PREPARATION OF PRASUGREL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE PREPARATION OF PRASUGREL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of prasugrel compound of structural formula-I and its pharmaceutically acceptable salts thereof. The process comprises treating a compound of structural formula IX with trifluoromethane sulfonic acid to get a compound of structural formula X and then converting compound of structural formula X into prasugrel compound of structural formula-I and its pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION
Prasugrel is chemically (2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl) - 4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridine and is known from U.S. Patent no. 5,288,726 and is represented by compound of structural formula I.


Formula I
The pharmaceutically acceptable salt of prasugrel is prasugrel hydrochloride and it is marketed in USA under trade name Effient. Effient is a P2Y12 platelet inhibitor indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome.
U.S. Patent No. 5,288,726 discloses a process for the preparation of prasugrel as described below in scheme no. I.

Sc heme-I

U.S. Patent No. 4,740,510 discloses a process for the preparation of an intermediate 5, 6, 7, 7a-tetrahydro-thieno [3, 2-C] pyridin-2(4H)-one of structural Formula-V as shown below in scheme no. II.

The deprotection of trityl group from a compound of structural formula IX by formic acid / hydrochloric acid resulted impurity of compound of structural formula XI, which is being removed by column chromatographic technique or by recrystallization process and hence resulted into a low yield of compound of structural formula V.

Formula-XI
And therefore there is a need in the art to develop an improved and commercially viable process of preparing prasugrel compound of structural formula-I and its pharmaceutically acceptable salts thereof.

SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide a commercial viable process for the preparation of prasugrel compound of structural formula-I and its pharmaceutically acceptable salts thereof, which obviates the prior art problems.
A second aspect of the present invention is to provide an improved process for the preparation of prasugrel compound of structural formula-I and its pharmaceutically acceptable salts thereof as described herein in scheme III.


A third aspect of the present invention is to provide an improve process for the preparation of a compound of formula X from compound of formula IX in presence of trifluoromethane sulfonic acid.

Formula-IX Formula-X
A fourth aspect of the present invention is to provide an improve process for the preparation of a prasugrel hydrochloride by treating a compound of structural formula I with Isopropanol. HC1 in acetone solvent.
A fifth aspect of the present invention is to provide a crystalline form of prasugrel hydrochloride as characterized by an X-ray diffraction pattern depicted in Figure I.
A sixth aspect of the present invention is to provide a process for the preparation of prasugrel compound of structural formula-I and its pharmaceutically acceptable salts thereof comprising the steps of:
a. treating a compound of structural formula IX with trifluoromethane sulfonic acid to get a compound of structural formula X,

Formula-IX Formula-X
b. reacting a compound of structural formula X with a compound of structural formula IV to get a compound of structural formula VI,


c. converting a compound of structural formula VI into a prasugrel compound of structural formula-I and

d. optionally converting prasugrel compound of structural formula-I into pharmaceutically acceptable salts thereof.
DETAIL DESCRIPTION OF THE INVENTION:
The compound of structural formula IX may be prepared by methods known in the art such as those described in U.S. Patent nos. 4,740,510; 5,874,581 and PCT publication no. 2009/066326, which are incorporated herein by reference only.
The reaction of a compound of structural formula IX with trifluoromethane sulfonic acid may be carried out in an ether solvent at a temperature in the range of 25°C-50°C for a period of 2 hours to 8 hours to get a compound of structural formula X.
The examples of ether solvent may include but not limited to tetrahydrofuran, 2-methyl tetrahydrofuran, 1, 4-dioxane, methyl tertiary butyl ether, diethyl ether, diisobutyl ether, di-n-butyl ether, di-n-propyl ether, di-isopropyl ether, dimethoxyethane or mixture(s) thereof.

The compound of a structural formula X may be isolated by filtration, centrifugation, washing, drying and combination thereof.
The limit of detection (LOD) of compound of formula XI in compound of structural formula X is 0.001 % weight/weight.
The limit of quantitation (LOQ) of compound of formula XI in compound of structural formula X is 0.01 % weight / weight.
The compound of structural formula X may be substantially free from a compound of structural formula XI.
The term "substantially free" described herein refer to the absence of compound of structural formula XI.
The reaction of a compound of structural formula X with a compound of structural formula IV may be carried out in the presence of inorganic base in a nitrile solvent at a temperature in the range of 0°C to 25°C for a period of 2 hours to 8 hours to get a compound of structural formula VI.
The examples of an inorganic base may include but not limited to sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium hydroxide or lithium carbonate.
The examples of nitrile solvents may include acetonitrile, propionitrile, butyronitrile or isobutyronitrile.
The compound of a structural formula VI may be isolated by quenching the reaction mixture with water followed by extracting the reaction mixture with above mentioned ether solvent, separate an organic layer and then concentrating an organic layer at a temperature in the range of 40-50°C under reduced pressure to get compound of structural formula VI.

The conversion of a compound of structural formula VI into a prasugrel compound of structural formula I may be carried out by reacting compound of structural formula VI with acetic anhydride or acetyl chloride in the presence of inorganic base in an aprotic solvent at a temperature in the range of 0°C to 30°C for a period of 2 hours to 8 hours to get a prasugrel compound of structural formula I.
The examples of inorganic base may include but not limited to sodium hydride, sodium hydroxide or potassium hydroxide.
The examples of aprotic solvents may include but not limited to dimethylsulfoxide, dimethylformamide, dimethylacetamide or mixture(s) thereof.
The prasugrel compound of structural formula may be isolated by quenching the reaction mixture with saturated ammonium chloride solution followed by extracting the reaction mixture with an alkyl acetate solvent, washing the organic layer with a saturated solution of sodium chloride followed by concentrating an organic layer under reduced pressure to get a prasugrel compound of structural formula I.
The examples of alkyl acetate solvents may include but not limited to methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixture(s) thereof.
The prasugrel compound of structural formula I may be purified by the recrystallization in an alcohol solvent and may be dried at a temperature in the range of 35°C to 45°C for a period of 3 hours to 5 hours.
The examples of alcohol solvents may include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or t-butyl alcohol.

The conversion of a prasugrel compound of structural formula I in to the pharmaceutically acceptable salt such as hydrochloride salt may be carried out by treating a prasugrel compound of structural formula I with isopropanolic hydrochloric acid in ketone solvent at a temperature in the range of 20°C to 30°C for a period of 30 minutes to 4 hours to get prasugrel hydrochloride.
The term isopropanolic hydrochloric acid refers to the 10% weight/ weight of hydrochloric acid gas dissolved in an isopropanol solvent.
The examples of ketone solvent may include but not limited to acetone, methyl isobutyl ketone, 2-butanone, 3-pentanone or mixture(s) thereof.
The prasugrel hydrochloride may be isolated by the steps of filtration, centrifugation, washing, drying and combination thereof.
The prasugrel hydrochloride may be dried at a temperature in the range of 50°C to 60°C under reduced pressure for a period of 8 hours to 10 hours.
The prasugrel hydrochloride obtained by following the present invention may be of crystalline in nature and it may be characterized by X-ray diffraction pattern having peaks at 8.3, 13.7, 14.3, 16.8, 19.6, 21.5, 23.9, 27.0, 29.0, 30.3, 33.0, 36.7, 37.6, 39.1, 39.8 ±0.2°two theta.
The crystalline form of prasugrel hydrochloride (herein after mentioned as Form F) obtained by the treating prasugrel with isopropanolic hydrochloric acid in ketone solvent may be characterized by following X-ray diffraction peaks:

Pos. [°2Th.] Height [cts] Area [cts*°2Th.l FWHM r°2Th.l d-spacing [A] Rel. Int. [%]
8.3229 1370.23 271.33 0.1338 10.61492 16.30
8.6418 143.19 24.81 0.1171 10.22401 1.70
13.0946 186.04 27.63 0.1004 6.75563 2.21
13.7905 2722.63 539.12 0.1338 6.41625 32.39
14.3520 267.97 26.53 0.0669 6.16644 3.19
14.8054 8406.90 1872.79 0.1506 5.97864 100.00
16.4514 1029.77 229.40 0.1506 5.38395 12.25

16.8088 138.25 20.53 0.1004 5.27027 1.64
17.1260 479.27 47.45 0.0669 5.17337 5.70
17.2550 417.90 62.06 0.1004 5.13499 4.97
17.7968 347.42 94.59 0.1840 4.97986 4.13
19.6672 136.09 33.69 0.1673 4.51027 1.62
20.1983 104.71 20.73 0.1338 4.39288 1.25
20.5359 717.50 159.84 0.1506 4.32142 8.53
20.9162 1188.52 235.35 0.1338 4.24368 14.14
21.2213 245.10 30.33 0.0836 4.18336 2.92
21.5463 687.52 153.16 0.1506 4.12099 8.18
22.3543 7673.18 1899.27 0.1673 3.97383 91.27
22.6787 764.53 170.31 0.1506 3.91771 9.09
22.9706 134.09 16.59 0.0836 3.86858 1.59
23.5374 103.20 25.54 0.1673 3.77669 1.23
23.9343 374.14 64.83 0.1171 3.71495 4.45
24.2544 389.56 86.78 0.1506 3.66665 4.63
24.7152 1935.10 478.98 0.1673 3.59932 23.02
25.4238 1064.76 237.19 0.1506 3.50058 12.67
25.7102 1859.77 368.26 0.1338 3.46224 22.12
26.1286 1596.19 355.58 0.1506 3.40773 18.99
27.0018 379.15 84.46 0.1506 3.29948 4.51
27.5785 2517.25 623.07 0.1673 3.23179 29.94
28.0498 930.43 207.27 0.1506 3.17854 11.07
28.4442 690.16 112.63 0.0816 3.13535 8.21
28.5070 695.55 86.08 0.0836 3.12859 8.27
29.0183 551.05 109.12 0.1338 3.07462 6.55
29.5111 2225.38 605.91 0.1840 3.02439 26.47
30.3601 4829.47 1195.39 0.1673 2.94172 57.45
31.7175 233.57 28.91 0.0836 2.81886 2.78
32.4252 711.70 88.08 0.0836 2.75893 8.47
33.0539 1034.74 409.79 0.2676 2.70787 12.31
34.2715 269.95 53.45 0.1338 2.61440 3.21
34.6523 609.61 181.07 0.2007 2.58654 7.25
35.0565 270.31 33.45 0.0836 2.55764 3.22
35.3338 464.34 68.96 0.1004 2.53820 5.52
35.6118 375.91 130.26 0.2342 2.51902 4.47
36.7059 509.80 88.33 0.1171 2.44641 6.06
37.2529 322.77 39.95 0.0836 2.41173 3.84
37.6360 543.76 134.59 0.1673 2.38805 6.47
38.2081 118.85 23.53 0.1338 2.35361 1.41
39.1850 80.78 7.27 0.0900 2.29715 0.96
39.8358 329.12 65.17 0.1338 2.26111 3.91
A pharmaceutical composition comprising crystalline form F of prasugrel hydrochloride and pharmaceutically acceptable carrier.

DESCRIPTION OF THE FIGURE
Figure 1 depicts the X-ray diffraction pattern of prasugrel hydrochloride crystalline form F
X-Ray Powder Diffraction (XRPD) pattern of prasugrel hydrochloride crystalline form F is obtained on D 8 -Advance, Bruker AXE, Germany, diffractometer equipped with Scintillation detector using Copper Kα (λ= 1.5406 A) radiation with scanning range between 2.00-39.98°2θ at scanning speed of 2%min.
EXAMPLE
In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of prasugrel hydrochloride
Step 1: Preparation of 5, 6, 7, 7a-tetrahydrothieno [3, 2-c] pyridin-2(4H)-one trifluoromethane
sulfonate compound of structural formula X.
A mixture of 5-trityl-5, 6, 7, 7a-tetrahydrothieno [3, 2-c] pyridin-2(4H)-one compound of
structural formula IX (40gm), trifluoromethane sulfonic acid (10 gm) and tetrahydrofuran
(600ml) was stirred at 50°C for 3 hours and then reaction mixture was stirred for 2 hours at 0°C
to 5°C. The resulting solids were filtered, washed with tetrahydrofuran (2x150ml) and then dried
at 40°C under reduced pressure to get title compound.
Yield: 30.7gm
Purity: 99.9% (By HPLC); Compound of formula XI: Not detectable.
Step 2: Preparation of l-cycIopropyl-2-(2-fluorophenyl)-2-(2-hydroxy-6, 7-dihydrothieno [3, 2-c] pyridin-5(4H)-yl) ethanone compound of structural formula VI.
A solution of 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone compound of structural formula IV (25gm) in acetonitrile (250ml) and potassium carbonate (2S.5gm) was added 5, 6, 7, 7a-tetrahydrothieno [3, 2-c] pyridin-2(4H)-one trifluoromethane sulfonate compound of structural formula X (27gm) at 0°C to 5°C in 30 minutes. The resulting reaction mixture was stirred for 4 hours at 0°C to 5°C and then it was quenched by water (250ml) and extracted by

diisopropyl ether (2x250ml). The organic layer was dried over anhydrous sodium sulfate (20gm)
and then it was concentrated under reduced pressure at 40°C to get title compound.
Yield: 32.1gm
Purity: 98.9% (By HPLC)
Step 3: Preparation of prasugrel compound of structural formula I.
A solution of l-cyclopropyl-2-(2-fluorophenyl)-2-(2-hydroxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)ethanone compound of structural formula VI (20gm) in dimethylformamide (75ml) was added acetic anhydride (9.23 gm) at 0°C to 5°C and then sodium hydride (2.4 lgm) was added and the resulting reaction mixture was agitated for 2 hours at 25°C. The reaction mixture was quenched by saturated ammonium chloride solution (100ml) and extracted by ethyl acetate (2x100ml). The organic layer was washed with saturated sodium chloride solution (100ml) and dried over anhydrous sodium sulfate (25gm). The organic layer was concentrated under reduced pressure to get crude prasugrel, which was recrystallized in methanol (200ml) and dried at 35°C to 40°C for 4 hours under reduced pressure to get title compound. Yield: 22.5gm Purity: 99.8% (By HPLC)
Step 4: Preparation of prasugrel hydrochloride.
A solution of prasugrel compound of structural formula I (10gm) in acetone (125ml) was added dropwise isopropanolic hydrochloric acid (100ml, 10% weight / weight) at 20°C to 25°C in 15 minutes. The resulting reaction mixture was stirred for 1 hour and then the resulting solids were filtered, washed with acetone (20ml) and dried at 50°C under reduced pressure for 10 hours to get title compound. Yield: 10.9gm Purity: 99.9%

WE CLAIM:
1. A process for the preparation of prasugrel compound of structural formula-I and its pharmaceutically acceptable salts thereof comprising the steps of:
a. treating a compound of structural formula IX with trifluoromethane sulfonic acid to get a compound of structural formula X,

Formula-IX Formula-X
b. reacting a compound of structural formula X with a compound of structural formula IV to get a compound of structural formula VI,

c. converting a compound of structural formula VI into a prasugrel compound of structural formula-I and

d. optionally converting prasugrel compound of structural formula-I into pharmaceutically acceptable salts thereof.

2. The process according to claim no. 1, wherein the reaction of a compound of structural formula IX with trifluoromethane sulfonic acid is carried out in an ether solvent at a temperature in the range of 25°C-50°C for a period of 2 hours to 8 hours to get a compound of structural formula X.
3. The process according to claim no. 2, wherein ether solvent is selected from the group comprising of tetrahydrofuran, 2-methyl tetrahydrofuran, 1, 4-dioxane, methyl tertiary butyl ether, diethyl ether, diisobutyl ether, di-n-butyl ether, di-n-propyl ether, di-isopropyl ether, dimethoxyethane or mixture(s) thereof.
4. The process according to claim no. 1 wherein the reaction of a compound of structural
formula X with a compound of structural formula IV is carried out in the presence of inorganic
base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide,
sodium bicarbonate, potassium bicarbonate, lithium hydroxide or lithium carbonate in a nitrile
solvent such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile at a temperature in the
range of 0°C to 25°C for a period of 2 hours to 8 hours to get a compound of structural formula
VI.
5. The process according to claim no. 1 wherein compound of structural formula VI is converted into a prasugrel compound of structural formula I by reacting a compound of structural formula VI with acetylating agent such as acetic anhydride or acetyl chloride in the presence of inorganic base such as sodium hydride, sodium hydroxide or potassium hydroxide in an aprotic solvent such as dimethylsulfoxide, dimethylformamide, dimethylacetamide or mixture(s) thereof at a temperature in the range of 0°C to 30°C for a period of 2 hours to 8 hours to get a prasugrel compound of structural formula I.
6. The process according to claim no.l, wherein prasugrel compound of structural formula I is converted into its pharmaceutically acceptable salt such as prasugrel hydrochloride salt by treating a prasugrel compound of structural formula I with isopropanolic hydrochloric acid in ketone solvent at a temperature in the range of 20°C to 30°C for a period of 30 minutes to 4 hours to get prasugrel hydrochloride.

7. The process according to claim no. 6, wherein ketone solvent is selected from the group comprising of acetone, methyl isobutyl ketone, 2-butanone, 3-pentanone or mixture(s) thereof.
8. The process according to claim no. 6 wherein prasugrel hydrochloride is isolated by the steps of filtration, centrifugation, washing, drying or combination thereof.
9. The process according to claim no. 6, wherein prasugrel hydrochloride is dried at a temperature in the range of 50-60°C under reduced pressure for a period of 8 hours to 10 hours.
10. The process according to claim no. 6 wherein prasugrel hydrochloride is crystalline in nature
which is characterized by X-ray diffraction pattern having peaks at 8.3, 13.7, 14.3, 16.8, 19.6,
21.5, 23.9, 27.0, 29.0, 30.3, 33.0, 36.7, 37.6, 39.1, 39.8 ± 0.2°two theta.